SYNTHESIS OF NOVEL FLAVONES AND ISOFLAVONES

This thesis is submitted in fulfilment of the degree of

Doctor of Philosophy

By

RUTH VANDANA DEVAKARAM

Supervisors: A/Prof. Naresh Kumar Prof. David StC. Black

School of Chemistry

The University of New South Wales Kensington, Australia

February 2011

CERTIFICATE OF ORIGINALITY

‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’

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ii COPYRIGHT STATEMENT

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iii ABSTRACT

The primary aim of this project is to synthesize new heterocyclic compounds derived from flavones and isoflavones and thereby, to investigate various methodologies for their synthesis.

The biflavonoid, dependensin was a major focus of our study since the benzopyrano[4,3- b]benzopyran ring system present in the natural product was unique and hence, desirable for biological applications. We targeted the acid-catalyzed reactions of 5-methoxy-, 6-methoxy- and 7-methoxyflavenes and found the dimerization to be dependent on the position of the methoxy substituent in the flavene ring. A series of benzopyrano[4,3-b]benzopyrans was generated from the acid-catalyzed reactions of 7-methoxyflavenes and 5,7,8-trimethoxyflavenes.

Interestingly, the acid-catalyzed reactions attempted on 5-methoxy- and 6-methoxyflavenes were found to undergo dimerization differently to yield a novel range of biflavonoids containing the tetrahydrochromeno[2,3-b]chromene ring system. A plausible mechanism for the observed rearrangement has also been proposed. The effect of various acids used as catalysts on the dimerization reactions has been evaluated and discussed in this thesis.

Similarly, the acid-catalyzed dimerization reactions on isoflavanols and their corresponding isoflavenes were studied in depth and dimerization was found to be dependent on the presence of electron rich substituents in ring B of the isoflavanols and also in performing the reaction in very cold conditions. A probable rationale to this rearrangement has been described.

The widespread applications of Mannich bases in medicinal chemistry are noteworthy. Hence, another part of the project was to study the Mannich reactions on flavones using various primary and secondary amines, aminals and amino acids and to probe into the regioselectivity and chemoselectivity of the products obtained. The key point of interest to note was the site of activation in the flavone ring, which was C5 in 6-hydroxyflavones and C8 in 7-hydroxyflavones. The primary amines yielded benzoxazines whereas the secondary amines, aminals and amino acids yielded simple Mannich bases. Further, the benzoxazines were found to undergo cleavage to generate the corresponding simple Mannich bases.

Our research group has previously worked on the synthesis of a series of 4-arylflavans and 4- arylisoflavans, but however, there are no reports on the synthesis of 4-arylazaflavans in the literature. Hence, 4-arylazaflavans were synthesized via the acid-catalyzed reactions of iv azaflavanols with nucleophiles such as naphthol and dimethoxyphenol, whereas 4- heteroarylazaflavans were obtained using heterocycles such as furan, indoles and isoflavenes.

Attempts were made to synthesize the corresponding azaflavenes with the primary aim on subjecting them to acid-catalyzed dimerization reactions similar to the flavenes. However, the dominant product isolated was the corresponding quinoline in all cases. Several experiments were conducted in order to oxidize the 4-arylazaflavans to the corresponding quinolines. The optimum conditions were achieved with the use of iodine as catalyst. This introduces a new strategy to the synthesis of 2,4-disubstituted quinolines.

v

ACKNOWLEDGEMENTS

I consider this page as the most important one in my entire thesis as I take time to thank all who have contributed in making this thesis successful.

First and foremost, I thank God Almighty for bringing me to this planet, Australia to do my doctorate. He has been so faithful to me, in providing all my needs and also helped me every step of the way till the very end. As I look back to the past three and half years, I should say that the path has not been smooth, but surely God’s grace has been sufficient for me and His presence so dearly felt to comfort, strengthen and guide me all the way through.

Next, I would like to express my gratitude to my supervisors, A/Prof. Naresh Kumar and Prof. David Black, for giving me the opportunity to work on flavonoid chemistry. I thank them for their valuable guidance and help throughout the course of the project.

I wish to thank all the faculty members in the School of Chemistry, especially the professional staff namely, Jim Hook, Hilda Stender, Donald Thomas, Adelle Moore, Don Craig, Mohan Bhadbhade, Barry Ward, Ian Aldred, Joseph Antoon, Toby Jackson, Ken McGuffin, Jodee Anning, Rick Chan, Nick Robert and Anne Ayres for their timely help. I am also grateful for the help received from Thanh, Michael, Sharif, Berta, Peta, Nancy and Sveto in the teaching labs.

I am thankful to the past and present members of the Kumar and Black group. I owe my thanks to Dr. Abel Salek for his help with the dimerization reactions of isoflavanols and isoflavenes. I wish to acknowledge Chin Fei Chee who worked with me from October to December 2008 on mannich reactions of flavones.

I am extremely grateful to my parents, who have been so dear to me. I owe my thanks to them for their love, prayers, constant support and moral encouragement throughout the course of my work. I also thank all my relatives and friends for their well wishes for my success.

I would also like to mention the Christian groups that I was part of, in Sydney who have always been around at all times to share my joys and my sorrows, and have made my stay in Sydney a pleasant and memorable one. I am thankful to the members of Randwick Presbyterian Church for their warmth and care. I am also grateful to the fellowship I had with my fellow Indians in vi FUESIA (Friends of UESI in Australia). I thank all at FOCUS (Fellowship of Overseas Christian University Students), especially the Friday night bible studies, which were so refreshing. I will be failing in my duty if I do not acknowledge my friends in UESI (Union of Evangelical Students in India), members of AMC (Annanagar Methodist Church), Chennai and my colleagues at Orchid Research Laboratories Limited, Chennai.

UIPA (University International Postgraduate Award) from UNSW during the three and half years is greatly acknowledged. I thank the School of Chemistry for the award of the supplementary Postgraduate Teaching Fellowship.

Finally, I thank one and all, who have helped me with this thesis.

vii TABLE OF CONTENTS

Certificate of originality ii

Copyright and authenticity statement iii

Abstract iv

Acknowledgements vi

Table of contents viii

Abbreviations xiii

Publications and presentations xv

CHAPTER 1: INTRODUCTION

1.1. General introduction .2

1.2. Phytoestrogens 2

1.3. Classification of phytoestrogens 3

1.4. Mechanism of action of phytoestrogens 5

1.4.1. Inhibition of aromatase 6

1.4.2. Mechanism of action via the estrogen receptor 9

1.5. Chemistry of the flavonoids 10

1.6. Medicinal uses of flavonoids and isoflavonoids 12

1.7. Biflavonoids 13

1.8. Biisoflavonoids 17

1.9. Limitations 18

1.10 Aims of the present work 18 viii CHAPTER 2: ACID-CATALYZED DIMERIZATION OF FLAVENES: SYNTHESIS

OF BENZOPYRANO[4,3-b]BENZOPYRANS

2.1. Introduction 21

2.1.1. Known synthetic methodologies 21

2.2. Dependensin 23

2.3. Synthesis of 7-methoxyflavenes 25

2.4. Acid-catalyzed reactions on 7-methoxyflavenes 29

2.4.1. Mechanism for the acid-catalyzed rearrangement 32

2.5. Synthesis of 5,7,8-trimethoxyflavenes 33

2.6. Acid-catalyzed reactions on 5,7,8-trimethoxyflavenes 35

2.6.1. Biological activity of dependensin analogues 38

2.7. Synthesis and acid-catalyzed reaction of 4c,5,7-trimethoxyflavene 39

2.8. Conclusion 41

CHAPTER 3: ACID-CATALYZED DIMERIZATION OF FLAVENES: SYNTHESIS

OF TETRAHYDROCHROMENO[2,3-b]CHROMENES

3.1. Introduction 43

3.1.1. Known synthetic methodologies 44

3.2. Synthesis of 5-methoxy- and 6-methoxyflavenes 46

3.3. Acid-catalyzed reactions on 6-methoxyflavenes 48

3.3.1. Mechanism for the acid-catalyzed rearrangement 51

3.4. Acid-catalyzed reactions on 5-methoxyflavenes 53 ix 3.4.1. Synthesis of flav-2-enes 55

3.4.2. Acid-catalyzed reactions on flav-2-enes 57

3.5. Reactions with diphenylethylene 58

3.5.1. Reaction mechanism 60

3.6. Synthesis of mixed dimers 60

3.7. Conclusion 62

CHAPTER 4: ACID-CATALYZED DIMERIZATION OF ISOFLAVANOLS

AND ISOFLAVENES

4.1. Introduction 64

4.2. Synthesis of isoflavanol precursors 67

4.3. Acid-catalyzed dimerization reactions of isoflavanols 69

4.3.1. Results and discussion 69

4.3.2. Mechanism for the acid-catalyzed rearrangement 73

4.4. Reactions with diphenylethylene 74

4.4.1. Synthesis and reactions with substituted diphenylethenes 75

4.4.2. Reaction mechanism with diphenylethylene 78

4.4.3. Reactions with indoles and other nucleophiles 79

4.5. Conclusion 81

CHAPTER 5: MANNICH REACTIONS ON FLAVONES

5.1. General background 83

x 5.2. The Mannich reaction 84

5.2.1. Mechanism of the Mannich reaction 85

5.2.2. Possibilities of Mannich base products 86

5.2.3. Chemoselectivity and regioselectivity of Mannich bases 87

5.3. Aims of the present work 89

5.4. Synthesis of hydroxyflavones 89

5.4.1. Known synthetic methodologies 89

5.4.2. Convenient one-pot synthesis of flavones 91

5.5. Mannich reactions of 6-hydroxyflavones 93

5.5.1. Reactions with primary amines 93

5.5.2. Reactions with secondary amines 96

5.5.3. Reactions with aminals 97

5.5.4. Reactions with amino acids 98

5.6. Mannich reactions of 7-hydroxyflavones 100

5.7. Mannich reactions of 5-hydroxyflavone 102

5.8. Conclusion 102

CHAPTER 6: SYNTHESIS OF 4-ARYLAZAFLAVANS AND QUINOLINES

6.1. Introduction 104

6.2. Known synthetic methodologies to 2,4-disubstituted-tetrahydroquinolines 105

6.3. Synthesis of azaflavanol 108

6.4. Results and discussion 109

xi 6.4.1. Synthesis of 4-arylazaflavans 109

6.4.2. Synthesis of 4-heteroarylazaflavans 112

6.4.3. Synthesis of 4-thiophenylazaflavans 117

6.5. Synthesis of 5,7-dimethoxyazaflavanol 118

6.6. Synthesis of 5,7-dimethoxy-4-arylazaflavans 121

6.7. Attempted synthesis of 1,2-dihydroquinoline 122

6.7.1. Attempted synthesis of 1,2-dihydroquinoline by reduction of

quinoline 124

6.8. Oxidation of 2,4-disubstituted azaflavans to quinolines 125

6.8.1. Introduction 125

6.8.2. Known synthetic methodologies for 2,4-disubstituted quinolines 126

6.8.3. Results and discussion 128

6.9. Conclusion 131

CHAPTER 7: EXPERIMENTAL

7.1. General information 134

7.1 Experimental details 135

CHAPTER 8: REFERENCES 236

APPENDIX X-ray crystallographic data 248

Publications

xii ABBREVIATIONS

AcONa sodium acetate AgOTf silver trifluoromethanesulphonate a.m.u. atomic mass unit

AuCl3 gold(III) chloride

BF3·OEt2 boron trifluoride diethyl etherate CAN ceric ammonium nitrate

CF3SO3H trifluoromethanesulphonic acid

CH3SO2Cl methane sulphonyl chloride

CF3COOH trifluoroacetic acid CNS central nervous system CoA coactivators CoR corepressors COX cyclooxygenase COSY correlation spectroscopy CuBr copper(I) bromide DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEPT distortionless enhancement by polarization transfer DNA deoxyribonucleic acid ER estrogen receptor ESI electrospray ionization

Et3N triethylamine HIV human immunodeficiency virus HMBC heteronuclear multiple bond correlation HMQC heteronuclear multiple quantum correlation

H2O2 hydrogen peroxide HPLC high-performance liquid chromatography HRMS high resolution mass spectrometry HSD hydroxysteroid dehydrogenase IC inhibitory concentration

In(OTf)3 indium trifluoromethanesulphonate

K3PO4 potassium phosphate LAH lithium aluminum hydride xiii LiHMDS lithium bis(trimethylsilyl)amide MALDI matrix assisted laser desorption ionization

Mn(OAc)3 manganese triacetate

NaBH4 sodium borohydride

NaCNBH3 sodium cyanoborohydride

Na2S2O3 sodium thiosulphate NBS N-bromosuccinimide NOESY nuclear overhauser enhancement spectroscopy ORTEP Oak Ridge thermal ellipsoid plot

Pd(OAc)2 palladium(II) acetate PET photoinduced electron transfer

POCl3 phosphorus oxychloride

P2O5 phosphorus pentoxide PPA polyphosphoric acid p-TSA p-toluenesulfonic acid

RuCl3 ruthenium(III) chloride

SeO2 selenium dioxide

SnCl4 stannic chloride TBAB tetra-n-butylammonium bromide t-BuOK potassium tertiary butoxide TFAA trifluoroacetic anhydride

Tf2NH triflic imide TMS tetramethylsilane

ZnCl2 zinc chloride

xiv PRESENTATIONS AND PUBLICATIONS

¾ Publication entitled “An efficient synthesis of novel tetrahydrochromeno[2,3- b]chromenes” in Tetrahedron Lett. 2010, 51, 3636-3638.

¾ Presented a poster entitled “Acid Catalyzed Dimerization of Flavenes: Synthesis of Dependensin Analogs?” at the research poster day held in the School of Chemistry, UNSW on 29 August 2008 and won the best poster award in the bioactive molecules group.

¾ Attended the Southern Highlands Conference on Heterocylic Chemistry held at Moss Vale from 31 August to 2 September 2008 and presented a poster on “Acid Catalyzed Dimerization of Flavenes: Synthesis of Dependensin Analogs?”

¾ Presented a talk on “Acid Catalyzed Dimerization of Flavenes: Synthesis of Dependensin Analogs?” at the RACI Natural Products Group Annual One-Day Symposium (NPG 08) on 3 October 2008 and won the best student presentation award.

¾ Attended the International Conference on New Developments in Drug Discovery from Natural Products and Traditional Medicines held at NIPER, Chandigarh from 16-20 November 2008 and gave an oral presentation on “Acid Catalyzed Dimerization of Flavenes.”

xv

CHAPTER 1

INTRODUCTION

1 1.1. General introduction Cancer is the leading cause of death in women falling in the age group between 30 and 54, with breast cancer being the most common of all.1 It affects approximately 116 per 100 000 women in the United Kingdom every year.2 A recent survey estimates that one out of eight American women develops breast cancer in their lifetime.1 A number of hormone-related risk factors are known to be associated with breast cancer such as the early onset of menarche, late onset of menopause, delayed age of first pregnancy and elevated free estradiol concentrations in post- menopausal women.2

In addition, diet and lifestyle are thought to play a major role in cancer risk.3-5 Generally, the incidence of breast cancer is known to be higher in Western populations in comparison with Asian populations.2-6 This finding has been associated with the consumption of a traditional low- fat, high-fiber, high-soy diet amongst Asian populations.2,3,5,6 This is in contrast to a Western diet, rich in fats and animal proteins, which alters the production, metabolism, and action of steroid hormones in the human body.3 The protection against breast cancer conferred on Asian women is however lost upon migration and exposure to Western lifestyles, thus linking lifestyle with breast cancer risk.2

1.2. Phytoestrogens In the past decade, researchers have made considerable efforts to link the various bioactive components present in plant foods to human health.7,8 The human diet, in addition to essential macro- and micro-nutrients, does consist of naturally occurring bioactive non-nutrients called phytochemicals. These chemicals show long-term health benefits, when consumed as an integral part of the daily diet.9 The bioactive components fall under a number of groups namely polyphenols, phytoestrogens, phytosterols, phytates and polyunsaturated fatty acids.7

Thus, phytoestrogens are naturally occurring nonsteroidal compounds, identified in at least 300 different plants from more than 16 different plant families. They can act as fungicides, deter- herbivores, regulate plant hormones, and protect plants against ultraviolet radiation.10

Plants related to human and animal food such as legumes (soybeans, chickpeas, clover), grains (wheat, barley, rice, rye, oat), vegetables (carrots, potatoes), fruits (apples, pears, grapes, dates, pomegranates, cherries), drinks (beer, coffee) and seasonings (fennel, aniseed, garlic, caraway) contain phytoestrogens.2-4,10,11

2 As already mentioned, a diet rich in phytoestrogens may be beneficial in the prevention or treatment of hormone-dependent diseases like breast and prostate cancer, due to the presence of these bioactive nonnutrients.3-5,9 It is said that phytoestrogens also protect against bowel and other non-hormonal cancers, cardiovascular diseases and osteoporosis.12

The phytoestrogens are similar in structure to the human female hormone 17E-estradiol 1.2,4 Hence, they are capable of acting either as agonists or as antagonists by competing with 17E- estradiol 1 for receptor binding.2,9,13 Their chemical structures derive their uniqueness due to the presence of a pair of hydroxyl groups and a phenolic ring, which are required for receptor binding.2,4,9 Thus the estrogenic effects of phytoestrogens can be rationalized by superimposing the structures of 17E-estradiol 1 and an isoflavone such as genistein 2 (Figure 1).

Figure 1. A superposition of the structures, genistein 2 and 17E-estradiol 1

The intramolecular distances between the hydroxyl groups at each end of the two molecules, 1 and 2 are almost identical, and facilitate their binding to the receptor.14

1.3. Classification of phytoestrogens The phytoestrogens are divided into two main groups (Figure 2):2-5,7,9,12 i) flavonoid and ii) non-flavonoid phytoestrogens The flavonoid phytoestrogens are further classified into: a) isoflavones e.g. genistein 2, b) flavones e.g. apigenin 3, and c) coumestans e.g. coumestrol 4. The non-flavonoid phytoestrogens are further classified into: a) lignans e.g. enterolactone, enterodiol 5, b) macrolides e.g. zearalenone 6, and c) stilbenes e.g. resveratrol 7.

3 H OH HO O

OH O OH HO 12

HO OH HO O O OH HO O OH

O

OH O OH HO 3 4 5

OH O OH

O HO

HO 7 6 O OH Figure 2. Examples of phytoestrogens with 17E-estradiol 1

Flavones have been isolated from almost all fruits and vegetables with their concentrations being highest in the outer layers. For example, flavonoid consumption can be drastically reduced if the peel of an apple is removed. However, citrus fruits like oranges have high amounts of flavonoids present in the pulp.7

Soybeans are considered unique among the legumes because of their rich isoflavones content.6,12 Other soy-based food products include tofu, textured soy protein and miso.4 The major glycosides found in soy beans are daidzin, genistin and glycitin.2,6,7 These compounds conjugated to glucose are inactive estrogenically. On consumption, they get hydrolyzed by the mammalian enzymes to form the corresponding active aglycones, daidzein, genistein 2 and glycitein.2,3 Daidzein is capable of undergoing further metabolism by the intestinal microflora to form the estrogenic compounds, equol (an isoflavan) and O-desmethylangolensin.2,4 Clover is another dietary source of isoflavones3 as it contains high concentrations of formononetin, a precursor of daidzein, and biochanin A, a precursor of genistein 2.12

Lignans are found widely distributed in oilseeds, seaweeds, legumes, seeds, fruits, vegetables and whole grains, and are particularly concentrated in flaxseed.7,12 The major lignans, which occur in the glycosidic form in foods, are matairesinol and seco-isolariciresinol.2,3 These plant 4 precursors are converted to enterolactone and enterodiol respectively by the intestinal bacteria.2,3,12 Enterodiol can undergo further transformation into enterolactone in the gut.2,3,12 The predominant dietary source of stilbenes is peanuts, grapes and red wine.4 Coumestrol is the most studied amongst the coumestans and is found to be present in clovers, soybean sprouts and in high amounts in mung bean sprouts.2

1.4. Mechanism of action of phytoestrogens The research into how phytoestrogens work and exhibit their effects in the human body is expanding rapidly. A significant number of these substances exhibit their effects through interaction with enzymes and nuclear receptors in specific manners. The most common effect is their biological response via the estrogen receptor. Genistein 2 is a typical example of an isoflavone, known as an agonist of the estrogen receptor,8 whose mechanism of action via the estrogen receptor is discussed in Section 1.4.2.

However, it is known that the anti-cancer mechanisms of phytoestrogens are not exclusively via the estrogen receptor; many of them are unrelated to the estrogenic properties of these compounds. Rather their effects are considered to be synergistic in nature.2,3,12

In vitro studies have revealed that numerous mechanisms may be involved such as inhibition of 3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase, 5α-reductase and aromatase, affecting the level of active steroid hormones, inhibition of DNA topoisomerases I and II, predicted to cause DNA damage and inhibition of protein tyrosine kinases.2,3,5,6,10,12, 15,16

Phytoestrogens also display their effects through transcriptional processes in which the transcription factor p53 currently is the most important tumor suppressor.10 More recently, it was suggested that genistein 2 might inhibit cell growth by increased production of transforming growth factor (TGF).2,4,6,10 Hsu et al. suggested that the inhibitory effects of biochanin A on breast cancer growth are linked to an inhibition of the production of nitric oxide, leading to cell apoptosis.17

Another mechanism to partially explain the anticancer activity of phytoestrogens involves their ability to inhibit angiogenesis.2,12 This process is involved in new blood vessel growth and is required for tumor growth and metastasis. Genistein 2 is capable of blocking this process.12 Hence, the other approach to cancer treatment involves the use of angiogenesis inhibitors, such as endostatin, along with the use of genistein 2 as its natural counterpart.10 5 At this point, it is worth mentioning that the preventive effects of phytoestrogens against cancer are not as definite as commonly said or reported.10,11 Certain literature references do describe the adverse effects of phytoestrogens in relation to breast cancer. Hence the quantity of phytoestrogens consumed, as well as the time of exposure to the appropriate diet play a vital role so as to increase or decrease cancer risk.2-4,11

1.4.1. Inhibition of aromatase

Aromatase is the cytochrome P450 enzyme complex, responsible for the biosynthesis of estrogenic steroids such as estrone 9 and 17E-estradiol 1 from androgens (androstenedione 8 and testosterone).5,8,13,18 Aromatase is present in breast tissue, and it is expressed in higher amounts in breast cancer cells and the surrounding adipose stromal cells than in non-cancerous breast cells.5,8,18

In estrogen-dependent breast tumors, estrogens are responsible for inducing the expression of growth factors needed for cancer cell proliferation. Thus, in situ generation of estrogen by aromatase plays a key role in promoting the growth of breast cancer (Figure 3).1,3,13

O O

Aromatase

HO O 89 Figure 3. The aromatase enzyme

Two primary approaches18 have been developed to reduce the growth-stimulatory effects of estrogens in breast cancer: 1) interfering with the ability of estrogen to bind to its receptor 2) decreasing circulating levels of estrogen. The first approach involves the use of anti-estrogens, which compete for binding to the estrogen receptors. Thereby, they reduce the number of receptors available for binding to endogenous estrogen. This has led to the development of efficacious anti-estrogens, such as the drugs tamoxifen 10 and raloxifene 11, which exhibit minimal toxicity.18,19

6 N

N O O

O

OH HO S 10 11

These compounds show great differences in activity, in the various estrogen target tissues, behaving as agonists in some tissues but as antagonists in others. Hence, Eli Lilly named these compounds as Selective Estrogen Receptor Modulators (SERMs)14,20,21 in the 1990s.19 For example, it has been found that tamoxifen 10 and raloxifene 11 are antagonists in breast tissue but agonists in bone, while only raloxifene 11 is a pure antagonist in the uterus.5

Inhibition of aromatase is the second approach for reducing growth-stimulatory effects of estrogen by decreasing circulating levels of estrogen. Therefore, suppression of estrogen biosynthesis by effective aromatase inhibitors (Figure 4) is considered a useful way to prevent and treat breast cancer.4,8,13,18

Figure 4. Action of enzymes, aromatase and 17β-HSD5 7 Both steroidal and nonsteroidal aromatase inhibitors have been shown to be clinically effective in the treatment of breast cancer. Exemestane 12 is a steroidal and mechanism-based inhibitor that is catalytically converted into chemically reactive intermediates by heme, leading to irreversible inactivation of aromatase.13 The nonsteroidal aromatase inhibitors include anastrozole 13 and letrozole 14 possessing a triazole functional group. These are capable of interacting with the heme prosthetic group of aromatase, and thus act as competitive inhibitors with respect to the androgen substrates.13,22

O N N N N H N N H H O NC CN NC CN 12 13 14

Exemestane 12 (Aromasin), anastrozole 13 (Arimidex) and letrozole 14 (Femara), developed in the early 1990s, are widely used as first-line drugs in the endocrine treatment of hormone- dependent breast cancer in post-menopausal patients.8,13,22

Several clinical studies carried out on aromatase inhibitors also suggest their use in the adjuvant setting for the treatment of early breast cancer. For instance, in case of hormone-dependent breast cancers, the use of an aromatase inhibitor as initial therapy or after treatment with tamoxifen 10 is highly recommended as adjuvant therapy.18

The phytochemical aromatase inhibitors are mainly the flavonoid phytoestrogens, containing the benzopyranone ring system.13 Some flavonoids such as the flavones, chrysin 15 (Passiflora coerulea) and apigenin 3 (Matricaria chamomilla), the flavanone, naringenin 16 (Petunia) and the flavonol, isolicoflavonol 17 (Glycyrrhiza uralensis) inhibit aromatase. Flavonoids that have no effect on aromatase activity are baicalein, 6-hydroxyflavone, daidzein, quercetin, catechin, and equol.13,23

8 OH OH

HO O HO O HO O

OH OH O OH O OH O 15 16 17

Although flavonoids possess only a weak inhibitory activity against aromatase, the benzopyranone-ring system of flavonoids is said to provide a good basis for the development of potential drugs in future.13

1.4.2. Mechanism of action via the estrogen receptor The theory postulated in the 1980s that phytoestrogens could have a protective effect against cancer was due to their similarity in structure to estrogens.2 Estrogens play an essential role in numerous physiological processes including the development and maintenance of female sexual organs, the reproductive cycle, reproduction, and various neuroendocrine functions. These hormones exhibit their normal physiological effects by binding to specific nuclear receptor proteins, one of which is the estrogen receptor.18

Two receptors, ERD and ERE, govern the biological effects shown by estrogen. ERE plays a major role in the physiology of many tissues, including the central nervous system, the cardiovascular system, the immune system, the urogenital tract, the gastrointestinal tract, the 19,21,24 kidneys, the lungs, the testis, ovary and colon. However, ERD dominates in few specific tissues such as the mammary gland and the uterus, and hence is mainly involved in reproductive events.19,24

The two estrogen receptors share a functionally conserved structure (domains A-F) consisting of a variable amino terminal region that is involved in transactivation (A/B), a centrally located DNA binding domain (C) a region involved in dimerization, a ligand binding domain (E), which synergizes with the transactivation functions in the A/B region, and a carboxyl-terminal (F) region, which appears to play a role in modulating transcriptional activation.5,19

There are two activation domains in the estrogen receptors, an N-terminal activation function (AF-1) that is ligand-independent and a C-terminal activation function (AF-2) that is ligand-

9 dependent. AF-1 and AF-2 can activate transcription independently, but in most cases they act synergistically to regulate gene transcription with the help of suitable coregulatory proteins.5,19

In the absence of hormone, the estrogen receptor rests in either the cytoplasm or in the nucleus of the target cells. It is associated with a large protein-chaperone complex, which sustains the receptor in a transcriptionally inactive form. On contact with a ligand, the receptor binds to it, enabling the receptor to transform itself from an inactive to a transcriptionally active form in cells. Thus, it brings about a conformational change leading to its displacement from the chaperone complex, followed by dimerization yielding homo- and hetero-dimers.19,21,25

In this biochemical state, the receptor complexes bind to specific DNA sequences that interact with coactivators (CoA) or corepressors (CoR). These coregulatory proteins act as signaling intermediates between the receptor and the general transcriptional machinery. They stabilize the pre-initiation complex formed and stimulate the transcription of responsive genes, thus producing the desired response (Figure 5).4,19,21,25

Figure 5. Process of transcription via the estrogen receptor19

1.5. Chemistry of the flavonoids The basic structural feature of flavonoids is the flavone nucleus (Figure 6), composed of aromatic rings (A and B), connected together through a heterocyclic pyrane C ring. The position of the aromatic B ring forms the basis for distinguishing between flavonoids 18 and isoflavonoids 19. The ring B at C2 forms the 2-phenyl-1,4-benzopyrones, the flavonoids 18 10 whereas, the ring B at C3 constitutes the 3-phenyl-1,4-benzopyrones, the isoflavonoids 19. However, this subtle difference in the position of aromatic ring B gives rise to significant differences in their reactivity and methodologies required for their synthesis.

8 1 B O O 7 OH A C 2 6 3 5 4 O O O 18 19 20

O O

O OH 21 22

O O O

OH O O 23 24 25 Figure 6. Classes of flavonoids

Further classification of compounds arising from the flavonoids is highly dependent on the arrangement of atoms in ring C of the nucleus. Chalcones 20 (1,3-diaryl-2-propen-1-ones) constitute the most important intermediates in the synthesis of flavones 18, isoflavones 19, flavanones 21, flavonols 25, and aurones 24. Chemically, they can be described as open-chain flavonoids in which the two aromatic rings A and B are joined by a three-carbon D,E- unsaturated carbonyl system.

Aurones 24 are formed by cyclization of chalcones, whereby the meta-hydroxyl group reacts with the D-carbon to form a five-membered ring heterocycle. The heterocycle of flavanones 21 contains a carbonyl group at C4, but indicated by the absence of unsaturation at C2-C3. Reduction of flavanones 21 can result in the formation of flavanols 22, which upon dehydration leads to flavenes 23.

11 1.6. Medicinal uses of flavonoids and isoflavonoids Flavonoids are generally considered nontoxic and known to manifest a diverse range of beneficial biological activities namely, antitumor,26 estrogenic,27 anti-lipoperoxidant,28 anti- platelet,29 anti-viral,30 anti-fungal,31 anti-bacterial,32 anti-hemolytic,33 anti-ischemic,34 antiallergic, anti-inflammatory; inhibition of cyclooxygenase and lipoxygenase activities.35-37

Lichochalcone A 26 (4,4c-dihydroxy-2-methoxy-5-C-prenylchalcone) and lichochalcone B 27 (3,4,4c-trihydroxy-2-methoxychalcone) isolated from Glycyrrhiza glabra have antioxidant activities comparable to that of vitamin E.38 Licochalcone C 28 (4,4c-dihydroxy-2c-methoxy-3c- prenylchalcone), on the other hand, is found to be active against Staphylococcus aureus with a minimum growth inhibitory concentration (MIC) of 6.25 Pg ml-1.39

HO OH HO OH

OH OO OO 26 27

HO OH

OO 28

The aerial parts of Ononis natrix (Leguminosae) were studied, which revealed the following three chalcones, 4,2c,6c-trihydroxy-4c-methoxydihydrochalcone, 2c,6c-dihydroxy-4c- methoxydihydrochalcone and 2c,4c-diacetoxychalcone having moderate activity against murine leukaemia, lung cancer and colon cancer respectively.40

Kitaoka et al. isolated 8-isopentenylnaringenin, a Thai crude drug, from the heartwood of Anaxagorea lutzonensis (Annonaceae) in 1998. In vitro tests done on this flavanone revealed good estrogen agonist activity, greater than that of the isoflavone, genistein 2. The 8-isopentenyl group has been found to be important for receptor binding.41

12 Flavanonols containing glucosides isolated from the rhizome extract of Smilax glabra (Liliaceae) showed their potential as hepatoprotective agents.42 Bergendorff and Sterner screened the traditional medicinal plants in Europe in 1995, and identified four flavonols from the aerial parts of Artemisia abrotanum (Labiatae) with spasmolytic activity.43

The sesquiterpene lactone artemisinin from Artemisia annua (Compositae) is well known for the prevention of malaria. However, Elford et al. showed the enhancement of anti-malarial activity in the presence of the flavonol, casticin 29 (5,3c-dihydroxy-3,4c,6,7-tetramethoxyflavone), thereby suggesting a synergistic effect between casticin and artemisinin.44

OH O

O O HO OH

O O OH O OH O 29 30 HO O

O OH 31

Certain flavonoids with anti-platelet activity have the capacity to inhibit platelet adhesion, aggregation and secretion. Examples of such compounds are 4,2c,4c-trihydroxy-3c- prenylchalcone 30 (isobavachalcone) and 4c,7-dihydroxy-3c-prenylisoflavone 31 (neobavaisoflavone), isolated from the seeds of Psoralea corylifolia (Leguminosae).45

In addition to these compounds, many natural flavonoids also exist as dimers, trimers and oligomers in which the flavonoid units are coupled together at various positions.

1.7. Biflavonoids Biflavonoids are naturally occurring polyphenolic molecules comprised of two identical (represented by A-A, B-B and C-C) or non-identical flavonoid units (represented by A-B, A-C and B-C) joined symmetrically or unsymetrically (Figure 7) through linkers (C-C, C-O-C etc.) of varying length.46 The large number of possibilities in the length, position and nature of

13 linkages, as well as in the number and nature of substituents, gives rise to an enormous structural diversity to the biflavonoids class.46-48

O O O

O O O A-B O A-A O O O O

O O O O B-C A-C O O O O O O B-B O O O C-C Figure 7. Biflavonoid linkages

Biflavonoids have received increasing recognition due to their wide spectrum of pharmacological properties, including anti-inflammatory, anti-microbial, anti-oxidant, anti- cancer, anti-viral, anti-HIV-1, anti-HBV, vasorelaxant, and anti-clotting activities.46,47,49

Biflavonoids, like flavonoids, also occur in fruits, vegetables, and plants.46 Numerous biflavonoids have been isolated from nature and characterized ever since the isolation of ginkgetin in 1929 by Furukawa from the leaves of the maidenhair tree, Ginko biloba (fossil tree or Japanese silver apricot).47,49

Huang and Zhang discovered chamaejasmine 32, a biflavanone in 1979 from a medicinal plant named Stellera chamaejasmae.50 This traditional herbal medicine (Langdu) from China, has derived its uniqueness due to the presence of a rare 3/3c C-C linkage.50 This biflavanone has also been identified as a C2-symmetric racemate dimer of naringenin 16 at the C3 position.50

14 OH OH H H HO O HO O 2 O OH O OH 3 H H H 3' H OH O OH O O OH O OH H H HO HO 32 33

The meso isomer of this compound, known as isochamaejasmine 33, along with other stereo isomers of chamaejasmine, glycoside and isomeric derivatives (i.e., diphysin and chamaechromone) have also been isolated from Langdu.50 Recently, Yamada et al. have tested the ethereal derivatives of chamaejasmine 32, which were shown to possess potent antimalarial activity in vitro against the chloroquinine-resistant strain of Plasmodium falciparum.51

Three other biflavanones, namely calycopterone, isocalycopterone and 4-demethylcalycopterone along with 5,5c-dihydroxy-3,6,7,3c-tetramethoxyflavone, were isolated from the flowers of Calycopteris floribunda (Combretaceae), which showed a wide range of cytotoxic activities against a number of human cell lines.52,53

OH OMe OH OH HO O MeO O 3' 8 3' 8 O OH O OH OH O OH O O O

HO HO 34 35

Amentoflavone 34, ginkgetin 35, ochnaflavone 36 and morelloflavone 37 have been shown to be dual inhibitors of phospholipase A2 and cyclooxygenase-2, leading to decrease in the synthesis of prostaglandins, the major mediators of inflammation.46,54,55 Hence, these biflavonoids can suppress inflammation in many disorders including cancer.46

Ochnaflavone 36 a medicinal herb product, isolated from Lonicera japonica, having C-O-C linkage is the first natural biflavonoid in which neither of the A-rings are involved in the interflavonyl linkage.46 Morelloflavone 37 was the first flavanone-flavone type biflavonoid,

15 isolated and identified from the seeds of Garcinia morella in 1967.56 It was obtained as a racemate mixture and its stereochemistry has not yet been established.57

O OH

OH OH O OH OH HO O OH 3' O 4' HO O

3 O OH O 36 8 OH O O

HO OH 37

The biflavones, robustaflavone 38 and hinokiflavone 39, isolated from the seed-kernels of Rhus succedanea have been found to be active against HIV-1 reverse transcriptase with IC50 values of 65 PM, thus causing inhibition of the enzymes required for viral replication.46,58 Hinokiflavone 39 has also been known for its procoagulant activity and can inhibit endoxin- and interleukin- 59 induced tissue factor expression with IC50 values of 18 and 48 nM, respectively.

OH OH O HO O OH 6 HO O HO O 3' OH O OH O 38 OH O HO O 39

OH O

Robustaflavone 38 is an inhibitor of hepatitis B virus (HBV) replication in vitro.23,60,61 It is composed of two units of apigenin 3 joined via a biaryl linkage between the 6-position of one unit and the 3-position of the other.60 The synthesis of biflavonoids such as amentoflavone 34 and robustaflavone 38 can be undertaken via Suzuki-Miyaura coupling of an apigenin boronic acid derivative with an appropriate iodoapigenin analogue.23,60

16 1.8. Biisoflavonoids Biisoflavonoids are naturally occurring compounds in which two isoflavonoid molecules are connected to each other. Like their biflavonoid counterparts, biisoflavonoids are also further classified into two groups: i) the biphenyl type, in which the two units are linked through a carbon-carbon bond, and ii) the biphenyl ether type, in which the linkage is through an oxygen atom. However, unlike biflavonoids, biisoflavonoids are much less known in the literature.

The first natural biisoflavonoid was isolated from the heartwood of Dalbergia nitidula and identified as (3S,4S)-3,4-trans-4-[(3S)-6c,7-dihydroxy-4c-methoxyisoflavan-3c-yl]-4c- methoxyisoflavan-2c,7-diol 40. The synthesis of this dimer was undertaken via acid-mediated condensation of the appropriate pterocarpan with isoflavan precursors.62

OH MeO OH HO O OH 3' 5 HO O HO O 2 2 OH O O OH O OH O HO OMe

40OH 41

The constituents of the red heartwood of Berchemia zeyheri were investigated and revealed the presence of the first natural isoflavanone-benzofuranoid biflavonoids, identified as (2S, 3R)- dihydrogenistein-(2E~5)-(2R)-maesopsin 41 and its 2S-epimer.63

O O O

O O O

42 O O

The phytochemical investigations of extracts from the branch barks of Andira surinamensis generated the dimeric isoflavonoid 42, an anthelmentic agent possessing an ethereal linkage.64

17 1.9. Limitations Although there are several examples of naturally occurring dimeric flavonoids and isoflavonoids with potent activity against several ailments, their use as medicaments has been limited due to the following reasons:65 i) low abundance of these compounds in the plant material, ii) tedious extraction and purification techniques which often require extraction with very large quantities of solvents, multiple chromatographic purifications, occasionally including HPLC purifications, and iii) unavailability of appropriate biological data.

One of the possible solutions to these problems is the development of efficient synthetic methodologies, which can produce not only the natural products but also their synthetic analogues for pharmacological applications.

Several chemical approaches utilizing coupling and rearrangement strategies have been developed to synthesize biflavonoids46 such as Ullmann coupling of halogenated flavones, Wessely–Moser rearrangements, dehydrogenation of biflavanones into biflavones, hydrogenation of biflavones into biflavanones and others. These pathways pave the way to the organic synthesis of dimeric flavones and isoflavones, which have widespread application in organic chemistry, specifically in forming a promising class of pharmacologically active compounds.

1.10. Aims of the present work The main aim of this project was to synthesize new heterocycles derived from flavonoids and isoflavonoids, and can broadly be divided into a few subdivisions.

Firstly, the project aimed at evaluating the acid-catalyzed dimerization reactions of flavenes, in order to develop a suitable methodology for the synthesis of biflavonoids, containing the benzopyrano[4,3-b]benzopyran ring system present in the natural product, dependensin.

Secondly, the acid-catalyzed dimerization reactions of isoflavanols and isoflavenes were to be studied in depth. It would perhaps be interesting to compare and contrast the differences arising from the chemistry of acid-catalyzed reactions of flavenes and isoflavenes.

18 Thirdly, the Mannich chemistry of 5-hydroxy-, 6-hydroxy- and 7-hydroxy-flavones using various primary and secondary amines, aminals and amino acids was to be investigated. The regioselectivity and chemoselectivity of the Mannich bases were to be studied.

Lastly, the biheterocylic compounds consisting of an azaflavone and a heterocyclic compound like an indole, furan or chromene are unknown in the literature. Hence, another aim was to generate 4-arylazaflavans via the acid-catalyzed coupling of azaflavanols with a variety of nucleophiles and also develop effective strategies to oxidize them to the corresponding quinolines.

19

CHAPTER 2

ACID-CATALYZED DIMERIZATION OF FLAVENES: SYNTHESIS OF BENZOPYRANO[4,3- b]BENZOPYRANS

20 2.1. Introduction Molecules with a benzopyran ring are widely found in nature. These moieties have drawn the attention of scientists as these compounds display varying pharmacological properties including antioxidant, anticancer, anti-inflammatory, anti-viral, anti-bacterial and anti-HIV activities.66 Their numerous applications in molecular electronics,67a optical memories67b and biological photoswitches67c are noteworthy. This wide range of interesting activities and properties has prompted studies into the development of convenient and efficient methodologies for synthesizing polyheterocycles with benzopyran moieties.

2.1.1. Known synthetic methodologies Recently, Lee et al. have developed an efficient one-pot synthetic approach to benzopyranobenzopyrans with stereochemically defined quaternary carbon centers as seen in 43. The key strategy involved ethylenediamine diacetate (EDDA) catalyzed cyclization by domino aldol-type reaction/hetero Diels-Alder reaction of resorcinols with benzaldehydes containing O- allyl ether groups.68

O O H H O O H O OH O O O H O OMe 43 44 45 OMe

Similarly, Tietze has described the synthesis of tetracycles such as 44 using intramolecular hetero Diels-Alder reaction of benzylidene-1,3-dicarbonyl compounds with O-allyl ethers of salicylaldehydes.69

Of particular resemblance to these structures is also the rotenoid group of natural products best known to be present in the Leguminosae family. A prominent member of this group is (−)-(6aS, 12aS, 5cR)-rotenone 45, which is a fish poison.70

Ahmad-Junan et al. in 1988 approached the synthesis of rotenoids via a radical cyclization method and produced the benzopyranobenzopyran 46 as a single stereoisomer by treating 2-((2- iodophenoxy)methyl)-4a,8a-dihydro-2H-chromene 47 with tributyltin hydride in refluxing

21 benzene using azaisobutyronitrile as an initiator (Scheme 1). The intramolecular 6-exo aryl radical addition observed in this reaction is known to be responsible for the formation of the cis isomer in the tetracycle 46.71

H O O O O I H 46 47 Scheme 1

The benzopyranobenzopyrans are relevant to our study, as the dimeric flavonoid dependensin 55 was found to contain the same ring system. This ring system, specifically referred to as benzopyrano[4,3-b]benzopyran, has been known since 1938. However, Da Re and his colleagues in 1976 described the synthesis of this homopterocarpane 52 as shown in Scheme 2.72

Scheme 2

The synthesis involved condensation of chromanone 49 with 2-benzyloxybenzaldehyde 48 to give 3-(2-benzyloxy)-benzylidenechroman-4-one 50. Its catalytic debenzylation followed by reduction afforded 3-(2-hydroxybenzyl)-chroman-4-ol 51 which on boiling with acetic acid

22 cyclized to 52. The last step of the synthesis presumably takes place stereospecifically, in order to afford the cis configuration of the vicinal protons, H6a and H12a.72

However, this chapter presents a different methodology to the synthesis of benzopyrano[4,3- b]benzopyrans, i.e. via the acid-catalyzed dimerization of flavenes.

2.2. Dependensin Tanzanian medicinal plants have been explored for their antimalarial activity and investigations done on the Uvaria species were of interest, as nine of its species screened for in vitro activity against the multidrug resistant strain of Plasmodium falciparum were active.73

Engl and Diels investigated the root bark of Uvaria dependens in detail and isolated three new flavonoids, 5,7,8-trimethoxyflav-3-ene 53, 2-hydroxy-3,4,6-trimethoxychalcone 54 and the dimeric benzopyran, which was then named dependensin 55. Besides these, (-)-pipoxide and a mixture of sitosterol and stigma sterol were also isolated.73

OMe OMe MeO O MeO OH

OMe OMe O 53 MeO OMe 54 OMe H O OMe H H O MeO H OMe

55

The crude extract of Uvaria dependens was found to be active against the malarial parasite having an IC50 value ranging between 10 and 49 Pg/ml. The isolated compounds however could not be tested for pharmacological activity; as they were either obtained in very poor yields, in which case the quantities were insufficient to carry out the various necessary tests, or the compounds were found to be unstable.73

23 Flavenes, in general, occur in nature very rarely, which may be due to their high chemical reactivity.74 For example, 5,7,8-trimethoxyflav-3-ene 53 was found to be unstable and sensitive to air. The main decomposition product was the corresponding chalcone 54 when treated with HCl gas and exposed to air (Scheme 3). Hence, the reverse chalcone 54 obtained was initially considered an artifact.73

OMe OMe HCl(g),air MeO O MeO OH

CHCl3,r.t.

OMe OMe O 53 54 Scheme 3

Hypothetically, dependensin 55 was thought to originate from the acid-catalyzed reaction of 5,7,8-trimethoxyflav-3-ene 53. But, since 55 was obtained as a racemic mixture, there were doubts if it could be considered an artifact as well. However, the decomposition products of 53 did not show any traces of 55, thereby enabling 53 to be considered a genuine component of Uvaria dependens.73

The heterocyclic ring system present in 55 is quite unique and contains a dense array of functionality and stereochemistry, which includes two fused benzopyran rings, four stereocentres and one trans double bond. The unique structural complexity of the moiety has generated interest in the development of suitable methodologies to dependensin 55 and its analogues, as new agents for the treatment of malaria.

Previous research in our group has shown that compound 56 containing the benzopyrano[4,3- b]benzopyran ring system present in dependensin 55 can be generated via the acid-catalyzed dimerization reaction of 4c,7-diacetoxyflav-3-ene 57 (Scheme 4). Also, the synthesis of 55 was found to be successful via the acid-catalyzed reaction of 53. But similar acid-catalyzed reactions of the corresponding 4c,5-diacetoxy- and 4c,6-diacetoxyflavenes gave a complex mixture of products.75

24 OH H HO O OAc H H O AcO O H

57

OH

OH 56 Scheme 4

Encouraged by these ideas on the synthesis of dimeric systems, the acid-catalyzed reactions of monomethoxyflavenes 58, having methoxy groups at C5, C6 and C7 of the flavene nucleus (Figure 8) were investigated in depth. Interestingly, it was observed that the dimerization products obtained were dependent on the position of the methoxy substituent in the flavene ring.

R position 7 O MeO

position 6 58

position 5

Figure 8. General structure of a monomethoxyflavene

The sections to follow report the facile synthesis of a series of benzopyrano[4,3-b]benzopyrans 74a-d via the acid-catalyzed reactions of 7-methoxyflavenes 73a-d. Additionally, the acid- catalyzed reactions of 5,7,8-trimethoxyflavenes 82a-d were also targeted in order to achieve direct analogues of dependensin 55.

2.3. Synthesis of 7-methoxyflavenes

As flav-3-enes were necessary precursors to the dimeric flavonoids, an efficient route to their synthesis had to be developed. Retrosynthetic analysis (Scheme 5) indicates that flavenes 59 can be obtained by the dehydration of flavanols 60, which in turn can be synthesized by the reduction of flavanones 61. The flavanones 61 can be generated by the cyclization of chalcones 62 in the presence of strong acids and the chalcones 62 can be derived from the base-catalyzed condensation of 2c-hydroxyacetophenones 64 with aldehydes 63. 25 R R R O O O RO RO RO

OH O 59 60 61

OH CHO OH RO RO R R O 64 63 O 62 Scheme 5

The literature suggests the protection of phenolic groups as an important step in the synthesis of chalcones 62, flavanones 61 and flavones 69.76 Therefore, one of the hydroxyl groups in the starting hydroxyacetophenone 65 was masked by methylation before condensation, in order to increase the yield as well as to facilitate clean progress and simpler purification of the subsequent reactions.

HO OH CH3I, K2CO3 MeO OH acetone reflux, 92% O O 65 66 Scheme 6

Hence, commercially available 2c,4c-dihydroxyacetophenone 65 was treated with anhydrous potassium carbonate and methyl iodide in dry acetone77a,77b to give 2c-hydroxy-4c- methoxyacetophenone 66 in 92% yield (Scheme 6). Dimethylsulfate can also be used as a methylating agent in place of methyl iodide.77c

The synthesis of chalcones 68a-d involved the aldol condensation of equimolar quantities of the protected acetophenone 66 with substituted benzaldehydes 67a-d in ethanol/methanol catalyzed by KOH78a or NaOH.78b,78c It was observed that the use of ethanolic NaOH solution suited well for the reactions shown in Scheme 7.

26 MeO OH CHO MeO OH R NaOH, ethanol, r.t.

R 65-73% 66 O 67a-dO 68a-d 67a R=H 68a R=H 67b R=Br 68b R=Br 67c R=Cl 68c R=Cl 67d R=OMe 68d R=OMe Scheme 7

The flavanones 61 can be accessible via the spontaneous cyclisation of the chalcones 62 in the presence of a mineral acid.79 However, intramolecular oxidation of 2'-hydroxychalcones 62 can afford the corresponding flavones 69 (Scheme 8).

R O OH RO RO R

O O 69 62 Scheme 8

80a 80b,80f Reagents that have been used for this purpose include I2-DMSO, SeO2-DMSO, DDQ- 80c 80d 80e 80f 80b dioxane, nickel peroxide-dioxane, H2O2-NaOH, Dowex-2-propanol, SeO2-dioxane and others. Most of these methods are of limited use, as yields are low and mixtures of products, containing flavones 69, flavanones 61, and aurones are obtained. Also, these procedures require prolonged reaction times, high temperatures and harsh reaction conditions.80c,80d,81,82

Further, reduction of the flavones 69 or flavanones 61 using appropriate reducing agents such as 74 75,83,84 84 Pd/C, NaBH4 or LAH was required to obtain the corresponding flavanols 60, which in 85 85 turn need to undergo dehydration using p-TSA-toluene or P2O5-DCM in order to generate the desired flavenes 59 (Scheme 5).

Flav-3-enes 59 may alternatively be prepared by dehydrobromination86,87a of 4-bromoflavans 70 (Scheme 9), obtained from the 2'-hydroxychalcones 62 via the flavanones 61 and flavanols 60, but this method has not been used much.

27 R R R O O O RO RO RO

Br OH 59 70 60 Scheme 9

Interestingly, Clark-Lewis and Jemison report the direct conversion of 2'-hydroxychalcones into the corresponding flav-3-enes by reduction with sodium borohydride in isopropanol.87 This reductive cyclization was discovered during the synthesis of hemiketals 71 related to peltogynol, obtained from the corresponding flavonol lactones 72 by reduction with lithium aluminium hydride.88

R R R R

R' O R' O

O O O OH O R, R' = H, OMe 71 72

The method of reductive cyclization has indeed developed into a versatile and convenient one- stage synthesis for preparing flav-3-enes. Therefore, NaBH4 reduction in IPA as solvent was utilized to produce the desired flavenes 73a-d in 50-58% yields as shown in Scheme 10.

R MeO OH R NaBH ,IPA,r.t. 4 MeO O 50-58% O 68a-d 73a-d 68a R=H 73a R=H 68b R=Br 73b R=Br 68c R=Cl 73c R=Cl 68d R=OMe 73d R=OMe Scheme 10

The above strategy generated the flavenes 73a-d in fewer steps as well as gave an increased overall yield. The flavenes so obtained were either low melting white solids or yellow oils. 28 In general, flav-3-enes are reported to be useful intermediates in the synthesis of the parent flavans, flavan-3,4-diols, and flavylium salts.87a Their conversion into 3,4-dibromoflavans, bromoflavanols, and other related compounds has also been investigated.86b

The 1H NMR spectrum of a typical flav-3-ene, for example, 4c-bromo-7-methoxyflavene 73b exhibited three doublets of doublets at G 5.61 (J = 3.4, 9.8 Hz), G 5.83 (J = 1.5, 3.4 Hz) and G 6.50 (J = 1.5, 9.8 Hz) corresponding to H3, H2 and H4 respectively. The 1H NMR spectra of the other flavenes 73a, 73c and 73d were found to exhibit similar coupling patterns for ring C. Further, DEPT-135 and the broadband decoupled 13C NMR spectrum of 73b indicated the absence of methylene (CH2) groups, confirming that the flav-2-ene was not formed.

The structure of 4c-bromo-7-methoxyflavene 73b was confirmed by X-ray crystallography, which showed the presence of the double bond at position 3 of the flavene nucleus. The ORTEP diagram of 73b is shown in Figure 9.

Figure 9. ORTEP diagram of 73b

2.4. Acid-catalyzed reactions on 7-methoxyflavenes

The 7-methoxyflavenes 73a-d were subjected to acid-catalyzed reactions in methanol and were found to undergo dimerization as anticipated to give a series of dimers 74a-d possessing the benzopyrano[4,3-b]benzopyran ring system in moderate yields of 65-71% (Scheme 11). Catalysts used for these reactions were HCl, TFA and glacial acetic acid. The results obtained were the same, irrespective of the acid employed.

29

Scheme 11

These dimers 74a-d contain four tertiary aliphatic protons, two of which are attached to oxygenated carbon atoms. Thus, the identification of protons H6, H7, H6a and H12a were of prime importance in assigning the structure of the product. In the dimeric flavonoid 74c (Figure 10), a doublet of doublet of doublets at G 2.43 (J = 2.1, 2.3, 10.6 Hz) correlated to H6a, a doublet of doublets at G 3.12 (J = 2.1, 6.4 Hz) correlated to H7, and two doublets at G 5.03 (J = 10.6 Hz) and G 5.06 (J = 2.3 Hz) correlated to H6 and H12a respectively. The protons present on the trans double bond, represented as HE and HD, were identified as a doublet at G 6.00 (J = 15.8 Hz) and a doublet of doublets at G 6.20 (J = 6.4, 15.8 Hz) respectively.

30 OMe

H12a

HD HE H6 H7 H6a

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 ppm

Figure 10. 1H NMR spectrum of compound 74c

The cis-fusion of the benzopyran rings was indicated by the coupling constant (J = 2.3 Hz) between H6a and H12a and from the presence of NOE between these protons. The other important NOEs giving evidence of the product formed were the connections between H7 and

HD, H7 and H8, HD and H2cc, H6 and H2c.

The HMBC correlations exhibited by the aliphatic protons also played an important role in making the necessary assignments to the structure 74c. Short range and long range HMBC correlations from H7 to C6a, C12a, C7a and C11a suggested its presence within the first benzopyran ring. HMBC connections from H6a to C6 and C7 indicated its presence between these two protons, whereas HMBC connections from H12a to C12b and C4a gave evidence of its attachment to the second benzopyran ring. The olefinic protons, HD and HE projected correlations to C7 and C1cc, thereby indicating the attachment of the styryl group at C7. Further, one of the aromatic protons of the other 1,4-disubstituted benzene ring, H2c showed correlations to C4c and C6, thus confirming the attachment of the aromatic ring at C6.

DEPT-135 along with a broadband decoupled 13C NMR spectrum indicated the absence of any

CH2 groups in the molecule. This together with other COSY, NOESY, HMQC and HMBC correlations confirmed the structure of the isolated compound 74c.

31 OMe OMe 3 MeO O MeO O12a 10 O 7 6 O

2'

2'' Cl Cl

Cl Cl

Important HMBCs for 74c Important NOESYs for 74c

Based on the above observations, the other dimeric flavonoids 74a, 74b and 74d were postulated to contain the same structure. However, attempts to crystallize these dimers 74a-d from various solvents to obtain a single crystal for one of them suitable for X-ray diffraction studies were unsuccessful.

2.4.1. Mechanism for the acid-catalyzed rearrangement

A possible mechanism for this rearrangement was proposed previously by Deodhar et al.,75 and is outlined briefly below in Scheme 12. Initially the flavene 73 in the presence of methanolic HCl, presumably could undergo protonation to give 75 followed by ring opening to give a highly stable benzylic carbocation 76. A second molecule of flavene 73 could attack this benzylic carbocation 76, in such a way as to generate a second highly stable benzylic carbocation 77, which upon cyclization gives the dimer 74.

32

Scheme 12

The 7-methoxyflavenes 73a-d were expected to follow a similar mechanism as outlined in Scheme 12.

2.5. Synthesis of 5,7,8-trimethoxyflavenes

Since it is already known that the synthesis of 55 involved the acid-catalyzed reaction of 53, the synthesis of 5,7,8-trimethoxyflav-3-enes 82a-d having varying substituents in ring B was undertaken with the aim of producing direct analogues of 55. The 5,7,8-trimethoxyflavenes 82a- d were readily accessible from the corresponding chalcones 78a-d using the same strategy developed previously for the synthesis of 7-methoxyflavenes 73a-d (Scheme 10). A review from

33 the literature indicated that the chalcones 78a-d could find their origin from 1,2,3,5- tetramethoxybenzene 79 (Scheme 13).

OMe OMe MeO OH R MeO OMe

OMe O OMe 78a-d 79

Scheme 13

Hence, commercially available 3,4,5-trimethoxyphenol 80 was methylated in 95% yield using methyl iodide in the presence of potassium carbonate as a base (Scheme 14). The product 79 was acetylated and demethylated in a one-pot reaction using acetyl chloride and aluminium chloride in ether in an inert atmosphere of nitrogen at 0 qC to furnish 2c-hydroxy-3c,4c,6c- trimethoxyacetophenone 81 in 58% yield (Scheme 14). This method has been reported previously in the literature89 as a means to selectively demethylate a methoxy group ortho to an acetyl group.

OMe OMe OMe MeO OMe MeO OH MeO OMe CH3I, K2CO3 AlCl3,CH3COCl acetone ether reflux, 95% 0 0Ctor.t.,58% OH OMe OMe O 80 79 81

Scheme 14

The chalcones 78a-d were synthesized in 61-77% yields by Claisen-Schmidt condensation of 2c- hydroxy-3c,4c,6c-trimethoxyacetophenone 81 with para-substituted benzaldehydes 67b-e in an alkaline alcoholic medium (Scheme 15).

34 CHO R OMe 67b-e OMe R MeO OH MeO OH NaOH, ethanol, r.t. 61-77% 67b R=Br OMe O 67c R=Cl OMe O 81 67d R=OMe 78a-d 67e R=Me 78a R=Br 78b R=Cl 78c R=OMe 78d R=Me Scheme 15

The flavenes 82a-d were obtained in a similar fashion as before in 56-63% yields by reductive cyclization using NaBH4 (Scheme 16).

R R OMe OMe MeO OH MeO O NaBH4,IPA,r.t. 56-63% OMe O OMe 78a-d 82a-d 78a R=Br 82a R=Br 78b R=Cl 82b R=Cl 78c R=OMe 82c R=OMe 78d R=Me 82d R=Me Scheme 16

2.6. Acid-catalyzed reactions on 5,7,8-trimethoxyflavenes

The 5,7,8-trimethoxyflavenes 82a-d were subjected to acid-catalyzed reactions in methanol as before. Interestingly, and unlike the acid catalyzed reactions of 7-methoxyflavenes 73a-d, the reaction outcome depended on the acid catalyst used. The reaction of flavenes 82a, 82b and 82d with HCl gave rise to the open chain compounds 83a, 83b and 83c (Scheme 17) in 38-43% yields instead of the expected dimerization products.

35

Scheme 17

These open chain compounds 83a, 83b and 83c represent o-cinnamylphenols, which have been reported in the literature90,91 as precursors to the synthesis of flav-3-enes. Cardillo et al. described the easy conversion of o-cinnamylphenols into flav-3-enes by dehydrogenation with DDQ.90a,90b Another literature reference reports the heterocyclization of o-cinnamylphenols with an alcoholic solution of iodine in the presence of H2SO4 and H2O2 to generate 3-iodoflavans, which can be converted to flav-3-enes by eliminating hydrogen iodide.90c

The structure of 83c was confirmed by X-ray crystallography and its ORTEP diagram is shown in Figure 11.

Figure 11. ORTEP diagram of 83c

But, surprisingly 82c when reacted under similar conditions produced a dihydrochalcone 84 in 51% yield (Scheme 18) and not the o-cinnamylphenols obtained previously. The probable reasons for the formation of 84 are discussed in Chapter 3.

36

Scheme 18

On the other hand, the use of TFA or glacial acetic acid as catalysts furnished direct analogues of the desired natural product 85a-d in 68-73% yields (Scheme 19).

MeO OMe OMe R H OMe MeO O OMe MeO O TFA, MeOH H H O 68-73% H OMe OMe 82a-d 82a R=Br R 82b R=Cl 82c R=OMe R 85a-d 82d R=Me 85a R=Br 85b R=Cl 85c R=OMe 85d R=Me

Scheme 19

The 1H NMR spectra of these dimers 85a-d were found to have coupling patterns similar to those dimers 74a-d achieved via the acid-catalyzed reactions of 7-methoxyflavenes 73a-d.

However, an attempt to obtain a single crystal of one of these dimeric products was successful. The X-ray crystal structure of compound 85c shown in Figure 12 confirmed the stereochemistry of the dimeric product, which was found to be identical to that of the parent dependensin 55 reported in the literature.73

The crystal structure reveals the presence of two trisubstituted benzopyran rings fused together at C6a and C12a. The vicinyl protons, C6a and C12a have a cis configuration between them. The presence of the styryl group at C7 and the other substituted aromatic ring at C6 is also evident from the ORTEP diagram.

37

Figure 12. ORTEP diagram of 85c

The acid catalyzed reactions of 7-methoxyflavenes 73a-d and 5,7,8-trimethoxyflavenes 82a-d however, can give rise to different diastereoisomers, owing to the presence of four chiral centres in their structures. It was interesting to observe the formation of a single diastereoisomer in all cases, evident from the coupling constants of the aliphatic protons. Hence, these acid-catalyzed reactions were regarded as highly stereoselective; one of the reasons may be attributed to the high stability of the carbocation intermediates generated during the course of their rearrangement. Further, a preliminary model was made previously in our research group indicated the stereochemical formation of the single diastereoisomer isolated from the acid- catalyzed reactions.

2.6.1. Biological activity of dependensin analogues

Plasmosium falciparum growth inhibition assays were carried using an isotopic microtest. Briefly, ring-stage P. falciparum 3D7 infected erythrocytes (0.5% parasitemia and 2.5% hematocrit) were seeded into triplicate wells of 96 well tissue culture plates containing serial dilutions of control (chloroquine) or test compounds. Following 48 hours incubation under standard P. falciparum culture conditions, 0.5 μCi [3H]-hypoxanthine was added to each well after which the plates cultured for a further 24 hours. Cells were harvested onto 1450 MicroBeta filter mats (Wallac) and 3H incorporation was determined using a 1450 MicroBeta liquid scintillation counter. Percentage inhibition of growth was compared to matched DMSO controls 38 (0.5%). IC50 values were calculated using linear interpolation of inhibition curves. The mean

IC50 (+/- SD) is shown for three independent experiments, each carried out in triplicate.

The natural product, dependensin 55 and it analogues 85a-d were screened for antimalarial activity against P. falciparum using this growth inhibition assay described above. The antimalarial drug, chloroquine was used as the test control. Table 1 gives the IC50 values of the tested compounds.

Table 1: Antimalarial growth inhibition assays

compound IC50(μM) SD (microM) 1.57 55 3.93 85a 2.94 1.77 85b 3.37 1.24

85c 3.27 0.66 85d 1.91 0.53 chloroquine 0.02 0.01

Among the compounds screened for activity, compound 85d having a methyl substituent was found to be the most active with an IC50 value of 1.91 μM. This was followed by the natural product dependensin 55 with an IC50 value of 3.93 μM. The compounds 85b and 85c were found to be moderately active amongst the tested compounds, while the compound 85a having a bromo substituent was least active having an IC50 value of 2.94 μM.

2.7. Synthesis and acid-catalyzed reaction of 4c,5,7-trimethoxyflavene

In order to substantiate further the effect of methoxy groups in ring A of the flavene nucleus on dimerization, it was decided to synthesize a 5,7-dimethoxyflavene and perform an acid- catalyzed reaction on it. However, it was envisaged that the resultant product would be an analogue of 55.

The synthesis of 4c,5,7-trimethoxyflavene 89 was undertaken using the same methodology adopted for the synthesis of 7-methoxyflavenes 73a-d and is shown in Scheme 20.

39 MeO OH HO OH CH3I, K2CO3 acetone

92% OH O OMe O 86 87

CHO NaOH, ethanol, r.t. 65% MeO 67d

OMe MeO OH OMe MeO O NaBH4,IPA,r.t.

54% OMe O OMe 89 88

Scheme 20

The dimethoxyflavene 89 was conveniently obtained in 54% yield by reductive cyclization of chalcone 88, which in turn was generated in 65% yield by Claisen-Schmidt condensation of 2c- hydroxy-4c,6c-dimethoxyacetophenone 87 with anisaldehyde 67d. 2c-Hydroxy-4c,6c- dimethoxyacetophenone 87 was produced from 2c,4c,6c-trihydroxyacetophenone 86 using standard conditions for methylation as before in 92% yield.

Acid-catalyzed reaction of 4c,5,7-trimethoxyflavene 89 in the presence of HCl as catalyst, gave a complex mixture of products, from which no single product was isolated. However, the use of TFA as catalyst generated the product 90 in 52% yield, which was a structural analogue of 55 as expected (Scheme 21).

MeO OMe H OMe MeO O TFA, MeOH H H MeO O O 52% H OMe

OMe

89 OMe

OMe 90

Scheme 21 40 Therefore, the presence of the methoxy groups at C5 and C7 in ring A of the flavene nucleus facilitated the process of dimerization to occur in such a manner as to give dependensin analogues. It was also observed that dimerization remained unaffected by the nature of the substituents present in ring B of the flavene. In general, it is possible to conclude that the large number of electron rich substituents in ring A of the flavene activated the ring to yield analogues of the natural product.

2.8. Conclusion

Acid-catalyzed reactions of 5,7,8-trimethoxyflavenes 82a-d generated a series of direct analogues 85a-d of the natural product, dependensin 55. In addition, the synthesis of benzopyrano[4,3-b]benzopyran ring system found in 55 could also be achieved in parallel via the acid-catalyzed reactions of 7-methoxyflavenes 73a-d and 5,7-dimethoxyflavene 89. A suitable mechanism for the observed acid-catalyzed rearrangement has also been elucidated. In short, a very simple and facile methodology for the synthesis of the highly functionalized benzopyrano[4,3-b]benzopyrans in a single step has been developed and discussed.

41

CHAPTER 3

ACID-CATALYZED DIMERIZATION OF FLAVENES: SYNTHESIS OF TETRAHYDROCHROMENO- [2,3-b]CHROMENES

42 3.1. Introduction In continuation of the course of our investigation into the synthesis of dimeric flavonoids, it was interesting to observe the acid-catalyzed reactions of 5-methoxy- and 6-methoxyflavenes as they underwent dimerization via a completely different route to yield a novel range of tetrahydrochromeno[2,3-b]chromenes, which constitute the central core of this chapter. The tetrahydrochromeno[2,3-b]chromenes can otherwise be referred to as benzopyrano[2,3- b]benzopyrans.

The literature cites examples of molecules from nature bearing close resemblance to the benzopyrano[2,3-b]benzopyran ring system. For example, albanol A 91 and albanol B 92, isolated from the root bark of Morus Alba, Moraceae (mulberry) were noteworthy, as pharmacological tests on this species showed marked hypotensive effect in rabbits.92

Biogenetically, albanol A 91 was derived by a [2 + 4] cycloaddition reaction between a chalcone and a C-isoprenyl-2-phenylbenzofuran to give mulberrofuran93 93 as an intermediate, which on intramolecular ketalization of the carbonyl group with the two adjoining phenolic hydroxyl groups yielded 91. The oxidation of the alicyclic ring in 91 to an aromatic ring resulted in albanol B 92.92

OH OH

OH OH OH OH HO O O HO O O O O H

H H OH OH 91 92 OH OH HO OH HO

O OH HO OH HO OH O OH O O OH

OH OH 93 94

43 Similarly, a systematic study performed on plants belonging to the Moraceae family showed the presence of antimicrobial activity in the extract of Sorocea ilicifolia,94 from which a number of phenolic components were isolated. One among them was the ketalized Diels-Alder type adduct, named sorocein L 94.95

3.1.1. Known synthetic methodologies The synthesis of 7a,15a-dihydro-naphtho[2,1-b]naphtho[1c,2c:5,6]pyrano[3,2-e]pyran 95 (Scheme 22) has been reported by Selvaraj et al in 1983 starting from naphtho[2,1-b]pyran carboxaldehyde 98. Their methodology involved oxidative Claisen rearrangement of 3- aryloxymethyl-(4H)-benzopyran 97 to generate 96 as an intermediate, which on catalytic reduction gave the desired dihydroderivative 95.96

Scheme 22

Later, Talinli and his workers investigated the condensation of dimethylol ketones 100 with 2- naphthol 99 using Amberlyst-15 as catalyst anticipating to achieve ketodinaphthols 101, but unexpectedly found pyranopyran type compounds 102 (Scheme 23), thus presenting a new methodology for the preparation of alkyl derivatives of 95.97

44

Scheme 23

Selvaraj and his workers have also developed a convenient and simple synthesis of 7a,15a- dihydro-7a-amino-15H,16H-naphtho[2,1-b]naphtho[1c,2c:5,6]pyrano[3,2-e]pyran 108 by reacting a phenolic Mannich base 103 with D-chloroacrylonitrile 104.98

Scheme 24

As Mannich bases of phenols are thermally unstable, they decompose to the corresponding secondary amine and o-quinone methide 105. The secondary amine generated undergoes a Michael addition with 104 to form a D-cyano enamine 106. Further, a [4 + 2] cycloaddition between the in situ generated quinone methide 105 and 106 leads to 2-aminonapthopyran 107,

45 which by way of another [4 + 2] cycloaddition with o-quinone methide 105 gives 108 (Scheme 24).98

Recently, Sugimoto et al. have also described the Diels-Alder cylcoaddition reactions of o- quinone methides 105, generated from 4H-1,2-benzoxazines with various dienophiles. Using this strategy, compound 109 was produced via 1,4-conjugation addition of quinone methide 105 with ethoxyethyne 110 (Scheme 25).99

O O O O

O

109 105 110 Scheme 25

However, there are no citations from literature for the synthesis of such fused benzopyran ring systems via the generation of carbocation intermediates mediated by acid-catalyzed reactions. This chapter reports a simple and convenient synthesis of highly functionalized tetrahydrochromeno[2,3-b]chromenes via the acid-catalyzed dimerization reactions of 5- methoxy- and 6-methoxyflav-3-enes.

3.2. Synthesis of 5-methoxy- and 6-methoxyflavenes The synthesis of flavene precursors (Scheme 26) was undertaken using the same strategy discussed in Section 2.3. Therefore, commercially available 2c,5c-dihydroxyacetophenone 111a and 2c,6c-dihydroxyacetophenone 111b were subjected to methylation with methyl iodide in boiling acetone in the presence of potassium carbonate as a base to generate 2c-hydroxy-5c- methoxyacetophenone 112a and 2c-hydroxy-6c-methoxyacetophenone 112b respectively.

46 OH OH CH3I, K2CO3, acetone 1 1 R 92-93% R R2 O R2 O 111a R1 =OMe,R2 =H 112a R1 =OMe,R2 =H 111b R2 =OMe,R1 =H 112b R2 =OMe,R1 =H

CHO NaOH,ethanol,r.t. 62-87% R 67a-e

R OH R O NaBH4,IPA,r.t. R1 1 65-80% R R2 O R2 114a-j 113a-j Scheme 26

The corresponding chalcones 113a-j were synthesized in 62-87% yields based on a Claisen condensation, in which 112a and 112b were reacted with a variety of para-substituted benzaldehydes 67a-e. The chalcones 113a-j were cyclized directly to the flavenes 114a-j using

NaBH4 in IPA in moderate to good yields ranging between 65 and 80% (Table 2).

Table 2. Synthesis of 5-methoxy- and 6-methoxyflavenes

Chalcone R1 R2 R Flavene Yields [%]a 113a OMe H H 114a 72 113b OMe H Br 114b 65 113c OMe H Cl 114c 68 113d OMe H OMe 114d 65 113e OMe H Me 114e 74 113f H OMe H 114f 77 113g H OMe Br 114g 70 113h H OMe Cl 114h 70 113i H OMe OMe 114i 80 113j H OMe Me 114j 79 aYields of isolated pure product

The yield of the flavenes 114a-j depended on the substituents present in the para position of ring B. In general, flavenes 114a, 114d, 114e, 114f, 114i and 114j bearing electron donating or electronically neutral groups were formed in better yields when compared to the flavenes 114b, 47 114c, 114g and 114h bearing electron withdrawing groups (Table 2). A similar trend was also observed with the 7-methoxyflavenes.

3.3. Acid-catalyzed reactions on 6-methoxyflavenes The 6-methoxyflavenes 114a, 114b, 114c and 114e were subjected to acid-catalyzed reactions in methanol and surprisingly, found to exhibit a different response to the dimerization reaction. This was evident from the 1H NMR spectra of these compounds 115a-d, which in comparison to dependensin analogues were found to have notable changes in coupling patterns especially in the aliphatic region.

However, high-resolution mass spectrometric analysis of the products 115a-d indicated the formation of dimeric compounds. Therefore, in order to elucidate the structures of the isolated products, one of the compounds 115b was subjected to extensive 1D and 2D NMR spectroscopy experiments.

For instance, the 1H NMR spectrum of compound 115b (Figure 13) showed the presence of four aliphatic protons corresponding to H11, H11a and H12 between G 2.84 and 3.46 ppm. These four aliphatic protons, in close proximity to each other were expected to couple to each other and appear as doublets, doublet of doublets or as triplets. However, it was observed that the three protons corresponding to H11a and H12 appeared as a singlet at G 2.84 ppm and the proton corresponding to H11 was seen as a doublet of doublets at G 3.46 (J = 3.4, 9.8 Hz). But, no suitable reason could be attributed for this strange coupling pattern. The protons on the trans double bond, HD and HE appeared as a doublet of doublets and a doublet at G 6.24 (J = 9.8 Hz, 15.8 Hz) and G 6.47 (J = 15.8 Hz) respectively.

48 OMe H11a, H12 HE

HD H11

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 ppm Figure 13. 1H NMR spectrum of compound 115b

The HMBC experiment showed two bond and three bond proton to carbon couplings from the four aliphatic protons to C5a at 100.4 ppm. DEPT-135 along with a broadband decoupled 13C

NMR spectrum indicated the presence of one CH2 group at C12 in the structure 115b. This together with COSY, HMQC and HMBC correlations helped in identifying the structure of the isolated product 115b.

49 Br

2'' 7 4 O O

11 12 MeO OMe 10 1 a b 115b Br 2' Br

Br O O O O

MeO OMe MeO OMe

Br Br

Important HMBCs for 115b Important COSYs for 115b

Further, a single crystal of compound 115b was obtained for X-ray crystallographic analysis (Figure 14), thus confirming the structure of the isolated compound. The X-ray crystal picture indicated that the unique structure consists of two symmetrically fused benzopyran units, flanked by the two aromatic rings on either side of the fused ring system together with an exocyclic trans double bond.

50

Figure 14. ORTEP diagram of 115b

By correlation of the 1H and 13C NMR spectra, the other dimeric products of 6-methoxyflavenes 115a, 115c and 115d were assigned to contain the same ring system (Scheme 27). These dimeric structures 115a-d were obtained in 70-74% yields.

Scheme 27

3.3.1. Mechanism for the acid-catalyzed rearrangement The reaction mechanism for the formation of this ring system (Scheme 28) is postulated to involve the protonation of the flavene 116, followed by ring opening leading to the formation of a highly stabilized benzylic carbocation intermediate 117. A second molecule of the flav-3-ene

51 114b can possibly undergo prototropic rearrangement in situ to the corresponding flav-2-ene isomer 118 under acidic conditions. This can attack the carbocation intermediate 117 giving rise to a second stable benzylic intermediate 119. The latter on ring closure produces the required dimer 115b.

Scheme 28

The other dimeric flavonoids 115a, 115c and 115d were believed to follow a similar mechanism.

52 3.4. Acid-catalyzed reactions on 5-methoxyflavenes Similar acid-catalyzed reactions were attempted on the 5-methoxyflavenes 114f-j and they produced the tetrahydrochromeno[2,3-b]chromenes 120a-e in 68-76% yields (Scheme 29), in parallel to the 6-methoxyflavenes. However, the role of the catalyst had an effect on the dimerization reaction. The use of TFA and glacial acetic acid generated a series of dimeric compounds 120a-e.

Scheme 29

Indeed, it was interesting to compare the 1H NMR spectrum of compound 120c (Figure 15) with compound 115b obtained via the dimerization of 114b. The protons of interest were the aliphatic ones corresponding to H11, H11a and H12, which were seen to split separately, as doublet of doublet at G 2.59 (J = 11.7, 17.3 Hz) and a doublet at G 2.77 (J = 17.3 Hz) correlating to H12, and doublet of doublets at G 2.91 (dd, J = 6.4, 11.7 Hz) and G 3.74 (J = 6.4, 9.0 Hz) correlating to H11a and H11.

53 OMe

HE H12

HD H11 H11a H12

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 ppm Figure 15. 1H NMR spectrum of compound 120c

The presence of a diastereotopic methylene unit in 120c was evident in its COSY spectrum (correlation between the protons at H12). In addition, analysis of the COSY NMR data led to the identification of the two 1,4-disubstituted and two trisubstituted benzene rings. A NOESY correlation of H11a with one of the diastereotopic protons at H12 suggested the proximity of these two protons along with the presence of a cis fusion between them. The other important

NOESY correlations of interest were those from H2cc to H11a, H11a to HD and HD to H3c, giving evidence of the structure formed.

Further assignments for 120c were determined on the basis of HMQC and HMBC data. The presence of a methylene group at H12 was also evident from its DEPT spectrum. HMBC correlations of the methylene proton at G 2.59 to C5a, C11 and C12a and the other methylene proton at G 2.77 to C5a, C11, C11a and C1 were noteworthy, indicating the presence of two fused benzopyran units. The aliphatic proton, H11a showed HMBC connections to C11, C12a and C1c and the other aliphatic proton, H11 showed HMBC connections to C5a, C6a, C10a, CE and C1c, thereby indicating the attachment of the styryl group to position 11. This was further confirmed by the HMBC correlations from the intermediate protons, HD and HE to both the benzopyran ring as well as to the 1,4-disubstituted benzene ring. Lastly, the attachment of the second 1,4-disubstituted benzene ring to C5a was evident from the HMBC connections from H2cc to C4cc and C5a, in accordance with the assigned structure.

54 Similar coupling patterns were observed in the other dimeric structures 120a-b, 120d-e. The dimerization reaction mechanism is expected to follow the same pathway taken by the 6- methoxyflavenes 114a, 114b, 114c and 114e.

The use of HCl as catalyst however resulted in the formation of the corresponding dihydrochalcones 121a and 121b in 52 and 58% yields (Scheme 30).

Scheme 30

The above observation can be attributed to the fact that flav-3-enes can possibly undergo prototropic rearrangement and isomerize to the flav-2-enes,100 as suggested in Section 3.3.1. Further, the literature reports the hydrolysis of flav-2-enes in aqueous AcOH to yield dihydrochalcones,100,101 that are in accordance with our results. However, the synthesis of flav-2- enes was undertaken in order to confirm the above hypothesis.

3.4.1. Synthesis of flav-2-enes Freudenberg and his coworkers reported the synthesis of the flav-2-ene, 5,7,3c,4c- tetramethoxyflav-2-ene 122 during their investigation on the structures of catechins. They showed that (-)-epicatechin tetramethyl ether 3-toluene-p-sulphonate 123 underwent smooth elimination of toluene-p-sulphonic acid with hydrazine to yield 5,7,3c,4c-tetramethoxyflav-2-ene 122 (Scheme 31).102

55

Scheme 31

It was later established that the flav-2-enes of compounds lacking a 3-substituent could be obtained by the reduction of flavylium salts with LAH87c,100,103a or sodium borohydride.103b,103c But, the reduction products of flavylium salts containing 3-oxygenated substituents were established to be flav-3-enes.100,104 Other reports of flav-2-enes include the formation of the parent compounds by reduction of flavones with lithium aluminium hydride86a,105 and by cyclization of 2c-hydroxydihydrochalcones.106

However, it has been proved by several groups that flav-3-enes can be conveniently converted into the corresponding flav-2-ene isomers by refluxing in benzene in the presence of alkoxy- or phenoxy- magnesium bromides.87c,100,107 This process seemed to be a straightforward method for us to prepare flav-2-enes, since the flav-3-enes were already synthesized and available for use.

Hence the above strategy was used for the preparation of flav-2-enes 124a and 124b, which were generated from the flav-3-enes, 114c and 114h by refluxing in toluene in the presence of the Grignard reagent, allyl magnesium bromide for 48 hours in 44-46% yields as shown in Scheme 32.

Scheme 32

56 Their formation was evident from the 1H NMR and 13C NMR spectra, which were different from those of flav-3-enes in the coupling patterns observed in ring C. The 1H NMR spectrum of 4c- chloro-6-methoxyflav-2-ene 124a exhibited a doublet at G 3.48 (J = 4.1 Hz, 2H) and a triplet at G 5.37 (J = 3.8 Hz, 1H) corresponding to H4 and H3 respectively. Further, DEPT-135 and the 13 broadband decoupled C NMR spectra of 124a indicated the presence of a methylene (CH2) group at G 25.3 ppm correlating to C4.

3.4.2. Acid-catalyzed reactions on flav-2-enes Acid-catalyzed reactions of flav-2-enes 124a and 124b were found to give the corresponding dihydrochalcones 126a and 126b (Scheme 33), indicating hydrolysis had taken place. Hence, the flav-2-enes 124a and 124b with aqueous acid can exhibit ring chain tautomerism100 and presumably proceed via the formation of the intermediate 2-hydroxyflavans100,108 125a and 125b produced by the addition of water, to yield the 2c-hydroxydihydrochalcones 126a and 126b in 59 and 61% yields respectively.

Scheme 33

However, a one-pot acid-catalyzed reaction containing flav-3-ene 114h and flav-2-ene 124b afforded a mixture of the dimer 120c and the dihydrochalcone 126b as anticipated (Scheme 34).

57

Scheme 34

Interestingly, reactions attempted on flav-2-enes and flav-3-enes possessing different substituents in ring B resulted in the formation of a complex mixture of products, from which no single compound could be isolated.

3.5. Reactions with diphenylethylene As already discussed in Section 3.3.1, the acid-catalyzed dimerization reactions proceeded via the generation of highly reactive stable carbocation intermediates. Therefore, an investigation was undertaken to see if these intermediates could be trapped with the use of suitable alkenes. Bradley et al. in 1971 studied the reactions between 2,2-diarylchromenes and 1,1-diarylethenes and found the latter were useful in trapping carbocations.109a

Hence, flavenes 114d and 114i were reacted with diphenylethylene 127 in glacial acetic acid and found to undergo acid-catalyzed reactions as desired to yield 128a and 128b in 56 and 59% yields respectively (Scheme 35).

58

Scheme 35

Cotterill et al. have reported the synthesis of the fused tetracycle 129 (Scheme 36) in high yield by the reaction between equimolar proportions of either 3-(2-hydroxy-1-naphthyl)-1,1-bis(2- methoxyphenyl)prop-2-en-1-ol 130 and 2,3-dihydro-1,3-bis(2-methoxyphenyl)-1H-naphtho[2,1- b]pyran-3-ol 131 or 3,3-bis(2-methoxyphenyl)-3H-naphtho[2,1-b]pyran 132 and 1,3-bis(2- methoxyphenyl)-1H-naphtho[2,1-b]pyran 133 in boiling acetic acid.109b In the reactions mentioned, it was observed that 130 and 133 serve as nucleophiles to trap the intermediate carbocations.

Scheme 36

59 The mechanism for the acid-catalyzed formation of 129 is proposed to be similar to the formation of adducts from 2,2-diarylchromenes and 1,1-diarylethenes.109b The pathway leading to the generation of such adducts is highlighted in Section 3.5.1.

3.5.1. Reaction mechanism The rearrangement (Scheme 37) involved protonation of the flavene ring 134, resulting in ring opening of the flavene nucleus generating the first stable benzylic carbocation intermediate 135. The alkene, diphenylethylene 127 attacks the carbocation intermediate 135 resulting in a second stable benzylic carbonium ion 136, which on recyclization by loss of a proton, gives the resultant structure 128a.

OMe OMe H O H+ O

MeO MeOH MeO 114d 134

HO

C6H5 CH2 OMe C6H5 135 127

OMe H OH C6H5 O C6H5 C6H5 C6H5 -H+ MeO MeO 136 128a

OMe OMe Scheme 37

3.6. Synthesis of mixed dimers To further substantiate the work on the synthesis of these dimeric systems, two flavenes were mixed together in the same reaction pot in order to observe the competing or dominating effect

60 of any of the carbocations generated as intermediates. This might possibly pave the way to generate interesting structures.

This can be done in two possible ways: 1. mixing flavenes having methoxy groups at the same position in ring A but having different substituents in ring B 2. mixing flavenes having the same substituents in ring B but having methoxy groups at different positions (positions 5, 6 or 7) in ring A

Based on the strategies mentioned above, several reactions were tried, but unfortunately a complex mixture of products was visible on TLC in most cases, and thus difficulties were encountered in isolating and characterizing all the spots. In certain experiments, when a single product was isolated, it was found to be a simple dimer and not a mixed one as desired.

Fortunately, after several attempts, two different 5-methoxyflavenes (4c-bromo-5-methoxyflav- 3-ene 114g and 4c,5-dimethoxyflav-3-ene 114i), in equimolar ratios were subjected to acid- catalyzed dimerization and the outcome of this reaction was a mixed dimer 137 in 42% yield (Scheme 38).

Scheme 38

The 1H NMR data of the isolated compound 137 showed the presence of three methoxy groups at G 3.61, G 3.69 and G 3.74 ppm respectively, giving sufficient evidence for the formation of a mixed dimer. Further elucidation of 137 was vital, as there was the possibility of formation of two products. Therefore, 137 was subjected to 2D experiments such as COSY, NOESY, HMQC

61 and HMBC. The correlations obtained from the data were used to allocate the position of bromo- and methoxy- substituents to the respective 1,4-disubstituted benzene rings, thus confirming the structure of the mixed dimer 137.

A NOESY correlation existed between H3cc and the protons attached to the corresponding methoxy substitutent. Further, HMBC correlations from H2cc to C5a at G 100.3 ppm and C4cc at G 157.3 ppm was evidence that the methoxy substituent was contained in that 1,4-disubstituted benzene ring. On the contrary, HMBC connections were found to exist from H2c to C1c, CE and C4c, which confirmed the position of the bromo-substituent to the second 1,4-disbustituted benzene ring attached to the trans olefinic bond.

A close look at the reaction mechanism indicates that the flavene 114g undergoes protonation first and ring opens resulting in the first stable benzylic carbocation. The second flavene molecule 114i presumably undergoes isomerization to its corresponding flav-2-ene, and attacks the first carbocation intermediate, thus giving rise to the second stable carbocation intermediate. This intermediate, on loss of a proton furnishes the mixed dimer 137.

In conclusion, no specific criteria can be framed for the formation of mixed dimers. Such formation is purely dependent on the fact that the carbocation intermediate formed by the first flavene molecule is competitively attacked by the second molecule of flavene and not by another molecule of the same flavene. Also, a complex mixture of products was obtained from these experiments suggesting a high probability for the presence of mixed dimers, but isolation of the desired products proved to be rather complicated.

3.7. Conclusion In summary, an efficient methodology for the synthesis of tetrahydrochromeno[2,3-b]chromenes 115a-d, 120a-e has been developed via the acid-catalyzed dimerization reactions of 6-methoxy- and 5-methoxyflavenes 114a-j. A rationale has also been proposed for the observed acid- catalyzed rearrangement. The substrate, diphenylethylene 127 was successful in trapping the intermediate carbocations formed during the course of the rearrangement. Lastly, one mixed dimer 137 was successfully synthesized via the acid-catalyzed reaction of two different 5- methoxyflavenes 114g and 114i.

62

CHAPTER 4

ACID-CATALYZED DIMERIZATION REACTIONS OF ISOFLAVANOLS AND ISOFLAVENES

63 4.1. Introduction Isoflavonoids are a large, varied and well-known group of natural compounds with a wide spectrum of biological activity. They have very low toxicity and have the potential to treat cancer by reversing the cancer process, rather than simply attempting to halt cancer growth. One metabolite of the isoflavones, the isoflavene, dehydroequol 138 (also known as phenoxodiol)110,111 is being developed as an anticancer drug and is currently undergoing Phase III clinical studies in Australia and in the United States.

HO O

138 OH

The success of dehydroequol 138 and other isoflavone derivatives in treating cancer has prompted the search for novel isoflavone analogues with superior pharmacokinetic and pharmacodynamic properties.

Dimeric isoflavones where two isoflavone molecules are directly attached via a carbon-carbon linkage or an ether linkage are naturally occurring compounds, which possess potent biological activity. For example, kudzuisoflavones A 139, B 140 and C 141 were isolated upon treatment of Pueraria lobata cell cultures with an elicitor yeast extract.112 It was further proposed that these metabolites are probably formed by non-specific oxidation of daidzein with peroxidase.

OH

HO O HO O O HO O O O OH O OH O 139 O O HO O 141 O O O OH

O OH 140

64 Compounds 142 and 143 have two genistein molecules attached to each other having linkages between C3′-C3′′ and C3′-C6 respectively. Compounds 140, 142 and 143 show 5D-reductase inhibitory activities, and hence have the potential for use in the treatment of prostate hyperplasia.113

HO O HO O OH 3" 3' OH O OH O OH

142 HO O HO O 6 3' OH O OH O OH OH 143

Tang et al.114 isolated dehydrohexaspermone C 144 from Ochna macrocalyx together with other anticancer and antibacterial compounds while biisoflavonoids 145-147 were isolated from the heartwood of Dalbergia odorifera.115

65 Our research group has previously worked on the acid-catalyzed reactions of isoflavanol 148 with a variety of different reactive nucleophiles. One such nucleophile was the isoflavene 149 (acetylated derivative of phenoxodiol) that resulted in the isoflavan-isoflavene dimer 150 via its acid-catalyzed coupling mechanism (Scheme 39).85

AcO O AcO O

AcO O 149 OAc AcO OAc

BF3.OEt2 OH OAc O

148 150 OAc Scheme 39

Heaton and Kumar have demonstrated that dimeric isoflavonoid compounds with the general formulae as depicted in 151 and 152 showed potent anticancer activities in a variety of cancer cell lines.116

RO O H AcO O H H H OR O 4 OR 4 3 2' RO OR H AcO O O OR OR R=H,Me,Ac RO 151 152

These dimeric structures 152 based on isoflavonoid compounds were considered unique due to their linkage by two carbon-carbon single bonds. Their basic skeleton is based on a naphtha[1,2- g]chrysene structure following from bis (4-4) and (2′-3) linking of two 3-phenylchroman ring systems as depicted in 152. The key requirement for this dimerization was that the ring B of the isoflavanol monomer needed to be activated, e.g. 3,4-dimethoxy groups etc. Further investigations into the chemistry of these unique dimeric structures along with the factors that affect the dimerization process constitute the central theme of this chapter.

66 4.2. Synthesis of isoflavanol precursors The isoflavan-4-ol monomers were the convenient starting materials for the synthesis of these dimeric molecules. They were synthesized readily in four steps discussed below. The first step involved the condensation of substituted phenols, resorcinol 153a, 2-methyl resorcinol 153b and orcinol 153c with 3,4-dimethoxyphenyl acetic acid 154 (Scheme 40). This was a typical Friedel- 117 Crafts reaction using the Lewis acid, BF3.Et2O as catalyst and solvent, that generated the intermediate deoxybenzoins 155a-c in moderate yields of 63-70% respectively.

Scheme 40

The second step involved formylation and subsequent cyclization with the help of a suitable one-carbon electrophile. A convenient approach for this is that of Baker et al.118 who used oxalyl chloride and pyridine as the cyclizing agent, whereas others have used ethyl formate,119 triethyl orthoformate,120 or carbon disulfide.121 However, long cyclization periods were a disadvantage, 122 121 for example, with POCl3 and DMF, along with the necessity to mask the hydroxyl groups with suitable protecting agents.

However, the reaction conditions using methanesulfonyl chloride reported by Bass123 worked well in the presence of BF3.OEt2 as the cyclization reagent. Hence, the deoxybenzoins, 155a-c were subjected to the above condition in DMF, which produced the isoflavones 156a-c in 64- 74% yields (Scheme 41).

67

Scheme 41

The 7-hydroxyisoflavones 156a-c were highly polar compounds, and therefore, direct reduction of these compounds proved inevitable, due to problems encountered with solubility. In addition, it is also said that the presence of free hydroxyl groups was not compatible with reduction as they could alter the reactivity pattern of the parent isoflavone system, besides decreasing the overall reactivity due to solubility issues.124 Hence, protection of the hydroxyl group was essential at this stage and therefore, simple methylation of the isoflavones was attempted.

Thus, the isoflavones 156a-c were subjected to the standard methylation conditions, using MeI in DMF in the presence of potassium carbonate as a base, which furnished the desired methylated isoflavones 157a-c in good yields of 91-94% (Scheme 42).

Scheme 42

Full reduction of the heterocyclic ring of isoflavones was possible with the use of 3.0 equiv of 124 NaBH4, that led to diastereomeric mixtures of isoflavanols 158a-c in 74-80% yields (Scheme 43). Apparently, it was presumed that the first step involved a 1,4-addition to give the isoflavanone enolates, which pick up a proton from the protic solvent (ethanol) and undergo

68 further reduction to the saturated alcohol. However, these reduction reactions showed no signs of the intermediate 1,2-reduction products, the allylic alcohols (2-isoflaven-4-ols), which correlated well with the fact that they appear relatively unknown in the chemical literature.124

Rigorous NMR analysis has indeed made it possible to establish cis- and trans-structures for the isoflavanol products. The isoflavanols 158a and 158b were obtained as a mixture of cis:trans (50:50) isomers.

Scheme 43

Interestingly, only the cis isomer was obtained for the isoflavanol 158c, which was established from the presence of an NOE correlation between H3 and H4. Since borohydride reductions are generally known to give a small preference for the cis products as suggested by Cram’s rule,125 the above observation can be attributed to this fact. Further, another reason for this observation could be due to the steric factors arising from the presence of a methyl group at C5.

The isoflavanols 158a-c were recrystallized from absolute ethanol, and obtained as pure white solids before subjection to the acid-catalyzed dimerization reactions.

4.3. Acid-catalyzed dimerization reactions of isoflavanols 4.3.1. Results and discussion In general, acid-catalyzed reactions of isoflavanols 158a-c would presumably result in the formation of the corresponding isoflavenes, as acid-catalyzed dehydration was expected to be the dominant reaction to occur. However, it was found that the same acid-catalyzed reactions carried out at extremely low temperatures (–78 0C) in a minimum quantity of solvent were found to yield dimerization products 159a-c, comprising of the naphtho[1,2-g]chrysene derivatives along with the corresponding isoflavenes 160a-c as by-products (Scheme 44).

69

Scheme 44

The dimeric molecules 159a-c contain two carbon-carbon linkages joining the two monomers. The C4-positions on the pyran ring of both isoflavonoid monomers are linked through direct attachment via a carbon-carbon bond. The second linkage joins the C2′-position (or C6′- position) on the pendant 3-phenyl ring of one monomer to the C3-position on the pyran ring of the second isoflavonoid monomer.

The preferred starting isoflavan-4-ol monomers were required to contain electron donating substituents on the pendant 3-phenyl ring for the ready formation of the 2-carbon bond in the dimers. Hence, the pendant phenyl ring of the 3-phenyl chroman structure should necessarily be electron donating and contain at least one ortho hydrogen atom to facilitate formation of the (2′- 3) bond during the dimerization process.

Dimerization to yield these naphtho[1,2-g]chrysene derivatives was performed in the presence of a suitable coupling/dehydrating agent. The coupling agent of choice was phosphorus pentoxide, although POCl3 and BF3.OEt2 could also be alternatively utilized. The dimerization reactions were carried out from very low to ambient temperatures, and it was observed that lower temperatures promoted cleaner reaction mixtures. Hence, the reactions were conveniently performed at –78 0C by way of acetone/dry ice baths. The solvent of choice for these dimerization reactions was DCM. It has been found that a high substrate to solvent ratio was essential, and the optimal DCM:substrate ratio was about 8:1 for the favoured bimolecular dehydration/cyclization reactions.

70 In order to confirm the structures of the isolated compounds as well as to assign their stereochemistry, one of the compounds 159b was subjected to extensive 2D NMR spectroscopy experiments. The 13C NMR spectral data of 159b confirmed the presence of a polycyclic skeleton with highly aromatic character. Preliminary assignments were based on the fully proton-coupled experiments, while the HSQC experiment allowed complete correlation of the protonated carbon resonances with proton signals. The quaternary aromatic carbons were also identified with the aid of long-range 1H -13C coupling in the fully 1H-coupled carbon spectrum.

The 1H NMR spectrum of 159b showed the presence of seven aliphatic protons, a doublet of a triplet at G 3.27 (J = 4.1, 11.3 Hz) and a doublet at G 3.56 (J = 11.3 Hz) correlating to H6b and H12b respectively. The diastereotopic protons corresponding to H7 were seen as a doublet of a doublet at G 3.70 (J = 4.1, 10.3 Hz) and a doublet at G 4.98 (J = 10.3 Hz). The singlet at G 4.15 corresponded to H12c and lastly, the two protons correlating to H2 appeared as doublets at G 4.29 and 4.82 ppm having a coupling constant of 12.0 Hz each. Further, DEPT-135 along with a broadband decoupled 13C NMR spectrum showed the presence of two methylene groups in the molecule at G 69.9 and 70.3 ppm corresponding to C7 and C2 respectively.

The formation of the C-C bond (2′-3) resulted in the disappearance of one of the aromatic protons in the electron rich pendant ring of the first isoflavonoid monomer. Therefore, the protons correlating to H3 and H6 of the pendant ring were seen as singlets at G 6.73 and 6.79 ppm. It was also proved by the presence of a quaternary carbon at G 131.4 ppm corresponding to C2b.

The linked dimer 159b was found to have trans stereochemistry with respect to the C3 aryl group established on the basis of a large coupling constant of 11.3 Hz between H6b and H12b. The exclusive formation of the trans isomer in the linked dimer 159b can be explained by the presence of the aryl group at C3 that prevents the attack of the incoming nucleophile from the same face of the molecule.

The presence of diastereotopic protons at C7 was evident from an NOE between H6b and H7 correlating to G 3.70 ppm. In addition, it was observed that an NOE existed between H12b and the other diastereotopic proton at C7 correlating to G 4.98 ppm. Further, NOEs observed between H12b and H7, H12b and H12 indicated its presence within the first benzopyran ring. Similarly, H12c showed NOEs to H13 and H2, giving evidence that it exists within the second

71 benzopyran nucleus. An NOE between H6b and H6 suggested proximity and attachment of the benzopyran unit to the first 3-phenyl pendant ring, while the NOE correlation between H2 and H6′ indicated the close vicinity of the second electron rich 3-phenyl pendant ring to the second benzopyran ring.

The formation of the bis (4-4) linkage was evident from one-bond HMBC correlations of the aliphatic protons, H12b and H12c. The proton H12b had correlations to C12a, C6b and C12c and H12c showed correlations to C2a, C12d and C12b. Two-bond correlations from H6b to C12c, H12 to C12b and H13 to C12c also gave further evidence of the C-C linkage. The presence of the second C-C linkage (2′-3) was confirmed by the presence of HMBC correlations from H2, H12c, H6b, H3 and H6 to the quaternary carbon correlating to C2b at G 131.4 ppm.

Two-bond connections from H12b to C12, C8a and C7 indicated the presence of the first benzopyran ring, while correlations from H6b to C6, C2b and C12a confirmed its attachment to the first electron-rich pendant ring. Similarly, HMBC correlations from H2 to C2a and C12c as well as from H12c to C13 and C16a indicated the presence of the second benzopyran nucleus. One-bond and two-bond correlations from the protons, H12b, H12c, H2 and H3 to the quaternary carbon at G 44.2 ppm were of significance, as they indicated the attachment of the 3- phenyl pendant ring of the second isoflavonoid monomer to C2a.

This together with other COSY, NOESY, HMQC and HMBC correlations confirmed the structure of the isolated compound 159b. Hence, the other dimeric compounds 159a and 159c were postulated to contain the similar ring system.

72 MeO O 7 MeO O 6 11 12b OMe OMe

12d 2a 14 OMe OMe

MeO O 2 OMe MeO O OMe

5' OMe OMe Important COSYs for 159b Important NOEs for 159b

MeO O

OMe

OMe

MeO O OMe

OMe

Important HMBCs for 159b

However, the major drawback in the above dimerization reactions was the very low yields of the products (Table 3) and hence, isolation and purification of these dimers was very difficult.

Table 3. Synthesis of dimers 159a-c and isoflavenes 160a-c

Isoflavanol Dimer Yields [%]a Isoflavene Yields [%]a 158a 159a 5 160a 24 158b 159b 4 160b 30 158c 159c 3 160c 21 aYields of isolated pure product

4.3.2. Mechanism for the acid-catalyzed rearrangement It is suggested that the dimerization reaction (Scheme 45) proceeds via the formation of an electron-rich olefin (isoflavene 160a obtained by dehydration of isoflavanol 158a), which quenches the stabilized benzylic carbocation intermediate 161 (generated from the isoflavanol 158a in the presence of the Lewis acid) at C4 of the chroman ring on the second monomer to generate the intermediate 162. Rearrangement is thought to promote a second carbocation at C3 of this second chroman ring, which is then quenched by the nucleophilic 2c (or 6c) position of the

73 electron-rich pendant phenyl ring leading to 163. Further appropriate rearrangement to regain the aromaticity of the electron-rich pendant ring affords the dimeric isoflavonoid 159a.

Scheme 45

The other dimeric structures 159b and 159c were postulated to follow a similar mechanism.

4.4. Reactions with diphenylethylene As discussed previously in Chapter 3, diphenylethylene 127 was a suitable reagent to trap the carbocation intermediate generated during the course of an acid-catalyzed reaction of a flavene.

74 Hence, similar reactions were attempted using the same alkene 127 with isoflavanols 158a and 158b. As anticipated, treatment of isoflavanols 158a and 158b with diphenylethylene 127 in the presence of a Lewis acid resulted in the generation of novel cyclized products 164a and 164b in good yields of 74 and 76% respectively (Scheme 46).

Scheme 46

The above reactions confirmed that the presence of electron rich substituents activated ring B greatly such that the alkene did not merely undergo nucleophilic substitution at C4 but also proceeded one step further to cyclize with the activated ring B of the isoflavanol. Unlike the dimerization products, the reactions with diphenylethylene 127 were high yielding, and therefore it was decided to generate a series of these cyclized products.

4.4.1. Synthesis and reactions with substituted diphenylethenes In order to produce a series of these novel cyclized products, it was necessary to synthesize substituted 1,1-diphenylethenes, which were the source of suitable alkenes.

MgBr O 165 R R BF .OEt ,DCM OH 3 2 ether, reflux R CH2 166a-d167a-d 168a-d 166a R=Cl not isolated 168a R=Cl 166b R=Br 168b R=Br 166c R=OMe 168c R=OMe 166d R=Me 168d R=Me Scheme 47

75 The substituted 1,1-diphenylethenes 168a-d were synthesized in two steps126 outlined in Scheme 47. The Grignard reagent, phenylmagnesium bromide 165 was treated with substituted acetophenones 166a-d in ether under reflux for 6 hours to give the corresponding 1,1- diphenylethanols 167a-d as intermediates. The 1,1-diphenylethanols 167a-d, without any purification were subsequently subjected to acid-catalyzed dehydration to afford the title compounds 168a-d in yields ranging between 47 and 52%.

The treatment of the synthesized diphenyl alkenes, 168a-d with isoflavanols 158a and 158b resulted in a series of cyclized structures 164c-j in good yields (Scheme 48).

Scheme 48

Table 4 shows the compounds obtained from the above nucleophilic reactions along with their yields. Table 4. Synthesis of cyclized products 164a-j

Isoflavanol R* Product Yields [%]a 158a H 164a 74 158b H 164b 76 158a Cl 164c 68 158b Cl 164d 74 158a Br 164e 71 158b Br 164f 64 158a OMe 164g 70 158b OMe 164h 72 158a Me 164i 69 158b Me 164j 71 aYields of isolated pure product *R represents the substituent present in diphenyl ethylene

76 The formation of the cyclized products was evident from the 1H and 13C NMR spectra of these compounds. The 1H NMR spectrum of compound 164j indicated that the structure shows trans stereochemistry due to the presence of a large coupling constant of 11.3 Hz between H4b and H10b. This was also evident from the absence of an NOE between them. Hence, the protons correlating to H10b and H4b were seen as a doublet of a doublet at G 2.75 (J = 3.0, 11.3 Hz) and a doublet of a triplet at G 3.27 (J = 3.8, 11.3 Hz) respectively.

The presence of diastereotopic protons at C5 and C11 were evident from the coupling constants of the corresponding protons. The protons corresponding to H5 appeared as a doublet (J = 10.2 Hz) and a doublet of a doublet (J = 3.8, 10.2 Hz) at G 4.04 and 5.03 ppm. Similarly, the protons correlating to the other set of diastereotopic protons at C11 were also seen as a doublet of a doublet (J = 3.0, 11.8 Hz) and a doublet (J = 11.8 Hz) at G 2.63 and 3.18 ppm. This was also confirmed from the NOESY spectrum of 164j wherein H4b showed correlations to one set of diastereotopic protons, H5 and H11 correlating to G 5.03 and 3.18 ppm, while H10b showed connections to the other two protons at G 4.04 and 2.63 ppm respectively.

The cyclization with the electron rich pendant ring was evident from the disappearance of one of the aromatic protons and the appearance of singlets at G 6.25 and 6.81 ppm corresponding to H4 and H1. Two-bond HMBC correlations from H4, H4b and H11 to the quaternary carbon at C12a corresponding to G 134.9 ppm gave further evidence for the observed cyclization.

The COSY spectrum showed connections between H5 and H4b, H4b and H10b, H10b and H11, H9 and H10 respectively. The other important NOEs that helped in identifying the structure were the correlations between H4b and H4, H10 and H11. Also, the diastereotopic protons at C5 showed NOEs to the methyl group at G 2.07 ppm corresponding to C7.

The HMBCs that were of significance were the correlations from the diastereotopic protons at C5 to the quaternary carbons corresponding to C6a, C10a and C4a. Similarly, the second set of diastereotopic protons at C11 showed correlations to the quaternary carbons corresponding to C10a, C12a and C4a respectively. Short-range and long range correlations from H1, H4, H4b, H10b and H11 to the quaternary carbon at C12 corresponding to G 54.3 ppm were noteworthy.

This together with other NOEs and HMBCs of 164j helped in confirmation of the isolated product.

77 CH3 CH3 MeO O 5 MeO O 4 9 OMe OMe

12 OMe OMe 1

CH3 CH3 Important COSYs for 164j Important NOEs for 164j CH3 MeO O

OMe

OMe

CH3 Important HMBCs for 164j

Based on the above observations, the other cyclized products 164a-i were assigned to contain the same ring system.

4.4.2. Reaction mechanism with diphenylethylene

The carbocation intermediate 161 generated from isoflavanol 158a is attacked by diphenylethylene 127. As previously, the electron rich substituents of the 3-phenyl pendant ring promote appropriate rearrangement resulting in the formation of the intermediates 169 and 170. Subsequent ring-closure by loss of a proton, leads to the cyclized structure 164a (Scheme 49).

78 MeO O MeO O

OMe Lewis Acid OMe

OH 161 OMe OMe 158a

127

MeO O

OMe

OMe

169

MeO O MeO O OMe OMe -H+ H OMe OMe

164a 170 Scheme 49

The pathway to the formation of the other cyclized compounds 164b-j should follow the same mechanism.

4.4.3. Reactions with indoles and other nucleophiles The indoles have been well known to possess good nucleophilicity and hence, isoflavanol 158a was reacted with N-methylindole 171 (Scheme 50) in the hope that the intermediate iminium species will react with the activated pendant ring. However, only formation of the corresponding 4-heteroaryl isoflavan 172 was observed, where the substitution in the indole ring was found to occur at C3. The electron rich pendant ring B did not proceed towards further cyclization, as seen in the case of diphenylethylene.

79 MeO O MeO O N OMe OMe 171 DCM, BF .OEt OMe OH 3 2 OMe 67% N

158a 172 Scheme 50

The exclusive formation of the trans isomer was evident from the 1H NMR spectrum of the compound, which showed a doublet of a doublet of a doublet at G 3.41 (J = 3.3, 7.6, 10.8 Hz) correlating to H3, while two doublet of doublets at G 4.21 (J = 7.6, 10.8 Hz) and 4.37 (J = 3.3, 10.8 Hz) correlated to H2. The proton H4 was seen as a doublet at G 4.42 having a coupling constant of 7.6 Hz.

Therefore, the isoflavanol 158b was reacted with an activated indole 275 (Scheme 51), with the anticipation that the indole would undergo substitution at C2 as well as cyclization at C3 with the electron rich pendant ring of the isoflavanol.

Br

OMe

MeO O

MeO O MeO N OMe H 275 Br OMe OMe DCM, BF3.OEt2 NH OH OMe 63% MeO 158b OMe 173 Scheme 51

However, a similar reaction as described previously was observed. The isolated product 173 was obtained in 63% yield, in which the C4 position of the isoflavan unit was attached to the activated C2 position of the indole.

80 Several reactions were attempted using chalcones, imines, phenylacetylene, ethyl acetoacetate, ethyl acrylate, styrene, methoxypropene and diphenylacetylene as nucleophiles. However, in all these reactions, the corresponding isoflavenes were the only product isolated. This indicated that elimination dominated nucleophilic substitution and the above nucleophiles acted as weak nucleophilic substrates.

Thus, the acid-catalyzed reactions of isoflavanols with indoles were found to be highly selective as well as stereospecific, generating only the trans isomers in good yields.

4.5. Conclusion Acid-catalyzed reactions of isoflavanols 158a-c were found to undergo dimerization at low temperatures to yield naphtho[1,2-g]chrysene derivatives 159a-c in low yields, along with the formation of the corresponding dehydrated products, the isoflavenes 160a-c. A rationale for the observed rearrangement has been proposed, in which the isoflavenes play a dominant role in the dimerization process. The intermediate carbocations produced during the course of the acid- catalyzed rearrangement were trapped using diphenylethylene derivatives, which served as good nucleophiles. Hence, these reactions were found to yield a new series of interesting cyclized structures 164a-j, possessing a similar skeleton present in the dimeric compounds 159a-c. Acid- catalyzed coupling reactions of 158a and 158b with indoles 171 and 275 resulted in the 4- heteroaryl isoflavans 172 and 173 respectively, exclusively generating the trans isomers in good yields.

81

CHAPTER 5

MANNICH REACTIONS ON FLAVONES

82 5.1. General Background The Mannich reaction has been studied by several groups of workers, over the past 60 years and has gained importance in the field of medicinal and pharmaceutical chemistry.127 Its synthetic utility in the preparation of Mannich bases is widely known, and it is of significance due to the pharmacological properties exhibited by Mannich bases and their derivatives. Many anti- bacterial, anti-cancer, analgesic and anti-inflammatory, anti-convulsant, anti-malarial, anti-viral, and CNS depressant drugs possess a Mannich base motif.128

N N N OH OH OH N HN HN HN N OMe

Cl N Cl N Cl N 174 175 176

NH NH

HO HO

NH NH Cl

Cl N Cl N 177 178

The emergence of multidrug-resistant strains of Plasmodia created the need for new anti- malarials that could circumvent the parasite’s resistance mechanism. This led to the emergence of Mannich base anti-malarials, amodiaquine 174, amopyroquine 175, pyronaridine 176 (also known as malaridine), tebuquine 177 and tert-butylamodiaquine 178.129a These semi-synthetic Mannich base derivatives of chloroquine showed potent in vitro and in vivo antimalarial activity.129b

In addition, the Mannich reaction has proved its utility and versatility in the total synthesis of the alkaloid, tropinone 182 by Robinson in 1917. Robinson identified a simple one-pot procedure, in which one molecule of succindialdehyde 180, methylamine 179, and acetone dicarboxylic acid

83 181 reacted together to afford the natural substance (Scheme 52). Two consecutive Mannich reactions were involved in this synthesis, the first one in an inter- and the second one in an intra- molecular fashion.130 COOH OHC

CH3NH2 O NO CHO COOH 179 180 181 182

Scheme 52

Of relevance to this study are the reports on N-substituted aminoalkyl derivatives of flavonoids and isoflavonoids, which have proved to be extremely active stimulants of the central nervous system and respiratory tracts. The same compounds are known to exhibit strong anti-convulsive, anti-allergic and analgesic activities.131 Hence, the Mannich bases arising from 5-hydroxy-, 6- hydroxy- and 7-hydroxyflavones constitute the central theme of this chapter.

5.2. The Mannich Reaction The Mannich reaction is a three-component condensation in which a substrate containing an active hydrogen atom 183 is allowed to react with formaldehyde 184 and an amine derivative 185. This one-pot reaction produces a Mannich base 186 having the N atom linked to the substrate through a methylene group (Scheme 53). The principal advantage of this reaction is that it enables two different molecules to be bonded together in a single step.

Scheme 53

The substrates usually employed in Mannich reactions are compounds such an enols (phenolic compounds) or activated aromatic and heterocylic rings, which can behave as good nucleophiles. The amine reagent of the Mannich reaction must have at least one reactive hydrogen atom, and hence aliphatic and aromatic primary and secondary amines are frequently used. Formaldehyde (either as an aqueous solution or in the form of paraformaldehyde) is the most commonly used aldehyde in Mannich aminoalkylation, however other suitable aldehydes may also be employed. 84 5.2.1. Mechanism of the Mannich reaction The Mannich reaction mechanism involves the formation of an iminium ion 187, generated by the condensation of formaldehyde 184 and a secondary amine 185. The reactive iminium intermediate 187 is then attacked by the nucleophilic species (eg. phenol 188) that undergoes electrophilic substitution to yield 189, which on loss of a proton produces the amino-alkylated product 190 (Scheme 54).132

H R2NH CO R2NCH2 185 H HO iminium ion 184 187

188

HO HO -H+ R N R2N 2 H 190 189 Scheme 54

The position ortho to the hydroxyl group is known to be the most preferred for attack under Mannich reaction conditions for all phenolic derivatives. This is explained by the reaction mechanism, according to which a H-bond is first formed between the Mannich reagent and the substrate, after which the o-position is attacked.132

H H CO H R1 R1 N N N R1 184 HO – H2O HO O

191 192 193 Scheme 55

85 With primary amines, however, there arises another possibility of cyclization to a benzoxazine. This occurs due to the aminoalkyl moiety on the newly formed Mannich base 191 reacting with another equivalent of formaldehyde 184 to generate a second iminium species 192. The adjacent hydroxyl group then attacks the intermediate 192 which cyclizes to form the benzoxazine 193 (Scheme 55).133

According to Burk et al. who investigated the Mannich reactions of p-substituted phenols 194 (Scheme 56), reactions with formaldehyde and primary amines taken in a molar ratio of 1:2:1 lead to the formation of 1,3-benzoxazines 195. However, equimolar quantities of the reactants gave o-alkylaminomethyl-p-substituted phenols 196, which are simple Mannich bases. Conversion of 196 to 195 is possible with formaldehyde in the presence of a basic catalyst.133a

Scheme 56

It is also known that 1,3-benzoxazines such as 195 on hydrolysis in aqueous acid (formic acid) can undergo cleavage, producing 196 with the evolution of formaldehyde.133a,133c,133d

5.2.2. Possibilities of Mannich base products Therefore, the Mannich base products are anticipated to fall under three main classes as follows: 1. formation of simple Mannich bases 2. formation of benzoxazines and 3. formation of dimers

The prime factors affecting the formation of these products are the nature of the amine component and the reagent ratios utilized in the reactions. In most cases, the first two possibilities would be in competition with each other. However, the factors that influence the 86 selectivity of one over the other are not clear. In some cases, it might be possible to modify the reaction conditions such that the formation of the product is controlled. But in most cases, it is anticipated that the analysis of the product would actually help in the identification of the reaction, which takes place. In general, it could be said that the first two strategies are closely linked to one another and have higher chances of occurrence.

Theoretically, the use of primary amines can also give rise to dimers if the simple Mannich base reacts further with an additional molecule of formaldehyde and substrate. For instance, the application of the Mannich reaction on the coumarin 197 led to the formation of the corresponding bis-compound 198 with the use of piperazine and formaldehyde (Scheme 57).134

HN NH O O N O N N N N NH N N HCHO S S S 197 198 Scheme 57

Similar to the 1,3-benzoxazines, these dimeric structures also possess the ability to undergo cleavage to regenerate the corresponding simple Mannich bases.133c,133d However, it was reported by Cass, that both the simple Mannich base and benzoxazine formation were favored over dimer formation even when the reagent ratios were optimally controlled such that the substrate was present at twice the concentration of the primary amine.135

5.2.3. Chemoselectivity and regioselectivity of Mannich bases Chemoselectivity in Mannich synthesis usually involves substrates having more than one site for reaction with the aminoalkylating agent, whereas issues concerning regioselectivity arise when aminoalkylation can occur in the ortho or para positions of a phenol or the CH or NH groups of a heterocycle.

The flavanone, naringenin 199, is a good example to understand these concepts. The presence of multiple hydroxyl groups in the molecule gives rise to many active sites (C6, C8, C3 and C2c) for aminoalkylation to occur. Structural analysis indicates that the A ring of naringenin 199, especially positions C6 and C8, might be more reactive towards electrophiles than the B ring. Though the phenolic hydroxyl groups in naringenin 199 are chemically similar, fine differences

87 exist in the chemical and electronic environments of each. A variety of conditions were investigated and finally, results demonstrated that the A ring of naringenin 199 is the most electron-rich with the C6 being the dominant site for electrophilic reactions (Figure 16).136

2' OH 8 B HO O 2' A C 3 6 OH O 199 Figure 16. Active sites in naringenin 199

Similarly, Omura et al. studied the Mannich reactions of 2c,4c-dihydroxyacetophenone 65, in which the sites of activation were expected to be C3 and C5 (ortho and para to the hydroxyl groups). Treatment of 65 with secondary amines introduced the corresponding aminoalkyl group at C3 as seen in 200, indicating clearly that C3 is the most active site for electrophilic substitution.137

O OH O OH O OH R 3 R2 1 N N OH O 5 OH 65 200 201 O OH R O O N 1

O OH 202 N 203 R1

The reactions of 65 with primary amines can produce the 1,3-benzoxazine derivatives 201, 202 or 203. However, these reactions were found to be highly regioselective generating only the benzoxazine 201 predominantly at the C3 position, wherein the selective incorporation of the hydroxyl group at C4 to the newly formed oxazine ring at C3 was noteworthy.137

88 5.3. Aims of the present work The primary aim of this work was to utilize the Mannich reaction in the synthesis of novel derivatives of 5-hydroxy- 204, 6-hydroxy- 205 and 7-hydroxyflavones 206.

R R R B O O HO O A C HO OH O O O 204 205 206

The Mannich chemistry of these analogues was investigated with the use of various primary and secondary amines, aminals and amino acids. Emphasis was focused on the chemoselectivities and regioselectivities of the Mannich bases generated from the reactions.

5.4. Synthesis of hydroxyflavones 5.4.1. Known synthetic methodologies A number of methods are currently available to synthesize ring A hydroxylated flavones, including the Allan-Robinson synthesis,138 the Baker-Venkataraman method,139 synthesis from chalcones140 and synthesis via an intramolecular Wittig strategy.141

The Allan-Robinson methodology for flavones includes the Kostanecki reaction, in which an appropriate acetophenone is heated with benzoic anhydride and sodium benzoate, followed by hydrolysis, to afford the corresponding flavone. However, the desired products were isolated in low yields from complex reaction mixtures that often yielded 3-aroylflavones as the main products.138

Another method was the intramolecular Wittig reaction (Scheme 58), wherein the reaction of an acetophenone 207 with benzoyl chloride followed by treatment with bromine and triphenylphosphine afforded the triphenylphosphonium salt 208, which on further treatment with sodium carbonate followed by hydrolysis with sodium hydroxide gave the flavone 209. This method effectively avoided the formation of 3-aroylflavones, but involved multiple steps.141

89

Scheme 58

The most commonly used method for the synthesis of flavones is the Baker-Venkataraman transformation (Scheme 59). In this process, a hydroxyacetophenone 207 is first converted into a benzoyl ester 210, which is subsequently treated with base, inducing an intramolecular Claisen condensation, resulting in a 1,3-diketone 211. Cyclization of the diketone 211 with acid leads to the generation of the desired chromone 212.139 Later, Ares et al. described a modified version of the Baker-Venkataraman synthesis employing a potassium tert-butoxide mediated diketone synthesis as the key step.77a

OH O pyridine COR HO HO O

O R Cl O 207 213 210

pyridine KOH

O R AcOH OH HO HO H2SO4 R

O O O 212 211 Scheme 59

However, the conventional Baker-Venkataraman approach was not suitable for synthesizing large amounts of flavones since low yields and product isolation complications were encountered in the benzoylation and Claisen condensation steps, respectively.

Cushman et al. further modified the above approach for the synthesis of the intermediate diketones 211 (Scheme 60).142

90 OH OH LiHMDS, THF AcOH O R HO HO HO O R H2SO4

O R Cl O O O 207 213 211 212 Scheme 60

In this strategy, the 1,3-diketones 211 were prepared in a single step by reacting acetophenones 207 with benzoyl chlorides 213, mediated by lithium bis(trimethylsilyl)amide (LiHMDS).142 However, this strategy required very low temperature (-78 °С) conditions and the use of relatively expensive LiHMDS.

5.4.2. Convenient one-pot synthesis of flavones A suitable one-pot synthesis was utilized in this study for the synthesis of hydroxyflavones, the desired substrates for the production of Mannich bases. During the investigation of 3- aroylchromones, Ganguly et al. and others established that 3-aroylflavones were versatile intermediates and served as precursors for the preparation of substituted flavones. Heating under reflux in an alkaline medium facilitated cleavage of the aroyl group affording the corresponding flavones.143

In this project, the synthesis of 3-aroylflavones 215a-g (Scheme 61) was undertaken via the condensation of appropriate acetophenones 65, 111a and 111b with benzoyl chlorides 214a-c in refluxing dry acetone in the presence of anhydrous potassium carbonate. This single step synthesis took place under mild conditions and did not require the use of pyridine or strong acidic conditions.144

Scheme 61

91 The intermediate 3-aroylflavones 215a-g (without any further purification) were conveniently converted to the corresponding flavones 216a-g by refluxing in 5% KOH in ethanol over a prolonged time period (Scheme 62).

Scheme 62

Although the triketones 217a-g were never isolated in these reactions, it is possible that the triketones 217a-g, generated from the 3-aroylflavones 215a-g were converted to the respective diketones 218a-g (similar to the Baker-Venkataraman reaction intermediates) followed by cyclisation to the flavones 216a-g.144a

Table 5 lists the various flavones synthesized using this one-pot methodology with their respective yields. The overall yields in these reactions were relatively low (26-52%), however, 5-hydroxyflavone 216g was obtained in better yield than the 6-hydroxyflavones 216a-c, which were formed in better yields in comparison to the 7-hydroxyflavones 216d-f.

92 Table 5. Synthesis of flavones R1 R2 R3 R Flavone Yields [%]a

H OH H H 216a 38 H OH H Cl 216b 32 H OH H OMe 216c 34 H H OH H 216d 30 H H OH Cl 216e 26 H H OH OMe 216f 27 OH H H H 216g 52 aYields of isolated pure product

The flavones showed a characteristic NMR signal corresponding to H3 in the pyrone ring. For instance, in the 1H NMR spectrum of 6-hydroxyflavone 216a this proton appeared as a singlet at G 7.01 ppm.

5.5. Mannich reactions of 6-hydroxyflavones 5.5.1. Reactions with primary amines The 6-hydroxyflavones 216a-b were reacted with formaldehyde and primary amines (methyl amine and benzyl amine) in a molar ratio of 1:2:1 in ethanol. Theoretically, four products 219, 220, 221 and 222 were possible in these reactions (Scheme 63). The use of primary amines could lead to simple Mannich bases 221 and 222 which could then cyclize further to 1,3- benzoxazines 219 and 220. As the ortho positions adjacent to the hydroxyl group were vacant, the Mannich reaction could occur at C5 or C7 or both, depending on the site of activation.

93 R

O 7

HO 5 O 216a-b

R R

O O

O HO O O N HN

R1 219 R1 221 OR OR R R

R1 O R O N 1 N H O HO O O

220 222 Scheme 63

However, in all cases, the reactions proceeded smoothly at C5 followed by cyclization to yield benzoxazines 219a-c (Scheme 64) in moderate yields. The most striking feature of the reactions of this type was that they proceeded with complete regioselectivity, that is, electrophilic substitution occurred exclusively at the C5 position and reaction at the C7 position was never observed. The presence of the electron withdrawing carbonyl group at C4 para to C7 is a possible reason for the above observation.

R R

O HCHO, R1NH2 O ethanol, reflux HO 38-46% O O O N 216a-b 219a-c R1 Scheme 64

The presence of the benzoxazine structure in compound 219b was established by its 1H NMR spectrum. The most significant signals were the singlets at δ 4.76 and 4.69 ppm integrating to 94 two protons each. The first one was indicative of the methylene group linking the oxygen and nitrogen atoms of the benzoxazine ring, while the latter represented the methylene group linking the aromatic ring and the nitrogen atom.

The regioselectivity of the product was confirmed by the large coupling constant (J = 9.0 Hz) seen as doublets at δ 7.12 and 7.43 ppm, which correlated to H7 and H8 respectively. DEPT-135 and the broadband decoupled 13C NMR spectrum of 219b indicated the presence of three methylene (CH2) groups at δ 51.3, 56.2 and 81.5 ppm, further confirming the formation of the benzoxazine.

The yields for the 5-substituted benzoxazines 219a-c from 6-hydroxyflavones 216a-b are given below (Table 6). Table 6. Synthesis of 1,3-benzoxazines 219a-c

a R1 R Benzoxazine Yields [%]

Me H 219a 39 Bn H 219b 46 Me Cl 219c 38 aYields of isolated pure product

A variety of experiments were conducted in order to investigate a number of parameters such as temperature, duration of the reactions and the effect of altering the molar ratio of the reactants.

Firstly, no reaction was observed at room temperature, but upon heating at reflux for a prolonged time period, i.e. 48 hours, the benzoxazines precipitated cleanly from the reaction mixture. This indicated that the duration of the reaction and the temperature had a role to play on the formation of the isolated product. This was found to hold true in the Mannich reactions that have been carried out with the flavanone, naringenin.136

Secondly, it was interesting to note that simultaneous mixing of reactants resulted in poor yields. However, the yields could be improved by the pre-treatment of formaldehyde with primary amines to generate the iminium ions133a,137 (in accordance with the reaction mechanism), followed by addition of the flavone. The higher initial concentration of the iminium ions probably led to increased reaction rates, thereby decreasing the potential formation of side products.

95 Thirdly, varying the molar ratio of the reactants had no effect on the formation of products; benzoxazine formation was always favored exclusively over the simple Mannich base in all reviewed cases. However, this contradicts results shown by Burk and others, who emphasized that the structures of the final reaction products depended on the ratio of the reagents used.133a, 145

Further, benzoxazine 219a was stirred in the presence of formic acid in ethanol at r.t. for 24 hours (Scheme 65). Ring opening of the benzoxazine was observed, which resulted in the formation of the corresponding simple Mannich base 223 in 39% yield.

O HCOOH, ethanol O r.t., 24 h O 39% HO O O N HN 219a 223 Scheme 65

5.5.2. Reactions with secondary amines The 6-hydroxyflavone 216a was subjected to Mannich conditions, in which primary amines were replaced with secondary amines such as morpholine and piperidine. These reactions were expected to yield only simple Mannich bases, as there was no possibility of further cyclization.

Surprisingly, the 6-hydroxyflavone 216a with secondary amines and formaldehyde (molar ratio of 1:1:1) in ethanol did not yield Mannich bases as expected. However, the use of dioxane as solvent turned out to be a good choice, producing simple Mannich bases 224a and 224b indicating the incorporation of the bases at the C5 position of the flavone ring (Scheme 66).

O HCHO, R2NH O dioxane, reflux HO 37-39% HO O O N R 216a 2 224a, 224b Scheme 66

96 O O

HO HO O O N N 224a 224b O

However, using two equivalents of amine and formaldehyde with respect to the substrate did not generate the 5,7-disubstituted Mannich base as anticipated. Therefore, it was clear that electrophilic substitution occurred only at C5 in 6-hydroxyflavones.

5.5.3. Reactions with aminals It is well known from literature that aminals can function as preformed amine substrates in the Mannich reaction. These highly reactive bis-(dialkylamino)methane derivatives can behave as strong electrophiles and do not require formaldehyde in the aminoalkylation process.146 They hasten the reaction rate as well as reduce the generation of unwanted side products.147

Treatment of 6-hydroxyflavone 216a with commercially available aminal, bis- (dimethylamine)methane 225 in dioxane at reflux produced the C5 aminoalkylated flavone 226 (Scheme 67) in 45% yield.

225

O N N O

dioxan HO HO O O N 216a 226 Scheme 67

However the use of excess aminal was not effective in activating C7, which was in accordance with our previous observation. A typical mechanism using aminals is shown below in Scheme 68:

97 O O –(CH3)2NH

HO HO O 216a O H N H 226 N N N N

225 227 Scheme 68

5.5.4. Reactions with amino acids Amino acids are biologically important molecules and their use as substrates in the Mannich reaction with flavones was a natural choice. Thus the reactions of 6-hydroxyflavones 216a-c with amino acids (L-valine, DL-alanine, L-methionine and L-proline) and formaldehyde in ethanol at reflux afforded the simple 5-aminoalkyl substituted Mannich bases 228a-h (Scheme 69).

R R

O HCHO, R1NH2 O ethanol, reflux HO 31-52% HO O O HN 216a-c 228a-h R1 Scheme 69

As amino acids were not soluble at room temperature in ethanol, they were first dissolved by heating in ethanol, followed by the addition of formaldehyde to generate the iminium ions. The flavones were generally added an hour later to the reaction mixture and the mixture was heated at reflux. In most cases, the formation of the products was indicated by their precipitation from the reaction mixture after a time interval of about 12 hours. The precipitates contained the desired Mannich bases along with unconsumed amino acids, which were removed by successive washings with hot water.

98 R R

O O

HO HO O O HN HN 228a,e,h 228c,g COOH S COOH

R R

O O

HO HO O O N HN 228d 228b,f COOH COOH

Table 7 lists the various 5-aminoalkyl substituted Mannich bases 228a-h with their respective yields. Table 7. Synthesis of 5-aminoalkyl Mannich bases 228a-h

R1 R Mannich Yields [%]a amino acid base

L-valine H 228a 43 DL-alanine H 228b 47 L-methionine H 228c 52 L-proline H 228d 37 L-valine Cl 228e 34 DL-alanine Cl 228f 31 L-methionine Cl 228g 44 L-valine OMe 228h 46 aYields of isolated pure product

Generally, the reaction of a simple Mannich base to the benzoxazine structure proceeds through a cyclic six-membered transition state and thus benzoxazine formation should be favored on kinetic grounds. Interestingly, the 1H NMR and HRMS spectra of the products 228a-h did not display any evidence of benzoxazine formation. In this work, it was observed that the simple Mannich base products 228a-h were highly insoluble in water and in nearly all common organic

99 solvents including DMSO. Solubility was only achieved in strong organic acids such as TFA and in concentrated aqueous sodium hydroxide. It is believed that extensive protonation or deprotonation of the amine or carboxylic acid groups in the zwitterionic Mannich product facilitated dissolution in these acidic and basic solvents respectively.

Therefore, in light of these observations, the lack of benzoxazine formation can be attributed to the extremely low solubility of the Mannich base products in aqueous ethanol. The precipitation of the product from the reaction mixture may have prevented further reaction with formaldehyde, thereby inhibiting the formation of the benzoxazine. Further, hydrogen bonding between the amino group of the attached amino acid and the adjacent hydroxyl group at C6 of the flavone nucleus might also hinder a further reaction.

Interestingly, in a recent literature report where the structurally related 3-heteroaryl-7- hydroxychromones were reacted with amino acids in the Mannich reaction, benzoxazine formation was observed.148 However, these products were found to be soluble in a range of organic solvents such as ethanol and acetonitrile, therefore it was likely that the simple Mannich bases were also sufficiently soluble in the reaction mixture to undergo further reaction to the benzoxazine.

5.6. Mannich reactions of 7-hydroxyflavones The application of the Mannich reaction to 7-hydroxychromones and flavones gave rise to the corresponding N-substituted 7-methoxy-8-aminomethyl- derivatives which were found to be powerful central nervous system stimulants, having cardio kinetic and hypertensive actions.131b The position of the introduced aminomethyl group was predicted on the basis of Rangaswami and Seshadri’s work. These authors, using the Claisen rearrangement on 7-allyloxyflavones, found that there was a peculiar distribution of aromatic double bonds in 7-hydroxyflavones, such as to render the C8 position more reactive, as shown by the fact that they obtained 8-allyl derivatives in those reactions.149 Hence, it is known that the most reactive position for electrophilic attack in 7-hydroxychromones is the C8.149,150

If this is substituted, aminomethylation by reactive agents was expected to occur on the activated position less favored in the first attack, that is, the C6 position.151 As Rangaswami and Seshadri observed in connection with the distribution of the aromatic double bonds in 7-hydroxyflavones, C6 can also become reactive. Thus the Mannich reaction of 7-hydroxychromone using two moles of amine and formaldehyde gave the 6,8-dialkylaminoalkyl derivative.149 100 Keeping the above facts in mind, the 7-hydroxyflavones 216d-f were subjected to standard Mannich conditions as before. Treatment with primary amines was found to yield the corresponding 1,3-benzoxazines 229a-d in 37-43% yields at C8 of the flavone ring (Scheme 70).

R1 R N R HCHO, R NH HO O 1 2 O O ethanol, reflux 37-43% O O 216d-f 229a-d 229a R=H,R1 =Bn 229b R=Cl,R1 =Me 229c R=Cl,R1 =Bn 229d R=OMe,R1 =Me Scheme 70

In a similar fashion, treatment of 216e with amino acids, L-valine and L-methionine produced 8- aminoalkylated simple Mannich bases 230a and 230b in 28 and 30% yields (Scheme 71).

R1 Cl HN Cl

HO O HCHO, R1NH2 HO O ethanol, reflux 28-30% O O

216e 230a, 230b Scheme 71

COOH S COOH

HN Cl HN Cl

HO O HO O

O O 230a 230b

However, increasing the molar ratio of the amine and formaldehyde with respect to the flavone was not found to yield the 6,8-dialkylaminoalkylated analogue as expected. Therefore, in our 101 observation, the C8 position was found to be the only reactive site towards electrophiles in 7- hydroxyflavones.

5.7. Mannich reactions of 5-hydroxyflavone Similar Mannich reactions were attempted using 5-hydroxyflavone 216g as the substrate. It was anticipated that they would not yield any Mannich products (Scheme 72), due to strong hydrogen bonding between the hydroxyl group of ring A and the adjacent carbonyl group of ring C.

HCHO, amine, O ethanol no reaction

OH O 216g Scheme 72

Our observations were found to be the same as expected.

5.8. Conclusion The Mannich reaction has been shown to be a facile method for the synthesis of aminoalkylated derivatives of flavones. The reactive site for electrophilic substitution in the flavone nucleus was dependent on the position of the hydroxyl group in ring A.

The reactions of 6-hydroxyflavones were found to yield the corresponding benzoxazine-flavones at C5 on treatment with primary amines. The use of secondary amines, aminals and amino acids generated the simple Mannich bases, with electrophilic substitution occurring only at C5. Interestingly, disubstituted Mannich products were not observed.

However, the most active site for electrophilic substitution in 7-hydroxyflavones was found to be C8, which was in accordance with literature.149,150 Thus, the reactions with primary amines produced benzoxazines-flavones via initial reaction at C8, whereas simple aminoalkylated Mannich bases at the same position were generated with the use of amino acids.

102

CHAPTER 6

SYNTHESIS OF 4- ARYLAZAFLAVANS AND

QUINOLINES

103 6.1. Introduction 4-Heteroaryl flavans such as imidazolylflavans 231 and 4-triazolylflavans 232 and 233 were tested for their biological evaluation against the aromatase enzyme, a target of pharmacological interest for the treatment of estrogen-dependent cancers. Interestingly, the introduction of an imidazolyl group at C4 on the flavan nucleus led to strong enhancement of enzyme inhibition

(IC50 of compound 231 = 0.091 μM). The treatment of the corresponding flavan-4-ols with 1,1'- carbonyldiimidazole in THF led to the formation of such azole derivatives e.g. 231.152

MeO O MeO O MeO O

N N N N N N NN

231 232 233

Similarly, the synthesis of 4-triazolylflavans, 232 and 233 was undertaken in which the triazole moiety was introduced by direct reaction of flavan-4-ols with 1,1'-sulfinylditriazole in dry acetonitrile. These compounds were also found to exhibit moderate to high inhibitory activity against aromatase.153

OH OH

HO O HO O

HO OH HO OH

R R

OH O O OH

234 R=CH2CH2CH3 236 R=CH2CH2CH3 235 R=Ph 237 R=Ph

Further, biologically active compounds can be found in the 4-arylflavan series as well. For example, myristinins B 234, C 235, E 236 and F 237 possess antifungal and selective COX-2 inhibitory activities. On the other hand, Hecht et al.154 have described compounds 235 and 237 as potent DNA E-polymerase inhibitors.

104 OH OH

HO O HO O HO O

Br H MeO HO O N OH

MeO OMe O OMe OMe 238 239 240

Therefore, synthesis of a series of 4-heteroaryl-substituted flavans 238 and 239 and 4-aryl substituted isoflavans 240 was undertaken previously in our research group. They were obtained by the reactions of activated aromatic or heteroaromatic compounds with the corresponding flavan-4-ols and isoflavan-4-ols in the presence of a Lewis acid.85

R H R O N RO RO

OH OH 241 242 Scheme 73

In this project, it was decided to design aza-analogues of flavan-4-ols (2-arylquinolin-4-ols), 242 that replaced the oxygen atom in flavan-4-ols 241 by the heterocyclic atom, nitrogen (Scheme 73), with the aim of introducing a convenient methodology to the synthesis of a new series of 2,4-disubstituted azaflavans.

6.2. Known synthetic methodologies to 2,4-disubstituted-tetrahydroquinolines The tetrahydroquinoline moiety is a core structure in many biologically important natural products such as flindersine 243, oricine 244 and veprisine 245. Derivatives of these alkaloids possess a wide range of biological activities such as psychotropic, antiallergic and anti- inflammatory behavior155a and are used as potent pharmaceuticals.155b

105 O O O MeO

N O MeO N OMe MeO N O H OMe 243 244 245

Hence, different approaches have been developed for the synthesis of molecules bearing the tetrahydroquinoline skeleton.

Scheme 74

Recently, Estibalez et al. have reported the preparation of 4-substituted-2- phenyltetrahydroquinolines 247 and 248 from N-alkenyl substituted 2-iodoanilines 246 via intramolecular carbolithiation reactions (Scheme 74). The cyclization of the aryllithiums from N-alkenyl substituted 2-iodoanilines using alkenes as internal electrophiles, generated the tetrahydroquinoline derivatives 247 and 248.156

Scheme 75

The [4+2] Diels-Alder reaction between N-arylimines and electron-rich dienophiles is reported as a powerful synthetic tool for constructing N-containing six-membered heterocyclic 106 compounds including tetrahydroquinolines. Zhang et al. utilized the synthetic potential of photo induced electron transfer (PET) reactions initiated by 2,4,6-triphenylpyrilium tetrafluoroborate (TPT), a photosensitizer to induce Diels-Alder reactions. They reported the first PET-catalyzed Diels-Alder reaction of N-arylimine 249 with D-methylstyrene 250, which produced tetrahydroquinolines 251 and 252 as a mixture of two stereo isomers (Scheme 75).157

254

H N OTMS N N oxidation

MeO cat. CF3SO3H MeO MeO OTMS

253

255 256 Scheme 76

Similarly, Akiyama and his co-workers have reported the use of CF3SO3H-catalyzed [4+2] Diels-Alder reaction of aldimine 253 with a silyl enol ether 254 (Scheme 76). The Diels-Alder reaction was found to take place smoothly to afford the tetrahydroquinoline 255, which on 158 subsequent in situ oxidation with Mn(OAc)3 furnished the corresponding quinoline 256.

Shindoh and his colleagues demonstrated a catalytic cascade inverse electron demand hetero- Diels-Alder reaction (Povarov reaction) for the synthesis of substituted quinolines. The reaction of arylaldimines with electron-rich olefins such as allylsilanes were found to produce the 1,2,3,4-tetrahydroquinolines in the presence triflic imide thus, involving auto tandem catalysis. The tetrahydroquinolines were found to undergo oxidation easily to the quinolines by the 159 assistance of the imine in the presence of catalytic amounts of Tf2NH.

Leardini et al. reported the above inverse electron demand Diels-Alder cycloaddition for reactions of aromatic imines with phenylacetylene or styrene in an acetonitrile solution of iron(III) chloride to give quinolines or their tetrahydro derivatives.160

However, our methodology for the synthesis of 2,4-disubstituted azaflavans involved an entirely different but simple approach, which is highlighted and discussed in detail in the sections to follow.

107 6.3. Synthesis of azaflavanol The retro synthetic analysis (Scheme 77) shows that 4-aryl- and 4-heteroarylazaflavans 257 can be synthesized by the reactions of activated aromatic or heteroaromatic compounds with a carbocation 258, which in turn can be obtained from the reaction of azaflavan-4-ol 259 with a Lewis acid.

H R H R H R N N N RO RO RO

OH Ar 258 257 259

activated aromatic or heteroaromatic compound Scheme 77

The azaflavan-4-ol in turn can be generated from the corresponding azaflavanone. In general, a recent trend has been observed where aza-analogs of natural oxygen heterocycles are synthesized and screened for biological properties. Their synthesis is usually carried out using acid- or base-catalyzed isomerization of substituted 2'-aminochalcones, mainly using corrosive reagents such as orthophosphoric acid, acetic acid or strong alkalis.161

However, Chandrasekhar et al. demonstrated that 2'-hydroxyacetophenones and aryl aldehydes undergo a smooth one-pot condensation cyclization in the presence of L-proline as organo catalyst to furnish flavanones in high yields.162a They extended this methodology for the synthesis of azaflavanones, which was found to be successful.162b

2'-Aminoacetophenone 260 and 4-chlorobenzaldehyde 67c in equimolar quantities were refluxed together in the presence of L-proline (30 mol %) in methanol. This furnished 2-(4'-chorophenyl)- 2,3-dihydroquinolin-4(1H)-one 261 as a clean product in 50% yield (Scheme 78).

108 CHO Cl H NH 2 L-proline, MeOH N reflux, 50%

O Cl O 260 67c 261 Scheme 78

Further, reduction of the ketone in 261 with sodium borohydride in ethanol at room temperature for 4 hours gave the corresponding tetrahydroquinolinol 262 in 95% yield as a cis- isomer (Scheme 79). The hydride attack on the opposite side from the phenyl group is probably responsible for the formation of the cis product. The cis stereochemistry of azaflavanol 262 was established on the basis of an NOE between H2 and H4.

Cl Cl H H N N NaBH4,EtOH r.t., 95% O OH 261 262 Scheme 79

Thus, azaflavanol 262 served as a good precursor for the synthesis of 4-arylazaflavans, 4- heteroarylazaflavans and 4-thiophenylazaflavans via its acid-catalyzed coupling with a variety of different nucleophiles. A wide range of nucleophiles was studied and the effect of various substituents on the yield and regioselectivity of the products formed were investigated.

6.4. Results and discussion 6.4.1. Synthesis of 4-arylazaflavans

Azaflavanol 262 was reacted with 2-naphthol 99 in the presence of BF3.OEt2 at room temperature for 12 hours. After aqueous work-up, the crude product was chromatographed to give azaflavan 263 in 62% yield (Scheme 80).

109 Cl OH H N 2 Cl 99 H 4 N DCM, BF3.OEt2 62% OH

3" OH 4" 262 263 Scheme 80

The 1H NMR spectrum of compound 263 showed a multiplet at G 2.29 corresponding to two H3 protons. The H4 proton appeared as a triplet at G 4.80 (J = 3.0 Hz), whereas a doublet of doublets at G 4.51 (J = 3.3, 10.3 Hz) corresponded to the H2 proton. The substitution at the C1 position of 2-naphthol was indicated by the presence of doublets at G 7.14 and 7.24 (J = 8.3 Hz), corresponding to H3'' and H4'' respectively. Most importantly, the trans stereochemistry of the product was established on the basis of the absence of NOE correlation between the H2 and H4 protons. The NOESY experiment also showed correlations between H4 and the naphthol protons, but however, no correlations were observed between H2 and the phenyl protons, due to the fact that H2 was farther away from the naphthol protons.

However, the reaction was not expected to be stereoselective as the incoming nucleophile can possibly attack from either face of the carbocation giving rise to a mixture of cis and trans isomers. But, the exclusive formation of the trans product observed in this reaction can be explained by the fact that the presence of the aryl group at the C2 position of the intermediate carbocation prevented the attack of the incoming nucleophile from the same side due to steric hindrance. This resulted in the attack from the opposite side of the C2 aryl group, giving rise to the trans product exclusively.

Thus, the BF3·OEt2 catalyzed arylation reaction was stereoselective and although the starting material azaflavanol 262 was a cis isomer, only the trans product was obtained in good yield.

With these encouraging results it was decided to extend the reaction methodology to some other activated phenolic compounds.

110 Cl H N Cl 264 OH H N DCM, BF .OEt 3 2 OH 31% 3" 4" OH

262 265 Scheme 81

Azaflavanol 262 was reacted with 1-naphthol 264 under similar conditions. The 1H NMR spectrum of the resultant compound 265 showed a multiplet at G 2.31 corresponding to two H3 protons. The proton H4 was seen as a triplet at G 4.90 (J = 3.0 Hz), whereas the H2 proton appeared as a doublet of doublets at G 4.24 (J = 3.0, 10.5 Hz). Again the reaction was found to proceed stereoselectively leading exclusively to the trans product 265 (Scheme 81). As observed previously, the position ortho to the hydroxyl group was found to undergo electrophilic substitution.

OMe Cl H N Cl MeO OH H 266 N DCM, BF3.OEt2 MeO OH 24% 5" 3" OH OMe 262 267 Scheme 82

A similar reaction with 3,5-dimethoxyphenol 266 gave azaflavan 267 (Scheme 82). The structure was again established on the basis of 1H NMR spectroscopy wherein the aliphatic protons H2, H3 and H4 were found to have coupling patterns similar to those observed in 263 and 265. The regioselectivity in this case can be attributed to the mild reaction conditions, which favored the reaction at the less hindered C1 position of the phenol over the C3 and C5 positions. Protons H3'' and H5'' were indicated as doublets at G 6.06 and 6.15 (J = 2.4 Hz) respectively.

111 With other phenolic substrates such as phenol, 3-methylcatechol, 3,4,5-trimethoxyphenol, 2'- hydroxy-5'-methoxyacetophenone and 2'-hydroxy-6'-methoxyacetophenone, a complex mixture was obtained and could not be separated, whereas reactions with phloroglucinol and pyrogallol were unsuccessful due to their insolubility in dichloromethane.

However, in a few cases, it was interesting to observe that the azaflavanol 262 underwent dehydration and oxidation resulting in the formation of the highly stable quinoline nucleus. The reasons for its formation are discussed in Section 6.7.

With these results in hand, reactions of azaflavanol 262 with some activated heterocyclic compounds such as indoles and chromenes were investigated.

6.4.2. Synthesis of 4-heteroarylazaflavans The few heterocyclic compounds required for the arylation reactions were synthesized following the reported procedures.

Reaction of 3,5-dimethoxyaniline 268 with benzoin 269 in the presence of aniline and acetic acid gave 4,6-dimethoxy-2,3-diphenylindole 270 in a single step in 63% yield (Scheme 83).163

OMe OMe O i) 125 oC ii) PhNH ,AcOH HO 2 MeO N MeO NH2 125 oC, 63% H

268 269 270 Scheme 83

4,6-Dimethoxy-3-(4'-bromophenyl)indole 275 was synthesized by a modified Bischler indole synthesis from 3,5-dimethoxyaniline 268 in four steps (Scheme 84).164 In the first step, aniline 267 was condensed with 4-bromophenacylbromide 271 to give compound 272, which on acetylation with acetic anhydride gave the N-acyl compound 273. Cyclization was carried out by refluxing compound 273 with trifluoroacetic acid to give N-acetylindole 274, which on hydrolysis with methanolic KOH gave indole 275.

112 Br

O Br Br 271 OMe OMe OMe Br O 0 O NaHCO3,ethanol Ac2O, 50 C reflux, 95% 89% MeO NH MeO N MeO N 2 H O 268 272 273

TFA reflux, 94%

Br Br

OMe OMe

KOH, MeOH MeO N r.t., 75% N H MeO O 275 274 Scheme 84

4',7-Dimethoxyisoflav-3-ene 276 was synthesized in 93% yield by the methylation of 4',7- dihydroxyisoflav-3-ene 138 (phenoxodiol) with methyl iodide in the presence of K2CO3 (Scheme 85).

HO O MeO O

MeI, K2CO3 acetone, reflux 93% 138OH 276 OMe Scheme 85

When azaflavanol 262 was reacted with a simple heterocycle such as furan 277, trans-2-(4- chlorophenyl)-4-(furan-2-yl)-1,2,3,4-tetrahydroquinoline 278 was obtained in 25% yield, and electrophilic substitution was found to take place at the C2 position of the furan ring (Scheme 86).

113 Cl O Cl 277 H H N N DCM, BF3.OEt2 25%

OH O

262 278 Scheme 86

The reaction of azaflavanol 262 with N-methylindole 171 resulted in the formation of the substituted tetrahydroquinoline 279 in 64% yield (Scheme 87). In this case, the most nucleophilic site in 171 was observed to be the C3. The compound was identified from its 1H NMR spectrum, in which proton H2cc of the indole nucleus appeared as a singlet at G 6.32 ppm. The protons correlating to H3 were identified as a multiplet at G 2.11 and a doublet of a triplet at G 2.27 (J = 3.0, 12.8 Hz), whereas H2 was seen as a doublet of doublet at G 4.21 (J = 3.0, 10.3 Hz) and H4 was observed as a triplet at G 4.36 (J = 4.0 Hz).

Cl N H Cl N 171 H N DCM, BF3.OEt2

64% H2" OH N

262 279 Scheme 87

The structure and the trans stereochemistry of compound 279 were further confirmed by X-ray crystal structure determination as shown in Figure 17.

114

Figure 17. ORTEP diagram of 279

The treatment of azaflavanol 262 with 2-phenylindole 280 produced the corresponding heteroaryl azaflavan 281 in 67% yield (Scheme 88). The disappearance of the singlet corresponding to H3'' of the indole ring suggested the attachment of C4 of the azaflavan unit to C3 of the indole subunit.

Cl N H Cl H N H 280 N DCM, BF3.OEt2 67%

OH NH

262 281 Scheme 88

The reaction of azaflavanol 262 with 3-(4c-bromophenyl)-4,6-dimethoxyindole 275 yielded the azaflavan 282 in 47% yield (Scheme 89). The most nucleophilic site in 275 was found to be the C2 position, indicated by the disappearance of the singlet corresponding to H2''. The protons correlating to H5'' and H7'' of the indole unit at G 6.23 and 6.36 (J = 1.9 Hz) remained intact, suggesting no substitution reactions have taken place at those positions.

115 Br

OMe Cl H N MeO N Cl H 275 H Br N DCM, BF3.OEt2 NH 47% MeO H7" OH H5" OMe 262 282 Scheme 89

However, the reaction of compound 262 with indole 270 gave azaflavan 283 in 63% yield (Scheme 90). Additional peaks were observed in the NMR spectrum due to the presence of atropisomers. In the 1H NMR spectrum of compound 283, a multiplet at G 2.19 (2H) and a triplet at G 5.10 (J = 3.8 Hz) (1H) corresponded to H3 and H4 protons respectively, whereas the proton H2 appeared as a doublet of doublets at G 4.45 (J = 2.6, 11.3 Hz). The H5'' proton appeared as a singlet at G 6.24 ppm, indicating the attachment of C4 of the azaflavan unit to C7 of the indole subunit.

OMe Cl H N

Cl MeO N 270 H H H N MeO N DCM, BF3.OEt2 63% H5" OH OMe

262 283 Scheme 90

When the reaction was attempted with 4',7-dimethoxyisoflav-3-ene 276, compound 284 was obtained in 20% yield (Scheme 91). The 1H NMR spectrum of compound 284 showed a multiplet at G 2.11 corresponding to two H3 protons. The H4 proton appeared as a triplet at G

116 4.46 (J = 3.8 Hz), whereas a doublet of doublets at G 4.24 (J = 2.6, 8.3 Hz) corresponded to the H2 proton. Two singlets as G 6.41 and 6.47 corresponded to H8'' and H5'' protons indicating that the C4 position of the azaflavan was attached to C6'' of the isoflavene subunit.

OMe Cl H N

Cl MeO O H 276 MeO N H5" DCM, BF3.OEt2 20% H8" O OH

262 284 OMe Scheme 91

Attempted reactions with 4',7-dihydroxyisoflav-3-ene (phenoxodiol) were unsuccessful due to its insolubility in dichloromethane. No reaction was observed when 7-acetoxyisoflav-3-ene was used as a substrate, presumably due to insufficient activation of the ring-A by the 7-acetoxy group.

6.4.3. Synthesis of 4-thiophenylazaflavans Similarly, azaflavanol 262 was subjected to reactions with p-substituted thiophenols, 285 and 286. These reactions proceeded to yield the corresponding 4-thiophenylazaflavans 287 and 288 in 73 and 71% yields respectively, possessing a thio linkage between the azaflavan ring and the aromatic ring (Scheme 92).

SH Cl R H N Cl 285 R=Cl H 286 R=OMe N DCM, BF3.OEt2 S 71-73%

OH R 262 287 R=Cl 288 R=OMe Scheme 92

117 The 1H NMR spectrum of the compound 287 exhibited a multiplet at G 2.01 correlating to two H3 protons, a triplet and a doublet of doublets at G 4.42 (J = 3.0 Hz) and 4.75 (J = 4.5, 9.7 Hz) correlating to H4 and H2 respectively.

Thus, acid-catalyzed arylation and heteroarylation using azaflavanol is an excellent method for the synthesis of 4-aryl-, 4-heteroaryl- and 4-thiophenylazaflavans. The reactions were highly stereoselective and gave trans products exclusively in favorably good yields.

6.5. Synthesis of 5,7-dimethoxyazaflavanol Having worked on the synthesis of 2,4-disubstituted azaflavans, it was then decided to extend the same methodology to the synthesis of the corresponding oxygenated analogues, as the oxygenation pattern is considered important for biological activity. In order to achieve the target molecules, 2-amino-4,6-dimethoxyacetophenone 292 was the required starting material, which could be readily obtained in three steps from commercially available 3,5-dimethoxyaniline 268 (Scheme 93).

MeO NH2 MeO NHCOCF3 TFAA, Et3N r.t., 82%

OMe OMe 268 289

acetyl chloride, SnCl4, DCE, r.t.

MeO NH2 MeO NHCOCF3 MeO NHCOCF3 K2CO3,MeOH reflux, 49%

OMe O OMe O O OMe

292 290 291 Scheme 93

Hence, 3,5-dimethoxyaniline 268 was initially protected by treatment with trifluoroacetic anhydride to give 2,2,2-trifluoro-N-(3,5-dimethoxyphenyl)acetamide 289 followed by standard Friedel-Crafts acetylation generating N-(2-acetyl-3,5-dimethoxyphenyl)-2,2,2- trifluoroacetamide 290 as a major product and N-(4-acetyl-3,5-dimethoxyphenyl)-2,2,2-

118 trifluoroacetamide 291 as a minor product. The 1H NMR spectrum of compound 290 displayed signals at G 2.61, 6.31, 7.90 and 13.30 ppm, which corresponded to the methyl, H4, H6 and NH protons respectively. In contrast, compound 291 had proton resonances at G 6.81 for H2, H6 and at G 8.21 for NH. Deprotection of N-(2-acetyl-3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide 290 with potassium carbonate in methanol165 gave the primary amine 292 in 49% yield.

The strategy used previously to generate the corresponding azaflavanone 293 by using the simple one-pot condensation cyclization method in the presence of L-proline as catalyst was attempted (Scheme 94). However, the reaction failed to proceed and the starting materials were found by TLC to remain intact.

Cl CHO H MeO NH2 L-proline, MeOH MeO N

OMe O Cl OMe O

292 67c 293 Scheme 94

The reaction was repeated using other polar solvents such as IPA and DMF, but still proved unsuccessful. It was then envisaged that the position of the methoxy groups in the aromatic nucleus had an effect on the reaction. However, the above methodology attempted on other substrates such as 2-amino-4-methoxyacetophenone was also unsuccessful.

Thus, the presence of electron-donating substituents in the aromatic ring of substrates 292 would lower the methyl ketone reactivity for the condensation reaction and subsequent cyclization failed to occur. In order to overcome the problem, the corresponding aminochalcone 294 was synthesized in 74% yield by Claisen-Schmidt condensation166a of 292 with 4- chlorobenzaldehyde 67c in an alkaline alcoholic medium (Scheme 95).

119 CHO MeO NH MeO NH2 Cl 2 NaOH, ethanol r.t., 74%

OMe O Cl OMe O

292 67c 294 Scheme 95

Acid-catalyzed cyclization reactions of 294 using standard conditions166a,166b such as conc. HCl/MeOH and PPA/glacial acetic acid furnished the azaflavanone 293 in low yields. However, it was observed that the cyclization of 294 proceeded cleanly by refluxing with zinc chloride in 166c CH3CN for 36 hours (Scheme 96). The cyclization was presumed to proceed by intramolecular conjugate addition (Michael addition) of the amino group of 294 to the D,E- unsaturated carbonyl group activated by zinc chloride as an organozinc complex.

Cl H MeO NH2 Cl MeO N ZnCl2,CH3CN reflux, 68% OMe O OMe O

294 293 Scheme 96

Finally, the azaflavanone 293 was subjected to sodium borohydride reduction in ethanol to generate the required azaflavanol 295 in 78% yield (Scheme 97).

Cl Cl H H MeO N MeO N NaBH4,EtOH r.t., 78% OMe O OMe OH

293 295 Scheme 97

The cis stereochemistry of azaflavanol 295 was once again established on the basis of an NOE correlation between the protons, H2 and H4.

120 6.6. Synthesis of 5,7-dimethoxy-4-arylazaflavans Similar acid-catalyzed coupling reactions with suitable nucleophiles were carried out on 5,7- dimethoxyazaflavanol 295.

Cl Cl H H MeO N MeO N

MeO OH MeO OH MeO

OMe 296 297

Hence, treatment of 295 with 2-naphthol 99 and 3,5-dimethoxyphenol 266 in the presence of

BF3.OEt2 resulted in the generation of the azaflavans 296 and 297, in 32% and 41% yields respectively. The stereochemistry was found to be trans in both cases similar to our previous observations.

Cl Cl H H MeO N MeO N

MeO MeO O NH

298 299

Reactions were also attempted using heterocycles such as 2-phenylindole 280 and furan 277, which generated the corresponding heteroaryl azaflavans 298 and 299 in 46% and 33% yields respectively.

Cl Cl H MeO N MeO N

OMe OMe

300 301 121 Along with the formation of 2,4-disubstituted azaflavans, it was observed that the above acid- catalyzed reactions of azaflavanol 295 were found to produce 2-(4-chlorophenyl)-5,7- dimethoxyquinoline 300 and 2-(4-chlorophenyl)-5,7-dimethoxy-1,2,3,4-tetrahydroquinoline 301 as by-products, presumably of a disproportionation process.

6.7. Attempted synthesis of 1,2-dihydroquinoline It was envisaged that dehydration of the azaflavanol 262 would result in the formation of the corresponding azaflavene 302, a 1,2-dihydroquinoline. One of the aims of this part of the project was to synthesize an azaflavene and subject it to an acid-catalyzed dimerization reaction in order to observe and compare their dimerization reactions with those of flavenes.

However, when 262 was subjected to acid-catalyzed conditions (Scheme 98), it was interesting to observe the formation of 2-(4-chlorophenyl)quinoline 303 as the only product from the reaction mixture. In a few cases, the formation of the reduced analogue, 2-(4-chlorophenyl)- 1,2,3,4-tetrahydroquinoline 304 was also observed in trace amounts.

Cl Cl H N N dehydration 70% OH 303 262

Cl H dehydration N

Cl 304 H N

302 Scheme 98

Various conditions were tried, such as BF3.OEt2 in DCM at r.t., refluxing p-TSA in toluene,

P2O5 in DCM at r.t. and conc. HCl in MeOH at r.t. In all cases, there was no formation of 2-(4- chlorophenyl)-1,2-dihydroquinoline 302 as desired. This seemed to suggest that

122 dehydrogenation at the 1,2-position of the ring always took place during the process of the acid- catalyzed dehydration reaction leading to the fully aromatic system.

Another strategy that was attempted for the synthesis of the intermediate 1,2-dihydroquinoline was to subject the azaflavanone to reaction with a suitable Grignard reagent. Hence, treatment of 261 with phenylmagnesium bromide in THF under reflux conditions resulted in the formation of 2-(4-chlorophenyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-4-ol 305 as an intermediate (Scheme 99). The intermediate 305 was characterized by a multiplet at G 2.39 ppm corresponding to two H3 protons while the proton, H2 was identified as a doublet of doublets at G 4.17 (J = 5.4, 9.4 Hz).

Cl Cl H H N N PhMgBr, THF refux, 29% OH O 261

305

dehydration DCM, BF3.OEt2 r.t., 78%

Cl Cl H N N

306 307 Scheme 99

However, acid-catalyzed dehydration of 305 did not result in the formation of the desired 2-(4- chlorophenyl)-4-phenyl-1,2-dihydroquinoline 306 but was found to generate the highly stabilized 2-(4-chlorophenyl)-4-phenylquinoline 307 moiety (Scheme 99). The above observation can be attributed to the fact that a simultaneous dehydrogenation reaction was found to occur along with dehydration, to give the more stable quinoline derivative, similarly to the previous observation. This was evident from the 1H NMR spectrum of 307 that showed the 123 disappearance of the aliphatic protons in 305 indicating H2 and H3. The presence of the singlet at G 7.78 ppm in 307 correlating to H3 was the key resonance signal for the identification of the compound.

The above results were however found to be consistent with literature references,167 that state that 1,2-dihydroquinolines, unsubstituted at the nitrogen but having at least one hydrogen on carbon-2 are unstable. Thereby, they have the ability to be rapidly oxidized by air to the quinoline, or undergo disproportionation by trace acids to a mixture of the quinoline and the tetrahydroquinoline.

6.7.1. Attempted synthesis of 1,2-dihydroquinoline by reduction of quinoline Dihydroquinoline syntheses by ring closure strategies are not commonly found in the literature. Although several of the ring closure reactions leading to quinolines (e.g. Skraup synthesis, Combes synthesis, Doebner-Miller synthesis) do pass through dihydroquinoline intermediates, the development of a dihydroquinoline synthesis from these reactions has not been accomplished easily.168

Although difficulties have been encountered in the preparation of 1,2-dihydroquinolines, some of them have been prepared by the reduction of the corresponding quinoline.166b Since 2-(4- chlorophenyl)quinoline 303 was obtained in a favorably good yield, attempts were then made to reduce 303 to 2-(4-chlorophenyl)-1,2-dihydroquinoline 302 (Scheme 100).

Cl Cl H N reduction N

303 302 Scheme 100

169a The following conditions were investigated: NaBH4 in ethanol at r.t. and heating, LAH in 169b 169c ether at r.t., NaCNBH3 in MeOH, saturated with HCl, NaCNBH3, BF3.OEt2 in MeOH. However, no reaction was found to occur utilizing any of the above-mentioned conditions.

124 Cl Cl H N LAH, THF N reflux, 61%

303 304 Scheme 101

However, on refluxing 303 with LAH in THF for 10 hours, complete reduction gave 2-(4- chlorophenyl)-1,2,3,4-tetrahydroquinoline 304 in 61% yield (Scheme 101).

Therefore, the synthesis of the intermediate 2-(4-chlorophenyl)-1,2-dihydroquinoline 302 could not be accomplished by the methodologies used in this project.

6.8. Oxidation of 2,4-disubstituted azaflavans to quinolines 6.8.1. Introduction Quinoline derivatives represent the major class of heterocycles, and a number of preparations have been known since the late 1800s. The presence of quinoline scaffolds in the frameworks of various pharmacologically active compounds, as well as in various natural products, has spurred the development of many methodologies for their synthesis. Amongst their different applications, functionalized quinolines are widely used as anti-malarial, anti-inflammatory, anti- asthmatic, anti-bacterial and anti-hypertensive agents.

Chimanine alkaloids, simple 2,4-disubstituted quinolines such as 308, 309, 310 and 311 were isolated from the bark of Galipea longiflora trees of the Rutaceae family.170 They were found to be effective against the parasites of Leishmania species, which are the agents of leishmaniasis, a protozoan disease of the tropical areas in South America.

N O N N N O HN N OMe R OMe H 308 309 R=H 311 312 310 R=OMe

Similarly, 2-(2-methylquinolin-4-ylamino)-N-phenylacetamide 312 was more active than the standard anti-leishmanial drug, sodium antimony gluconate.171 125

The structural core of quinoline has generally been synthesized by various conventional named reactions such as Skraup,172a Doebner-von Miller,172b Pfitzinger,172c Conrad-Limpach172d and Combes synthesis.172b Recent developments in the chemistry of quinoline derivatives have demonstrated that new metal-catalyzed coupling cyclizations or acid-catalyzed cycloaddition of appropriate precursors could compete with classical synthesis in the efficacy and rapidity of the quinoline construction.

However, due to their importance as substructures in a broad range of natural and designed products, significant effort continues to be directed into the development of new quinoline-based structures as well as new methods for their construction.

6.8.2. Known synthetic methodologies for 2,4-disubstituted quinolines The Friedlander annulation using o-acylanilines and appropriate ketones has been reported to be the simple, straightforward and most widely used protocol for the synthesis of quinolines.173 However, various modifications to the above approach have indeed resulted in relatively selective and low-cost protocols for their synthesis.

NH2 N O CH In(OTf)3 solvent-free MW 314

313 315 Scheme 102

For example, the preparation of 2,4-diphenyl quinoline 315 (Scheme 102) has been developed by a simple alkynylation-cyclization reaction of 2-aminoaryl ketone 313 (serving as the electrophilic partner) with phenyl acetylene 314 in the presence of In(OTf)3 under microwave irradiation and solvent-free conditions.174 The above regioselective hydroamination of terminal alkynes with anilines was also undertaken using a ruthenium carbonyl catalyst such as 175 [Ru3(CO)12].

126 O N NH2 RuCl (dmso) O 2 4 48 h 316

313 315 Scheme 103

Martinez and his colleagues176 have also reported the solvent free indirect Friedlander synthesis of polysubstituted quinolines such as 315 (Scheme 103) catalyzed by the RuCl2(dmso)4 complex. In this strategy, different carbonyl compounds possessing acidic D-hydrogen atoms such as 316 were employed as source of the nucleophile. Later, they extended the scope of the reaction, reporting the synthesis of similar substrates without the use of transition metal catalysts, but employing bases such as t-BuOK as catalysts.177

Similarly, the Friedlander coupling condensation reactions between various acetophenone derivatives and appropriate 2-aminoacetophenone derivatives utilizing microwave assisted solvent free technology in the presence of acidic catalysts such as diphenylphosphate (DPP) also resulted in a library of 2,4-disubstituted quinoline derivatives.178

Scheme 104

The three-component reaction of aldehydes, amines and alkynes was also another important strategy leading to the synthesis of quinolines via the formation of the intermediate N-aryl-2- 179 179a 179b propynylamines. Metal complexes such as AuCl3/CuBr, RuCl3/CuBr and 179c AuCl3/AgOTf catalyzed this one-pot reaction. For example, the one-pot reaction of 314, 317 and 318 catalyzed by AuCl3/CuBr produced 319 in good yield (Scheme 104).

127

Scheme 105

An efficient and convenient nickel-catalyzed cyclization of 2-haloanilines 320 with alkynyl aryl ketones like 321 has also been reported for the synthesis of 315 (Scheme 105). The possible pathway is suggested to proceed via the formation of the o-aminochalcone, involving Meyer- Schuster rearrangement.180

N

N PhB(OH)2,K3PO4 Pd(OAc)2,TBAB EtOH, r.t. I 322 315 Scheme 106

Lastly, Arcadi et al. utilized the well-known palladium-catalyzed Suzuki-Miyaura cross- coupling reaction181 of 4-iodoquinoline 322 with phenylboronic acid at r.t. to produce 315 in good yield (Scheme 106).

6.8.3. Results and discussion Our strategy to the synthesis of 2,4-disubstituted quinolines was via the oxidation of the corresponding 2,4-disubstituted tetrahydroquinolines. The treatment of tetrahydroquinolines with suitable oxidants has been suggested for the production of the corresponding quinolines.158,159 Since the synthesis of 2,4-disubstituted tetrahydroquinolines involved a new strategy, i.e. via the acid-catalyzed reaction of azaflavanol with nucleophiles, this dehydrogenation of the saturated ring system of the synthesized 2,4-tetrahydroquinolines would pave way to the synthesis of novel 2,4-diaryl- and 2-aryl-4-heteroaryl quinolines. In general, dehydrogenation is typically achieved with a number of common reagents such as 2,3-dichloro- 128 5,6-dicyano-1,4-benzoquinone (DDQ), iodine, cerric ammonium nitrate (CAN), manganese triacetate (Mn(OAc)3), thallium salts , selenium dioxide (SeO2), or N-bromosuccinimide (NBS).

Hence, the 4-arylazaflavan 263 was treated with DDQ159 and refluxed in THF for 48 hours. TLC showed disappearance of the starting material. Unfortunately, the isolated product did not give the expected 2,4-diarylquinoline, but it resulted in the intermediate 1-(2-(4-chlorophenyl)-3,4- dihydroquinolin-4-yl)naphthalen-2-ol 323 in 70% yield, wherein a double bond was introduced between C2 and C3 (Scheme 107).

Cl Cl H N N

DDQ, THF OH reflux, 70% OH

263 323 Scheme 107

The formation of 323 was confirmed from the 1H NMR spectrum of the compound, in which a multiplet at G 2.36 correlated to two H3 protons and a triplet at G 4.82 (J = 2.8 Hz) correlated to H4. The disappearance of the proton corresponding to H2 gave evidence of the presence of unsaturation at that position.

The next reagent of choice for the complete oxidation of 263 was NBS.46 Hence, compound 263 was treated with NBS and refluxed in DMSO. However, a complex mixture of compounds was obtained from this reaction and isolation of each of the individual products for characterization was not possible.

The use of I2 as catalyst in glacial acetic acid in the presence of potassium acetate has been successful in the transformation of biflavanones to biflavones.46 An ideal example is the dehydrogenation of 3,4-dihydrocoumarin by iodine and KOAc in boiling acetic acid to generate the corresponding 4-phenylcoumarin.182

129 Hence, 263 was stirred at room temperature for 7 days in acetic acid, in the presence of I2 and potassium acetate, and complete oxidation was found to occur generating the desired oxidized product 324 in 24% yield (Scheme 108).

Cl Cl H N N I2,KOAc, glacial acetic acid H3

OH 24% OH

263 324 Scheme 108

The reaction was presumed to involve the iodination of 263 at C4 followed by dehydrohalogenation to yield the quinoline derivative 324. The disappearance of the aliphatic protons corresponding to H2, H3 and H4 in 263 along with the appearance of a singlet at G 7.95 ppm corresponding to H3 in 324 gave evidence of the product formed. In the 13C NMR spectrum, the aliphatic carbon C4 present at G 32.8 ppm in 263 shifted to G 148.5 ppm in 324 and was seen as an aromatic quaternary carbon.

Based on the above observations, compound 265 was used as the substrate, and reacted under similar conditions. It was also found to undergo successful oxidation to generate the oxidized product 325 in 19% yield (Scheme 109).

Cl Cl H N N

I2,KOAc, glacial acetic acid OH OH 19%

265 325 Scheme 109

130 In a similar fashion, the 4-arylazaflavan 267 was reacted with I2 in the presence of KOAc in acetic acid and was found to furnish the corresponding 2,4-diarylquinoline derivative 326 in 22% yield (Scheme 110).

Cl Cl H N N

I2,KOAc, MeO OH glacial acetic acid MeO OH 22%

OMe OMe 267 326 Scheme 110

Lastly, the 4-heteroarylazaflavan 278 was subjected to the same reaction conditions and was observed to undergo complete dehydrogenation as desired to yield the 2-aryl-4- heteroarylquinoline 327 in 20% yield (Scheme 111).

Cl Cl H N N I2,KOAc, glacial acetic acid 20% O O

278 327 Scheme 111

Therefore, 4-arylazaflavans and 4-heteroarylazaflavans were found to undergo oxidation successfully to give the corresponding 2,4-diarylquinolines, thus indicating a new strategy to the synthesis of these compounds.

6.9. Conclusion

BF3·OEt2 catalyzed reactions of azaflavan-4-ols with activated aryl, heteroaryl and thiophenyl compounds gave trans isomers of 4-arylazaflavans, 4-heteroarylazaflavans and 4- thiophenylazaflavans in a single step. However, acid-catalyzed dehydration of the azaflavanol was found to result in the formation of the highly stable quinoline nucleus, and did not yield the intermediate 1,2-dihydroquinoline. Attempts to dehydrogenate 2,4-disubstituted tetrahydroquinolines to the corresponding quinolines were successful with the use of iodine as 131 catalyst. Therefore, a new strategy to the synthesis of 2,4-disubstituted quinolines has been developed via the oxidation of the corresponding 2,4-disubstituted tetrahydroquinolines.

132

CHAPTER 7

EXPERIMENTAL

133 7.1. General Information All reactions requiring anhydrous conditions were performed under an argon atmosphere.

MeOH, EtOH and EtOAc were obtained from commercial sources. Light petroleum (hexane) was distilled and the fraction 60-80 °C was used for chromatography and recrystallization. Anhydrous THF was distilled from sodium metal and benzophenone under argon. Anhydrous

DCM was freshly distilled from calcium hydride under argon. Anhydrous CH3CN was freshly distilled from phosphorus pentoxide and stored over 4Å molecular sieves under argon.

Melting points were measured using a Mel-Temp melting point apparatus, and are uncorrected.

Microanalyses were performed on a Carlo Erba Elemental Analyzer EA 1108 at the Campbell Microanalytical Laboratory, University of Otago, New Zealand.

NMR spectra were recorded in the designated solvents on a Bruker Avance DPX300 (300 MHz) or a Bruker DMX600 (600 MHz) spectrometer at the designated frequency and were internally referenced to the solvent peaks. 1H NMR spectral data are reported as follows: chemical shift measured in parts per million (ppm) downfield from TMS (δ); multiplicity; observed coupling constant (J) in Hertz (Hz); proton count; assignment. Multiplicities are recorded as singlet (s), broad singlet (bs), doublet (d), triplet (t), quartet (q), quintet (p), multiplet (m), doublet of doublets (dd), doublet of triplets (dt) and combinations of these. 13C NMR chemical shifts are reported in ppm downfield from TMS (δ), and identifiable carbons are given. Acid-free deuterated chloroform was obtained by passing the solvent through a short column of anhydrous

K2CO3 prior to use.

Low-resolution mass spectrometric analysis was carried out at the Biomedical Mass Spectrometry Facility, UNSW, and the spectra were recorded on Q-TOF Ultima API (Micro mass). High-resolution mass spectra were performed at the Campbell Microanalytical Laboratory, University of Otago, New Zealand. High resolution mass is reported up to 4 decimal places and the low resolution mass is reported up to 2 decimal places.

Infrared spectra were recorded with a Thermo Nicolet 370 FTIR spectrometer. Ultraviolet- visible spectra were recorded using a Varian Cary 100 Scan spectrometer, and the absorption maxima together with the molar absorptivity (ε) are reported.

134 Gravity column chromatography was carried out using Grace Davison LC60A 40-63 micron silica gel. Suction column chromatography was carried out using Grace Davison LC60A 6-35 micron silica gel and this method involved the use of suction at the base of the column via a water aspirator or vacuum pressure line.

Reactions were monitored using thin layer chromatography, performed on Merck DC aluminium plates coated with silica gel GF254. Compounds were detected by short and long wavelength ultraviolet light, charring with vanillin or permanganate solutions and iodine vapour.

7.2. Experimental details General procedure 1 (for the preparation of chalcones) To a solution of the appropriate acetophenone (1.0 equiv) in EtOH (50 mL) was added the corresponding aldehyde (1.0 equiv). This was followed by slow addition of crushed NaOH pellets (2.5 equiv). The reaction mixture was stirred for 12 h at r.t., poured into ice (250 g) and acidified using conc. HCl to pH 3. The solid so obtained was filtered and air-dried. Recrystallization from EtOH afforded the desired chalcones as yellow/orange crystals.

In cases when the chalcones did not precipitate out on acidification, the aqueous layer was extracted with DCM (3 X 100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue so obtained was then recrystallized from EtOH.

General procedure 2 (for the preparation of flavenes) To a solution of the appropriate chalcone (1.0 equiv) in isopropanol (30 mL) at 50 qC was slowly added NaBH4 (3.0 equiv) in small portions over 15 minutes. The reaction mixture was cooled to r.t. and left to stir overnight. The solvent was evaporated partially, ice (50 g) was added and the resulting solution was acidified using 10% AcOH to pH 5. The solution was extracted with DCM (2 X 150 mL), and the organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. Purification of the residue by column chromatography over silica gel using DCM/light petroleum (20:80) afforded the desired flavene and further elution using DCM/light petroleum (40:60) gave the unreacted chalcone. The flavenes so obtained were either low melting white solids or yellow sticky oily residues. As the flavenes were found to be relatively unstable, they were immediately used in the subsequent step of dimerization. Otherwise, they were dissolved in MeOH and stored at room temperature to avoid decomposition. 135 General procedure 3 (for acid-catalyzed reactions) To a solution of the appropriate flavene in MeOH (20 mL) was added 10 drops of acid (10 M HCl, conc. TFA or glacial AcOH) and the solution was heated at 60-70 qC for 12 h. The solvent was partially removed under reduced pressure and EtOAc (25 mL) was added. The organic layer was washed with saturated NaHCO3 solution (20 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. Purification of the crude product by column chromatography over silica gel using DCM/light petroleum (30:70) eluted the open chain compound and further elution using DCM/light petroleum (50:50) gave the desired dimer. The dimers were recrystallized twice from absolute EtOH to yield analytically pure products.

General procedure 4 (for the preparation of flavones)

Anhydrous K2CO3 (5.0 equiv) was added to a stirred solution of the appropriate hydroxyacetophenone (1.0 equiv) in acetone (60 mL). The mixture was stirred at r.t. for 10 min and then the appropriate benzoyl chloride (2.0 equiv) was added dropwise and the mixture was stirred at r.t. for an additional 0.5 h. After refluxing for 24 h, the solvent was evaporated under reduced pressure. The residue was cooled to r.t. and acidified using 2M HCl to pH 3. The precipitate formed was filtered off and air-dried to give 3-aroylflavone as an intermediate, which was used in the subsequent step without any purification. The 3-aroylflavone was added to 5% ethanolic KOH (75 mL) at r.t., and the mixture was stirred and heated to reflux for 3 h. After cooling to r.t., the mixture was diluted with ice cold water and acidified using conc. HCl to pH 4. The precipitated product was filtered, washed with water and dried. The crude product was purified by flash chromatography over silica gel using EtOAc/light petroleum (60:40) to afford the desired flavone.

General procedure 5 (for the preparation of Mannich products) Formaldehyde (12.0 equiv) was added to EtOH (10 mL) followed by the addition of the appropriate primary amine or amino acid or aminal (2.0 equiv) and the mixture was refluxed for 1 h to generate the intermediate iminium ions. To the reaction mixture was added the appropriate flavone (1.0 equiv) and the mixture was refluxed further for an additional 48 h.

The benzoxazines usually precipitated cleanly from the reaction mixture and hence collected by filtration and dried. In cases when they did not immediately precipitate, the reaction mixture was cooled in an ice bath to facilitate precipitation of the product.

136 The simple Mannich bases precipitated from the reaction mixture; hence they were filtered and washed thoroughly with hot water to remove the unreacted amino acid and air-dried.

2c-Hydroxy-4c-methoxyacetophenone (66)

To a solution of 2c,4c-dihydroxyacetophenone 65 (5.0 g, 32.86 mmol) in MeO OH acetone (75 mL), was added K2CO3 (9.1 g, 65.72 mmol). The reaction mixture was cooled to 0 qC and MeI (2.1 mL, 32.86 mmol) was slowly. O The reaction mixture was then refluxed for 24 h. The solvent was evaporated, and the residue was acidified using 2M HCl to pH 3. The mixture was extracted with EtOAc (3 X 100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was recrystallized from EtOAc/light petroleum (2:8) to afford the title compound as off- 183 1 white crystals (5.0 g, 92%). M.p. 53-55 °C, lit. 52-54 °C; H NMR (300 MHz, CDCl3): G 2.52

(s, 3H, CH3CO), 3.81 (s, 3H, CH3O), 6.39 (d, J = 2.3 Hz, 1H, H3c), 6.41 (dd, J = 2.3, 8.7 Hz, 13 1H, H5c), 7.60 (d, J = 8.7 Hz, 1H, H6c), 12.72 (s, 1H, 2c OH); C NMR (75.6 MHz, CDCl3): G

26.1 (CH3CO), 55.4 (CH3O), 100.7 (C3c), 107.5 (C5c), 113.8 (C1c), 132.2 (C6c), 165.1 (C2c), 166.0 (C4c), 202.5 (CO).

2c-Hydroxy-4c-methoxychalcone (68a) The title compound was synthesized following general procedure 1 using 2c-hydroxy-4c-methoxyacetophenone 66 (2.5 g, 15.04 mmol), benzaldehyde 67a (1.5 mL, 15.04 mmol) and NaOH pellets (1.5 g, 37.61 mmol). The chalcone was obtained as yellow crystals (2.8 g, 72%). M.p. 107-108 °C, lit.184 104-105 °C; 1H NMR (300 MHz,

CDCl3): G 3.86 (s, 3H, CH3O), 6.49 (d, J = 3.4 Hz, 1H, H3c), 6.52 (dd, J = 3.4, 9.8 Hz, 1H, H5c),

7.41-7.44 (m, 3H, H3, H4, H5), 7.58 (d, J = 15.8 Hz, 1H, HD), 7.63-7.67 (m, 2H, H2, H6), 7.83 13 (d, J = 9.8 Hz, 1H, H6c), 7.89 (d, J = 15.8 Hz, 1H, HE), 13.41 (s, 1H, 2c OH); C NMR (75.6

MHz, CDCl3): G 55.5 (CH3O), 101.0 (C3c), 107.7 (C5c), 114.0 (C1c), 120.3 (CD), 128.4 (C2, C6),

128.9 (C3, C5), 130.6 (C4), 131.2 (C6c), 134.7 (C1), 144.3 (CE), 166.2 (C2c), 166.6 (C4c), 191.8 (CO).

137 4-Bromo-2c-hydroxy-4c-methoxychalcone (68b) The title compound was synthesized following general procedure 1 using 2c-hydroxy-4c-methoxyacetophenone 66 (2.5 g, 15.04 mmol), 4-bromobenzaldehyde 67b (2.8 g, 15.04 mmol) and NaOH pellets (1.5 g, 37.62 mmol). The chalcone was obtained as yellow crystals (3.3 g, 65%). M.p. 138-140 °C, lit.185 138-140 °C; UV -1 -1 (MeOH): Omax 204 (H 33160 cm M ), 229 (16027), 324 (26253) nm; IR (KBr): Qmax 3006, 2962, 2840, 2661, 1637, 1578, 1504, 1485, 1443, 1362, 1273, 1219, 1127, 1017, 959, 835, 791, 762, -1 1 611 cm ; H NMR (300 MHz, CDCl3): G 3.86 (s, 3H, CH3O), 6.41 (d, J = 3.3 Hz, 1H, H3c), 6.46

(dd, J = 3.3, 9.0 Hz, 1H, H5c), 7.47 (d, J = 8.3 Hz, 2H, H3, H5), 7.50 (d, J = 15.4 Hz, 1H, HD),

7.56 (d, J = 8.3 Hz, 2H, H2, H6), 7.80 (d, J = 9.0 Hz, 1H, H6c), 7.82 (d, J = 15.4 Hz, 1H, HE), 13 13.35 (s, 1H, 2c OH); C NMR (75.6 MHz, CDCl3): G 55.5 (CH3O), 101.0 (C3c), 107.8 (C5c),

113.9 (C1c), 120.8 (CD), 124.9 (C4), 129.8 (C2, C6), 131.1 (C6c), 132.2 (C3, C5), 133.6 (C1),

142.8 (CE), 166.3 (C2c), 166.7 (C4c), 191.4 (CO).

4-Chloro-2c-hydroxy-4c-methoxychalcone (68c) The title compound was synthesized following general procedure 1 using 2c-hydroxy-4c-methoxyacetophenone 66 (2.5 g, 15.04 mmol), 4-chlorobenzaldehyde 67c (2.1 g, 15.04 mmol) and NaOH pellets (1.5 g, 37.61 mmol). The chalcone was obtained as yellow crystals (3.2 g, 73%). M.p. 100-102 °C, lit.186 109-110 °C; UV -1 -1 1 (MeOH): Omax 204 (H 42292 cm M ), 227 (25085), 319 (35600) nm; H NMR (300 MHz,

CDCl3): G 3.86 (s, 3H, CH3O), 6.48 (d, J = 1.5 Hz, 1H, H3c), 6.49 (dd, J = 1.5, 8.6 Hz, 1H, H5c), 7.40 (d, J = 8.3 Hz, 2H, H3, H5), 7.58 (d, J = 8.3 Hz, 2H, H2, H6), 7.60 (d, J = 15.5 Hz, 1H, 13 HD), 7.82 (d, J = 15.5 Hz, 1H, HE), 7.84 (d, J = 8.6 Hz, 1H, H6c), 13.36 (s, 1H, 2c OH); C NMR

(75.6 MHz, CDCl3): G 55.5 (CH3O), 101.0 (C3c), 107.8 (C5c), 113.9 (C1c), 120.7 (CD), 124.8

(C1), 129.8 (C3, C5), 131.1 (C6c), 132.1 (C2, C6), 133.6 (C4), 142.8 (CE), 166.3 (C2c), 166.7 (C4c), 191.4 (CO).

2c-Hydroxy-4,4c-dimethoxychalcone (68d) The title compound was synthesized following general procedure 1 using 2c-hydroxy-4c-methoxyacetophenone 66 (2.5 g, 15.04 mmol), 4-methoxybenzaldehyde 67d (1.8 mL, 15.04 mmol) and NaOH pellets (1.5 g, 37.61 mmol). The chalcone was obtained as 138 187 1 yellow crystals (3.0 g, 71%). M.p. 114-116 °C, lit. 116-118 °C; H NMR (300 MHz, CDCl3):

G 3.79 (s, 3H, CH3O), 3.84 (s, 3H, CH3O), 6.38 (d, J = 1.5 Hz, 1H, H3c), 6.39 (dd, J = 1.5, 8.7 Hz, 1H, H5c), 6.96 (d, J = 8.6 Hz, 2H, H3, H5), 7.58 (d, J = 8.6 Hz, 2H, H2, H6), 7.67 (d, J =

15.4 Hz, 1H, HD), 7.79 (d, J = 8.7 Hz, 1H, H6c), 7.92 (d, J = 15.4 Hz, 1H, HE), 12.71 (s, 1H, 2c 13 OH); C NMR (75.6 MHz, CDCl3): G 55.4 (CH3O), 55.5 (CH3O), 100.8 (C3c), 107.4 (C5c),

114.2 (C1c), 114.4 (C3, C5), 119.5 (CD), 129.8 (C1), 131.8 (C2, C6), 132.2 (C6c), 144.2 (CE), 164.5 (C4), 165.1 (C2c), 166.0 (C4c), 190.7 (CO).

7-Methoxyflav-3-ene (73a) The compound was prepared as described in general procedure 2 using 2c-hydroxy-4c-methoxychalcone 68a (1.0 g, 3.93 mmol) and

NaBH4 (0.45 g, 11.80 mmol). The flavene was obtained as a 188 1 white solid (0.54 g, 58%). M.p. 103-105 °C, lit. 102-103 °C; H NMR (300 MHz, CDCl3): G

3.76 (s, 3H, CH3O), 5.67 (dd, J = 3.4, 9.8 Hz, 1H, H3), 5.89 (dd, J = 1.5, 3.4 Hz, 1H, H2), 6.40 (d, J = 2.3 Hz, 1H, H8), 6.45 (dd, J = 2.3, 8.3 Hz, 1H, H6), 6.50 (dd, J = 1.5, 9.8 Hz, 1H, H4), 6.93 (d, J = 8.3 Hz, 1H, H5), 7.32-7.50 (m, 5H, H2c, H3c, H4c, H5c, H6c); 13C NMR (75.6 MHz,

CDCl3): G 55.2 (CH3O), 77.2 (C2), 101.7 (C8), 107.0 (C6), 114.6 (C4a), 121.8 (C4), 123.6 (C3), 127.0 (C2c, C6c), 127.2 (C5), 128.3 (C4c), 128.6 (C3c, C5c), 140.9 (C1c), 154.3 (C8a), 160.9 (C7).

4c-Bromo-7-methoxyflav-3-ene (73b) The compound was prepared as described in general procedure 2 using 4-bromo-2c-hydroxy-4c-methoxychalcone

68b (1.0 g, 3.0 mmol) and NaBH4 (0.34 g, 9.0 mmol). The flavene was obtained as a yellow sticky residue (0.50 g, -1 -1 53%). UV (MeOH): Omax 202 (H 46842 cm M ), 230 (50861), 306 (11829) nm; IR (KBr): Qmax 3448, 3022, 2975, 2934, 2843, 1614, 1503, 1444, 1308, 1275, 1198, 1154, 1110, 1026, 968, 812, -1 1 708 cm ; H NMR (300 MHz, CDCl3): G 3.75 (s, 3H, CH3O), 5.61 (dd, J = 3.4, 9.8 Hz, 1H, H3), 5.83 (dd, J = 1.5, 3.4 Hz, 1H, H2), 6.37 (d, J = 2.3 Hz, 1H, H8), 6.43 (dd, J = 2.3, 8.3 Hz, 1H, H6), 6.50 (dd, J = 1.5, 9.8 Hz, 1H, H4), 6.92 (d, J = 8.3 Hz, 1H, H5), 7.32 (d, J = 8.7 Hz, 2H, 13 H2c, H6c), 7.49 (d, J = 8.7 Hz, 2H, H3c, H5c); C NMR (75.6 MHz, CDCl3): G 55.2 (CH3O), 76.4 (C2), 101.8 (C8), 107.1 (C6), 114.4 (C4a), 121.3 (C4), 122.3 (C4c), 124.0 (C3), 127.3 (C5), 128.7 (C2c, C6c), 131.7 (C3c, C5c), 139.8 (C1c), 154.0 (C8a), 160.9 (C7); (TOF-ESI) m/z Calcd.

139 + 79 79 for C16H13BrO2Na (M + Na) 339.00 (Br ). Found 339.04 (Br ); Anal. Calcd. for C16H13BrO2: C, 60.59; H, 4.13. Found: C, 60.87; H, 4.35.

4c-Chloro-7-methoxyflav-3-ene (73c) The compound was prepared as described in general procedure 2 using 4-chloro-2c-hydroxy-4c-methoxychalcone

68c (1.0 g, 3.46 mmol) and NaBH4 (0.39 g, 10.39 mmol). The flavene was obtained as a white solid (0.47 g, 50%). M.p. 76- -1 -1 78 °C; UV (MeOH): Omax 203 (H 26199 cm M ), 230 (27838), 306 (6703) nm; IR (KBr): Qmax 3442, 3022, 2978, 2933, 2842, 1614, 1503, 1444, 1313, 1275, 1252, 1198, 1154, 1110, 1026, -1 1 969, 812, 705 cm ; H NMR (300 MHz, CDCl3): G 3.75 (s, 3H, CH3O), 5.63 (dd, J = 3.8, 9.8 Hz, 1H, H3), 5.85 (dd, J = 1.9, 3.8 Hz, 1H, H2), 6.37 (d, J = 2.3 Hz, 1H, H8), 6.43 (dd, J = 2.3, 8.3 Hz, 1H, H6), 6.51 (dd, J = 1.9, 9.8 Hz, 1H, H4), 6.92 (d, J = 8.3 Hz, 1H, H5), 7.31-7.39 (m, 13 4H, H2c, H3c, H5c, H6c); C NMR (75.6 MHz, CDCl3): G 55.2 (CH3O), 76.3 (C2), 101.8 (C8), 107.1 (C6), 114.4 (C4a), 121.1 (C4), 124.0 (C3), 127.3 (C5), 128.4 (C2c, C6c), 128.7 (C3c, C5c),

134.1 (C4c), 139.3 (C1c), 154.0 (C8a), 160.9 (C7); MS (TOF-ESI) m/z Calcd. for C16H13ClO2 (M + + 1) 273.07. Found 273.08; Anal. Calcd. for C16H13ClO2.1/10H2O: C, 70.00; H, 4.85. Found: C, 70.09; H, 4.47.

4c,7-Dimethoxyflav-3-ene (73d) The compound was prepared as described in general procedure 2 using 2c-hydroxy-4,4c-dimethoxychalcone 68d

(1.0 g, 3.52 mmol) and NaBH4 (0.40 g, 10.55 mmol). The flavene was obtained as a white solid (0.51 g, 54%). M.p. 189 1 79-81 °C, lit. 81-82 °C; H NMR (300 MHz, CDCl3): G 3.74 (s, 3H, CH3O), 3.80 (s, 3H,

CH3O), 5.65 (dd, J = 3.4, 9.8 Hz, 1H, H3), 5.83 (dd, J = 1.9, 3.4 Hz, 1H, H2), 6.36 (d, J = 2.3 Hz, 1H, H8), 6.42 (dd, J = 2.3, 8.3 Hz, 1H, H6), 6.50 (dd, J = 1.9, 9.8 Hz, 1H, H4), 6.89 (d, J = 8.3 Hz, 1H, H5), 6.92 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.38 (d, J = 8.7 Hz, 2H, H2c, H6c); 13C NMR

(75.6 MHz, CDCl3): G 55.2 (2 X CH3O), 76.9 (C2), 101.8 (C8), 106.9 (C6), 113.9 (C3c, C5c), 114.6 (C4a), 121.8 (C4), 123.6 (C3), 127.1 (C5), 128.6 (C2c, C6c), 132.9 (C1c), 154.3 (C8a), 159.7 (C4c), 160.8 (C7).

140 6a,12a-Dihydro-3,10-dimethoxy-6-phenyl-7-[(1E)-2-(phenylethenyl)]-6H,7H- [1]benzopyrano[4,3-b][1]benzopyran (74a) The title compound was synthesized following general procedure 3 using 7-methoxyflavene 73a (0.1 g, 0.42 mmol) and was obtained as a white solid (130 mg, 65%). -1 - M.p. 110-112 °C; UV (MeOH): Omax 207 (H 39892 cm M 1 ), 285 (3618) nm; IR (KBr): Qmax 3421, 3026, 2954, 2910, 2834, 1610, 1587, 1504, 1443, 1268, 1198, 1160, 1130, 1112, 1033, 1010, 958, 834 cm-1; 1H NMR (300 MHz,

CDCl3): G 2.50 (ddd, J = 2.1, 2.3, 10.6 Hz, 1H, H6a), 3.17 (dd, J = 2.1, 6.4 Hz, 1H, H7), 3.78 and 3.79 (2s, 6H, 2 X CH3O), 5.04 (d, J = 10.6 Hz, 1H, H6), 5.08 (d, J = 2.3 Hz, 1H, H12a),

6.04 (d, J = 15.8 Hz, 1H, HE), 6.24 (dd, J = 6.4, 15.8 Hz, 1H, HD), 6.50-6.52 (m, 3H, H4, H9, H11), 6.59 (dd, J = 2.3, 8.3 Hz, 1H, H2), 6.85 (d, J = 9.0 Hz, 1H, H8), 7.30-7.42 (m, 11H, H1, 13 H2c, H3c, H4c, H5c, H6c, H2cc, H3cc, H4cc, H5cc, H6cc); C NMR (75.6 MHz, CDCl3): G 37.9 (C7),

41.4 (C6a), 55.2 (CH3O), 55.3 (CH3O), 67.1 (C12a), 76.8 (C6), 101.2 (C4), 101.8 (C11), 108.1 (C9), 108.3 (C2), 112.1 (C7a), 113.5 (C12b), 126.1 (C4c), 127.3 (C4cc), 127.4 (C2c, C6c), 127.4

(C2cc, C6cc), 128.0 (CE), 128.4 (C3cc, C5cc), 128.7 (C3c, C5c), 131.0 (C1), 131.8 (C8), 133.2 (CD), 136.7 (C1cc), 138.6 (C1c), 153.5 (C4a), 155.7 (C11a), 159.8 (C10), 161.5 (C3); HRMS (ESI) m/z + Calcd. for C32H28O4Na (M + Na) 499.1888. Found 499.1847; Anal. Calcd. for C32H28O4.MeOH: C, 77.93; H, 6.34. Found: C, 77.77; H, 6.22.

6a,12a-Dihydro-3,10-dimethoxy-6-(4c-bromophenyl)-7-[(1E)-2-(4cc-bromophenylethenyl)]- 6H,7H-[1]benzopyrano[4,3-b][1]benzopyran (74b) The title compound was synthesized following general procedure 3 using 4c-bromo-7-methoxyflavene 73b (0.1 g, 0.32 mmol) and was obtained as a white solid (142 mg,

71%). M.p. 128-130 °C; UV (MeOH): Omax 206 (H 84733 -1 -1 cm M ), 267 (29112) nm; IR (KBr): Qmax 3431, 3018, 2953, 2911, 2833, 1610, 1587, 1504, 1443, 1267, 1197, 1160, 1130, 1112, 1034, 1009, 965, 826, 807 cm-1; 1H

NMR (300 MHz, CDCl3): G 2.43 (ddd, J = 2.1, 2.3, 10.9

Hz, 1H, H6a), 3.13 (dd, J = 2.1, 6.4 Hz, 1H, H7), 3.78 and 3.79 (2s, 6H, 2 X CH3O), 5.03 (d, J =

10.9 Hz, 1H, H6), 5.05 (d, J = 2.3 Hz, 1H, H12a), 5.99 (d, J = 15.8 Hz, 1H, HE), 6.22 (dd, J =

6.4, 15.8 Hz, 1H, HD), 6.52 (dd, J = 2.3, 8.3 Hz, 1H, H9), 6.55 (d, J = 2.3 Hz, 2H, H4, H11), 141 6.61 (dd, J = 2.3, 8.3 Hz, 1H, H2), 6.84 (d, J = 8.3 Hz, 1H, H8), 7.12 (d, J = 8.6 Hz, 2H, H2c, H6c), 7.21 (d, J = 8.3 Hz, 2H, H3cc, H5cc), 7.32 (d, J = 8.3 Hz, 1H, H1), 7.38 (d, J = 8.3 Hz, 2H,

13 H2cc, H6cc), 7.55 (d, J = 8.6 Hz, 2H, H3c, H5c); C NMR (75.6 MHz, CDCl3): G 38.0 (C7), 41.3

(C6a), 55.2 and 55.3 (2 X CH3O), 66.9 (C12a), 75.9 (C6), 101.2 (C4), 101.4 (C11), 108.2 (C9), 108.5 (C2), 111.5 (C7a), 113.4 (C12b), 121.2 (C4c), 122.7 (C4cc), 127.7 (C2cc, C6cc), 129.0 (C2c,

C6c), 130.8 (CE), 130.9 (C8), 131.2 (C1), 131.5 (C3c, C5c), 131.9 (C3cc, C5cc), 133.8 (CD), 135.5 (C1cc), 137.6 (C1c), 153.4 (C4a), 155.4 (C11a), 160.0 (C10), 161.6 (C3); MS (TOF-ESI) m/z + 79 79 Calcd. for C32H26Br2O4 (M + 1) 633.03 (Br ). Found 632.98 (Br ); Anal. Calcd. for

C32H26Br2O4: C, 60.59; H, 4.13. Found: C, 60.37; H, 4.16.

6a,12a-Dihydro-3,10-dimethoxy-6-(4c-chlorophenyl)-7-[(1E)-2-(4cc-chlorophenylethenyl)]- 6H,7H-[1]benzopyrano[4,3-b][1]benzopyran (74c) The title compound was synthesized following general procedure 3 using 4c-chloro-7-methoxyflavene 73c (0.1 g, 0.37 mmol) and was obtained as a white solid (138 mg,

69%). M.p. 131-133 °C; UV (MeOH): Omax 206 (H 44459 -1 -1 cm M ), 261 (10880) nm; IR (KBr): Qmax 3454, 3021, 2958, 2910, 2835, 1610, 1587, 1504, 1443, 1267, 1198, 1160, 1130, 1111, 1034, 1013, 959, 836, 803 cm-1; 1H

NMR (300 MHz, CDCl3): G 2.43 (ddd, J = 2.1, 2.3, 10.6

Hz, 1H, H6a), 3.12 (dd, J = 2.1, 6.4 Hz, 1H, H7), 3.76 and 3.78 (2s, 6H, 2 X CH3O), 5.03 (d, J =

10.6 Hz, 1H, H6), 5.06 (d, J = 2.3 Hz, 1H, H12a), 6.00 (d, J = 15.8 Hz, 1H, HE), 6.20 (dd, J =

6.4, 15.8 Hz, 1H, HD), 6.49-6.54 (m, 3H, H4, H9, H11), 6.60 (dd, J = 2.3, 8.3 Hz, 1H, H2), 6.83 (d, J = 8.3 Hz, 1H, H8), 7.19 (d, J = 8.3 Hz, 2H, H2c, H6c), 7.26 (d, J = 8.3 Hz, 2H, H3c, H5c), 7.30 (d, J = 8.3 Hz, 1H, H1), 7.32 (d, J = 8.6 Hz, 2H, H3cc, H5cc), 7.40 (d, J = 8.6 Hz, 2H, H2cc,

13 H6cc); C NMR (75.6 MHz, CDCl3): G 37.9 (C7), 41.4 (C6a), 55.2 and 55.3 (2 X CH3O), 66.9 (C12a), 76.1 (C6), 101.2 (C11), 101.3 (C4), 108.2 (C9), 108.5 (C2), 111.5 (C7a), 113.4 (C12b),

127.4 (C3c, C5c), 128.5 (C2c, C6c), 128.6 (C3cc, C5cc), 128.9 (CE), 130.9 (C2cc, C6cc), 131.1 (C4c),

133.0 (C4cc), 133.7 (C1), 133.9 (CD), 134.5 (C8), 135.1 (C1cc), 137.1 (C1c), 153.4 (C4a), 155.5 + (C11a), 160.0 (C3), 161.6 (C10); HRMS (ESI) m/z Calcd. for C32H26Cl2O4Na (M + Na)

567.1108. Found 567.1090; Anal. Calcd. for C32H26Cl2O4.1/4MeOH: C, 69.99; H, 4.92. Found: C, 70.26; H, 5.22.

142 6a,12a-Dihydro-3,10-dimethoxy-6-(4c-methoxyphenyl)-7-[(1E)-2-(4cc- methoxyphenylethenyl)]-6H,7H-[1]benzopyrano[4,3-b][1]benzopyran (74d) The title compound was synthesized following general procedure 3 using 4c,7-dimethoxyflavene 73d (0.1 g, 0.37 mmol) and was obtained as a white solid (132 mg, 66%). -1 - M.p. 113-115 °C; UV (MeOH): Omax 204 (H 137728 cm M 1 ), 272 (29148) nm; IR (KBr): Qmax 3454, 3010, 2928, 2919, 2843, 1608, 1594, 1511, 1469, 1443, 1410, 1250, 1178, -1 1 1088, 1033, 834, 777 cm ; H NMR (300 MHz, CDCl3): G 2.48 (ddd, J = 2.1, 2.3, 10.9 Hz, 1H, H6a), 3.15 (dd, J = 2.1,

6.0 Hz, 1H, H7), 3.78 (s, 6H, 2 X CH3O), 3.85 (s, 6H, 2 X CH3O), 5.01 (d, J = 10.9 Hz, 1H,

H6), 5.09 (d, J = 2.3 Hz, 1H, H12a), 5.99 (d, J = 15.8 Hz, 1H, HE), 6.11 (dd, J = 6.0, 15.8 Hz,

1H, HD), 6.49-6.53 (m, 3H, H4, H9, H11), 6.59 (dd, J = 2.3, 8.3 Hz, 1H, H2), 6.79-6.86 (m, 3H, H8, H3c, H5c), 6.95 (d, J = 8.7 Hz, 2H, H3cc, H5cc), 7.21 (d, J = 8.6 Hz, 2H, H2c, H6c), 7.26 (d, J

13 = 8.7 Hz, 2H, H2cc, H6cc), 7.32 (d, J = 8.3 Hz, 1H, H1); C NMR (75.6 MHz, CDCl3): G 37.9

(C7), 41.5 (C6a), 55.2 (2 X CH3O), 55.3 (2 X CH3O), 67.2 (C12a), 76.5 (C6), 101.1 (C4), 101.2 (C11), 108.0 (C9), 108.2 (C2), 112.3 (C7a), 113.6 (C12b), 113.8 (C3c, C5c), 114.1 (C3cc, C5cc),

127.3 (C2c, C6c), 128.6 (CE), 128.7 (C2cc, C6cc), 129.5 (C1cc), 130.6 (C1c), 131.1 (C1), 131.2

(C8), 133.0 (CD), 153.5 (C4a), 155.8 (C11a), 159.0 (C4c), 159.5 (C4cc), 159.7 (C10), 159.8 (C3); + MS (TOF-ESI) m/z Calcd. for C34H32O6 (M + 1) 537.23. Found 537.22; Anal. Calcd. for

C34H32O6: C, 76.10; H, 6.01. Found: C, 76.26; H, 6.29.

1,2,3,5-Tetramethoxybenzene (79) To a solution of 3,4,5-trimethoxyphenol 80 (5.0 g, 27.1 mmol) in acetone

(75 mL) was added anhydrous K2CO3 (7.5 g, 54.3 mmol). The reaction mixture was cooled to 0 qC and MeI (1.7 mL, 27.1 mmol) was slowly added to it. The reaction mixture was refluxed for 24 h. The solvent was removed under reduced pressure, and the residue was acidified using 2M HCl to pH 3. The mixture was extracted with EtOAc (3 × 100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was recrystallized from EtOAc/light petroleum (2:8) to afford the title compound as off-white crystals (5.1 g, 95%). 190 1 M.p. 46-47 qC, lit. 47 qC; H NMR (300 MHz, CDCl3): G 3.78, 3.79, 3.81 and 3.84 (4s, 12H, 4 13 X CH3O), 6.03 (2s, 2H, H4, H6); C NMR (75.6 MHz, CDCl3): G 55.5, 55.8, 56.0 and 60.9 (4 X

CH3O), 91.7 (C4), 92.9 (C6), 131.3 (C2), 152.8 (C1), 153.5 (C3), 156.3 (C5). 143 2c-Hydroxy-3c,4c,6c-trimethoxyacetophenone (81) A solution of 1,2,3,5-tetramethoxybenzene 79 (5.0 g, 25.23 mmol) in dry ether (30 mL) was cooled to 0 qC in an atmosphere of argon. Aluminium chloride (5.0 g, 37.9 mmol) was added in small portions followed by the dropwise addition of acetyl chloride (4.5 mL, 63.1 mmol). The reaction mixture was maintained at 0 qC for 3 h and stirred at r.t. overnight. The reaction was quenched by crushed ice (150 g) and the slow addition of 10M HCl (20 mL). The precipitated solid was filtered and air-dried. The crude product was chromatographed over silica gel using DCM/light petroleum (60:40) as eluent to yield the title compound as yellow-green crystals (3.3 g, 58%). 191 1 M.p. 104-106 qC, lit. 103-105 qC; H NMR (300 MHz, CDCl3): G 2.59 (s, 3H, CH3CO), 3.79, 13 3.87 and 3.91 (3s, 9H, 3 X CH3O), 5.95 (s, 1H, H5c), 13.77 (s, 1H, 2c OH); C NMR (75.6

MHz, CDCl3): G 33.0 (CH3CO), 55.5, 55.9 and 60.6 (3 X CH3O), 86.4 (C5c), 106.2 (C1c), 130.4 (C3c), 158.3 (C6c), 158.7 (C2c), 158.9 (C4c), 203.6 (CO).

4-Bromo-2c-hydroxy-3c,4c,6c-trimethoxychalcone (78a) The title compound was synthesized following general procedure 1 using 2c-hydroxy-3c,4c,6c- trimethoxyacetophenone 81 (2.5 g, 11.05 mmol), 4- bromobenzaldehyde 67b (2.0 g, 11.05 mmol) and NaOH pellets (1.1 g, 27.64 mmol). The chalcone was obtained as orange crystals (2.7 g, 61%). M.p. -1 -1 154-156 °C; UV (MeOH): Omax 204 (H 31027 cm M ), 217 (23632), 236 (14439), 344 (28457) nm; IR (KBr): Qmax 2969, 2932, 2859, 2849, 1634, 1558, 1487, 1435, 1420, 1331, 1210, 1126, -1 1 1010, 978, 815, 770 cm ; H NMR (300 MHz, CDCl3): G 3.83, 3.94 and 3.95 (3s, 9H, 3 X

CH3O), 6.00 (s, 1H, H5c), 7.36 (d, J = 8.3 Hz, 2H, H3, H5), 7.51 (d, J = 8.3 Hz, 2H, H2, H6), 13 7.70 (d, J = 15.8 Hz, 1H, HD), 7.82 (d, J = 15.8 Hz, 1H, HE), 13.83 (s, 1H, 2c OH); C NMR

(75.6 MHz, CDCl3): G 55.9, 56.0 and 60.7 (3 X CH3O), 87.0 (C5c), 106.7 (C1c), 127.8 (CD),

129.1 (C2, C6), 129.4 (C3, C5), 130.8 (C4), 133.9 (C3c), 135.9 (C1), 140.9 (CE), 158.5 (C2c), + 158.7 (C6c), 159.3 (C4c), 192.9 (CO); HRMS (ESI) m/z Calcd. for C18H17BrO5 (M + 1) 393.0339 (Br79). Found 393.0295 (Br79).

144 4-Chloro-2c-hydroxy-3c,4c,6c-trimethoxychalcone (78b) The title compound was synthesized following general procedure 1 using 2c-hydroxy-3c,4c,6c- trimethoxyacetophenone 81 (2.5 g, 11.05 mmol), 4- chlorobenzaldehyde 67c (1.6 g, 11.05 mmol) and NaOH pellets (1.1 g, 27.64 mmol). The chalcone was obtained as yellow crystals (2.5 g, 64%). M.p. -1 -1 153-155 °C; UV (MeOH): Omax 204 (H 40958 cm M ), 218 (32657), 236 (20420), 344 (38650) nm; IR (KBr): Qmax 2978, 2932, 2861, 2849, 1635, 1560, 1470, 1429, 1420, 1333, 1210, 1127, -1 1 1015, 979, 818, 770 cm ; H NMR (300 MHz, CDCl3): G 3.83, 3.93 and 3.94 (3s, 9H, 3 X

CH3O), 6.00 (s, 1H, H5c), 7.44 (d, J = 8.7 Hz, 2H, H3, H5), 7.52 (d, J = 8.7 Hz, 2H, H2, H6), 13 7.68 (d, J = 15.8 Hz, 1H, HD), 7.83 (d, J = 15.8 Hz, 1H, HE), 13.83 (s, 1H, 2c OH); C NMR

(75.6 MHz, CDCl3): G 55.9, 56.0 and 60.7 (3 X CH3O), 87.0 (C5c), 106.7 (C1c), 124.2 (C3c),

128.0 (CD), 129.6 (C3, C5), 130.8 (C1), 132.0 (C2, C6), 134.3 (C4), 141.0 (CE), 158.5 (C2c), 159.2 (C6c), 159.5 (C4c), 192.9 (CO).

2c-Hydroxy-3c,4,4c,6c-tetramethoxychalcone (78c) The title compound was synthesized following general procedure 1 using 2c-hydroxy-3c,4c,6c- trimethoxyacetophenone 81 (2.5 g, 11.05 mmol), 4- methoxybenzaldehyde 67d (1.3 mL, 11.05 mmol) and NaOH pellets (1.1 g, 27.64 mmol). The chalcone was obtained as yellow crystals (2.8 g, 74%). 192 1 M.p. 136-138 °C, lit. 138-140 °C; H NMR (300 MHz, CDCl3): G 3.83, 3.84 and 3.93 (3s,

12H, 4 X CH3O), 5.99 (s, 1H, H5c), 6.91 (d, J = 8.6 Hz, 2H, H3, H5), 7.54 (d, J = 8.6 Hz, 2H, 13 H2, H6), 7.79 (d, J = 15.8 Hz, 2H, HD, HE), 14.03 (s, 1H, 2c OH); C NMR (75.6 MHz, CDCl3):

G 55.3, 55.9, 56.0 and 60.6 (4 X CH3O), 87.0 (C5c), 106.8 (C1c), 114.3 (C3, C5), 124.9 (CD),

128.1 (C1), 130.1 (C2, C6), 130.8 (C3c), 142.7 (CE), 158.1 (C2c), 158.4 (C6c), 159.3 (C4c), 161.4 (C4), 193.0 (CO).

2c-Hydroxy-3c,4c,6c-trimethoxy-4-methylchalcone (78d) The title compound was synthesized following general procedure 1 using 2c-hydroxy-3c,4c,6c- trimethoxyacetophenone 81 (2.5 g, 11.05 mmol), 4- methylbenzaldehyde 67e (1.3 mL, 11.05 mmol) and NaOH pellets (1.1 g, 27.64 mmol). The chalcone was obtained as dark orange crystals (2.8 g, 77%). 145 -1 -1 M.p. 140-142 °C; UV (MeOH): Omax 206 (H 13770 cm M ), 238 (12434), 348 (11401) nm; IR

(KBr): Qmax 2976, 2928, 2859, 2839, 1617, 1556, 1481, 1441, 1421, 1334, 1208, 1129, 1019, -1 1 977, 818, 786 cm ; H NMR (300 MHz, CDCl3): G 2.38 (s, 3H, CH3), 3.84, 3.94 and 3.95 (3s,

9H, 3 X CH3O), 6.00 (s, 1H, H5c), 7.20 (d, J = 7.9 Hz, 2H, H3, H5), 7.49 (d, J = 7.9 Hz, 2H, H2, 13 H6), 7.80 (d, J = 15.4 Hz, 2H, HD, HE), 13.95 (s, 1H, 2c OH); C NMR (75.6 MHz, CDCl3): G

21.4 (CH3), 55.9 (CH3O), 56.0 (CH3O), 60.6 (CH3O), 87.0 (C5c), 106.9 (C1c), 126.3 (CD), 128.3

(C2, C6), 129.6 (C3, C5), 130.8 (C3c), 132.6 (C1), 140.6 (C4), 142.8 (CE), 158.3 (C2c), 158.5 + (C6c), 159.3 (C4c), 193.2 (CO); HRMS (ESI) m/z Calcd. for C19H20O5 (M + 1) 329.1391. Found 329.1339.

4c-Bromo-5,7,8-trimethoxyflav-3-ene (82a) The compound was prepared as described in general procedure 2 using 4-bromo-2c-hydroxy-3c,4c,6c- trimethoxychalcone 78a (1.0 g, 2.54 mmol) and NaBH4 (0.29 g, 7.63 mmol). The flavene was obtained as a yellow sticky - residue (0.54 g, 56%). UV (MeOH): Omax 204 (H 61481 cm 1 -1 M ), 223 (49023), 296 (15338) nm; IR (KBr): Qmax 3438, 3010, 2933, 2840, 1609, 1561, 1504, -1 1 1464, 1437, 1347, 1239, 1206, 1138, 1116, 1070, 1010, 811 cm ; H NMR (300 MHz, CDCl3):

G 3.66, 3.82 and 3.86 (3s, 9H, 3 X CH3O), 5.66 (dd, J = 3.8, 10.2 Hz, 1H, H3), 5.84 (dd, J = 1.5, 3.8 Hz, 1H, H2), 6.06 (s, 1H, H6), 6.82 (dd, J = 1.5, 10.2 Hz, 1H, H4), 7.34 (d, J = 8.3 Hz, 2H,

13 H2c, H6c), 7.46 (d, J = 8.3 Hz, 2H, H3c, H5c); C NMR (75.6 MHz, CDCl3): G 55.8, 56.0 and

61.2 (3 X CH3O), 75.7 (C2), 89.3 (C6), 105.1 (C4a), 119.1 (C4), 122.2 (C4c), 126.8 (C3), 128.8 (C2c, C6c), 130.4 (C3c, C5c), 139.3 (C8), 146.2 (C8a), 146.5 (C1c), 151.7 (C5), 153.2 (C7); MS + 79 79 (TOF-ESI) m/z Calcd. for C18H17BrO4 (M + 1) 377.04 (Br ). Found 376.96 (Br ); Anal. Calcd. for C18H17BrO4: C, 57.31; H, 4.54. Found: C, 57.53; H, 4.83.

4c-Chloro-5,7,8-trimethoxyflav-3-ene (82b) The compound was prepared as described in general procedure 2 using 4-chloro-2c-hydroxy-3c,4c,6c- trimethoxychalcone 78b (1.0 g, 2.87 mmol) and NaBH4 (0.33 g, 8.6 mmol). The flavene was obtained as a yellow sticky - residue (0.55 g, 58%). UV (MeOH): Omax 204 (H 103221 cm 1 -1 M ), 221 (74779), 297 (18053) nm; IR (KBr): Qmax 3431, 3015, 2934, 2838, 1610, 1505, 1465, -1 1 1435, 1351, 1239, 1214, 1136, 1116, 1066, 1031, 809 cm ; H NMR (300 MHz, CDCl3): G 3.80, 146 3.83 and 3.86 (3s, 9H, 3 X CH3O), 5.66 (dd, J = 3.0, 9.8 Hz, 1H, H3), 5.85 (dd, J = 1.5, 3.0 Hz, 1H, H2), 6.05 (s, 1H, H6), 6.85 (dd, J = 1.5, 9.8 Hz, 1H, H4), 7.30 (d, J = 8.6 Hz, 2H, H2c, H6c),

13 7.40 (d, J = 8.6 Hz, 2H, H3c, H5c); C NMR (75.6 MHz, CDCl3): G 55.8, 56.0 and 61.1 (3 X

CH3O), 75.7 (C2), 89.3 (C6), 105.1 (C4a), 119.0 (C4), 128.4 (C2c, C6c), 128.5 (C3), 128.6 (C3c, C5c), 134.0 (C4c), 138.8 (C8), 138.9 (C1c), 146.5 (C8a), 151.2 (C5), 153.7 (C7); MS (TOF-ESI) + m/z Calcd. for C18H17ClO4Na (M + Na) 355.07. Found 355.01; Anal. Calcd. for

C18H17ClO4.H2O: C, 61.63; H, 5.46. Found: C, 61.80; H, 5.42.

4c,5,7,8-Tetramethoxyflav-3-ene (82c) The compound was prepared as described in general procedure 2 using 2c-hydroxy-3c,4,4c,6c- tetramethoxychalcone 78c (1.0 g, 2.9 mmol) and NaBH4 (0.33 g, 8.71 mmol). The flavene was obtained as a yellow sticky residue (0.60 g, 63%). UV (MeOH): Omax -1 -1 204 (H 25961 cm M ), 232 (20630), 274 (8299) nm; IR (KBr): Qmax 3434, 3008, 2935, 2839, 1607, 1511, 1464, 1439, 1347, 1246, 1211, 1135, 1114, 1064, 1032, 811 cm-1; 1H NMR (300

MHz, CDCl3): G 3.61, 3.78, 3.82 and 3.84 (4s, 12H, 4 X CH3O), 5.68 (dd, J = 3.8, 10.2 Hz, 1H, H3), 5.84 (dd, J = 1.5, 3.8 Hz, 1H, H2), 6.06 (s, 1H, H6), 6.85 (dd, J = 1.5, 10.2 Hz, 1H, H4), 6.87 (d, J = 8.3 Hz, 2H, H3c, H5c), 7.38 (d, J = 8.3 Hz, 2H, H2c, H6c); 13C NMR (75.6 MHz,

CDCl3): G 55.2, 55.8, 56.0 and 61.1 (4 X CH3O), 76.2 (C2), 89.1 (C6), 105.3 (C4a), 113.6 (C3c, C5c), 119.7 (C4), 127.4 (C3), 128.7 (C2c, C6c), 131.7 (C1c), 139.3 (C8), 146.7 (C8a), 151.1 (C5),

+ 153.5 (C7), 159.5 (C4c); MS (TOF-ESI) m/z Calcd. for C19H20O5Na (M + Na) 351.12. Found

351.04; Anal. Calcd. for C19H20O5.1/2H2O: C, 67.64; H, 6.27. Found: C, 67.59; H, 6.17.

5,7,8-Trimethoxy-4c-methylflav-3-ene (82d) The compound was prepared as described in general procedure 2 using 2c-hydroxy-3c,4c,6c-trimethoxy-4-methylchalcone 78d

(1.0 g, 3.05 mmol) and NaBH4 (0.35 g, 9.14 mmol). The flavene was obtained as a yellow sticky residue (0.60 g, 63%). -1 -1 UV (MeOH): Omax 205 (H 15503 cm M ), 257 (5150) nm; IR

(KBr): Qmax 3363, 3003, 2926, 2840, 1606, 1510, 1460, 1425, 1352, 1240, 1214, 1139, 1113, -1 1 1068, 1032, 795 cm ; H NMR (300 MHz, CDCl3): G 3.64 (s, 3H, CH3), 3.81, 3.83 and 3.87 (3s,

9H, 3 X CH3O), 5.69 (dd, J = 3.8, 9.8 Hz, 1H, H3), 5.87 (dd, J = 1.5, 3.8 Hz, 1H, H2), 6.05 (s, 1H, H6), 6.83 (dd, J = 1.5, 9.8 Hz, 1H, H4), 7.14 (d, J = 8.3 Hz, 2H, H3c, H5c), 7.35 (d, J = 8.3 147 13 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 21.3 (CH3), 55.8, 56.0 and 61.0 (3 X CH3O), 76.5 (C2), 89.3 (C6), 105.4 (C4a), 120.5 (C4), 126.8 (C3), 127.1 (C2c, C6c), 129.1 (C3c, C5c), 137.4 (C4c), 137.9 (C1c), 139.8 (C8), 146.8 (C8a), 151.1 (C5), 153.5 (C7); MS (TOF-ESI) m/z + Calcd. for C19H20O4Na (M + Na) 335.13. Found 335.06; Anal. Calcd. for C19H20O4.3/4MeOH: C, 70.52; H, 6.89. Found: C, 70.82; H, 7.12.

2-(3-(4-Bromophenyl)allyl)-3,5,6-trimethoxyphenol (83a) The compound was prepared as described in general procedure 3 using 4c-bromo-5,7,8-trimethoxyflavene 82a (0.1 g, 0.27 mmol) and few drops of 10M HCl. The open chain compound was obtained as an off-white solid (38 mg,

-1 -1 38%). M.p. 77-79 °C; UV (MeOH): Omax 206 (H 36339 cm M ), 260 (18291) nm; IR (KBr): Qmax 3354, 3009, 2970, 2931, 2842, 1619, 1603, 1510, 1490, 1459, 1425, 1353, 1243, 1174, 1112, -1 1 1034, 876, 797, 787 cm ; H NMR (300 MHz, CDCl3): G 3.48 (d, J = 5.6 Hz, 2H, CH2), 3.81,

3.86 and 3.88 (3s, 9H, 3 X CH3O), 5.88 (s, 1H, 2c OH), 6.10 (s, 1H, H5c), 6.32-6.36 (m, 2H, HD, 13 HE), 7.18-7.26 (m, 4H, H2, H3, H5, H6); C NMR (75.6 MHz, CDCl3): G 26.4 (CH2), 55.9, 60.0 and 61.1 (3 X CH3O), 88.8 (C5c), 107.1 (C1c), 125.7 (C4), 127.2 (C2, C6), 127.4 (CD), 130.0

(C3c), 130.6 (CE), 132.0 (C3, C5), 136.5 (C1), 147.8 (C4c), 150.6 (C6c), 154.1 (C2c); HRMS + 79 79 (ESI) m/z Calcd. for C18H19BrO4 (M + 1) 379.0547 (Br ). Found 379.0568 (Br ).

2-(3-(4-Chlorophenyl)allyl)-3,5,6-trimethoxyphenol (83b) The compound was prepared as described in general procedure 3 using 4c-chloro-5,7,8-trimethoxyflavene 82b (0.1 g, 0.30 mmol) and few drops of 10M HCl. The open chain compound was obtained as an off-white solid (43 -1 -1 mg, 43%). M.p. 66-68 °C; UV (MeOH): Omax 206 (H 32267 cm M ), 261 (17374) nm; IR (KBr):

Qmax 3394, 3015, 2996, 2942, 2835, 1610, 1605, 1509, 1486, 1466, 1428, 1349, 1247, 1173, -1 1 1114, 1033, 876, 794, 784 cm ; H NMR (300 MHz, CDCl3): G 3.48 (d, J = 5.3 Hz, 2H, CH2),

3.80, 3.85 and 3.87 (3s, 9H, 3 X CH3O), 5.87 (s, 1H, 2c OH), 6.09 (s, 1H, H5c), 6.32-6.36 (m, 13 2H, HD, HE), 7.18 (d, J = 8.3 Hz, 2H, H3, H5), 7.35 (d, J = 8.3 Hz, 2H, H2, H6); C NMR (75.6

MHz, CDCl3): G 26.4 (CH2), 55.9, 60.0 and 61.1 (3 X CH3O), 88.8 (C5c), 107.0 (C1c), 127.3

(CD), 127.5 (C3, C5), 130.7 (CE), 130.8 (C3c), 131.3 (C2, C6), 132.2 (C4), 136.9 (C1), 147.8 + (C4c), 149.9 (C6c), 154.1 (C2c); HRMS (ESI) m/z Calcd. for C18H19ClO4Na (M + Na) 357.0872. Found 357.0849. 148 2,3,5-Trimethoxy-6-(3-p-tolylallyl)phenol (83c) The compound was prepared as described in general procedure 3 using 5,7,8-trimethoxy-4c-methylflavene 82d (0.1 g, 0.32 mmol) and few drops of 10M HCl. The open chain compound was obtained as an off-white solid (43 mg, -1 -1 43%). M.p. 82-84 °C; UV (MeOH): Omax 206 (H 109188 cm M ), 258 (42388) nm; IR (KBr):

Qmax 3356, 3015, 2968, 2931, 2842, 1619, 1603, 1510, 1458, 1436, 1424, 1354, 1241, 1173, -1 1 1128, 1031, 969, 875, 795, 787 cm ; H NMR (300 MHz, CDCl3): G 2.30 (s, 3H, CH3), 3.49 (d,

J = 5.6 Hz, 2H, CH2), 3.81, 3.85 and 3.87 (3s, 9H, 3 X CH3O), 5.88 (s, 1H, 2c OH), 6.10 (s, 1H,

H5c), 6.23-6.40 (m, 2H, HD, HE), 7.05 (d, J = 8.3 Hz, 2H, H3, H5), 7.22 (d, J = 8.3 Hz, 2H, H2, 13 H6); C NMR (75.6 MHz, CDCl3): G 21.0 (CH3), 26.4 (CH2), 55.9, 56.0 and 61.1 (3 X CH3O),

88.9 (C5c), 107.6 (C1c), 125.8 (C2, C6), 127.7 (CD), 128.9 (C3, C5), 130.0 (C3c), 130.3 (CE), 135.2 (C1), 136.1 (C4), 147.8 (C4c), 150.5 (C6c), 154.1 (C2c); MS (TOF-ESI) m/z Calcd. for + C19H22O4Na (M + Na) 337.14. Found 337.55; Anal. Calcd. for C19H22O4: C, 72.59; H, 7.05. Found: C, 72.59; H, 7.27.

3-(2-Hydroxy-3,4,6-trimethoxyphenyl)-1-(4-methoxyphenyl)propan-1-one (84) The compound was prepared as described in general procedure 3 using 4c,5,7,8-tetramethoxyflavene 82c (0.1 g, 0.30 mmol) and few drops of 10M HCl. The open chain compound was obtained as an off-white solid (54 -1 -1 mg, 51%). M.p. 130-132 °C; UV (MeOH): Omax 205 (H 66136 cm M ), 274 (17374) nm; IR

(KBr): Qmax 3278, 3004, 2940, 2841, 1651, 1598, 1572, 1458, 1350, 1257, 1175, 1055, 1027, -1 1 883, 840, 796, 764 cm ; H NMR (300 MHz, CDCl3): G 2.98 (t, J = 7.2 Hz, 2H, CH2), 3.18 (t, J

= 7.2 Hz, 2H, CH2), 3.78, 3.84 and 3.85 (3s, 12H, 4 X CH3O), 6.07 (s, 1H, 2c OH), 6.88 (s, 1H, H5c), 6.91 (d, J = 8.7 Hz, 2H, H3, H5), 7.97 (d, J = 8.7 Hz, 2H, H2, H6); 13C NMR (75.6 MHz,

CDCl3): G 18.1 and 38.2 (2 X CH2), 55.3, 55.6, 56.0 and 61.0 (4 X CH3O), 88.7 (C5c), 109.0 (C1c), 113.5 (C3, C5), 129.8 (C3c), 130.5 (C2, C6), 130.8 (C1), 148.4 (C2c), 150.9 (C4c), 154.0

+ (C6c), 163.4 (C4), 200.0 (CO); MS (TOF-ESI) m/z Calcd. for C19H22O6Na (M + Na) 369.13.

Found 369.06; Anal. Calcd. for C19H22O6.1/2H2O: C, 64.21; H, 6.52. Found: C, 64.45; H, 6.56.

149 6a,12a-Dihydro-1,3,4,8,10,11-hexamethoxy-6-(4c-bromophenyl)-7-[(1E)-2-(4cc- bromophenylethenyl)]-6H,7H-[1]benzopyrano[4,3-b][1]benzopyran (85a) The title compound was synthesized following general procedure 3 using 4c-bromo-5,7,8-trimethoxyflavene 82a (0.1 g, 0.27 mmol) and was obtained as a white solid (136 mg, 68%). M.p. 172-174 °C; UV (MeOH): Omax 208 (H -1 -1 15726 cm M ), 263 (3702) nm; IR (KBr): Qmax 3479, 2933, 2839, 1736, 1613, 1503, 1463, 1347, 1241, 1205, 1105, -1 1 1064, 961, 928, 809 cm ; H NMR (300 MHz, CDCl3): G 2.24 (ddd, J = 1.5, 2.3, 10.9 Hz, 1H, H6a), 3.31 (dd, J =

1.5, 5.3 Hz, 1H, H7), 3.69, 3.73, 3.82, 3.86, 3.89 and 3.90 (6s, 18H, 6 X CH3O), 4.93 (d, J =

10.9 Hz, 1H, H6), 5.36 (d, J = 2.3 Hz, 1H, H12a), 5.95 (d, J = 15.8 Hz, 1H, HE), 6.13 (dd, J =

5.3, 15.8 Hz, 1H, HD), 6.16 (s, 1H, H2), 6.18 (s, 1H, H9), 7.15 (d, J = 8.6 Hz, 2H, H2c, H6c), 7.18 (d, J = 8.3 Hz, 2H, H3cc, H5cc), 7.35 (d, J = 8.3 Hz, 2H, H2cc, H6cc), 7.52 (d, J = 8.6 Hz, 2H,

13 H3c, H5c); C NMR (75.6 MHz, CDCl3): G 32.9 (C7), 40.9 (C6a), 55.7, 55.8, 56.0, 56.2, 60.8 and 60.9 (6 X CH3O), 61.4 (C12a), 75.9 (C6), 89.4 (C2), 89.5 (C9), 102.3 (C12b), 104.2 (C7a),

120.7 (C4c), 122.4 (C4cc), 127.7 (CE), 128.9 (C2c, C6c), 129.0 (C2cc, C6cc), 129.5 (C3c, C5c),

130.2 (CD), 131.2 (C11), 131.6 (C4), 132.9 (C3cc, C5cc), 136.1 (C1cc), 137.8 (C1c), 149.1 (C3), 149.9 (C10), 153.2 (C1), 153.9 (C8), 153.9 (C11a), 154.5 (C4a); MS (TOF-ESI) m/z Calcd. for + 79 79 C36H34Br2O8Na (M + Na) 775.05 (Br ). Found 775.02 (Br ); Anal. Calcd. for C36H34Br2O8: C, 57.31; H, 4.54. Found: C, 57.58; H, 4.82.

6a,12a-Dihydro-1,3,4,8,10,11-hexamethoxy-6-(4c-chlorophenyl)-7-[(1E)-2-(4cc- chlorophenylethenyl)]-6H,7H-[1]benzopyrano[4,3-b][1]benzopyran (85b) The title compound was synthesized following general procedure 3 using 4c-chloro-5,7,8-trimethoxyflavene 82b (0.1 g, 0.30 mmol) and was obtained as a white solid (140 mg, 70%). M.p. 166-168 °C; UV (MeOH): Omax 210 (H -1 -1 98869 cm M ), 261 (38495) nm; IR (KBr): Qmax 3476, 2934, 2839, 1726, 1610, 1502, 1456, 1348, 1242, 1205, 1115, 1061, 974, 938, 812 cm-1; 1H NMR (300 MHz,

CDCl3): G 2.24 (ddd, J = 1.1, 2.3, 11.3 Hz, 1H, H6a), 3.31

(dd, J = 1.1, 6.0 Hz, 1H, H7), 3.69, 3.73, 3.82, 3.86, 3.88 and 3.90 (6s, 18H, 6 X CH3O), 4.94 (d,

J = 11.3 Hz, 1H, H6), 5.37 (d, J = 2.3 Hz, 1H, H12a), 5.96 (d, J = 15.8 Hz, 1H, HE), 6.14 (dd, J 150 = 6.0, 15.8 Hz, 1H, HD), 6.18 (2s, 2H, H2, H9), 7.20 (d, J = 8.6 Hz, 2H, H2c, H6c), 7.23 (d, J = 8.6 Hz, 2H, H3c, H5c), 7.26 (d, J = 8.7 Hz, 2H, H3cc, H5cc), 7.37 (d, J = 8.7 Hz, 2H, H2cc, H6cc);

13 C NMR (75.6 MHz, CDCl3): G 32.9 (C7), 41.0 (C6a), 55.7, 56.0, 56.3, 56.4, 60.8 and 60.9 (6

X CH3O), 61.4 (C12a), 75.9 (C6), 89.4 (C2), 89.5 (C9), 102.4 (C12b), 104.3 (C7a), 127.4 (C3c,

C5c), 127.8 (CE), 128.5 (C2c, C6c), 128.5 (C3cc, C5cc), 128.7 (C2cc, C6cc), 130.6 (CD), 131.3 (C11), 131.5 (C4), 132.8 (C4c), 134.2 (C4cc), 135.6 (C1cc), 137.3 (C1c), 148.0 (C3), 149.1 (C10), 152.2 (C1), 153.3 (C8), 154.0 (C11a), 154.8 (C4a); MS (TOF-ESI) m/z Calcd. for + C36H34Cl2O8Na (M + Na) 687.15. Found 687.06; Anal. Calcd. for C36H34Cl2O8: C, 64.97; H, 5.15. Found: C, 65.13; H, 5.26.

6a,12a-Dihydro-1,3,4,8,10,11-hexamethoxy-6-(4c-methoxyphenyl)-7-[(1E)-2-(4cc- methoxyphenylethenyl)]-6H,7H-[1]benzopyrano[4,3-b][1]benzopyran (85c) The title compound was synthesized following general procedure 3 using 4c,5,7,8-tetramethoxyflavene 82c (0.1 g, 0.30 mmol) and was obtained as a white solid (142 mg,

71%). M.p. 188-190 °C; UV (MeOH): Omax 210 (H 68254 -1 -1 cm M ), 265 (18123) nm; IR (KBr): Qmax 3442, 2934, 2838, 1735, 1609, 1510, 1464, 1349, 1246, 1204, 1112, -1 1 1060, 974, 928, 820 cm ; H NMR (300 MHz, CDCl3): G 2.26 (ddd, J = 1.1, 2.3, 11.3 Hz, 1H, H6a), 3.34 (dd, J =

1.1, 5.3 Hz, 1H, H7), 3.67, 3.73, 3.76, 3.83, 3.85, 3.86, 3.89 and 3.90 (8s, 24H, 8 X CH3O), 4.91

(d, J = 11.3 Hz, 1H, H6), 5.39 (d, J = 2.3 Hz, 1H, H12a), 5.95 (d, J = 15.8 Hz, 1H, HE), 6.05 (dd,

J = 5.3, 15.8 Hz, 1H, HD), 6.14 (s, 1H, H2), 6.17 (s, 1H, H9), 6.78 (d, J = 8.7 Hz, 2H, H3c, H5c), 6.92 (d, J = 8.6 Hz, 2H, H3cc, H5cc), 7.20 (d, J = 8.7 Hz, 2H, H2c, H6c), 7.23 (d, J = 8.6 Hz, 2H,

13 H2cc, H6cc); C NMR (75.6 MHz, CDCl3): G 32.9 (C7), 41.1 (C6a), 55.1, 55.8, 56.0, 56.2, 56.3,

56.4, 60.8 and 60.9 (8 X CH3O), 61.6 (C12a), 76.2 (C6), 89.2 (C2), 89.6 (C9), 103.3 (C12b),

104.6 (C7a), 113.7 (C3c, C5c), 113.8 (C3cc, C5cc), 127.2 (C2c, C6c), 127.6 (CE), 128.5 (C2cc,

C6cc), 130.1 (C1cc), 130.4 (C1c), 130.4 (CD), 131.3 (C4), 131.5 (C11), 147.1 (C3), 149.5 (C10), 151.9 (C1), 152.2 (C8), 152.9 (C11a), 153.5 (C4a), 158.9 (C4c), 159.7 (C4cc); MS (TOF-ESI) + m/z Calcd. for C38H40O10Na (M + Na) 679.25. Found 679.10; Anal. Calcd. for C38H40O10: C, 69.50; H, 6.14. Found: C, 69.69; H, 6.41.

151 6a,12a-Dihydro-1,3,4,8,10,11-hexamethoxy-6-p-tolyl-7-[(1E)-2-p-tolylethenyl]-6H,7H- [1]benzopyrano[4,3-b][1]benzopyran (85d) The title compound was synthesized following general procedure 3 using 5,7,8-trimethoxy-4c-methylflavene 82d (0.1 g, 0.32 mmol) and was obtained as a white solid (146 mg, 73%). M.p. 167-169 °C; UV (MeOH): Omax 210 (H -1 -1 38692 cm M ), 263 (8242) nm; IR (KBr): Qmax 3477, 2932, 2839, 1726, 1610, 1504, 1456, 1348, 1243, 1205, 1119, 1061, 961, 939, 807 cm-1; 1H NMR (300 MHz,

CDCl3): G 2.26 (ddd, J = 1.1, 2.3, 10.9 Hz, 1H, H6a), 2.31 and 2.39 (2s, 6H, 2 X CH3), 3.37 (dd, J = 1.1, 5.6 Hz, 1H, H7), 3.68, 3.75, 3.82, 3.83, 3.85 and

3.86 (6s, 18H, 6 X CH3O), 4.93 (d, J = 10.9 Hz, 1H, H6), 5.39 (d, J = 2.3 Hz, 1H, H12a), 5.96

(d, J = 15.8 Hz, 1H, HE), 6.14 (dd, J = 5.6, 15.8 Hz, 1H, HD), 6.15 and 6.17 (2s, 2H, H2, H9), 7.05 (d, J = 8.3 Hz, 2H, H3c, H5c), 7.13 (d, J = 8.6 Hz, 2H, H3cc, H5cc,), 7.15 (d, J = 8.3 Hz, 2H,

13 H2c, H6c), 7.19 (d, J = 8.6 Hz, 2H, H2cc, H6cc); C NMR (75.6 MHz, CDCl3): G 21.0 and 21.2 (2

X CH3), 32.9 (C7), 40.9 (C6a), 55.7, 55.9, 56.2, 56.4, 60.8 and 60.9 (6 X CH3O), 61.5 (C12a),

76.5 (C6), 89.2 (C2), 89.6 (C9), 103.2 (C12b), 104.5 (C7a), 126.0 (C2c, C6c), 127.1 (CE), 127.2

(C3c, C5c), 129.0 (C2cc, C6cc), 131.3 (C3cc, C5cc), 131.5 (CD), 134.5 (C4), 135.8 (C11), 136.0 (C1cc), 136.7 (C1c), 137.9 (C4c), 138.0 (C4cc), 149.5 (C3), 149.9 (C10), 152.2 (C1), 153.4 (C8), + 154.0 (C11a), 154.6 (C4a); HRMS (ESI) m/z Calcd. for C38H40O8Na (M + Na) 647.2623. Found

647.2615; Anal. Calcd. for C38H40O8: C, 73.06; H, 6.45. Found: C, 72.80; H, 6.70.

2c-Hydroxy-4c,6c-dimethoxyacetophenone (87) To a solution of 2c,4c,6c-trihydroxyacetophenone 86 (5.0 g, 29.74 mmol) in acetone (75 mL), was added K2CO3 (12.3 g, 89.21 mmol). The reaction mixture was cooled to 0 qC and MeI (3.7 mL, 59.47 mmol) was added slowly. The reaction mixture was then refluxed for 24 h. The solvent was evaporated, and the resulting residue was acidified using 2M HCl to pH 3. The mixture was extracted with EtOAc (3

X 100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was recrystallized from EtOAc/light petroleum (2:8) to afford the title compound as an off-white solid (5.4 g, 92%). M.p. 82-84 °C, lit.193 82-83 °C; 1H NMR (300

MHz, CDCl3): G 2.50 (s, 3H, CH3CO), 3.79 (s, 3H, CH3O), 3.82 (s, 3H, CH3O), 6.32 (d, J = 2.3 13 Hz, 1H, H3c), 6.41 (d, J = 2.3 Hz, 1H, H5c), 11.67 (s, 1H, 2c OH); C NMR (75.6 MHz, CDCl3):

152 G 28.5 (CH3CO), 56.0 (CH3O), 56.2 (CH3O), 102.5 (C5c), 105.6 (C3c), 110.9 (C1c), 163.4 (C2c), 164.2 (C6c), 164.9 (C4c), 205.2 (CO).

2c-Hydroxy-4,4c,6c-trimethoxychalcone (88) The title compound was synthesized following general procedure 1 using 2c-hydroxy-4c,6c- dimethoxyacetophenone 87 (2.0 g, 10.19 mmol), 4- methoxybenzaldehyde 67d (1.2 mL, 10.19 mmol) and NaOH pellets (1.0 g, 25.49 mmol) and obtained as a yellow solid (2.1 g, 65%). M.p. 110-112 194 1 °C, lit. 112 °C; H NMR (300 MHz, CDCl3): G 3.82 (s, 3H, CH3O), 3.84 (s, 3H, CH3O), 3.88

(s, 3H, CH3O), 5.95 (d, J = 2.6 Hz, 1H, H3c), 6.09 (d, J = 2.6 Hz, 1H, H5c), 6.92 (d, J = 8.7 Hz,

2H, H3, H5), 7.55 (d, J = 8.7 Hz, 2H, H2, H6), 7.79 (d, J = 15.1 Hz, 1H, HD), 7.84 (d, J = 15.1 13 Hz, 1H, HE), 10.51 (s, 1H, 2c OH); C NMR (75.6 MHz, CDCl3): G 55.3 (CH3O), 55.5 (CH3O),

55.7 (CH3O), 91.1 (C5c), 93.7 (C3c), 106.3 (C1c), 114.3 (C3, C5), 125.0 (CD), 128.2 (C1), 130.0

(C2, C6), 142.4 (CE), 161.3 (C4), 161.4 (C2c), 166.0 (C6c), 168.3 (C4c), 192.5 (CO).

4c,5,7-Trimethoxyflav-3-ene (89)195 The compound was prepared as described in general procedure 2 using 2c-hydroxy-4,4c,6c-trimethoxychalcone 88

(1.0 g, 3.18 mmol) and NaBH4 (0.36 g, 9.54 mmol). The flavene was obtained as a yellow sticky residue (0.51 g, 1 54%). H NMR (300 MHz, CDCl3): G 3.74, 3.80 and 3.81

(3s, 9H, 3 X CH3O), 5.61 (dd, J = 3.4, 10.2 Hz, 1H, H3), 5.79 (dd, J = 1.9, 3.4 Hz, 1H, H2), 6.03 (s, 1H, H6), 6.04 (s, 1H, H8), 6.82 (dd, J = 1.9, 10.2 Hz, 1H, H4), 6.89 (d, J = 9.0 Hz, 2H, H3c,

13 H5c), 7.39 (d, J = 9.0 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 55.3, 55.4 and 55.5 (3

X CH3O), 76.1 (C2), 91.9 (C6), 93.7 (C8), 104.3 (C4a), 118.9 (C3c, C5c), 119.5 (C4), 128.4 (C3), 128.8 (C2c, C6c), 139.7 (C1c), 148.2 (C8a), 150.5 (C5), 154.3 (C7), 159.2 (C4c).

153 6a,12a-Dihydro-1,3,8,10-tetramethoxy-6-(4c-methoxyphenyl)-7-[(1E)-2-(4cc- methoxyphenylethenyl)]-6H,7H-[1]benzopyrano[4,3-b][1]benzopyran (90) The title compound was synthesized following general procedure 3 using 4c,5,7-trimethoxyflavene 89 (0.1 g, 0.34 mmol) and was obtained as a white solid (104 mg, 52%). -1 - M.p. 196-198 °C; UV (MeOH): Omax 210 (H 169909 cm M 1 ), 264 (44727) nm; IR (KBr): Qmax 3466, 1616, 1592, 1513, 1465, 1249, 1200, 1149, 1111, 1034, 815 cm-1; 1H NMR

(300 MHz, CDCl3): G 2.22 (ddd, J = 1.5, 2.3, 11.3 Hz, 1H, H6a), 3.22 (dd, J = 1.5, 4.9 Hz, 1H, H7), 3.58, 3.68, 3.69,

3.70, 3.72 and 3.77 (6s, 18H, 6 X CH3O), 4.82 (d, J = 11.3 Hz, 1H, H6), 5.31 (d, J = 2.3 Hz, 1H,

H12a), 5.92 (d, J = 14.7 Hz, 1H, HE), 5.95 (dd, J = 4.9, 14.7 Hz, 1H, HD), 6.01 (d, J = 2.3 Hz, 1H, H2), 6.03 (d, J = 2.3 Hz, 1H, H4), 6.04 (d, J = 2.3 Hz, 1H, H9), 6.10 (d, J = 2.3 Hz, 1H, H11), 6.71 (d, J = 8.6 Hz, 2H, H3c, H5c), 6.85 (d, J = 8.6 Hz, 2H, H3cc, H5cc), 7.13 (d, J = 8.6 Hz,

13 2H, H2c, H6c), 7.15 (d, J = 8.6 Hz, 2H, H2cc, H6cc); C NMR (75.6 MHz, CDCl3): G 33.2 (C7),

41.5 (C6a), 55.6, 55.7, 55.8, 56.0, 56.2 and 56.3 (6 X CH3O), 61.8 (C12a), 76.9 (C6), 92.3 (C2), 92.4 (C9), 93.5 (C4), 93.7 (C11), 102.1 (C12b), 103.9 (C7a), 114.2 (C3c, C5c), 114.4 (C3cc,

C5cc), 127.4 (CE), 127.7 (C2c, C6c), 129.0 (C2cc, C6cc), 130.6 (C1cc), 130.8 (CD), 131.4 (C1c), 149.2 (C3), 149.5 (C10), 153.5 (C1), 154.1 (C8), 154.3 (C11a), 154.8 (C4a), 159.2 (C4c), 159.6

+ (C4cc); HRMS (ESI) m/z Calcd. for C36H36O8Na (M + Na) 619.2310. Found 619.2298; Anal.

Calcd. for C36H36O8: C, 72.47; H, 6.08. Found: C, 72.60; H, 6.20.

2c-Hydroxy-5c-methoxyacetophenone (112a) To a solution of 2c,5c-dihydroxyacetophenone 111a (5.0 g, 32.86 mmol) in acetone (75 mL), was added K2CO3 (9.1 g, 65.72 mmol). The reaction mixture was cooled to 0 qC and MeI (2.1 mL, 32.86 mmol) was added slowly. The reaction mixture was then refluxed for 24 h. The solvent was evaporated, and the residue was acidified using 2M HCl to pH 3. The mixture was extracted with EtOAc (3 X 100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was recrystallized from EtOAc/light petroleum (2:8) to afford the title compound as 196 1 yellow crystals (5.1 g, 93%). M.p. 52-54 °C, lit. 51-52 °C; H NMR (300 MHz, CDCl3): G

2.61 (s, 3H, CH3CO), 3.78 (s, 3H, CH3O), 6.90 (d, J = 9.0 Hz, 1H, H3c), 7.09 (dd, J = 3.0, 9.0 13 Hz, 1H, H4c), 7.15 (d, J = 3.0 Hz, 1H, H6c), 11.83 (s, 1H, 2c OH); C NMR (75.6 MHz, CDCl3):

154 G 26.6 (CH3CO), 55.9 (CH3O), 113.4 (C6c), 119.1 (C3c), 121.3 (C1c), 124.1 (C4c), 151.6 (C5c), 156.7 (C2c), 203.9 (CO).

2c-Hydroxy-6c-methoxyacetophenone (112b) To a solution of 2c,6c-dihydroxyacetophenone 111b (5.0 g, 32.86 mmol) in acetone (75 mL), was added K2CO3 (9.1 g, 65.72 mmol). The reaction mixture was cooled to 0 qC and MeI (2.1 mL, 32.86 mmol) was added slowly. The reaction mixture was then refluxed for 24 h. The solvent was evaporated, and the residue was acidified using 2M HCl to pH 3. The mixture was extracted with EtOAc (3 X 100 mL), washed with brine (100 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was recrystallized from EtOAc/light petroleum (2:8) to afford the title compound as pale yellow 197 1 crystals (5.0 g, 92%). M.p. 54-56 °C, lit. 56-57 °C; H NMR (300 MHz, CDCl3): G 2.50 (s,

3H, CH3CO), 3.79 (s, 3H, CH3O), 6.48 (d, J = 8.3 Hz, 1H, H3c), 6.53 (d, J = 8.3 Hz, 1H, H5c), 13 7.31 (t, J = 8.3 Hz, 1H, H4c), 11.82 (s, 1H, 2c OH); C NMR (75.6 MHz, CDCl3): G 26.5

(CH3CO), 56.0 (CH3O), 110.0 (C5c), 114.3 (C3c), 117.0 (C1c), 141.2 (C4c), 159.8 (C6c), 163.3 (C2c), 204.7 (CO).

2c-Hydroxy-5c-methoxychalcone (113a) The title compound was synthesized following general procedure 1 using 2c-hydroxy-5c-methoxyacetophenone 112a (2.5 g, 15.04 mmol), benzaldehyde 67a (1.5 mL, 15.04 mmol) and NaOH pellets (1.5 g, 37.61 mmol). The chalcone was obtained as yellow crystals 198 1 (3.3 g, 87%). M.p. 50-52 °C, lit. 48-50 °C; H NMR (300 MHz, CDCl3): G 3.84 (s, 3H,

CH3O), 6.92 (d, J = 9.0 Hz, 1H, H3c), 6.98 (dd, J = 3.0, 9.0 Hz, 1H, H4c), 7.16 (d, J = 3.0 Hz,

1H, H6c), 7.35-7.61 (m, 5H, H2, H3, H4, H5, H6), 7.64 (d, J = 15.5 Hz, 1H, HD), 7.92 (d, J = 13 15.5 Hz, 1H, HE), 12.36 (s, 1H, 2c OH); C NMR (75.6 MHz, CDCl3): G 56.1 (CH3O), 112.8

(C6c), 113.4 (C1c), 119.3 (CD), 120.0 (C3c), 123.9 (C4c), 128.6 (C2, C6), 129.0 (C3, C5), 130.9

(C4), 134.5 (C1), 145.5 (CE), 151.6 (C5c), 157.9 (C2c), 193.3 (CO).

4-Bromo-2c-hydroxy-5c-methoxychalcone (113b) The title compound was synthesized following general procedure 1 using 2c-hydroxy-5c-methoxyacetophenone 112a (2.5 g, 15.04 mmol), 4-bromobenzaldehyde 67b (2.8 g, 15.04 mmol) and NaOH pellets (1.5 g, 37.61 mmol). The chalcone was obtained as 155 199 yellow crystals (4.2 g, 84%). M.p. 112-114 °C, lit. 115-116 °C; UV (MeOH): Omax 203 (H -1 -1 47060 cm M ), 233 (29847), 320 (42617) nm; IR (KBr): Qmax 3002, 2954, 2931, 2846, 1646, 1579, 1485, 1360, 1261, 1218, 1179, 1035, 980, 822, 791, 744 cm-1; 1H NMR (300 MHz,

CDCl3): G 3.84 (s, 3H, CH3O), 6.98 (d, J = 9.0 Hz, 1H, H3c), 7.16 (dd, J = 3.0, 9.0 Hz, 1H, H4c), 7.34 (d, J = 3.0 Hz, 1H, H6c), 7.52 (d, J = 8.7 Hz, 2H, H3, H5), 7.58 (d, J = 8.7 Hz, 2H, H2, H6),

13 7.61 (d, J = 15.4 Hz, 1H, HD), 7.85 (d, J = 15.4 Hz, 1H, HE), 12.28 (s, 1H, 2c OH); C NMR

(75.6 MHz, CDCl3): G 56.1 (CH3O), 112.9 (C6c), 119.3 (CD), 119.5 (C1c), 120.6 (C3c), 124.0

(C4c), 125.2 (C4), 129.9 (C2, C6), 132.2 (C3, C5), 133.4 (C1), 144.0 (CE), 151.7 (C5c), 157.9 (C2c), 193.0 (CO).

4-Chloro-2c-hydroxy-5c-methoxychalcone (113c) The title compound was synthesized following general procedure 1 using 2c-hydroxy-5c-methoxyacetophenone 112a (2.5 g, 15.04 mmol), 4-chlorobenzaldehyde 67c (2.1 g, 15.04 mmol) and NaOH pellets (1.5 g, 37.61 mmol). The chalcone was obtained as yellow orange crystals (3.7 g, 86%). M.p. 113-115 °C, lit.199 111- -1 -1 1 112 °C; UV (MeOH): Omax 203 (H 52127 cm M ), 230 (32873), 320 (50746) nm; H NMR (300

MHz, CDCl3): G 3.84 (s, 3H, CH3O), 6.98 (d, J = 9.0 Hz, 1H, H3c), 7.15 (dd, J = 3.0, 9.0 Hz, 1H, H4c), 7.33 (d, J = 3.0 Hz, 1H, H6c), 7.41 (d, J = 8.3 Hz, 2H, H3, H5), 7.54 (d, J = 15.5 Hz, 1H,

13 HD), 7.58 (d, J = 8.3 Hz, 2H, H2, H6), 7.85 (d, J = 15.5 Hz, 1H, HE), 12.29 (s, 1H, 2c OH); C

NMR (75.6 MHz, CDCl3): G 56.1 (CH3O), 112.9 (C6c), 119.3 (CD), 119.8 (C1c), 120.5 (C3c),

123.9 (C4c), 129.3 (C3, C5), 129.7 (C2, C6), 133.0 (C1), 136.8 (C4), 144.0 (CE), 151.7 (C5c), 157.9 (C2c), 193.0 (CO).

2c-Hydroxy-4,5c-dimethoxychalcone (113d) The title compound was synthesized following general procedure 1 using 2c-hydroxy-5c-methoxyacetophenone 112a (2.5 g, 15.04 mmol), 4-methoxybenzaldehyde 67d (1.8 mL, 15.04 mmol) and NaOH pellets (1.5 g, 37.61 mmol). The chalcone was obtained as orange crystals (2.8 g, 65%). M.p. 83-85 °C, lit.200 87-89 -1 -1 1 °C; UV (MeOH): Omax 203 (H 26810 cm M ), 231 (17050), 348 (24000) nm; H NMR (300

MHz, CDCl3): G 3.84 (s, 3H, CH3O), 3.87 (s, 3H, CH3O), 6.95 (d, J = 8.6 Hz, 2H, H3, H5), 6.98 (d, J = 9.0 Hz, 1H, H3c), 7.13 (dd, J = 3.0, 9.0 Hz, 1H, H4c), 7.36 (d, J = 3.0 Hz, 1H, H6c), 7.47

156 (d, J = 15.4 Hz, 1H, HD), 7.63 (d, J = 8.6 Hz, 2H, H2, H6), 7.90 (d, J = 15.4 Hz, 1H, HE), 12.41 13 (s, 1H, 2c OH); C NMR (75.6 MHz, CDCl3): G 55.3 (CH3O), 56.0 (CH3O), 112.8 (C6c), 114.4

(C3, C5), 117.5 (CD), 119.2 (C3c), 121.3 (C1c), 123.5 (C4c), 127.2 (C1), 130.5 (C2, C6), 145.4

(CE), 151.6 (C5c), 157.8 (C2c), 161.9 (C4), 193.2 (CO).

2c-Hydroxy-5c-methoxy-4-methylchalcone (113e) The title compound was synthesized following general procedure 1 using 2c-hydroxy-5c-methoxyacetophenone 112a (2.5 g, 15.04 mmol), 4-methylbenzaldehyde 67e (1.8 mL, 15.04 mmol) and NaOH pellets (1.5 g, 37.61 mmol). The chalcone was obtained as orange crystals (2.5 g, 62%). M.p. 92-93 °C, lit.201 93-94 °C; UV -1 -1 1 (MeOH): Omax 204 (H 39557 cm M ), 234 (23057), 328 (35714) nm; H NMR (300 MHz,

CDCl3): G 2.40 (s, 3H, CH3), 3.84 (s, 3H, CH3O), 6.97 (d, J = 9.0 Hz, 1H, H3c), 7.14 (dd, J = 3.0, 9.0 Hz, 1H, H4c), 7.24 (d, J = 8.7 Hz, 2H, H3, H5), 7.36 (d, J = 3.0 Hz, 1H, H6c), 7.55 (d, J

= 15.5 Hz, 1H, HD), 7.56 (d, J = 8.7 Hz, 2H, H2, H6), 7.90 (d, J = 15.5 Hz, 1H, HE), 12.41 (s, 13 1H, 2c OH); C NMR (75.6 MHz, CDCl3): G 21.5 (CH3), 56.1 (CH3O), 112.9 (C6c), 119.0 (CD), 119.2 (C3c), 119.6 (C1c), 123.6 (C4c), 128.6 (C2, C6), 129.7 (C3, C5), 131.8 (C1), 141.6 (C4),

145.6 (CE), 151.6 (C5c), 157.8 (C2c), 193.3 (CO).

2c-Hydroxy-6c-methoxychalcone (113f) The title compound was synthesized following general procedure 1 using 2c-hydroxy-6c-methoxyacetophenone 112b (2.5 g, 15.04 mmol), benzaldehyde 67a (1.5 mL, 15.04 mmol) and NaOH pellets (1.5 g, 37.61 mmol). The chalcone was obtained as yellow crystals (2.7 g, 70%). M.p. 68-70 °C, 184 1 lit. 65 °C; H NMR (300 MHz, CDCl3): G 3.73 (s, 3H, CH3O), 6.53 (d, J = 9.0 Hz, 1H, H3c), 6.56 (d, J = 9.0 Hz, 1H, H5c), 7.25 (t, J = 9.0 Hz, 1H, H4c), 7.29-7.42 (m, 5H, H2, H3, H4, H5,

13 H6), 7.66 (d, J = 15.4 Hz, 1H, HD), 7.87 (d, J = 15.4 Hz, 1H, HE), 10.40 (s, 1H, 2c OH); C

NMR (75.6 MHz, CDCl3): G 55.9 (CH3O), 104.1 (C5c), 110.8 (C3c), 111.9 (C1c), 127.5 (C4),

128.4 (C3, C5), 128.9 (C2, C6), 130.3 (CD), 134.8 (C4c), 135.9 (C1), 142.9 (CE), 161.0 (C2c), 164.8 (C6c), 194.4 (CO).

157 4-Bromo-2c-hydroxy-6c-methoxychalcone (113g) The title compound was synthesized following general procedure 1 using 2c-hydroxy-6c-methoxyacetophenone 112b (2.5 g, 15.04 mmol), 4-bromobenzaldehyde 67b (2.8 g, 15.04 mmol) and NaOH pellets (1.5 g, 37.61 mmol). The chalcone was obtained as yellow crystals 202 -1 -1 (3.2 g, 64%). M.p. 128-130 °C, lit. 125-127 °C; UV (MeOH): Omax 204 (H 27163 cm M ), 228

(11733), 321 (14435) nm; IR (KBr): Qmax 3049, 2977, 2949, 2843, 1634, 1584, 1480, 1438, -1 1 1359, 1244, 1191, 1010, 977, 852, 790, 743 cm ; H NMR (300 MHz, DMSO-d6): G 3.72 (s,

3H, CH3O), 6.52 (d, J = 8.3 Hz, 1H, H3c), 6.55 (d, J = 8.3 Hz, 1H, H5c), 7.18 (d, J = 15.8 Hz,

1H, HD), 7.24 (t, J = 8.3 Hz, 1H, H4c), 7.30 (d, J = 15.8 Hz, 1H, HE), 7.58 (d, J = 8.7 Hz, 2H, H3, H5), 7.64 (d, J = 8.7 Hz, 2H, H2, H6), 10.40 (s, 1H, 2c OH); 13C NMR (75.6 MHz, DMSO- d6): G 56.1 (CH3O), 102.7 (C5c), 109.4 (C3c), 115.9 (C1c), 124.2 (C4), 129.5 (CD), 130.8 (C2,

C6), 131.3 (C4c), 132.3 (C3, C5), 134.1 (C1), 142.5 (CE), 157.6 (C2c), 158.6 (C6c), 194.6 (CO).

4-Chloro-2c-hydroxy-6c-methoxychalcone (113h) The title compound was synthesized following general procedure 1 using 2c-hydroxy-6c-methoxyacetophenone 112b (2.5 g, 15.04 mmol), 4-chlorobenzaldehyde 67c (2.1 g, 15.04 mmol) and NaOH pellets (1.5 g, 37.61 mmol). The chalcone was obtained as 203 yellow crystals (3.5 g, 80%). M.p. 128-130 °C, lit. 125-126 °C; UV (MeOH): Omax 204 (H -1 -1 12247 cm M ), 225 (6145), 321 (9968) nm; IR (KBr): Qmax 3026, 2968, 2952, 2840, 1646, 1580, 1487, 1465, 1360, 1264, 1200, 1176, 1038, 983, 822, 793, 775 cm-1; 1H NMR (300 MHz,

DMSO-d6): G 3.72 (s, 3H, CH3O), 6.53 (d, J = 8.3 Hz, 1H, H3c), 6.55 (d, J = 8.3 Hz, 1H, H5c),

7.16 (d, J = 16.2 Hz, 1H, HD), 7.24 (t, J = 8.3 Hz, 1H, H4c), 7.30 (d, J = 16.2 Hz, 1H, HE), 7.44 (d, J = 8.3 Hz, 2H, H3, H5), 7.69 (d, J = 8.3 Hz, 2H, H2, H6), 10.45 (s, 1H, 2c OH); 13C NMR

(75.6 MHz, DMSO-d6): G 56.2 (CH3O), 102.7 (C5c), 109.4 (C3c), 116.0 (C1c), 129.4 (CD), 130.6

(C3, C5), 132.3 (C2, C6), 133.7 (C1), 135.4 (C4), 136.8 (C4c), 142.4 (CE), 157.4 (C2c), 158.5 (C6c), 194.6 (CO).

2c-Hydroxy-4,6c-dimethoxychalcone (113i) The title compound was synthesized following general procedure 1 using 2c-hydroxy-6c-methoxyacetophenone 112b (2.5 g, 15.04 mmol), 4-methoxybenzaldehyde 67d (1.8 mL,

158 15.04 mmol) and NaOH pellets (1.5 g, 37.61 mmol). The chalcone was obtained as orange 204 - crystals (3.3 g, 76%). M.p. 100-102 °C, lit. 98-100 °C; UV (MeOH): Omax 204 (H 28827 cm 1 -1 1 M ), 234 (10813), 347 (24156) nm; H NMR (300 MHz, CDCl3): G 3.85 (s, 3H, CH3O), 3.95

(s, 3H, CH3O), 6.43 (d, J = 8.3 Hz, 1H, H3c), 6.61 (d, J = 8.3 Hz, 1H, H5c), 6.93 (d, J = 8.6 Hz, 2H, H3, H5), 7.34 (t, J = 8.3 Hz, 1H, H4c), 7.58 (d, J = 8.6 Hz, 2H, H2, H6), 7.78 (d, J = 15.8

13 Hz, 1H, HD), 7.83 (d, J = 15.8 Hz, 1H, HE), 13.24 (s, 1H, 2c OH); C NMR (75.6 MHz, DMSO- d6): G 55.7 (CH3O), 56.1 (CH3O), 102.7 (C5c), 109.4 (C3c), 114.9 (C3, C5), 116.0 (C1c), 126.5

(CD), 127.3 (C1), 130.7 (C2, C6), 132.2 (C4c), 144.2 (CE), 157.7 (C4), 158.6 (C2c), 161.7 (C6c), 194.6 (CO).

2c-Hydroxy-6c-methoxy-4-methylchalcone (113j) The title compound was synthesized following general procedure 1 using 2c-hydroxy-6c-methoxyacetophenone 112b (2.5 g, 15.04 mmol), 4-methylbenzaldehyde 67e (1.8 mL, 15.04 mmol) and NaOH pellets (1.5 g, 37.61 mmol). The chalcone was obtained as -1 -1 yellow orange crystals (3.1 g, 77%). M.p. 80-82 °C; UV (MeOH): Omax 204 (H 33743 cm M ),

226 (12743), 329 (26336) nm; IR (KBr): Qmax 3007, 2972, 2941, 2836, 1632, 1567, 1511, 1473, -1 1 1453, 1359, 1278, 1238, 1090, 1033, 972, 874, 790, 743 cm ; H NMR (300 MHz, CDCl3): G

2.39 (s, 3H, CH3), 3.93 (s, 3H, CH3O), 6.42 (d, J = 8.3 Hz, 1H, H3c), 6.61 (d, J = 8.3 Hz, 1H, H5c), 7.21 (d, J = 7.9 Hz, 2H, H3, H5), 7.34 (t, J = 8.3 Hz, 1H, H4c), 7.51 (d, J = 7.9 Hz, 2H,

13 H2, H6), 7.82 (d, J = 15.5 Hz, 2H, HD, HE), 13.23 (s, 1H, 2c OH); C NMR (75.6 MHz, CDCl3):

G 21.5 (CH3), 55.8 (CH3O), 101.5 (C5c), 110.8 (C3c), 111.9 (C1c), 126.4 (CD), 128.5 (C2, C6),

129.6 (C3, C5), 132.5 (C1), 135.7 (C4c), 140.8 (C4), 143.1 (CE), 160.9 (C2c), 164.8 (C6c), 194.4 + (CO); (TOF-ESI) m/z Calcd. for C17H16O3 (M + 1) 269.12. Found 269.12; Anal. Calcd. for

C17H16O3: C, 76.10; H, 6.01. Found: C, 75.94; H, 6.25.

6-Methoxyflavene (114a)205 The compound was prepared as described in general procedure 2 using 2c-hydroxy-5c-methoxychalcone 113a (1.0 g, 3.93 mmol) and NaBH4 (0.45 g, 11.80 mmol). The flavene was obtained as a colorless sticky residue (0.67 g, 72%). UV (MeOH): Omax 204 (H -1 -1 11257 cm M ), 231 (46379), 293 (14841) nm; IR (KBr): Qmax 3425, 3018, 2959, 2926, 2852, -1 1 1615, 1493, 1465, 1431, 1269, 1203, 1159, 1039, 968, 807 cm ; H NMR (300 MHz, CDCl3): G

159 3.77 (s, 3H, CH3O), 5.84 (dd, J = 3.0, 10.9 Hz, 1H, H3), 5.88 (dd, J = 1.5, 3.0 Hz, 1H, H2), 6.52 (dd, J = 1.5, 10.9 Hz, 1H, H4), 6.60 (d, J = 3.0 Hz, 1H, H5), 6.68 (dd, J = 3.0, 8.7 Hz, 1H, H7), 6.75 (d, J = 8.7 Hz, 1H, H8), 7.32-7.47 (m, 5H, H2c, H3c, H4c, H5c, H6c); 13C NMR (75.6 MHz,

CDCl3): G 55.7 (CH3O), 76.9 (C2), 111.7 (C5), 114.4 (C7), 116.5 (C8), 122.0 (C4a), 124.1 (C4), 125.8 (C3), 127.0 (C2c, C6c), 128.2 (C4c), 128.6 (C3c, C5c), 140.6 (C1c), 147.0 (C8a), 154.0 (C6).

4c-Bromo-6-methoxyflav-3-ene (114b) The compound was prepared as described in general procedure 2 using 4-bromo-2c-hydroxy-5c-methoxychalcone

113b (1.0 g, 3.0 mmol) and NaBH4 (0.34 g, 9.0 mmol). The flavene was obtained as a white solid (0.61 g, 65%). M.p. 98- -1 -1 100 °C; UV (MeOH): Omax 202 (H 34171 cm M ), 232 (39101), 330 (4329) nm; IR (KBr): Qmax 3441, 3006, 2958, 2931, 2831, 1608, 1580, 1490, 1461, 1427, 1271, 1219, 1152, 1028, 971, 821

-1 1 cm ; H NMR (300 MHz, CDCl3): G 3.76 (s, 3H, CH3O), 5.80 (dd, J = 3.0, 10.9 Hz, 1H, H3), 5.83 (dd, J = 1.5, 3.0 Hz, 1H, H2), 6.52 (dd, J = 1.5, 10.9 Hz, 1H, H4), 6.61 (d, J = 3.0 Hz, 1H, H5), 6.68 (dd, J = 3.0, 8.7 Hz, 1H, H7), 6.74 (d, J = 8.7 Hz, 1H, H8), 7.32 (d, J = 8.3 Hz, 2H, 13 H2c, H6c), 7.49 (d, J = 8.3 Hz, 2H, H3c, H5c); C NMR (75.6 MHz, CDCl3): G 55.6 (CH3O), 76.0 (C2), 111.8 (C5), 114.6 (C7), 116.5 (C8), 121.8 (C4a), 122.2 (C4c), 124.5 (C4), 125.1 (C3), 128.7 (C2c, C6c), 131.7 (C3c, C5c), 139.6 (C1c), 146.7 (C8a), 154.1 (C6); MS (TOF-ESI) m/z + 79 79 Calcd. for C16H13BrO2 (M + 1) 317.02 (Br ). Found 316.95 (Br ); Anal. Calcd. for

C16H13BrO2: C, 60.59; H, 4.13. Found: C, 60.82; H, 4.26.

4c-Chloro-6-methoxyflav-3-ene (114c) The compound was prepared as described in general procedure 2 using 4-chloro-2c-hydroxy-5c-methoxychalcone

113c (1.0 g, 3.46 mmol) and NaBH4 (0.39 g, 10.39 mmol). The flavene was obtained as a white solid (0.65 g, 68%). -1 -1 M.p. 65-67 °C; UV (MeOH): Omax 204 (H 45814 cm M ), 229 (33355), 331 (2951) nm; IR

(KBr): Qmax 3456, 3006, 2950, 2937, 2833, 1610, 1576, 1491, 1468, 1433, 1271, 1215, 1148, -1 1 1042, 966, 834 cm ; H NMR (300 MHz, CDCl3): G 3.76 (s, 3H, CH3O), 5.80 (dd, J = 3.8, 10.9 Hz, 1H, H3), 5.84 (dd, J = 1.9, 3.8 Hz, 1H, H2), 6.52 (dd, J = 1.9, 10.9 Hz, 1H, H4), 6.59 (d, J = 2.6 Hz, 1H, H5), 6.67 (dd, J = 2.6, 8.7 Hz, 1H, H7), 6.72 (d, J = 8.7 Hz, 1H, H8), 7.32 (d, J = 13 8.3 Hz, 2H, H2c, H6c), 7.35 (d, J = 8.3 Hz, 2H, H3c, H5c); C NMR (75.6 MHz, CDCl3): G 55.6 160 (CH3O), 76.0 (C2), 111.8 (C5), 114.6 (C7), 116.5 (C8), 121.8 (C4a), 124.5 (C4), 125.2 (C3), 128.3 (C2c, C6c), 128.7 (C3c, C5c), 134.1 (C4c), 139.0 (C1c), 146.7 (C8a), 154.1 (C6); MS (TOF- + ESI) m/z Calcd. for C16H13ClO2 (M + 1) 273.07. Found 273.00; Anal. Calcd. for

C16H13ClO2.1/10H2O: C, 70.00; H, 4.85. Found: C, 69.97; H, 4.96.

4c,6-Dimethoxyflav-3-ene (114d)205 The compound was prepared as described in general procedure 2 using 2c-hydroxy-4,5c-dimethoxychalcone

113d (1.0 g, 3.52 mmol) and NaBH4 (0.40 g, 10.55 mmol). The flavene was obtained as a light brown solid (0.60 g, 1 65%). M.p. 72-74 °C; H NMR (300 MHz, CDCl3): G 3.76 (s, 3H, CH3O), 3.80 (s, 3H, CH3O), 5.81 (dd, J = 3.4. 9.4 Hz, 1H, H3), 5.86 (dd, J = 1.1, 3.4 Hz, 1H, H2), 6.52 (dd, J = 1.1, 9.4 Hz, 1H, H4), 6.61 (d, J = 2.6 Hz, 1H, H5), 6.66 (dd, J = 2.6, 8.7 Hz, 1H, H7), 6.71 (d, J = 8.7 Hz, 1H, H8), 6.89 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.38 (d, J = 8.7 Hz, 2H, H2c, H6c); 13C NMR (75.6

MHz, CDCl3): G 55.2 (CH3O) 55.6 (CH3O), 76.5 (C2), 111.6 (C5), 113.9 (C3c, C5c), 114.4 (C7), 116.5 (C8), 122.0 (C4a), 124.1 (C4), 125.9 (C3), 128.6 (C2c, C6c), 132.6 (C1c), 147.0 (C8a), 153.9 (C6), 159.6 (C4c).

6-Methoxy-4c-methylflav-3-ene (114e) The compound was prepared as described in general procedure 2 using 2c-hydroxy-5c-methoxy-4-methylchalcone 113e (1.0 g,

3.73 mmol) and NaBH4 (0.42 g, 11.18 mmol). The flavene was obtained as a colorless sticky residue (0.70 g, 74%). UV -1 -1 (MeOH): Omax 204 (H 81758 cm M ), 255 (27838), 290 (16061) nm; IR (KBr): Qmax 3435, 3011, 2999, 2921, 2833, 1610, 1583, 1495, 1464, 1430, 1263, 1201, 1153, 1036, 971, 804 cm-1; 1H

NMR (300 MHz, CDCl3): G 2.35 (s, 3H, CH3), 3.76 (s, 3H, CH3O), 5.82 (dd, J = 3.4. 9.4 Hz, 1H, H3), 5.86 (dd, J = 1.1, 3.4 Hz, 1H, H2), 6.51 (dd, J = 1.1, 9.4 Hz, 1H, H4), 6.59 (d, J = 2.6 Hz, 1H, H5), 6.67 (dd, J = 2.6, 8.7 Hz, 1H, H7), 6.72 (d, J = 8.7 Hz, 1H, H8), 7.17 (d, J = 8.3 13 Hz, 2H, H3c, H5c), 7.34 (d, J = 8.3 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 21.1

(CH3) 55.6 (CH3O), 76.5 (C2), 111.6 (C5), 114.4 (C7), 116.5 (C8), 122.0 (C4a), 124.1 (C4), 125.9 (C3), 127.0 (C2c, C6c), 129.2 (C3c, C5c), 137.6 (C4c), 138.1 (C1c), 147.0 (C8a), 153.9 + (C6); (TOF-ESI) m/z Calcd. for C17H16O2K (M + K) 291.12. Found 291.08; Anal. Calcd. for

C17H16O2.1.6H2O: C, 72.63; H, 6.88. Found: C, 72.55; H, 6.69.

161 5-Methoxyflav-3-ene (114f)83 The compound was prepared as described in general procedure 2 using

2c-hydroxy-6c-methoxychalcone 113f (1.0 g, 3.93 mmol) and NaBH4 (0.45 g, 11.80 mmol). The flavene was obtained as a white solid (0.72 -1 -1 g, 77%). M.p. 89-91 °C; UV (MeOH): Omax 204 (H 13733 cm M ),

228 (12076), 283 (4156) nm; IR (KBr): Qmax 3418, 3013, 2961, 2938, 2840, 1601, 1582, 1466, -1 1 1438, 1272, 1246, 1202, 1107, 1033, 837, 752 cm ; H NMR (300 MHz, CDCl3): G 3.84 (s, 3H,

CH3O), 5.77 (dd, J = 3.4, 10.4 Hz, 1H, H3), 5.86 (dd, J = 1.9, 3.4 Hz, 1H, H2), 6.45 (d, J = 8.3 Hz, 2H, H6, H8), 6.90 (dd, J = 1.9, 10.4 Hz, 1H, H4), 7.06 (t, J = 8.3 Hz, 1H, H7), 7.28-7.42 (m, 13 5H, H2c, H3c, H4c, H5c, H6c); C NMR (75.6 MHz, CDCl3): G 55.6 (CH3O), 76.6 (C2), 103.4 (C6), 109.1 (C8), 110.8 (C4a), 118.7 (C4), 122.8 (C3), 127.0 (C2c, C6c), 128.2 (C4c), 128.5 (C3c, C5c), 129.2 (C7), 140.8 (C1c), 153.9 (C5), 155.3 (C8a).

4c-Bromo-5-methoxyflav-3-ene (114g) The compound was prepared as described in general procedure 2 using 4-bromo-2c-hydroxy-6c-methoxychalcone 113g (1.0 g, 3.0 mmol) and NaBH4 (0.34 g, 9.0 mmol). The flavene was obtained as a white solid (0.69 g, 70%). M.p. 56-58 °C; UV (MeOH): Omax 203 -1 -1 (H 66797 cm M ), 226 (63329), 283 (18772) nm; IR (KBr): Qmax 3423, 3007, 2963, 2934, 2838, 1601, 1580, 1467, 1439, 1272, 1244, 1196, 1098, 1012, 899, 742 -1 1 cm ; H NMR (300 MHz, DMSO-d6): G 3.76 (s, 3H, CH3O), 5.84 (dd, J = 3.4, 9.8 Hz, 1H, H3), 5.88 (dd, J = 1.9, 3.4 Hz, 1H, H2), 6.39 (d, J = 8.3 Hz, 1H, H6), 6.53 (d, J = 8.3 Hz, 1H, H8), 6.78 (dd, J = 1.9, 9.8 Hz, 1H, H4), 7.06 (t, J = 8.3 Hz, 1H, H7), 7.34 (d, J = 8.6 Hz, 2H, H2c,

13 H6c), 7.54 (d, J = 8.6 Hz, 2H, H3c, H5c); C NMR (75.6 MHz, CDCl3): G 55.6 (CH3O), 75.7 (C2), 103.5 (C6), 109.0 (C8), 110.7 (C4a), 119.2 (C4), 122.1 (C3), 122.3 (C4c), 128.7 (C2c, C6c), 129.4 (C7), 131.6 (C3c, C5c), 139.7 (C1c), 153.6 (C5), 155.3 (C8a); MS (TOF-ESI) m/z Calcd. + 79 79 for C16H13BrO2 (M + 1) 317.02 (Br ). Found 316.99 (Br ); Anal. Calcd. for C16H13BrO2: C, 60.59; H, 4.13. Found: C, 60.78; H, 4.24.

162 4c-Chloro-5-methoxyflav-3-ene (114h) The compound was prepared as described in general procedure 2 using 4-chloro-2c-hydroxy-6c-methoxychalcone 113h (1.0 g, 3.46 mmol) and NaBH4 (0.39 g, 10.39 mmol). The flavene was obtained as a yellow sticky residue (0.66 g, 70%). UV (MeOH): Omax 204 (H -1 -1 79277 cm M ), 222 (58394), 275 (18204) nm; IR (KBr): Qmax 3439, 3043, 2983, 2945, 2825, 1736, 1611, 1593, 1470, 1438, 1377, 1268, 1154, 1091, 1013, 829, 780, 750 cm-1; 1H NMR (300

MHz, DMSO-d6): G 3.76 (s, 3H, CH3O), 5.83 (dd, J = 3.8, 9.8 Hz, 1H, H3), 5.88 (dd, J = 1.9, 3.8 Hz, 1H, H2), 6.40 (d, J = 8.3 Hz, 1H, H6), 6.52 (d, J = 8.3 Hz, 1H, H8), 6.79 (dd, J = 1.9, 9.8 Hz, 1H, H4), 7.04 (t, J = 8.3 Hz, 1H, H7), 7.39-7.43 (m, 4H, H2c, H3c, H5c, H6c); 13C NMR

(75.6 MHz, CDCl3): G 55.6 (CH3O), 75.7 (C2), 103.5 (C6), 109.0 (C8), 110.7 (C4a), 119.1 (C4), 122.2 (C3), 128.4 (C2c, C6c), 128.7 (C3c, C5c), 129.4 (C7), 134.0 (C4c), 139.2 (C1c), 153.6 (C5), + 155.3 (C8a); MS (TOF-ESI) m/z Calcd. for C16H13ClO2Na (M + Na) 295.05. Found 295.03;

Anal. Calcd. for C16H13ClO2.H2O: C, 66.10; H, 5.20. Found: C, 66.20; H, 5.45.

4c,5-Dimethoxyflav-3-ene (114i) The compound was prepared as described in general procedure 2 using 2c-hydroxy-4,6c-dimethoxychalcone 113i (1.0 g, 3.52 mmol) and NaBH4 (0.40 g, 10.55 mmol). The flavene was obtained as a white solid (0.75 g, 80%). M.p. 61-63 °C; UV

-1 -1 (MeOH): Omax 203 (H 21185 cm M ), 229 (20204), 282 (7936) nm; IR (KBr): Qmax 3428, 3013, 2965, 2940, 2843, 1601, 1584, 1466, 1426, 1271, 1240, 1204, -1 1 1103, 1029, 833, 747 cm ; H NMR (300 MHz, DMSO-d6): G 3.70 (s, 3H, CH3O), 3.76 (s, 3H,

CH3O), 5.83 (dd, J = 3.8, 9.4 Hz, 1H, H3), 5.85 (dd, J = 1.9, 3.8 Hz, 1H, H2), 6.33 (d, J = 8.3 Hz, 1H, H6), 6.42 (d, J = 8.3 Hz, 1H, H8), 6.78 (dd, J = 1.9, 9.4 Hz, 1H, H4), 6.89 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.03 (t, J = 8.3 Hz, 1H, H7), 7.29 (d, J = 8.7 Hz, 2H, H2c, H6c); 13C NMR

(75.6 MHz, CDCl3): G 55.2 (CH3O), 55.6 (CH3O), 76.3 (C2), 103.3 (C6), 109.1 (C8), 110.8 (C4a), 113.9 (C3c, C5c), 118.7 (C4), 122.9 (C3), 128.7 (C2c, C6c), 129.2 (C7), 132.8 (C1c), 153.8

+ (C5), 155.3 (C8a), 159.6 (C4c); HRMS (ESI) m/z Calcd. for C17H16O3Na (M + Na) 291.0999.

Found 291.1011; Anal. Calcd. for C17H16O3: C, 76.10; H, 6.01. Found: C, 76.11; H, 6.04.

163 5-Methoxy-4c-methylflav-3-ene (114j) The compound was prepared as described in general procedure 2 using 2c-hydroxy-6c-methoxy-4-methylchalcone 113j (1.0 g, 3.73 mmol) and NaBH4 (0.42 g, 11.18 mmol). The flavene was obtained as a colorless sticky residue (0.74 g, 79%). UV (MeOH): Omax 205 (H -1 -1 27890 cm M ), 224 (16588), 275 (6161) nm; IR (KBr): Qmax 3454, 3002, 2978, 2924, 2838, 1605, 1583, 1468, 1439, 1268, 1235, 1098, 1018, 818, 745 cm-1; 1H

NMR (300 MHz, CDCl3): G 2.39 (s, 3H, CH3), 3.86 (s, 3H, CH3O), 5.79 (dd, J = 3.4, 9.8 Hz, 1H, H3), 5.87 (dd, J = 1.9, 3.4 Hz, 1H, H2), 6.46 (d, J = 8.3 Hz, 1H, H6), 6.50 (d, J = 8.3 Hz, 1H, H8), 6.94 (dd, J = 1.9, 9.8 Hz, 1H, H4), 7.09 (t, J = 8.3 Hz, 1H, H7), 7.21 (d, J = 8.6 Hz, 13 2H, H3c, H5c), 7.27 (d, J = 8.6 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 21.1 (CH3),

55.6 (CH3O), 76.5 (C2), 103.3 (C6), 109.1 (C8), 110.8 (C4a), 118.7 (C4), 123.0 (C3), 127.1 (C2c, C6c), 129.2 (C3c, C5c), 129.7 (C7), 137.8 (C4c), 138.0 (C1c), 153.9 (C5), 155.3 (C8a); MS + (TOF-ESI) m/z Calcd. for C17H16O2 (M + 1) 253.12. Found 253.12; Anal. Calcd. for

C17H16O2.H2O: C, 75.53; H, 6.71. Found: C, 75.77; H, 6.38.

(E)-2,9-Dimethoxy-5a-phenyl-11-styryl-5a,11,11a,12-tetrahydrochromeno[2,3-b]chromene (115a) The title compound was synthesized following general procedure 3 using 6-methoxyflavene 114a (0.1 g, 0.42 mmol) and was obtained as a white solid (140 mg, 70%). - M.p. 204-206 °C; UV (MeOH): Omax 204 (H 45414 cm 1M-1), 231 (14449), 256 (16881), 293 (8914) nm; IR

(KBr): Qmax 3440, 3003, 2933, 2837, 1612, 1498, 1464, 1430, 1273, 1231, 1203, 1153, 1035, 972, 952, 823, 802 -1 1 cm ; H NMR (300 MHz, CDCl3): G 2.88 (s, 3H, H11a,

H12), 3.49 (dd, J = 3.0, 9.0 Hz, 1H, H11), 3.69 (s, 3H, CH3O), 3.73 (s, 3H, CH3O), 6.28 (dd, J =

9.0, 15.8 Hz, 1H, HD), 6.51 (d, J = 15.8 Hz, 1H, HE), 6.63 (d, J = 3.0 Hz, 2H, H1, H10), 6.72 (dd, J = 3.0, 8.7 Hz, 1H, H3), 6.80 (dd, J = 3.0, 8.7 Hz, 1H, H8), 6.88 (d, J = 8.7 Hz, 1H, H4), 6.98 (d, J = 8.7 Hz, 1H, H7), 7.28-7.52 (m, 10H, H2c, H3c, H4c, H5c, H6c, H2cc, H3cc, H4cc, H5cc,

13 H6cc); C NMR (75.6 MHz, CDCl3): G 23.2 (C12), 37.9 (C11a), 42.4 (C11), 55.5 (CH3O), 55.6

(CH3O), 100.9 (C5a), 113.6 (C1), 113.8 (C10), 113.9 (C3), 114.3 (C8), 117.1 (C7), 117.5 (C4), 121.6 (C12a), 122.6 (C10a), 125.9 (ArCH), 126.3 (ArCH), 126.8 (ArCH), 127.7 (ArCH), 127.9

(ArCH), 128.6 (ArCH), 128.8 (CD), 133.7 (CE), 136.7 (C1c), 140.5 (C1cc), 145.7 (C4a), 146.3 164 + (C6a), 154.1 (C9), 154.2 (C2); HRMS (ESI) m/z Calcd. for C32H28O4Na (M + Na) 499.1888.

Found 499.1860; Anal. Calcd. for C32H28O4.1/2EtOH: C, 79.33; H, 6.25. Found: C, 79.23; H, 6.29.

(E)-5a-(4cc-Bromophenyl)-11-(4c-bromostyryl)- 2,9-dimethoxy-5a,11,11a,12- tetrahydrochromeno[2,3-b]chromene (115b) The title compound was synthesized following general procedure 3 using 4c-bromo-6-methoxyflavene 114b (0.1 g, 0.32 mmol) and was obtained as a white solid (146 mg,

73%). M.p. 212-214 °C; UV (MeOH): Omax 203 (H 61384 cm-1M-1), 230 (28486), 263 (34167), 291 (17870) nm; IR

(KBr): Qmax 3444, 3006, 2929, 2833, 1615, 1489, 1464, 1427, 1275, 1230, 1200, 1154, 1041, 971, 951, 803 cm-1; 1 H NMR (300 MHz, CDCl3): G 2.84 (s, 3H, H11a, H12),

3.46 (dd, J = 3.4, 9.8 Hz, 1H, H11), 3.70 (s, 3H, CH3O),

3.73 (s, 3H, CH3O), 6.24 (dd, J = 9.8, 15.8 Hz, 1H, HD),

6.47 (d, J = 15.8 Hz, 1H, HE), 6.55 (d, J = 2.3 Hz, 1H, H10), 6.60 (d, J = 3.0 Hz, 1H, H1), 6.72 (dd, J = 3.0, 8.6 Hz, 1H, H3), 6.80 (dd, J = 2.3, 8.3 Hz, 1H, H8), 6.87 (d, J = 8.6 Hz, 1H, H4), 6.96 (d, J = 8.3 Hz, 1H, H7), 7.24 (d, J = 8.6 Hz, 2H, H2cc, H6cc), 7.37 (d, J = 8.3 Hz, 2H, H3c, H5c), 7.41 (d, J = 8.3 Hz, 2H, H2c, H6c), 7.44 (d, J = 8.6 Hz, 2H, H3cc, H5cc); 13C NMR (75.6

MHz, CDCl3): G 23.6 (C12), 37.8 (C11a), 42.3 (C11), 55.5 (CH3O), 55.6 (CH3O), 100.4 (C5a), 113.6 (C1), 113.7 (C10), 114.0 (C3), 114.4 (C8), 117.2 (C7), 117.5 (C4), 121.3 (C4c), 121.6

(C12a), 122.1 (C10a), 123.1(C4cc), 125.8 (C2cc, C6cc), 127.8 (C2c, C6c), 128.5 (CD), 131.6 (C3c,

C5c), 131.7 (C3cc, C5cc), 133.2 (CE), 135.4 (C1c), 139.5 (C1cc), 145.5 (C4a), 145.9 (C6a), 154.2 + 79 (C9), 154.3 (C2); HRMS (ESI) m/z Calcd. for C32H26Br2O4Na (M + Na) 655.0098 (Br ). Found 79 655.0086 (Br ); Anal. Calcd. for C32H26Br2O4: C, 60.59; H, 4.13. Found: C, 60.32; H, 4.13.

165 (E)-5a-(4cc-Chlorophenyl)-11-(4c-chlorostyryl)-2,9-dimethoxy-5a,11,11a,12- tetrahydrochromeno[2,3-b]chromene (115c) The title compound was synthesized following general procedure 3 using 4c-chloro-6-methoxyflavene 114c (0.1 g, 0.37 mmol) and was obtained as a white solid

(148 mg, 74%). M.p. 180-182 °C; UV (MeOH): Omax 203 (H 11232 cm-1M-1), 221 (6487), 268 (18721) nm; IR

(KBr): Qmax 3434, 3003, 2942, 2833, 1614, 1492, 1464, 1426, 1278, 1231, 1197, 1152, 1038, 976, 953, 820, 809 -1 1 cm ; H NMR (300 MHz, CDCl3): G 2.84 (s, 3H, H11a, H12), 3.46 (dd, J = 3.4, 9.0 Hz, 1H, H11), 3.70 (s, 3H,

CH3O), 3.73 (s, 3H, CH3O), 6.23 (dd, J = 9.0, 15.8 Hz, 1H, HD), 6.48 (d, J = 15.8 Hz, 1H, HE), 6.56 (d, J = 3.0 Hz, 1H, H10), 6.60 (d, J = 3.0 Hz, 1H, H1), 6.72 (dd, J = 3.0, 8.7 Hz, 1H, H3), 6.80 (dd, J = 3.0, 9.0 Hz, 1H, H8), 6.87 (d, J = 8.7 Hz, 1H, H4), 6.97 (d, J = 9.0 Hz, 1H, H7), 7.25 (d, J = 8.3 Hz, 2H, H2cc, H6cc), 7.28 (d, J = 8.3 Hz, 2H, H3cc, H5cc), 7.34 (d, J = 8.6 Hz, 2H,

13 H3c, H5c), 7.45 (d, J = 8.6 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 23.6 (C12), 37.8

(C11a), 42.3 (C11), 55.5 (CH3O), 55.6 (CH3O), 100.4 (C5a), 113.6 (C1), 113.7 (C10), 114.0 (C3), 114.3 (C8), 117.2 (C4), 117.5 (C7), 121.3 (C12a), 122.2 (C10a), 127.5 (C3cc, C5cc), 128.0

(CD), 128.3 (C2cc, C6cc), 128.7 (C3c, C5c), 128.8 (C2c, C6c), 133.1 (CE), 133.4 (C4cc), 134.8 (C4c), 135.0 (C1c), 138.9 (C1cc), 145.5 (C4a), 145.9 (C6a), 154.2 (C9), 154.3 (C2); HRMS (ESI) m/z + Calcd. for C32H26Cl2O4Na (M + Na) 567.1108. Found 567.1095; Anal. Calcd. for

C32H26Cl2O4.EtOH: C, 69.04; H, 5.45. Found: C, 69.27; H, 5.14.

(E)-2,9-Dimethoxy-11-(4c-methylstyryl)-5a-p-tolyl-5a,11,11a,12-tetrahydrochromeno[2,3- b]chromene (115d) The title compound was synthesized following general procedure 3 using 6-methoxy-4c-methylflavene 114e (0.1 g, 0.40 mmol) and was obtained as a white solid (144 mg,

72%). M.p. 217-219 °C; UV (MeOH): Omax 204 (H 31109 cm-1M-1), 229 (15067), 261 (11049), 290 (5107) nm; IR

(KBr): Qmax 3435, 2998, 2922, 2832, 1614, 1492, 1464, 1427, 1272, 1232, 1200, 1153, 1039, 971, 951, 820, 803 -1 1 cm ; H NMR (300 MHz, CDCl3): G 2.32 (s, 3H, CH3),

166 2.35 (s, 3H, CH3), 2.85 (s, 3H, H11a, H12), 3.50 (dd, J = 3.0, 9.4 Hz, 1H, H11), 3.69 (s, 3H,

CH3O), 3.73 (s, 3H, CH3O), 6.22 (dd, J = 9.4, 15.8 Hz, 1H, HD), 6.43 (d, J = 15.8 Hz, 1H, HE), 6.53 (d, J = 3.0 Hz, 1H, H10), 6.60 (d, J = 3.0 Hz, 1H, H1), 6.72 (dd, J = 3.0, 9.0 Hz, 1H, H3), 6.78 (dd, J = 3.0, 8.7 Hz, 1H, H8), 6.87 (d, J = 9.0 Hz, 1H, H4), 6.97 (d, J = 8.7 Hz, 1H, H7), 7.14 (d, J = 8.3 Hz, 2H, H3cc, H5cc), 7.18 (d, J = 8.3 Hz, 2H, H3c, H5c), 7.29 (d, J = 8.3 Hz, 2H,

13 H2cc, H6cc), 7.42 (d, J = 8.3 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 20.9 (CH3), 21.2

(CH3), 23.9 (C12), 37.8 (C11a), 42.4 (C11), 55.5 (CH3O), 55.6 (CH3O), 100.9 (C5a), 113.5 (C1), 113.7 (C10), 113.9 (C3), 114.2 (C8), 117.1 (C7), 117.5 (C4), 121.6 (C12a), 122.7 (C10a),

125.8 (C3cc, C5cc), 126.5 (C2cc, C6cc), 128.8 (CD), 129.0 (C2c, C6c), 129.2 (C3c, C5c), 133.9 (CE), 134.0 (C1c), 137.4 (C4cc), 137.5 (C4c), 138.6 (C1cc), 145.7 (C4a), 146.3 (C6a), 153.9 (C9), 154.1 + (C2); HRMS (ESI) m/z Calcd. for C34H32O4Na (M + Na) 527.2201. Found 527.2187; Anal.

Calcd. for C34H32O4.EtOH: C, 78.52; H, 6.96. Found: C, 78.71; H, 6.66.

(E)-1,10-Dimethoxy-5a-phenyl-11-styryl-5a,11,11a,12-tetrahydrochromeno[2,3- b]chromene (120a) The title compound was synthesized following general procedure 3 using 5-methoxyflavene 114f (0.1 g, 0.42 mmol) and was obtained as a white solid (150 mg, 75%). M.p. 127-129 °C; UV (MeOH): -1 -1 Omax 206 (H 48225 cm M ), 258 (10664) nm; IR (KBr): Qmax 3418, 3026, 2933, 2836, 1594, 1489, 1469, 1438, 1349, 1266, 1208, 1096, -1 1 1029, 961, 830, 780 cm ; H NMR (300 MHz, CDCl3): G 2.71 (dd, J = 12.4, 17.3 Hz, 1H, H12), 2.79 (d, J = 17.3 Hz, 1H, H12), 2.99

(dd, J = 6.4, 12.4 Hz, 1H, H11a), 3.64 (s, 3H, CH3O), 3.71 (s, 3H,

CH3O), 3.78 (dd, J = 6.4, 9.0 Hz, 1H, H11), 6.19 (dd, J = 9.0, 15.4 Hz, 1H, HD), 6.33 (d, J =

15.4 Hz, 1H, HE), 6.39 (d, J = 8.3 Hz, 1H, H2), 6.51 (d, J = 8.3 Hz, 1H, H9), 6.69 (d, J = 8.3 Hz, 1H, H4), 6.72 (d, J = 8.3 Hz, 1H, H7), 7.06 (t, J = 8.3 Hz, 2H, H3, H8), 7.10-7.56 (m, 10H, H2c,

13 H3c, H4c, H5c, H6c, H2cc, H3cc, H4cc, H5cc, H6cc); C NMR (75.6 MHz, CDCl3): G 20.3 (C12),

37.0 (C11a), 38.8 (C11), 55.3 (CH3O), 55.6 (CH3O), 100.5 (C5a), 103.0 (C2), 104.0 (C9), 109.1 (C4), 109.7 (C7), 110.7 (C12a), 111.3 (C10a), 125.7 (C4cc), 125.9 (C2cc, C6cc), 126.0 (C3), 126.6

(C8), 127.9 (CD), 128.1 (C4c), 128.3 (C3cc, C5cc), 128.5 (C2c, C6c), 129.7 (C3c, C5c), 131.2 (CE), 136.9 (C1c), 140.5 (C1cc), 152.8 (C4a), 153.7 (C6a), 157.4 (C1), 158.7 (C10); HRMS (ESI) m/z + Calcd. for C32H28O4Na (M + Na) 499.1888. Found 499.1878; Anal. Calcd. for

C32H28O4.1/4EtOH: C, 79.98; H, 6.09. Found: C, 80.18; H, 6.32.

167 (E)-5a-(4cc-Bromophenyl)-11-(4c-bromostyryl)-1,10-dimethoxy-5a,11,11a,12- tetrahydrochromeno[2,3-b]chromene (120b) The title compound was synthesized following general procedure 3 using 4c-bromo-5-methoxyflavene 114g (0.1 g, 0.32 mmol) and was obtained as a white solid (136 mg, 68%). M.p. 118-120 °C; UV -1 -1 (MeOH): Omax 204 (H 103747 cm M ), 265 (11329) nm; IR (KBr):

Qmax 3459, 3005, 2932, 2830, 1593, 1487, 1468, 1350, 1269, 1210, -1 1 1088, 1054, 978, 832, 770 cm ; H NMR (300 MHz, CDCl3): G 2.59 (dd, J = 12.0, 17.7 Hz, 1H, H12), 2.77 (d, J = 17.7 Hz, 1H,

H12), 2.94 (dd, J = 6.4, 12.0 Hz, 1H, H11a), 3.61 (s, 3H, CH3O),

3.70 (s, 3H, CH3O), 3.72 (dd, J = 6.4, 9.0 Hz, 1H, H11), 6.05 (dd, J

= 9.0, 15.8 Hz, 1H, HD), 6.30 (d, J = 15.8 Hz, 1H, HE), 6.35 (d, J = 8.3 Hz, 1H, H2), 6.49 (d, J = 8.3 Hz, 1H, H9), 6.64 (d, J = 8.3 Hz, 2H, H4, H7), 6.79 (t, J = 8.3 Hz, 2H, H3, H8), 7.06 (d, J = 8.3 Hz, 2H, H2cc, H6cc), 7.16 (d, J = 8.3 Hz, 2H, H3c, H5c), 7.27 (d, J = 8.3 Hz, 2H, H2c, H6c),

13 7.49 (d, J = 8.3 Hz, 2H, H3cc, H5cc); C NMR (75.6 MHz, CDCl3): G 21.5 (C12), 36.7 (C11a),

38.8 (C11), 55.3 (2 X CH3O), 99.7 (C5a), 103.4 (C2), 104.3 (C9), 107.5 (C4), 108.8 (C7), 109.4 (C12a), 110.8 (C10a), 119.9 (C4cc), 122.8 (C4c), 126.5 (C3), 127.8 (C2c, C6c), 128.0 (C2cc, C6cc),

128.6 (CD), 128.9 (C8), 130.4 (C3cc, C5cc), 131.0 (C3c, C5c), 131.9 (CE), 135.9 (C1c), 139.8 (C1cc), 152.3 (C4a), 153.8 (C6a), 157.8 (C1), 158.4 (C10); MS (TOF-ESI) m/z Calcd. for + 79 79 C32H26Br2O4 (M + 1) 633.03 (Br ). Found 633.02 (Br ); Anal. Calcd. for C32H26Br2O4: C, 60.59; H, 4.13. Found: C, 60.32; H, 4.36.

(E)-5a-(4cc-Chlorophenyl)-11-(4c-chlorostyryl)-1,10-dimethoxy-5a,11,11a,12- tetrahydrochromeno[2,3-b]chromene (120c) The title compound was synthesized following general procedure 3 using 4c-chloro-5-methoxyflavene 114h (0.1 g, 0.37 mmol) and was obtained as a white solid (144 mg, 72%). M.p. 120-122 °C; UV -1 -1 (MeOH): Omax 205 (H 56444 cm M ), 264 (15800) nm; IR (KBr): Qmax 3420, 3008, 2930, 2837, 1594, 1491, 1469, 1439, 1347, 1267, 1210, -1 1 1094, 1052, 967, 831, 772 cm ; H NMR (300 MHz, CDCl3): G 2.59 (dd, J = 11.7, 17.3 Hz, 1H, H12), 2.77 (d, J = 17.3 Hz, 1H, H12), 2.91

(dd, J = 6.4, 11.7 Hz, 1H, H11a), 3.61 (s, 3H, CH3O), 3.70 (s, 3H,

CH3O), 3.74 (dd, J = 6.4, 9.0 Hz, 1H, H11), 6.04 (dd, J = 9.0, 15.8

Hz, 1H, HD), 6.29 (d, J = 15.8 Hz, 1H, HE), 6.32 (d, J = 8.3 Hz, 1H, H2), 6.49 (d, J = 8.3 Hz, 1H, 168 H9), 6.65 (d, J = 8.3 Hz, 2H, H4, H7), 6.85 (t, J = 8.3 Hz, 2H, H3, H8), 7.11 (d, J = 8.3 Hz, 2H, H2cc, H6cc), 7.18 (d, J = 8.3 Hz, 2H, H3cc, H5cc), 7.29 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.44 (d, J =

13 8.7 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 20.8 (C12), 36.4 (C11a), 38.5 (C11),

55.3 (CH3O), 55.6 (CH3O), 100.0 (C5a), 103.1 (C2), 104.0 (C9), 108.9 (C7), 109.7 (C4), 110.5

(C12a), 111.0 (C10a), 127.1 (C3), 127.3 (C3c, C5c), 127.5 (C3cc, C5cc), 128.1 (C8), 128.4 (CD),

128.6 (C2cc, C6cc), 128.9 (C2c, C6c), 131.3 (CE), 132.1 (C4cc), 134.6 (C4c), 136.2 (C1c), 139.2 (C1cc), 152.3 (C4a), 153.7 (C6a), 157.3 (C1), 158.4 (C10); HRMS (ESI) m/z Calcd. for + C32H26Cl2O4Na (M + Na) 567.1108. Found 567.1079; Anal. Calcd. for C32H26Cl2O4.1/4H2O: C, 69.89; H, 4.86. Found: C, 70.08; H, 4.87.

(E)-1,10-Dimethoxy-5a-(4cc-methoxyphenyl)-11-(4c-methoxystyryl)-5a,11,11a,12- tetrahydrochromeno[2,3-b]chromene (120d) The title compound was synthesized following general procedure 3 using 4c,5-dimethoxyflavene 114i (0.1 g, 0.37 mmol) and was obtained as a white solid (152 mg, 76%). M.p. 134-136 °C; UV -1 -1 (MeOH): Omax 204 (H 36939 cm M ), 267 (9405) nm; IR (KBr): Qmax 3429, 3001, 2933, 2835, 1594, 1489, 1468, 1439, 1348, 1251, 1215,

-1 1 1089, 1034, 981, 834, 777 cm ; H NMR (300 MHz, CDCl3): G 2.70 (dd, J = 12.1, 17.1 Hz, 1H, H12), 2.81 (d, J = 17.1 Hz, 1H, H12),

2.91 (dd, J = 6.4, 12.1 Hz, 1H, H11a), 3.61 (s, 3H, CH3O), 3.68 (s,

3H, CH3O), 3.77 (s, 3H, CH3O), 3.79 (s, 3H, CH3O), 3.80 (dd, J =

6.4, 9.8 Hz, 1H, H11), 6.04 (dd, J = 9.8, 16.2 Hz, 1H, HD), 6.31 (d, J = 16.2 Hz, 1H, HE), 6.36 (d, J = 8.3 Hz, 1H, H2), 6.47 (d, J = 8.3 Hz, 1H, H9), 6.60-6.86 (m, 4H, H3, H4, H7, H8), 6.94 (d, J = 8.7 Hz, 2H, H3cc, H5cc), 7.15 (d, J = 9.0 Hz, 2H, H3c, H5c), 7.37 (d, J = 8.7 Hz, 2H, H2cc,

13 H6cc), 7.44 (d, J = 9.0 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 22.9 (C12), 38.8

(C11a), 39.8 (C11), 55.1 (CH3O), 55.2 (CH3O), 55.4 (2 X CH3O), 99.6 (C5a), 102.8 (C2), 103.6 (C9), 109.5 (C4), 109.7 (C7), 113.5 (C12a), 113.6 (C10a), 126.9 (C3cc, C5cc), 127.0 (C3), 127.2

(C3c, C5c), 127.8 (C8), 128.3 (CD), 128.8 (C2cc, C6cc), 129.9 (C2c, C6c), 131.8 (CE), 136.3 (C1c), 139.6 (C1cc), 152.8 (C4a), 152.9 (C6a), 157.6 (C1), 158.5 (C10), 158.9 (C4cc), 159.7 (C4c); + HRMS (ESI) m/z Calcd. for C34H32O6Na (M + Na) 559.2099. Found 559.2071; Anal. Calcd. for

C34H32O6: C, 76.10; H, 6.01. Found: C, 76.22; H, 6.29.

169 (E)-1,10-Dimethoxy-11-(4c-methylstyryl)-5a-p-tolyl-5a,11,11a,12-tetrahydrochromeno[2,3- b]chromene (120e) The title compound was synthesized following general procedure 3 using 5-methoxy-4c-methylflavene 114j (0.1 g, 0.40 mmol) and was obtained as a white solid (148 mg, 74%). M.p. 186-188 °C; UV -1 -1 (MeOH): Omax 204 (H 50304 cm M ), 261 (11142) nm; IR (KBr):

Qmax 3432, 3023, 2933, 2837, 1593, 1485, 1468, 1437, 1350, 1268, -1 1 1208, 1087, 1055, 976, 825, 770 cm ; H NMR (300 MHz, CDCl3):

G 2.24 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.63 (dd, J = 12.4, 17.3 Hz, 1H, H12), 2.72 (d, J = 17.3 Hz, 1H, H12), 2.81 (dd, J = 6.3, 12.4 Hz,

1H, H11a), 3.61 (dd, J = 6.3, 8.3 Hz, 1H, H11), 3.66 (s, 3H, CH3O),

3.78 (s, 3H, CH3O), 5.33 (dd, J = 8.3, 15.5 Hz, 1H, HD), 6.09 (d, J = 15.5 Hz, 1H, HE), 6.47 (d, J = 8.3 Hz, 2H, H2, H9), 6.61 (d, J = 8.3 Hz, 1H, H4), 6.70 (d, J = 8.3 Hz, 1H, H7), 6.87 (t, J = 8.3 Hz, 2H, H3, H8), 7.00 (d, J = 8.3 Hz, 2H, H3cc, H5cc), 7.08 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.16 (d, J = 8.3 Hz, 2H, H2cc, H6cc), 7.33 (d, J = 8.7 Hz, 2H, H2c, H6c); 13C NMR (75.6 MHz,

CDCl3): G 21.0 (2 X CH3), 22.9 (C12), 38.7 (C11a), 39.8 (C11), 55.3 (CH3O), 55.4 (CH3O), 99.7 (C5a), 102.7 (C2), 103.5 (C9), 109.5 (C4), 109.6 (C7), 109.7 (C12a), 111.5 (C10a), 125.8 (C3cc,

C5cc), 126.9 (CD), 127.2 (C3), 128.3 (C8), 128.8 (C2cc, C6cc), 129.0 (C2c, C6c), 129.3 (C3c, C5c),

130.9 (CE), 133.9 (C1c), 136.2 (C4cc), 137.5 (C4c), 138.5 (C1cc), 152.7 (C4a), 152.9 (C6a), 157.5 + (C1), 158.9 (C10); HRMS (ESI) m/z Calcd. for C34H32O4Na (M + Na) 527.2201. Found

527.2193; Anal. Calcd. for C34H32O4.EtOAc: C, 77.00; H, 6.80. Found: C, 77.30; H, 6.54.

3-(2-Hydroxy-6-methoxyphenyl)-1-(4-methoxyphenyl)propan-1-one (121a) The compound was prepared as described in general procedure 3 using 4c,5-dimethoxyflavene 114i (0.1 g, 0.37 mmol) and few drops of 10M HCl. The 2c-hydroxydihydrochalcone was obtained as a white solid (55 mg, 52%). M.p. 132-134 °C; UV -1 -1 (MeOH): Omax 204 (H 52560 cm M ), 273 (19331) nm; IR (KBr): Qmax 3238, 3077, 2959, 2835, 1645, 1603, 1575, 1471, 1366, 1249, 1182, 1090, 1030, 836, 781, 736 cm-1; 1H NMR (300 MHz,

CDCl3): G 3.01 (t, J = 5.3 Hz, 2H, CH2), 3.38 (t, J = 5.3 Hz, 2H, CH2), 3.82 (s, 3H, CH3O), 3.86

(s, 3H, CH3O), 6.42 (d, J = 8.3 Hz, 1H, H3c), 6.61 (d, J = 8.3 Hz, 1H, H5c), 6.90 (d, J = 9.0 Hz, 2H, H3, H5), 7.06 (t, J = 8.3 Hz, 1H, H4c), 7.96 (d, J = 9.0 Hz, 2H, H2, H6), 8.75 (s, 1H, 2c OH);

13 C NMR (75.6 MHz, CDCl3): G 16.8 (CH2), 38.3 (CH2), 55.4 (2 X CH3O), 102.2 (C5c), 110.6

170 (C3c), 113.6 (C3, C5), 116.4 (C1c), 127.5 (C2, C6), 129.2 (C1), 130.7 (C4c), 155.7 (C2c), 158.3

+ (C6c), 163.9 (C4), 201.5 (CO); MS (TOF-ESI) m/z Calcd. for C17H18O4 (M + 1) 287.13. Found

287.09; Anal. Calcd. for C17H18O4: C, 71.31; H, 6.34. Found: C, 71.06; H, 6.33.

3-(2-Hydroxy-6-methoxyphenyl)-1-p-tolylpropan-1-one (121b) The compound was prepared as described in general procedure 3 using 5-methoxy-4c-methylflavene 114j (0.1 g, 0.40 mmol) and few drops of 10M HCl. The 2c-hydroxydihydrochalcone was obtained as a white solid (61 mg, 58%). M.p. 117-119 °C; UV -1 -1 (MeOH): Omax 205 (H 5719 cm M ), 254 (1600) nm; IR (KBr): Qmax 3349, 2994, 2936, 2829, 1664, 1606, 1574, 1471, 1350, 1259, 1186, 1095, 1030, 819, 777, 736 cm-1; 1H NMR (300 MHz,

CDCl3): G 2.40 (s, 3H, CH3), 3.02 (t, J = 5.3 Hz, 2H, CH2), 3.41 (t, J = 5.3 Hz, 2H, CH2), 3.83 (s,

3H, CH3O), 6.43 (d, J = 8.3 Hz, 1H, H3c), 6.61 (d, J = 8.3 Hz, 1H, H5c), 7.06 (t, J = 8.3 Hz, 1H, H4c), 7.23 (d, J = 8.3 Hz, 2H, H2, H6), 7.88 (d, J = 8.3 Hz, 2H, H3, H5), 8.61 (s, 1H, 2c OH);

13 C NMR (75.6 MHz, CDCl3): G 16.8 (CH2), 21.6 (CH3), 38.6 (CH2), 55.4 (CH3O), 102.3 (C5c), 110.6 (C3c), 116.3 (C1c), 127.5 (C2, C6), 128.4 (C3, C5), 129.2 (C4c), 133.6 (C1), 144.6 (C4),

+ 155.7 (C2c), 158.3 (C6c), 202.7 (CO); MS (TOF-ESI) m/z Calcd. for C17H18O3 (M + 1) 271.13.

Found 271.10; Anal. Calcd. for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.98; H, 6.75.

4c-Chloro-6-methoxyflav-2-ene (124a) To a solution of 4c-chloro-6-methoxyflav-3-ene 114c (500 mg, 1.83 mmol) in toluene (30 mL), was added in drops, 1M solution in ether of allyl magnesium bromide (0.78 mL, 4.58 mmol) and the mixture was refluxed for 48 h. The reaction mixture was quenched by the addition of NH4Cl solution (25 mL, 25%). It was extracted with EtOAc (2 X 100 mL). The combined organic layers were collected, washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. Column chromatography of the crude product over silica gel using DCM/light petroleum (35:65) eluted the title compound as a -1 -1 light brown solid (220 mg, 44%). M.p. 108-110 °C; UV (MeOH): Omax 203 (H 42465 cm M ),

247 (32594), 291 (7050) nm; IR (KBr): Qmax 3435, 1668, 1498, 1259, 1213, 1096, 1047, 845, -1 1 824, 777 cm ; H NMR (300 MHz, CDCl3): G 3.48 (d, J = 4.1 Hz, 2H, H4), 3.71 (s, 3H, CH3O), 5.37 (t, J = 3.8 Hz, 1H, H3), 6.52 (d, J = 3.0 Hz, 1H, H5), 6.66 (dd, J = 3.0, 9.0 Hz, 1H, H7), 6.88 (d, J = 9.0 Hz, 1H, H8), 7.26 (dd, J = 1.9, 6.8 Hz, 2H, H2c, H6c), 7.52 (dd, J = 1.9, 6.8 Hz,

13 2H, H3c, H5c); C NMR (75.6 MHz, CDCl3): G 25.3 (C4), 56.1 (CH3O), 96.2 (C3), 113.6 (C7), 171 113.7 (C5), 117.8 (C8), 120.6 (C4a), 126.2 (C3c, C5c), 128.8 (C2c, C6c), 133.5 (C1c), 134.3

+ (C4c), 146.2 (C8a), 148.6 (C2), 155.9 (C6); MS (TOF-ESI) m/z Calcd. for C16H13ClO2 (M + 1)

273.07. Found 273.04; Anal. Calcd. for C16H13ClO2.0.3CH2Cl2: C, 65.65; H, 4.60. Found: C, 65.95; H, 4.70.

4c-Chloro-5-methoxyflav-2-ene (124b) To a solution of 4c-chloro-5-methoxyflav-3-ene 114h (500 mg, 1.83 mmol) in toluene (30 mL), was added in drops, 1M solution in ether of allyl magnesium bromide (0.78 mL, 4.58 mmol) and the mixture was refluxed for 48 h. The reaction mixture was quenched by the addition of NH4Cl solution (25 mL, 25%). It was extracted with EtOAc (2 X 100 mL). The combined organic layers were collected, washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. Column chromatography of the crude product over silica gel using DCM/light petroleum (35:65) eluted the title compound as a -1 -1 light brown solid (230 mg, 46%). M.p. 76-78 °C; UV (MeOH): Omax 203 (H 50595 cm M ), 241

(30039), 276 (9064) nm; IR (KBr): Qmax 3444, 1673, 1486, 1264, 1230, 1092, 1052, 837, 823, -1 1 781 cm ; H NMR (300 MHz, CDCl3): G 3.33 (d, J = 3.8 Hz, 2H, H4), 3.73 (s, 3H, CH3O), 5.40 (t, J = 3.8 Hz, 1H, H3), 6.45 (d, J = 8.3 Hz, 1H, H6), 6.55 (d, J = 8.3 Hz, 1H, H8), 7.03 (t, J = 8.3 Hz, 1H, H7), 7.24 (dd, J = 1.9, 6.8 Hz, 2H, H2c, H6c), 7.50 (dd, J = 1.9, 6.8 Hz, 2H, H3c,

13 H5c); C NMR (75.6 MHz, CDCl3): G 18.8 (C4), 54.5 (CH3O), 95.9 (C3), 103.5 (C6), 107.7 (C8), 107.9 (C4a), 124.6 (C3c, C5c), 126.3 (C7), 127.4 (C2c, C6c), 131.9 (C1c), 132.8 (C4c), + 146.4 (C2), 151.3 (C8a), 156.4 (C5); MS (TOF-ESI) m/z Calcd. for C16H13ClO2 (M + 1)

273.07. Found 273.04; Anal. Calcd. for C16H13ClO2.1/4H2O: C, 69.32; H, 4.91. Found: C, 69.14; H, 5.00.

1-(4-Chlorophenyl)-3-(2-hydroxy-5-methoxyphenyl)propan-1-one (126a) To a solution of 4c-chloro-6-methoxyflav-2-ene 124a (200 mg, 0.73 mmol) in MeOH (20 mL) was added 10 drops of TFA and the solution was heated at 60-70 qC for 12 h. The solvent was partially removed under reduced pressure and EtOAc (25 mL) was added. The organic layer was washed with saturated NaHCO3 solution (20 mL), dried over anhydrous

Na2SO4 and evaporated under reduced pressure. Purification of the crude product by column chromatography over silica gel using DCM/light petroleum (30:70) eluted the title compound as -1 -1 a white solid (126 mg, 59%). M.p. 83-85 °C; UV (MeOH): Omax 204 (H 53664 cm M ), 251 172 -1 1 (29153) nm; IR (KBr): Qmax 3296, 1661, 1590, 1398, 1245, 1176, 1091, 1047, 828 cm ; H NMR

(300 MHz, CDCl3): G 2.92 (t, J = 6.0 Hz, 2H, CH2), 3.31 (t, J = 6.0 Hz, 2H, CH2), 3.66 (s, 3H,

CH3O), 6.57 (d, J = 7.5 Hz, 1H, H3c), 6.60 (d, J = 2.3 Hz, 1H, H6c), 6.76 (dd, J = 2.3, 7.5 Hz, 1H, H4c), 7.33 (dd, J = 1.9, 6.8 Hz, 2H, H3, H5), 7.82 (dd, J = 1.9, 6.8 Hz, 2H, H2, H6); 13C

NMR (75.6 MHz, CDCl3): G 24.2 (CH2), 40.7 (CH2), 56.1 (CH3O), 113.3 (C4c), 116.3 (C6c), 118.4 (C3c), 129.0 (C1c), 129.4 (C3, C5), 130.1 (C2, C6), 134.8 (C1), 140.6 (C4), 148.6 (C2c),

+ 154.0 (C5c), 200.9 (CO); MS (TOF-ESI) m/z Calcd. for C16H15ClO3 (M + 1) 291.08. Found

291.04; Anal. Calcd. for C16H15ClO3: C, 66.10; H, 5.20. Found: C, 66.01; H, 5.26.

1-(4-Chlorophenyl)-3-(2-hydroxy-6-methoxyphenyl)propan-1-one (126b) To a solution of 4c-chloro-5-methoxyflav-2-ene 124b (200 mg, 0.73 mmol) in MeOH (20 mL) was added 10 drops of TFA and the solution was heated at 60-70 qC for 12 h. The solvent was partially removed under reduced pressure and EtOAc (25 mL) was added. The organic layer was washed with saturated NaHCO3 solution (20 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. Purification of the crude product by column chromatography over silica gel using DCM/light petroleum (30:70) eluted the title compound as a white solid (132 mg, -1 -1 61%). M.p. 128-130 °C; UV (MeOH): Omax 204 (H 39097 cm M ), 251 (12764) nm; IR (KBr): -1 1 Qmax 3289, 1664, 1589, 1402, 1242, 1170, 1091, 1011, 839 cm ; H NMR (300 MHz, CDCl3): G

2.94 (t, J = 5.6 Hz, 2H, CH2), 3.31 (t, J = 5.6 Hz, 2H, CH2), 3.75 (s, 3H, CH3O), 6.36 (d, J = 8.3 Hz, 1H, H3c), 6.53 (d, J = 8.3 Hz, 1H, H5c), 6.99 (t, J = 8.3 Hz, 1H, H4c), 7.33 (dd, J = 1.9, 6.8 Hz, 2H, H3, H5), 7.84 (dd, J = 1.9, 6.8 Hz, 2H, H2, H6), 8.24 (s, 1H, 2c OH); 13C NMR (75.6

MHz, CDCl3): G 17.3 (CH2), 39.2 (CH2), 55.9 (CH3O), 102.9 (C5c), 111.0 (C3c), 116.4 (C1c), 128.1 (C4c), 129.3 (C3, C5), 130.2 (C2, C6), 134.9 (C1), 140.6 (C4), 155.9 (C2c), 158.8 (C6c), + 202.3 (CO); MS (TOF-ESI) m/z Calcd. for C16H15ClO3 (M + 1) 291.08. Found 291.05; Anal.

Calcd. for C16H15ClO3: C, 66.10; H, 5.20. Found: C, 66.01; H, 5.36.

173 (E)-6-Methoxy-4-(4-methoxystyryl)-2,2-diphenylchroman (128a) To a solution of 4c,6-dimethoxyflavene 114d (250 mg, 0.93 mmol) in 20 mL of anhydrous DCM, was added diphenylethylene

127 (1.0 mL) and 5 drops of BF3·OEt2. The reaction mixture was stirred overnight at r.t. It was quenched by the addition of Na2CO3 solution (15 mL, 20%) and extracted with DCM (20 mL). The organic layer was dried over anhydrous Na2SO4, and evaporated. Chromatography over silica gel using DCM/light petroleum (40:60) eluted the title compound as a white solid (235 mg, 56%). -1 -1 M.p. 128-130 °C; UV (MeOH): Omax 204 (H 80774 cm M ) nm; -1 1 IR (KBr): Qmax 3435, 1510, 1493, 1441, 1249, 1220, 1108, 1040, 701 cm ; H NMR (300 MHz,

CDCl3): G 2.49-2.54 (m, 2H, H3), 2.74-2.78 (m, 1H, H4), 3.72 (s, 3H, CH3O), 3.83 (s, 3H,

CH3O), 6.33-6.39 (m, 1H, HE), 6.68-6.73 (m, 1H, HD), 6.79 (d, J = 1.5 Hz, 1H, H5), 6.91 (dd, J = 1.5, 8.3 Hz, 1H, H7), 6.98 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.00 (d, J = 8.3 Hz, 1H, H8), 7.14 (d,

13 J = 8.7 Hz, 2H, H2c, H6c), 7.20-7.40 (m, 10H, ArH); C NMR (75.6 MHz, CDCl3): G 37.4 (C4),

41.8 (C3), 55.2 (CH3O), 55.3 (CH3O), 80.7 (C2), 112.1 (C7), 113.2 (C8), 114.1 (C3c, C5c), 114.3

(C5), 126.6 (ArCH), 126.8 (ArCH), 127.1 (ArCH), 127.2 (ArCH), 127.8 (CD), 128.0 (ArCH),

128.2 (ArCH), 128.3 (C1c), 129.7 (CE), 131.5 (C2c, C6c), 138.1 (C4a), 142.8 (ArC), 142.9 (ArC), + 143.0 (C8a), 154.3 (C6), 160.0 (C4c); MS (TOF-ESI) m/z Calcd. for C31H28O3 (M + 1) 449.21.

Found 449.18; Anal. Calcd. for C31H28O3: C, 83.01; H, 6.29. Found: C, 83.03; H, 6.24.

(E)-5-Methoxy-4-(4-methoxystyryl)-2,2-diphenylchroman (128b) To a solution of 4c,5-dimethoxyflavene 114i (250 mg, 0.93 mmol) in 20 mL of anhydrous DCM, was added diphenylethylene 127 (1.0 mL) and 5 drops of BF3·OEt2. The reaction mixture was stirred overnight at r.t. It was quenched by the addition of Na2CO3 (15 mL, 20%) and extracted with DCM (20 mL). The organic layer was dried over anhydrous

Na2SO4, and evaporated. Chromatography over silica gel using DCM/light petroleum (40:60) eluted the title compound as a white solid - (247 mg, 59%). M.p. 132-134 °C; UV (MeOH): Omax 204 (H 83450 cm 1 -1 -1 1 M ) nm; IR (KBr): Qmax 3488, 1510, 1493, 1444, 1247, 1221, 1102, 1030, 700 cm ; H NMR

(300 MHz, CDCl3): G 2.24-2.29 (m, 2H, H3), 2.58-2.61 (m, 1H, H4), 3.68 (s, 3H, CH3O), 3.73

(s, 3H, CH3O), 6.08-6.12 (m, 1H, HE), 6.42-6.49 (m, 1H, HD), 6.78 (d, J = 8.3 Hz, 1H, H6), 6.82 (d, J = 8.3 Hz, 1H, H8), 6.92 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.10 (t, J = 8.3 Hz, 1H, H7), 7.19 (d, 174 13 J = 8.7 Hz, 2H, H2c, H6c), 7.25-7.40 (m, 10H, ArH); C NMR (75.6 MHz, CDCl3): G 38.3 (C4),

42.1 (C3), 55.7 (CH3O), 55.9 (CH3O), 81.8 (C2), 111.6 (C6), 112.1 (C4a), 112.9 (C8), 114.9

(C3c, C5c), 126.2 (C7), 126.6 (ArCH), 127.2 (CD), 127.8 (ArCH), 128.0 (ArCH), 128.2 (ArCH),

129.0 (ArCH), 129.4 (ArCH), 129.7 (C1c), 129.9 (CE), 130.2 (C2c, C6c), 142.3 (ArC), 142.8 + (ArC), 143.8 (C8a), 155.0 (C5), 160.9 (C4c); MS (TOF-ESI) m/z Calcd. for C31H28O3 (M + 1)

449.21. Found 449.16; Anal. Calcd. for C31H28O3: C, 83.01; H, 6.29. Found: C, 83.28; H, 6.18.

(E)-5a-(4cc-Methoxyphenyl)-11-(4c-bromostyryl)-1,10-dimethoxy-5a,11,11a,12- tetrahydrochromeno[2,3-b]chromene (137) To a solution of 4c-bromo-5-methoxyflav-3-ene 114g (236 mg, 0.75 mmol) and 4c,5-dimethoxyflav-3-ene 114i (200 mg, 0.75 mmol) in MeOH (20 mL) was added 10 drops of TFA and the solution was heated at 60-70 qC for 12 h. The solvent was partially removed under reduced pressure and EtOAc (25 mL) was added. The organic layer was washed with saturated NaHCO3 solution (20 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. Purification of the crude product by column chromatography over silica gel using DCM/light petroleum (50:50) eluted the title compound as a white solid (183 mg, 42%). M.p. 204-206 °C; UV (MeOH): Omax 204 (H 163246 -1 -1 cm M ), 266 (32672) nm; IR (KBr): Qmax 3439, 1607, 1593, 1513, 1468, 1250, 1211, 1180, -1 1 1088, 1033, 837 cm ; H NMR (300 MHz, CDCl3): G 2.61 (dd, J = 12.0, 17.3 Hz, 1H, H12),

2.75 (d, J = 17.3 Hz, 1H, H12), 2.94 (m, 1H, H11a), 3.61 (s, 3H, CH3O), 3.69 (s, 3H, CH3O),

3.74 (s, 3H, CH3O), 3.77 (dd, J = 6.4, 9.0 Hz, 1H, H11), 6.09 (dd, J = 9.0, 15.4 Hz, 1H, HD),

6.29 (d, J = 15.4 Hz, 1H, HE), 6.32 (d, J = 8.3 Hz, 1H, H2), 6.48 (d, J = 8.3 Hz, 1H, H9), 6.65 (d, J = 8.3 Hz, 1H, H4), 6.67 (d, J = 8.3 Hz, 1H, H7), 6.80 (d, J = 8.3 Hz, 2H, H3cc, H5cc), 6.84 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.05 (t, J = 8.3 Hz, 1H, H3), 7.15 (t, J = 8.3 Hz, 1H, H8), 7.27 (d, J =

13 8.3 Hz, 2H, H2cc, H6cc), 7.43 (d, J = 8.7 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 20.8

(C12), 36.5 (C11a), 38.7 (C11), 55.1 (CH3O), 55.3 (CH3O), 55.5 (CH3O), 100.3 (C5a), 103.0 (C2), 103.8 (C9), 109.1 (C4), 109.8 (C7), 110.7 (C12a), 111.1 (C10a), 113.8 (C3cc, C5cc), 120.1

(C4c), 127.2 (C3), 127.3 (C8), 127.5 (CD), 128.3 (C2cc, C6cc), 128.7 (C2c, C6c), 131.0 (CE), 131.9 (C3c, C5c), 132.7 (C1cc), 136.8 (C1c), 152.6 (C4a), 153.9 (C6a), 157.3 (C4cc), 158.5 (C10), 159.7 + 79 (C1); HRMS (ESI) m/z Calcd. for C33H29BrO5Na (M + Na) 607.1098 (Br ). Found 607.1047 79 (Br ); Anal. Calcd. for C33H29BrO5: C, 67.70; H, 4.99. Found: C, 67.78; H, 5.18.

175 2,4-Dihydroxy-3c,4c-dimethoxydeoxybenzoin (155a) A mixture of resorcinol 153a (3.0 g, 27.24 mmol), 3,4- dimethoxyphenylacetic acid 154 (5.3 g, 27.24 mmol) and

BF3·OEt2 (25 mL) was heated at 100 °C for 2.5 h. The mixture was cooled to room temperature and stirred at r.t. for 1 h. The precipitated product was filtered, dried and recrystallized from EtOH to yield the title compound as off-white crystals (5.0 g, 63%). M.p. 173-175 °C, lit.206 177.5 °C; 1H NMR

(300 MHz, DMSO-d6): G 4.20 and 4.22 (2s, 6H, 2 X CH3O), 4.64 (s, 2H, CH2), 6.77 (d, J = 1.9 Hz, 1H, H3), 6.88 (dd, J = 1.9, 9.0 Hz, 1H, H5), 7.18 (dd, J = 1.9, 8.3 Hz, 1H, H6c), 7.31 (d, J = 8.3 Hz, 1H, H5c), 7.40 (d, J = 1.9 Hz, 1H, H2c), 8.40 (d, J = 9.0 Hz, 1H, H6), 9.87 (s, 1H, 4 OH),

13 13.17 (s, 1H, 2 OH); C NMR (75.6 MHz, DMSO-d6): G 44.0 (CH2), 55.8 and 55.9 (2 X CH3O), 102.8 (C3), 108.6 (C5), 112.3 (C5c), 112.5 (C1), 113.8 (C2c), 121.9 (C6c), 127.8 (C1c), 133.9 (C6), 148.0 (C4c), 149.0 (C3c), 165.0 (C4), 165.3 (C2), 202.8 (CO).

2,4-Dihydroxy-3c,4c-dimethoxy-3-methyldeoxybenzoin (155b) A mixture of 2-methylresorcinol 153b (3.0 g, 24.17 mmol), 3,4-dimethoxyphenylacetic acid 154 (4.7 g, 24.17 mmol) and

BF3·OEt2 (25 mL) was heated at 100 °C for 2.5 h. The mixture was cooled to room temperature and stirred at r.t. for 1 h. The precipitated product was filtered, dried and recrystallized from EtOH to yield the title compound as off-white crystals (5.1 g, 70%). M.p. 207 1 164-166 °C, lit. 168-170 °C; H NMR (300 MHz, DMSO-d6): G 1.93 (s, 3H, CH3), 3.80 and

3.81 (2s, 6H, 2 X CH3O), 4.16 (s, 2H, CH2), 6.45 (d, J = 8.7 Hz, 1H, H5), 6.78 (d, J = 1.9 Hz, 1H, H2c), 6.81 (dd, J = 1.9, 8.3 Hz, 1H, H6c), 6.87 (d, J = 8.3 Hz, 1H, H5c), 7.81 (d, J = 8.7 Hz,

13 1H, H6), 10.53 (s, 1H, 4 OH), 12.98 (s, 1H, 2 OH); C NMR (75.6 MHz, DMSO-d6): G 7.9

(CH3), 43.8 (CH2), 55.8 and 55.9 (2 X CH3O), 107.6 (C5), 110.7 (C3), 111.9 (C1), 112.3 (C5c), 113.7 (C2c), 121.8 (C6c), 127.9 (C1c), 130.6 (C6), 148.0 (C4c), 149.0 (C3c), 161.9 (C4), 163.1 (C2), 203.2 (CO).

2,4-Dihydroxy-3c,4c-dimethoxy-6-methyldeoxybenzoin (155c) A mixture of orcinol 153c (3.0 g, 24.16 mmol), 3,4- dimethoxyphenylacetic acid 154 (4.7 g, 24.16 mmol) and

BF3·OEt2 (25 mL) was heated at 100 °C for 2.5 h. The mixture was cooled to room temperature and stirred at r.t. 176 for 1 h. The precipitated product was filtered and air-dried. The title compound was obtained as -1 -1 a yellow solid (4.8 g, 65%). M.p. 208-210 °C; UV (MeOH): Omax 204 (H 60490 cm M ), 280 -1 1 (13648) nm; IR (KBr): Qmax 3355, 1617, 1519, 1446, 1343, 1264, 1161, 1142, 1025, 845 cm ; H

NMR (300 MHz, DMSO-d6): G 1.94 (s, 3H, CH3), 3.69 and 3.72 (2s, 6H, 2 X CH3O), 4.02 (s,

2H, CH2), 6.07 (s, 1H, H3), 6.22 (s, 1H, H5), 6.68 (d, J = 8.0 Hz, 1H, H6c), 6.74 (s, 1H, H2c), 6.85 (d, J = 8.0 Hz, 1H, H5c), 10.92 (s, 1H, 4 OH), 12.33 (s, 1H, 2 OH); 13C NMR (75.6 MHz,

DMSO-d6): G 20.2 (CH3), 50.4 (CH2), 55.7 and 55.8 (2 X CH3O), 100.5 (C3), 109.3 (C5), 112.0 (C5c), 113.7 (C2c), 120.2 (C1), 122.0 (C6c), 128.1 (C1c), 138.5 (C6), 147.8 (C4c), 148.7 (C3c), + 157.2 (C4), 159.6 (C2), 203.9 (CO); MS (TOF-ESI) m/z Calcd. for C17H18O5 (M + 1) 303.12.

Found 303.00; Anal. Calcd. for C17H18O5: C, 67.54; H, 6.00. Found: C, 67.56; H, 6.08.

7-Hydroxy-3c,4c-dimethoxyisoflavone (156a) A solution of 2,4-dihydroxy-3c,4c-dimethoxydeoxybenzoin 155a (3.0 g, 10.41 mmol) in DMF (25 mL), was placed in an inert atmosphere of nitrogen. BF3·OEt2 (5 mL) was added in drops to the reaction mixture with the use of a dropping funnel, followed by the slow addition of methanesulphonyl chloride (2.4 mL, 31.22 mmol) in DMF (5 mL). The reaction mixture was heated to reflux for 3 h. It was then poured into crushed ice (200 g), and washed subsequently with AcONa solution (200 mL, 20%). The precipitated solid was filtered, air-dried and recrystallized from EtOH to give the title compound as a yellow 208 1 solid (2.0 g, 64%). M.p. 253-255 °C, lit. 255 °C; H NMR (300 MHz, DMSO-d6): G 3.75 (2s,

6H, 2 X CH3O), 6.84 (d, J = 2.3 Hz, 1H, H8), 6.92 (dd, J = 2.3, 8.7 Hz, 1H, H6), 6.96 (d, J = 8.3 Hz, 1H, H5c), 7.08 (dd, J = 1.9, 8.3 Hz, 1H, H6c), 7.16 (d, J = 1.9 Hz, 1H, H2c), 7.95 (d, J = 8.7

13 Hz, 1H, H5), 8.30 (s, 1H, H2), 10.98 (s, 1H, 7 OH); C NMR (75.6 MHz, DMSO-d6): G 55.9 (2

X CH3O), 102.5 (C8), 111.9 (C5c), 113.2 (C2c), 115.6 (C6), 116.9 (C4a), 121.6 (C6c), 123.6 (C3), 124.9 (C1c), 127.7 (C5), 148.6 (C4c), 149.0 (C3c), 153.7 (C2), 157.8 (C8a), 163.0 (C7), 175.0 (C4).

7-Hydroxy-3c,4c-dimethoxy-8-methylisoflavone (156b) A solution of 2,4-dihydroxy-3c,4c-dimethoxy-3- methyldeoxybenzoin 155b (3.0 g, 9.92 mmol) in DMF (25 mL), was placed under a nitrogen atmosphere. BF3·OEt2 (5 mL) was added in drops to the reaction mixture with the use of a dropping funnel, followed by the slow addition of methanesulphonyl chloride (2.3 mL, 177 29.77 mmol) in DMF (5 mL). The reaction mixture was heated to reflux for 3 h. It was then poured into crushed ice (200 g), and washed subsequently with AcONa solution (200 mL, 20%). The precipitated solid was filtered, air-dried and recrystallized from EtOH to give the title compound as an off-white solid (2.3 g, 74%). M.p. 236-238 °C, lit.207 234 °C; 1H NMR (300

MHz, DMSO-d6): G 2.21 (s, 3H, CH3), 3.78 (2s, 6H, 2 X CH3O), 6.97 (d, J = 9.0 Hz, 2H, H6, H5c), 7.10 (dd, J = 2.3, 9.0 Hz, 1H, H6c), 7.16 (d, J = 2.3 Hz, 1H, H2c), 7.82 (d, J = 9.0 Hz, 1H,

13 H5), 8.40 (s, 1H, H2), 11.87 (s, 1H, 7 OH); C NMR (75.6 MHz, DMSO-d6): G 8.3 (CH3), 55.9

(2 X CH3O), 111.3 (C8), 111.9 (C6), 113.1 (C5c), 114.3 (C2c), 117.0 (C4a), 121.6 (C6c), 123.1 (C3), 124.2 (C5), 125.0 (C1c), 148.6 (C4c), 148.9 (C3c), 153.8 (C2), 155.9 (C8a), 160.4 (C7), 175.5 (C4).

7-Hydroxy-3c,4c-dimethoxy-5-methylisoflavone (156c) A solution of 2,4-dihydroxy-3c,4c-dimethoxy-6- methyldeoxybenzoin 155c (3.0 g, 9.92 mmol) in DMF (25 mL), was placed under a nitrogen atmosphere. BF3·OEt2 (5 mL) was added in drops to the reaction mixture with the use of a dropping funnel, followed by the slow addition of methanesulphonyl chloride (2.3 mL, 29.77 mmol) in DMF (5 mL). The reaction mixture was heated to reflux for 3 h. It was then poured into crushed ice (200 g), and washed subsequently with AcONa solution (200 mL, 20%). The precipitated solid was filtered, air-dried and recrystallized from EtOH to give the title compound as an off-white solid (2.1 g, 68%). M.p. 260-261 °C; UV (MeOH): Omax 204 (H 20857 -1 -1 cm M ), 220 (17260), 255 (17558) nm; IR (KBr): Qmax 3248, 1633, 1592, 1518, 1283, 1268, -1 1 1203, 1173, 1030, 837 cm ; H NMR (300 MHz, DMSO-d6): G 2.68 (s, 3H, CH3), 3.75 (2s, 6H,

2 X CH3O), 6.64 (s, 1H, H8), 6.66 (s, 1H, H6), 6.95 (d, J = 8.3 Hz, 1H, H5c), 7.03 (dd, J = 1.6, 8.3 Hz, 1H, H6c), 7.11 (d, J = 1.6 Hz, 1H, H2c), 8.17 (s, 1H, H2), 10.66 (s, 1H, 7 OH); 13C NMR

(75.6 MHz, DMSO-d6): G 23.3 (CH3), 55.9 (2 X CH3O), 100.9 (C8), 111.8 (C5c), 113.4 (C2c), 115.6 (C4a), 117.4 (C6), 121.8 (C6c), 124.6 (C3), 125.2 (C1c), 142.6 (C5), 148.5 (C4c), 148.8

(C3c), 152.1 (C2), 159.2 (C8a), 161.4 (C7), 176.9 (C4); MS (TOF-ESI) m/z Calcd. for C18H16O5 + (M + 1) 313.11. Found 313.00; Anal. Calcd. for C18H16O5: C, 69.22; H, 5.16. Found: C, 69.52; H, 5.14.

178 3c,4c,7-Trimethoxyisoflavone (157a) To a solution of 7-hydroxy-3c,4c-dimethoxyisoflavone 156a (2.0 g, 6.7 mmol) in DMF (25 mL) was added anhydrous

K2CO3 (1.9 g, 13.41 mmol). The reaction mixture was cooled to 0 qC and MeI (0.42 mL, 6.7 mmol) was slowly added to it. The reaction mixture was refluxed for 24 h. It was then poured into crushed ice (250 g) and washed with 2M HCl (100 mL). The precipitated solid was filtered and air-dried to afford the title compound as a white solid (1.9 g, 91%). M.p. 155-157 °C, lit.209 158-159 °C; 1H NMR

(300 MHz, DMSO-d6): G 3.78 and 3.90 (2s, 9H, 3 X CH3O), 6.99 (d, J = 8.3 Hz, 1H, H5c), 7.07 (dd, J = 2.3, 8.3 Hz, 1H, H6c), 7.13 (dd, J = 1.5, 9.0 Hz, 1H, H6), 7.16 (d, J = 2.3 Hz, 1H, H2c), 7.20 (d, J = 1.5 Hz, 1H, H8), 8.03 (d, J = 9.0 Hz, 1H, H5), 8.43 (s, 1H, H2); 13C NMR (75.6

MHz, DMSO-d6): G 55.9 and 56.4 (3 X CH3O), 100.8 (C8), 111.9 (C5c), 113.1 (C2c), 115.1 (C6), 117.9 (C4a), 121.6 (C6c), 123.8 (C3), 124.7 (C1c), 127.3 (C5), 148.6 (C4c), 149.0 (C3c), 154.0 (C2), 157.7 (C8a), 164.1 (C7), 175.0 (C4).

3c,4c,7-Trimethoxy-8-methylisoflavone (157b) To a solution of 7-hydroxy-3c,4c-dimethoxy-8- methylisoflavone 156b (2.0 g, 6.4 mmol) in DMF (25 mL) was added anhydrous K2CO3 (1.8 g, 12.81 mmol). The reaction mixture was cooled to 0 qC and MeI (0.40 mL, 6.4 mmol) was slowly added. The reaction mixture was refluxed for 24 h. It was then poured into crushed ice (250 g) and washed with 2M HCl (100 mL). The precipitated solid was filtered and air-dried to afford the title compound as a white -1 -1 solid (1.9 g, 93%). M.p. 141-143 °C; UV (MeOH): Omax 204 (H 31761 cm M ), 219 (27667),

252 (27590) nm; IR (KBr): Qmax 3442, 1650, 1613, 1522, 1426, 1274, 1254, 1176, 1098, 1030, -1 1 793 cm ; H NMR (300 MHz, DMSO-d6): G 2.26 (s, 3H, CH3), 3.78 and 3.94 (2s, 9H, 3 X

CH3O), 7.00 (d, J = 8.3 Hz, 1H, H5c), 7.15 (dd, J = 1.9, 8.3 Hz, 1H, H6c), 7.21 (d, J = 1.9 Hz, 1H, H2c), 7.22 (d, J = 8.6 Hz, 1H, H6), 7.99 (d, J = 8.6 Hz, 1H, H5), 8.48 (s, 1H, H2); 13C NMR

(75.6 MHz, DMSO-d6): G 8.3 (CH3), 54.8, 55.9 and 56.7 (3 X CH3O), 109.8 (C6), 111.9 (C5c), 113.1 (C2c), 113.2 (C8), 118.0 (C4a), 121.6 (C6c), 123.1 (C3), 124.6 (C5), 124.8 (C1c), 148.6 (C4c), 148.9 (C3c), 154.2 (C2), 154.9 (C8a), 161.2 (C7), 175.5 (C4); MS (TOF-ESI) m/z Calcd. + for C19H18O5 (M + 1) 327.12. Found 326.98; Anal. Calcd. for C19H18O5: C, 69.93; H, 5.56. Found: C, 69.71; H, 5.55.

179 3c,4c,7 -Trimethoxy-5-methylisoflavone (157c) To a solution of 7-hydroxy-3c,4c-dimethoxy-5- methylisoflavone 156c (2.0 g, 6.4 mmol) in DMF (25 mL) was added anhydrous K2CO3 (1.8 g, 12.81 mmol). The reaction mixture was cooled to 0 qC and MeI (0.40 mL, 6.4 mmol) was slowly added to it. The reaction mixture was refluxed for 24 h. It was then poured into crushed ice (250 g) and washed with 2M HCl (100 mL). The precipitated solid was filtered and air-dried to afford the title compound as a white solid (2.0 g, 94%). M.p. 136-138 °C; UV -1 -1 (MeOH): Omax 204 (H 27322 cm M ), 219 (22702), 255 (23000) nm; IR (KBr): Qmax 3448, 1643, -1 1 1609, 1513, 1445, 1281, 1263, 1169, 1138, 1028, 800 cm ; H NMR (300 MHz, CDCl3): G 2.83

(s, 3H, CH3), 3.86, 3.89 and 3.91 (3s, 9H, 3 X CH3O), 6.69 (d, J = 2.6 Hz, 1H, H6), 6.71 (d, J = 2.6 Hz, 1H, H8), 6.90 (d, J = 8.3 Hz, 1H, H5c), 7.01 (dd, J = 2.0, 8.3 Hz, 1H, H6c), 7.11 (d, J =

13 2.0 Hz, 1H, H2c), 7.80 (s, 1H, H2); C NMR (75.6 MHz, CDCl3): G 23.4 (CH3), 55.5, 55.9 and

56.0 (3 X CH3O), 98.3 (C8), 111.0 (C5c), 112.6 (C6), 116.4 (C2c), 116.9 (C4a), 121.4 (C6c), 124.8 (C3), 125.8 (C1c), 143.2 (C5), 148.6 (C4c), 148.9 (C3c), 150.7 (C2), 159.4 (C8a), 161.4 + (C7), 177.6 (C4); MS (TOF-ESI) m/z Calcd. for C19H18O5 (M + 1) 327.12. Found 326.96; Anal.

Calcd. for C19H18O5: C, 69.93; H, 5.56. Found: C, 69.68; H, 5.56.

3c,4c,7-Trimethoxyisoflavanol (158a)210 To a solution of 3c,4c,7-trimethoxyisoflavone 157a (1.0 g,

3.2 mmol) in EtOH (30 mL) was added NaBH4 (0.36 g, 9.6 mmol) in small quantities. The reaction mixture was allowed to stir at r.t. for 12 h. The solvent was distilled off partially under vacuum, ice (50 g) was added and the resulting solution was acidified using 10% AcOH to pH 5. The solution was extracted with EtOAc (2 X 50 mL), and the organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give a residue, which was recrystallized from EtOH to yield the title compound, as white crystals of 2:1 mixture of cis:trans (750 mg, 74%) isomers. The cis/trans mixture was used in subsequent reactions without further separation.

1 cis isomer: H NMR (300 MHz, CDCl3): G 3.16 (dt, J = 3.0, 11.3 Hz, 1H, H3), 3.69, 3.76 and

3.79 (3s, 9H, 3 X CH3O), 4.30 (ddd, J = 1.4, 10.5, 11.3 Hz, 1H, H2), 4.55 (dd, J = 10.5, 11.3 Hz, 1H, H2), 4.65 (dd, J = 1.4, 3.0 Hz, 1H, H4), 6.40 (d, J = 2.5 Hz, 1H, H8), 6.55 (dd, J = 2.5, 8.5 Hz, 1H, H6), 6.75-6.89 (m, 3H, H2c, H5c, H6c), 7.20 (d, J = 8.5 Hz, 1H, H5); 13C NMR (75.6 180 MHz, CDCl3): G 44.3 (C3), 55.7, 56.2 and 56.3 (3 X CH3O), 67.2 (C4), 68.5 (C2), 101.4 (C8), 108.3 (C6), 111.7 (C5c), 111.9 (C2c), 116.7 (C4a), 120.2 (C6c), 130.6 (C1c), 131.7 (C5), 148.7 (C4c), 149.6 (C3c), 155.6 (C8a), 161.4 (C7).

1 trans isomer: H NMR (300 MHz, CDCl3): G 2.98 (ddd, J = 3.6, 7.9, 9.0 Hz, 1H, H3), 3.71, 3.74 and 3.78 (3s, 9H, 3 X CH3O), 4.22 (dd, J = 9.0, 11.0 Hz, 1H, H2), 4.37 (dd, J = 3.6, 11.0 Hz, 1H, H2), 4.77 (d, J = 7.9 Hz, 1H, H4), 6.43 (d, J = 2.5 Hz, 1H, H8), 6.53 (dd, J = 2.5, 8.5 Hz, 1H, H6), 6.75-6.89 (m, 3H, H2c, H5c, H6c), 7.35 (d, J = 8.5 Hz, 1H, H5); 13C NMR (75.6 MHz,

CDCl3): G 47.0 (C3), 55.9, 56.4 and 56.9 (3 X CH3O), 64.7 (C2), 69.5 (C4), 101.6 (C8), 108.3 (C6), 111.8 (C5c), 112.0 (C2c), 117.4 (C4a), 120.7 (C6c), 129.7 (C1c), 131.1 (C5), 148.8 (C4c), 149.6 (C3c), 155.6 (C8a), 160.9 (C7).

3c,4c,7-Trimethoxy-8-methylisoflavanol (158b) To a solution of 3c,4c,7-trimethoxy-8-methylisoflavone 157b (1.0 g, 3.06 mmol) in EtOH (30 mL) was added

NaBH4 (0.35 g, 9.19 mmol) in small quantities. The reaction mixture was allowed to stir at r.t. for 12 h. The solvent was distilled off partially under vacuum, ice (50 g) was added and the resulting solution was acidified using 10% AcOH to pH 5. The solution was extracted with EtOAc (2 X 50 mL), and the organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give a solid which was recrystallized from EtOH to yield the title compound as white crystals of 1:1 mixture of cis:trans (810 mg, 80%) isomers. The cis/trans mixture was used in subsequent reactions without further -1 -1 separation. M.p. 146-148 °C; UV (MeOH): Omax 206 (H 110667 cm M ), 283 (13867), 335 + (18533) nm; HRMS (ESI) m/z Calcd. for C19H22O5Na (M + Na) 353.1367. Found 353.1352.

1 cis isomer: H NMR (300 MHz, CDCl3): G 2.02 (s, 3H, CH3), 3.16 (dt, J = 3.4, 11.3 Hz, 1H,

H3), 3.76, 3.78 and 3.80 (3s, 9H, 3 X CH3O), 4.31 (ddd, J = 1.4, 10.5, 11.3 Hz, 1H, H2), 4.50 (dd, J = 10.5, 11.3 Hz, 1H, H2), 4.71 (dd, J = 1.4, 3.4 Hz, 1H, H4), 6.43 (d, J = 8.3 Hz, 1H, H6), 6.68 (dd, J = 1.9, 7.1 Hz, 1H, H6c), 6.71 (d, J = 1.9 Hz, 1H, H2c), 6.78 (d, J = 7.1 Hz, 1H, H5c),

13 7.02 (d, J = 8.3 Hz, 1H, H5); C NMR (75.6 MHz, CDCl3): G 8.6 (CH3), 46.9 (C3), 55.3, 56.0 and 56.1 (3 X CH3O), 68.4 (C2), 70.1 (C4), 103.8 (C6), 111.7 (C2c), 111.9 (C5c), 113.9 (C8), 117.0 (C4a), 120.7 (C6c), 128.0 (C5), 130.9 (C1c), 148.7 (C4c), 149.6 (C3c), 153.3 (C8a), 158.9 (C7). 181

1 trans isomer: H NMR (300 MHz, CDCl3): G 2.09 (s, 3H, CH3), 2.97 (ddd, J = 3.8, 7.9, 9.0 Hz,

1H, H3), 3.69, 3.71 and 3.76 (3s, 9H, 3 X CH3O), 4.17 (dd, J = 9.0, 11.4 Hz, 1H, H2), 4.34 (dd, J = 3.8, 11.4 Hz, 1H, H2), 4.77 (d, J = 7.9 Hz, 1H, H4), 6.45 (d, J = 8.3 Hz, 1H, H6), 6.69 (dd, J = 1.9, 7.1 Hz, 1H, H6c), 6.73 (d, J = 1.9 Hz, 1H, H2c), 6.80 (d, J = 7.1 Hz, 1H, H5c), 7.16 (d, J =

13 8.3 Hz, 1H, H5); C NMR (75.6 MHz, CDCl3): G 8.6 (CH3), 44.2 (C3), 55.4, 55.9 and 56.7 (3 X

CH3O), 64.8 (C2), 67.7 (C4), 103.9 (C6), 111.8 (C2c), 112.0 (C5c), 113.7 (C8), 117.7 (C4a), 120.2 (C6c), 126.0 (C5), 131.8 (C1c), 148.7 (C4c), 149.6 (C3c), 153.2 (C8a), 158.5 (C7). cis-3c,4c,7-Trimethoxy-5-methylisoflavanol (158c) To a solution of 3c,4c,7-trimethoxy-5-methylisoflavone 157c (1.0 g, 3.06 mmol) in EtOH (30 mL) was added

NaBH4 (0.35 g, 9.19 mmol) in small quantities. The reaction mixture was allowed to stir at r.t. for 12 h. The solvent was distilled off partially under vacuum, ice (50 g) was added and the resulting solution was acidified using 10% AcOH to pH 5. The solution was extracted with EtOAc (2 X 50 mL), and the organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give a solid which was recrystallized from EtOH to yield the title compound, a white solid as the cis (790 mg, 78%) isomer. M.p. 132-134 °C; UV -1 -1 1 (MeOH): Omax 208 (H 230556 cm M ), 228 (65556), 279 (19815) nm; H NMR (300 MHz,

CDCl3): G 2.34 (s, 3H, CH3), 3.17 (dt, J = 3.1, 12.4 Hz, 1H, H3), 3.75, 3.86 and 3.89 (3s, 9H, 3

X CH3O), 4.23 (ddd, J = 1.5, 10.2, 12.4 Hz, 1H, H2), 4.47 (dd, J = 10.2, 12.4 Hz, 1H, H2), 4.77 (dd, J = 1.5, 3.1 Hz, 1H, H4), 6.28 (d, J = 2.0 Hz, 1H, H6), 6.38 (d, J = 2.0 Hz, 1H, H8), 6.78 (d, J = 1.9 Hz, 1H, H2c), 6.80 (dd, J = 1.9, 8.0 Hz, 1H, H6c), 6.87 (d, J = 8.0 Hz, 1H, H5c); 13C

NMR (75.6 MHz, CDCl3): G 18.3 (CH3), 44.3 (C3), 55.1, 55.8 and 55.9 (3 X CH3O), 63.5 (C4), 64.4 (C2), 98.8 (C8), 109.6 (C6), 111.4 (C5c), 111.6 (C2c), 114.5 (C4a), 120.2 (C6c), 130.4 (C1c), 140.0 (C5), 148.3 (C4c), 149.1 (C3c), 155.4 (C8a), 160.3 (C7); HRMS (ESI) m/z Calcd. + for C19H22O5Na (M + Na) 353.1367. Found 353.1350.

182 3c,4c,7-Trimethoxyisoflavene (160a) and 2a-(3,4-Dimethoxyphenyl)-2,2a,6b,7,12b,12c- hexahydro-4,5,10,15-tetramethoxynaphtho[1,2-c: 4,3-cc]bis[1]benzopyran (159a) 3c,4c,7-Trimethoxyisoflavanol 158a (0.25 g, 0.79 mmol) was taken in a dry 25 mL round bottom flask. The reaction mixture was chilled to –78 °C using an acetone/dry ice bath. 2.5 mL of anhydrous DCM was chilled simultaneously to –78 °C and added slowly to the reaction mixture. This was followed by the addition of P2O5 (0.17 g, 1.19 mmol) and the reaction mixture was left to stir at –78 °C for 7 h, and then left to stir overnight at r.t. It was quenched by the addition of NaHCO3 solution (10 mL, 25%). The aqueous layer was extracted with DCM (2 X 10 ml). The organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4. The residue so obtained was purified by column chromatography over silica gel using DCM/light petroleum (50:50) to elute the isoflavene 160a as a white solid (57 mg, 24%). M.p. 112-114 °C, lit.211 112-114 °C; 1H

NMR (300 MHz, CDCl3): G 3.73, 3.83 and 3.87 (3s, 9H, 3 X CH3O), 5.04 (s, 2H, H2), 6.38 (d, J = 2.3 Hz, 1H, H2c), 6.41 (dd, J = 2.3, 8.3 Hz, 1H, H6c), 6.61 (s, 1H, H4), 6.79 (d, J = 8.3 Hz, 1H, H5c), 6.85 (dd, J = 1.9, 8.3 Hz, 1H, H6), 6.88 (d, J = 1.9 Hz, 1H, H8), 6.93 (d, J = 8.3 Hz, 1H,

13 H5); C NMR (75.6 MHz, CDCl3): G 55.8, 56.4 and 56.7 (3 X CH3O), 67.7 (C2), 101.8 (C8), 107.8 (C6), 108.3 (C2c), 111.5 (C5c), 116.7 (C4a), 117.8 (C6c), 118.9 (C4), 127.8 (C5), 128.9 (C3), 130.4 (C1c), 149.3 (C4c), 149.6 (C3c), 154.8 (C8a), 160.8 (C7).

Fraction 2 was eluted using 100% DCM, which gave the dimeric compound 159a as a white solid (24 mg, 5%). -1 - M.p. 176-178 °C; UV (MeOH): Omax 206 (H 282900 cm M 1 ), 281 (26050) nm; IR (KBr): Qmax 3435, 2932, 1609, 1518, 1465, 1266, 1220, 1028, 801 cm-1; 1H NMR (300 MHz,

CDCl3): G 2.75 (dt, J = 3.6, 11.5 Hz, 1H, H6b), 3.26 (d, J = 11.5 Hz, 1H, H12b), 3.68 (dd, J = 3.6, 10.2 Hz, 1H, H7),

3.74 (s, 3H, CH3O), 3.79 (s, 3H, CH3O), 3.82 (s, 3H, CH3O), 3.85 (s, 3H, CH3O), 3.88 (s, 3H,

CH3O), 3.90 (s, 3H, CH3O), 4.07 (s, 1H, H12c), 4.56 (d, J = 11.0 Hz, 1H, H2), 4.70 (d, J = 11.0 Hz, 1H, H2), 4.83 (d, J = 10.2 Hz, 1H, H7), 6.09 (d, J = 8.5 Hz, 1H, H12), 6.32 (d, J = 8.5 Hz, 1H, H13), 6.41 (s, 1H, H3), 6.46 (d, J = 2.0 Hz, 2H, H9, H16), 6.60 (dd, J = 2.0, 8.5 Hz, 1H, H11), 6.65 (dd, J = 2.0, 8.5 Hz, 1H, H14), 6.68-6.76 (m, 3H, H2c, H5c, H6c), 6.87 (s, 1H, H6);

13 C NMR (75.6 MHz, CDCl3): G 36.4 (C12b), 44.2 (C2a), 47.9 (C6b), 51.2 (C12c), 55.9 (CH3O),

56.0 (CH3O), 56.1 (CH3O), 56.2 (CH3O), 56.4 (CH3O), 56.5 (CH3O), 69.9 (C7), 70.3 (C2), 183 100.4 (C9), 100.6 (C16), 102.9 (C11), 103.6 (C14), 107.9 (C6), 110.2 (C5c), 111.5 (C3), 113.8 (C2c), 114.1 (C12a), 114.3 (C12d), 118.0 (C6c), 129.7 (C6a), 130.2 (C12), 131.3 (C13), 131.4 (C2b), 141.7 (C1c), 147.7 (C5), 148.1 (C4c), 148.2 (C4), 149.4 (C3c), 154.4 (C8a), 154.9 (C16a), + 157.1 (C10), 157.4 (C15); HRMS (ESI) m/z Calcd. for C36H36O8Na (M + Na) 619.2310. Found 619.2499.

3c,4c,7-Trimethoxy-8-methylisoflavene (160b) and 2a-(3,4-Dimethoxyphenyl)- 2,2a,6b,7,12b,12c-hexahydro-4,5,10,15-tetramethoxy-9,16-dimethylnaphtho[1,2-c: 4,3- cc]bis[1]benzopyran (159b) 3c,4c,7-Trimethoxy-8-methylisoflavanol 158b (0.25 g, 0.76 mmol) was taken in a dry 25 mL round bottom flask. The reaction mixture was chilled to –78 °C using an acetone/dry ice bath. 2.5 mL of anhydrous DCM was chilled simultaneously to –78 °C and added slowly to the reaction mixture. This was followed by the addition of P2O5 (0.16 g, 1.14 mmol) and the reaction mixture was left to stir at –78 °C for 7 h, and then left to stir overnight at r.t. It was quenched by the addition of NaHCO3 solution (10 mL, 25%). The aqueous layer was extracted with DCM (2 X 10 ml). The organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4. The residue so obtained was purified by column chromatography over silica gel using DCM/light petroleum (50:50) to elute the isoflavene 160b as a white solid (70 mg, 30%). M.p. 122-124 °C; UV (MeOH): Omax 206 (H -1 -1 60670 cm M ), 337 (42873) nm; IR (KBr): Qmax 3452, 1608, 1518, 1489, 1249, 1150, 1117, -1 1 1024, 805 cm ; H NMR (300 MHz, CDCl3): G 2.03 (s, 3H, CH3), 3.75, 3.82 and 3.86 (3s, 9H, 3

X CH3O), 5.04 (s, 2H, H2), 6.38 (d, J = 8.3 Hz, 1H, H6), 6.61 (d, J = 1.1 Hz, 1H, H2c), 6.78 (d, J = 8.3 Hz, 1H, H5), 6.81 (d, J = 8.7 Hz, 1H, H5c), 6.86 (dd, J = 1.1, 8.7 Hz, 1H, H6c), 6.92 (s,

13 1H, H4); C NMR (75.6 MHz, CDCl3): G 8.5 (CH3), 56.0, 56.3 and 56.5 (3 X CH3O), 67.6 (C2), 103.7 (C6), 108.2 (C2c), 111.5 (C5c), 113.8 (C4a), 116.8 (C8), 117.5 (C6c), 119.4 (C5), 124.5 (C4), 129.0 (C3), 130.5 (C1c), 149.2 (C4c), 149.5 (C3c), 152.2 (C8a), 158.9 (C7); MS (TOF-ESI) + m/z Calcd. for C19H20O4 (M + 1) 313.14. Found 313.08; Anal. Calcd. for C19H20O4: C, 73.06; H, 6.45. Found: C, 73.17; H, 6.58.

184 Fraction 2 was eluted using 100% DCM, which gave the dimeric compound 159b as a light brown solid (19 mg,

4%). M.p. 140-142 °C; UV (MeOH): Omax 207 (H 153929 -1 -1 cm M ), 286 (17179) nm; IR (KBr): Qmax 3448, 2934, 1609, 1518, 1465, 1269, 1219, 1026, 809 cm-1; 1H NMR

(300 MHz, CDCl3): G 2.09 (s, 3H, CH3), 2.11 (s, 3H, CH3), 3.27 (dt, J = 4.1, 11.3 Hz, 1H, H6b), 3.56 (d, J = 11.3 Hz,

1H, H12b), 3.70 (dd, J = 4.1, 10.3 Hz, 1H, H7), 3.77 (s, 3H, CH3O), 3.78 (s, 3H, CH3O), 3.84 (s,

3H, CH3O), 3.89 (s, 3H, CH3O), 3.92 (s, 3H, CH3O), 3.94 (s, 3H, CH3O), 4.15 (s, 1H, H12c), 4.29 (d, J = 12.0 Hz, 1H, H2), 4.82 (d, J = 12.0 Hz, 1H, H2), 4.98 (d, J = 10.3 Hz, 1H, H7), 6.23 (d, J = 8.7 Hz, 1H, H11), 6.35 (d, J = 8.3 Hz, 1H, H14), 6.51 (d, J = 8.3 Hz, 1H, H13), 6.60 (d, J = 8.7 Hz, 1H, H12), 6.73 (s, 1H, H3), 6.79 (s, 1H, H6), 6.84 (d, J = 8.3 Hz, 1H, H5c), 7.05 (d, J

13 = 2.3 Hz, 1H, H2c), 7.09 (dd, J = 2.3, 8.3 Hz, 1H, H6c); C NMR (75.6 MHz, CDCl3): G 8.6

(CH3), 8.7 (CH3), 36.4 (C12b), 44.2 (C2a), 47.9 (C6b), 51.2 (C12c), 55.9 (CH3O), 56.0 (CH3O),

56.1 (CH3O), 56.2 (CH3O), 56.4 (CH3O), 56.5 (CH3O), 69.9 (C7), 70.3 (C2), 102.9 (C11), 103.6 (C14), 107.9 (C6), 110.2 (C5c), 111.5 (C3), 113.8 (C2c), 114.1 (C12a), 114.3 (C12d), 116.4 (C9), 118.0 (C6c), 119.6 (C16), 125.2 (C12), 126.3 (C13), 129.7 (C6a), 131.4 (C2b), 141.7 (C1c), 147.7 (C5), 148.1 (C4c), 148.2 (C4), 149.4 (C3c), 154.4 (C8a), 154.9 (C16a), 157.1 (C10), + 157.4 (C15); HRMS (ESI) m/z Calcd. for C38H40O8Na (M + Na) 647.2623. Found 647.2561.

3c,4c,7-Trimethoxy-5-methylisoflavene (160c) and 2a-(3,4-Dimethoxyphenyl)- 2,2a,6b,7,12b,12c-hexahydro-4,5,10,15-tetramethoxy-12,13-dimethylnaphtho[1,2-c: 4,3- cc]bis[1]benzopyran (159c) 3c,4c,7-Trimethoxy-5-methylisoflavanol 158c (0.25 g, 0.76 mmol) was taken in a dry 25 mL round bottom flask. The reaction mixture was chilled to –78 °C using an acetone/dry ice bath. 2.5 mL of anhydrous DCM was chilled simultaneously to –78 °C and added slowly to the reaction mixture. This was followed by the addition of P2O5 (0.16 g, 1.14 mmol) and the reaction mixture was left to stir at –78 °C for 7 h, and then left to stir overnight at r.t. It was quenched by the addition of NaHCO3 solution (10 mL, 25%). The aqueous layer was extracted with DCM (2 X 10 ml). The organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4. The residue so obtained was purified by column chromatography over silica gel using DCM/light petroleum (50:50) to elute the isoflavene 160c as an off-white solid (50 mg, 21%). M.p. 76-78 °C; UV (MeOH): Omax 205 (H

185 -1 -1 89923 cm M ), 335 (29712) nm; IR (KBr): Qmax 3439, 1608, 1517, 1463, 1250, 1147, 1120, -1 1 1024, 809 cm ; H NMR (300 MHz, CDCl3): G 2.35 (s, 3H, CH3), 3.77, 3.90 and 3.94 (3s, 9H, 3

X CH3O), 5.04 (s, 2H, H2), 6.32 (d, J = 2.6 Hz, 1H, H8), 6.61 (d, J = 1.1 Hz, 1H, H2c), 6.77 (d, J = 8.5 Hz, 1H, H5c), 6.85 (d, J = 2.6 Hz, 1H, H6), 6.93 (dd, J = 1.1, 8.5 Hz, 1H, H6c), 6.98 (s,

13 1H, H4); C NMR (75.6 MHz, CDCl3): G 18.7 (CH3), 55.2, 55.9 and 56.0 (3 X CH3O), 66.9 (C2), 100.0 (C8), 107.9 (C2c), 109.3 (C6), 111.1 (C5c), 115.9 (C4a), 117.3 (C6c), 124.1 (C4), 128.4 (C3), 130.4 (C1c), 135.4 (C5), 149.1 (C4c), 149.5 (C3c), 153.2 (C8a), 159.6 (C7); MS + (TOF-ESI) m/z Calcd. for C19H20O4 (M + 1) 313.14. Found 313.05; Anal. Calcd. for C19H20O4: C, 73.06; H, 6.45. Found: C, 72.99; H, 6.63.

Fraction 2 was eluted using 100% DCM, which gave the dimeric compound 159c as a light brown solid (14 mg, - 3%). M.p. 90-92 °C; UV (MeOH): Omax 203 (H 15531 cm 1 -1 M ), 238 (78694), 331 (123167) nm; IR (KBr): Qmax 3444, 2926, 1610, 1516, 1464, 1261, 1229, 1025, 804 cm-1; 1H

NMR (300 MHz, CDCl3): G 2.02 (s, 3H, CH3), 2.10 (s, 3H,

CH3), 3.18 (dt, J = 4.0, 11.2 Hz, 1H, H6b), 3.51 (d, J =

11.2 Hz, 1H, H12b), 3.72 (dd, J = 4.0, 10.3 Hz, 1H, H7), 3.75 (s, 3H, CH3O), 3.77 (s, 3H,

CH3O), 3.81 (s, 3H, CH3O), 3.84 (s, 3H, CH3O), 3.85 (s, 3H, CH3O), 3.91 (s, 3H, CH3O), 4.11 (s, 1H, H12c), 4.22 (d, J = 12.2 Hz, 1H, H2), 4.79 (d, J = 12.2 Hz, 1H, H2), 4.92 (d, J = 10.3 Hz, 1H, H7), 6.17 (d, J = 2.0 Hz, 1H, H9), 6.29 (d, J = 2.0 Hz, 1H, H14), 6.60 (d, J = 2.0 Hz, 1H, H11), 6.62 (d, J = 2.0 Hz, 1H, H16), 6.64 (s, 1H, H3), 6.71 (s, 1H, H6), 6.92 (d, J = 8.3 Hz, 1H, H5c), 7.10 (d, J = 2.6 Hz, 1H, H2c), 7.19 (dd, J = 2.6, 8.3 Hz, 1H, H6c); 13C NMR (75.6 MHz,

CDCl3): G 8.6 (CH3), 8.7 (CH3), 36.4 (C12b), 44.2 (C2a), 47.9 (C6b), 51.2 (C12c), 55.9 (CH3O),

56.0 (CH3O), 56.1 (CH3O), 56.2 (CH3O), 56.4 (CH3O), 56.5 (CH3O), 69.9 (C7), 70.3 (C2), 100.4 (C9), 101.2 (C16), 102.9 (C11), 103.6 (C14), 107.9 (C6), 110.2 (C5c), 111.5 (C3), 113.8 (C2c), 114.1 (C12a), 114.3 (C12d), 118.0 (C6c), 120.4 (C12), 121.3 (C13), 129.7 (C6a), 131.4 (C2b), 141.7 (C1c), 147.7 (C5), 148.1 (C4c), 148.2 (C4), 149.4 (C3c), 154.4 (C8a), 154.9 (C16a), + 157.1 (C10), 157.4 (C15); HRMS (ESI) m/z Calcd. for C38H40O8Na (M + Na) 647.2623. Found 647.2563.

186 (4bR,10bS)-2,3,8-Trimethoxy-12,12-diphenyl-5,10b,11,12-tetrahydro-4bH-naphtho[1,2- c]chromene (164a) To a solution of 3c,4c,7-trimethoxyisoflavanol 158a (250 mg, 0.79 mmol) in 20 mL of anhydrous DCM, was added diphenylethylene 127 (1.0 mL) and 5 drops of BF3·OEt2. The reaction mixture was stirred overnight at r.t. It was quenched by the addition of Na2CO3 solution (15 mL, 20%) and extracted with DCM (20 mL). The organic layer was dried over anhydrous Na2SO4, and evaporated. Chromatography over silica gel using DCM/light petroleum (50:50) eluted the title compound as a white solid (280 mg, 74%). M.p. -1 -1 196-198 °C; UV (MeOH): Omax 207 (H 215289 cm M ), 288 (16077) nm; IR (KBr): Qmax 3451, 2933, 1619, 1506, 1489, 1465, 1443, 1317, 1247, 1221, 1120, 1059, 1033, 704 cm-1; 1H NMR

(300 MHz, CDCl3): G 2.56 (dd, J = 3.4, 12.0 Hz, 1H, H11), 2.63 (dd, J = 3.4, 11.2 Hz, 1H,

H10b), 3.13 (d, J = 12.0 Hz, 1H, H11), 3.20 (dt, J = 3.8, 11.2 Hz, 1H, H4b), 3.42 (s, 3H, CH3O),

3.67 (s, 3H, CH3O), 3.84 (s, 3H, CH3O), 3.95 (d, J = 10.9 Hz, 1H, H5), 4.85 (dd, J = 3.8, 10.9 Hz, 1H, H5), 6.19 (s, 1H, H4), 6.32 (dd, J = 2.6, 8.3 Hz, 1H, H9), 6.36 (d, J = 2.6 Hz, 1H, H7), 6.72 (s, 1H, H1), 6.94 (d, J = 8.3 Hz, 1H, H10), 7.07-7.22 (m, 10H, ArH); 13C NMR (75.6 MHz,

CDCl3): G 33.9 (C10b), 40.5 (C4b), 42.7 (C11), 55.2 (C12), 55.7 (CH3O), 56.0 (CH3O), 56.3

(CH3O), 70.8 (C5), 101.9 (C7), 106.7 (C9), 108.1 (C1), 116.1 (C4), 118.2 (C10a), 125.9 (C10), 126.6 (ArCH), 126.7 (ArCH), 127.8 (C4a), 128.4 (ArCH), 129.7 (ArCH), 129.8 (ArCH), 135.2 (C12a), 147.6 (C2), 148.0 (C3), 149.1 (ArC), 149.8 (ArC), 155.5 (C6a), 159.7 (C8); MS (TOF- + ESI) m/z Calcd. for C32H30O4 (M + 1) 479.22. Found 479.14; Anal. Calcd. for C32H30O4: C, 80.31; H, 6.32. Found: C, 80.53; H, 6.27.

(4bR,10bS)-12-(4-Chlorophenyl)-2,3,8-trimethoxy-12-phenyl-5,10b,11,12-tetrahydro-4bH- naphtho[1,2-c]chromene (164c) To a solution of 3c,4c,7-trimethoxyisoflavanol 158a (250 mg, 0.79 mmol) in 20 mL of anhydrous DCM, was added 1-chloro-4-(1-phenylvinyl)benzene 168a (1.0 mL) and 5 drops of BF3·OEt2. The reaction mixture was stirred overnight at r.t. It was quenched by the addition of Na2CO3 solution (15 mL, 20%) and extracted with DCM (20 mL).

The organic layer was dried over anhydrous Na2SO4, and evaporated. Chromatography over silica gel using DCM/light petroleum (50:50) eluted the title compound as a white solid (275

187 -1 -1 mg, 68%). M.p. 170-172 °C; UV (MeOH): Omax 205 (H 249632 cm M ), 287 (26974) nm; IR

(KBr): Qmax 3450, 2932, 1619, 1513, 1492, 1464, 1444, 1319, 1260, 1219, 1131, 1071, 1039, 701 -1 1 cm ; H NMR (300 MHz, CDCl3): G 2.60 (dd, J = 3.0, 11.8 Hz, 1H, H11), 2.72 (dd, J = 3.0, 11.4 Hz, 1H, H10b), 3.18 (d, J = 11.8 Hz, 1H, H11), 3.28 (dt, J = 3.6, 11.4 Hz, 1H, H4b), 3.57

(s, 3H, CH3O), 3.78 (s, 3H, CH3O), 3.88 (s, 3H, CH3O), 3.99 (d, J = 11.0 Hz, 1H, H5), 4.97 (dd, J = 3.6, 11.0 Hz, 1H, H5), 6.28 (s, 1H, H4), 6.45 (dd, J = 2.6, 8.3 Hz, 1H, H9), 6.48 (d, J = 2.6 Hz, 1H, H7), 6.70 (s, 1H, H1), 6.96 (d, J = 8.3 Hz, 1H, H10), 7.02-7.42 (m, 9H, ArH); 13C NMR

(75.6 MHz, CDCl3): G 33.8 (C10b), 40.9 (C4b), 42.8 (C11), 54.9 (C12), 55.5 (CH3O), 55.9

(CH3O), 56.2 (CH3O), 70.8 (C5), 101.9 (C7), 107.0 (C9), 107.9 (C1), 115.9 (C4), 117.9 (C10a), 125.8 (C10), 126.8 (ArCH), 127.9 (C4a), 128.8 (ArCH), 129.6 (ArCH), 129.9 (ArCH), 130.1 (ArCH), 131.4 (ArC), 133.7 (C12a), 147.9 (C2), 148.2 (C3), 148.8 (ArC), 149.3 (ArC), 155.8 + (C6a), 159.9 (C8); MS (TOF-ESI) m/z Calcd. for C32H29ClO4 (M + 1) 513.18. Found 513.13;

Anal. Calcd. for C32H29ClO4: C, 74.92; H, 5.70. Found: C, 74.89; H, 5.81.

(4bR,10bS)-12-(4-Bromophenyl)-2,3,8-trimethoxy-12-phenyl-5,10b,11,12-tetrahydro-4bH- naphtho[1,2-c]chromene (164e) To a solution of 3c,4c,7-trimethoxyisoflavanol 158a (250 mg, 0.79 mmol) in 20 mL of anhydrous DCM, was added 1-bromo-4-(1-phenylvinyl)benzene 168b (1.0 mL) and 5 drops of BF3·OEt2. The reaction mixture was stirred overnight at r.t. It was quenched by the addition of Na2CO3 solution (15 mL, 20%) and extracted with DCM (20 mL).

The organic layer was dried over anhydrous Na2SO4, and evaporated. Chromatography over silica gel using DCM/light petroleum (50:50) eluted the title compound as a white solid (310 -1 -1 mg, 71%). M.p. 174-176 °C; UV (MeOH): Omax 204 (H 151455 cm M ), 288 (16705) nm; IR

(KBr): Qmax 3441, 2931, 1618, 1505, 1497, 1464, 1444, 1311, 1261, 1221, 1131, 1070, 1034, 702 -1 1 cm ; H NMR (300 MHz, CDCl3): G 2.64 (dd, J = 3.3, 12.0 Hz, 1H, H11), 2.76 (dd, J = 3.3, 11.2 Hz, 1H, H10b), 3.12 (d, J = 12.0 Hz, 1H, H11), 3.25 (dt, J = 3.8, 11.2 Hz, 1H, H4b), 3.55

(s, 3H, CH3O), 3.75 (s, 3H, CH3O), 3.91 (s, 3H, CH3O), 3.98 (d, J = 10.9 Hz, 1H, H5), 4.98 (dd, J = 3.8, 10.9 Hz, 1H, H5), 6.24 (s, 1H, H4), 6.41 (dd, J = 2.6, 8.0 Hz, 1H, H9), 6.45 (d, J = 2.6 Hz, 1H, H7), 6.79 (s, 1H, H1), 6.97 (d, J = 8.0 Hz, 1H, H10), 7.00-7.44 (m, 9H, ArH); 13C NMR

(75.6 MHz, CDCl3): G 33.3 (C10b), 40.0 (C4b), 42.4 (C11), 54.4 (C12), 55.2 (CH3O), 55.6

(CH3O), 55.8 (CH3O), 70.2 (C5), 101.5 (C7), 106.3 (C9), 107.7 (C1), 115.4 (C4), 117.4 (C10a), 120.4 (ArC), 125.3 (C10), 126.4 (ArCH), 127.4 (C4a), 128.0 (ArCH), 129.1 (ArCH), 129.2

188 (ArCH), 130.8 (ArCH), 134.1 (C12a), 147.3 (C2), 147.7 (C3), 148.5 (ArC), 148.7 (ArC), 155.1 + 79 (C6a), 159.3 (C8); MS (TOF-ESI) m/z Calcd. for C32H29BrO4 (M + 1) 557.13 (Br ). Found 79 557.02 (Br ); Anal. Calcd. for C32H29BrO4: C, 68.94; H, 5.24. Found: C, 68.71; H, 5.43.

(4bR,10bS)- 2,3,8-Trimethoxy-12-(4-methoxyphenyl)-12-phenyl-5,10b,11,12-tetrahydro- 4bH-naphtho[1,2-c]chromene (164g) To a solution of 3c,4c,7-trimethoxyisoflavanol 158a (250 mg, 0.79 mmol) in 20 mL of anhydrous DCM, was added 1-methoxy-4-(1-phenylvinyl)benzene 168c (0.5 g) and 5 drops of BF3·OEt2. The reaction mixture was stirred overnight at r.t. It was quenched by the addition of

Na2CO3 solution (15 mL, 20%) and extracted with DCM

(20 mL). The organic layer was dried over anhydrous Na2SO4, and evaporated. Chromatography over silica gel using DCM/light petroleum (50:50) eluted the title compound as a white solid -1 -1 (280 mg, 70%). M.p. 167-169 °C; UV (MeOH): Omax 206 (H 282103 cm M ), 283 (29385) nm;

IR (KBr): Qmax 3441, 2937, 1608, 1510, 1493, 1464, 1443, 1320, 1261, 1212, 1129, 1078, 1032, -1 1 703 cm ; H NMR (300 MHz, CDCl3): G 2.64 (dd, J = 3.4, 11.9 Hz, 1H, H11), 2.71 (dd, J = 3.4, 11.3 Hz, 1H, H10b), 3.14 (d, J = 11.9 Hz, 1H, H11), 3.25 (dt, J = 3.6, 11.3 Hz, 1H, H4b), 3.55

(s, 3H, CH3O), 3.74 (s, 3H, CH3O), 3.80 (s, 3H, CH3O), 3.92 (s, 3H, CH3O), 4.01 (d, J = 11.3 Hz, 1H, H5), 5.02 (dd, J = 3.6, 11.3 Hz, 1H, H5), 6.27 (s, 1H, H4), 6.41 (dd, J = 2.6, 8.3 Hz, 1H, H9), 6.45 (d, J = 2.6 Hz, 1H, H7), 6.81 (d, J = 8.3 Hz, 1H, H10), 6.86 (s, 1H, H1), 7.02-7.30 (m, 13 9H, ArH); C NMR (75.6 MHz, CDCl3): G 33.4 (C10b), 40.1 (C4b), 42.2 (C11), 54.0 (C12),

55.2 (CH3O), 55.5 (CH3O), 55.6 (CH3O), 55.8 (CH3O), 70.3 (C5), 101.4 (C7), 106.2 (C9), 107.6 (C1), 113.1 (ArCH), 115.5 (C4), 117.8 (C10a), 125.4 (C10), 126.1 (ArCH), 127.2 (C4a), 127.8 (ArCH), 129.2 (ArCH), 130.4 (ArCH), 135.0 (C12a), 147.2 (C2), 147.5 (C3), 147.9 (ArC),

149.6 (ArC), 155.1 (C6a), 157.7 (ArC), 159.3 (C8); MS (TOF-ESI) m/z Calcd. for C33H32O5 (M + + 1) 509.23. Found 509.17; Anal. Calcd. for C33H32O5.0.1EtOH: C, 77.70; H, 6.40. Found: C, 77.56; H, 6.70.

189 (4bR,10bS)- 2,3,8-Trimethoxy-12-phenyl-12-p-tolyl-5,10b,11,12-tetrahydro-4bH- naphtho[1,2-c]chromene (164i) To a solution of 3c,4c,7-trimethoxyisoflavanol 158a (250 mg, 0.79 mmol) in 20 mL of anhydrous DCM, was added 1-methyl-4-(1-phenylvinyl)benzene 168d (1.0 mL) and 5 drops of BF3·OEt2. The reaction mixture was stirred overnight at r.t. It was quenched by the addition of Na2CO3 solution (15 mL, 20%) and extracted with DCM (20 mL).

The organic layer was dried over anhydrous Na2SO4, and evaporated. Chromatography over silica gel using DCM/light petroleum (50:50) eluted the title compound as a white solid (270 -1 -1 mg, 69%). M.p. 154-156 °C; UV (MeOH): Omax 206 (H 208167 cm M ), 288 (14933) nm; IR

(KBr): Qmax 3449, 2931, 1618, 1505, 1492, 1458, 1443, 1317, 1263, 1201, 1132, 1066, 1035, 705 -1 1 cm ; H NMR (300 MHz, CDCl3): G 2.33 (s, 3H, CH3), 2.63 (dd, J = 3.3, 12.0 Hz, 1H, H11), 2.70 (dd, J = 3.3, 11.4 Hz, 1H, H10b), 3.20 (d, J = 12.0 Hz, 1H, H11), 3.27 (dt, J = 3.8, 11.4 Hz,

1H, H4b), 3.54 (s, 3H, CH3O), 3.76 (s, 3H, CH3O), 3.93 (s, 3H, CH3O), 4.05 (d, J = 10.2 Hz, 1H, H5), 4.95 (dd, J = 3.8, 10.2 Hz, 1H, H5), 6.28 (s, 1H, H4), 6.42 (dd, J = 2.6, 8.3 Hz, 1H, H9), 6.46 (d, J = 2.6 Hz, 1H, H7), 6.81 (s, 1H, H1), 7.06 (d, J = 8.3 Hz, 1H, H10), 7.07-7.33 (m, 13 9H, ArH); C NMR (75.6 MHz, CDCl3): G 20.8 (CH3), 33.4 (C10b), 40.0 (C4b), 42.2 (C11),

54.4 (C12), 55.2 (CH3O), 55.6 (CH3O), 55.8 (CH3O), 70.3 (C5), 101.4 (C7), 106.3 (C9), 107.6 (C1), 115.6 (C4), 117.8 (C10a), 125.4 (C10), 126.1 (ArCH), 127.3 (C4a), 127.8 (ArCH), 128.6 (ArCH), 129.1 (ArCH), 129.3 (ArCH), 135.0 (C12a), 135.7 (ArC), 147.2 (C2), 147.5 (C3),

147.8 (ArC), 149.5 (ArC), 155.1 (C6a), 159.3 (C8); MS (TOF-ESI) m/z Calcd. for C33H32O4 (M + + 1) 493.24. Found 493.17; Anal. Calcd. for C33H32O4: C, 80.46; H, 6.55. Found: C, 80.57; H, 6.82.

(4bR,10bS)-2,3,8-Trimethoxy-7-methyl-12,12-diphenyl-5,10b,11,12-tetrahydro-4bH- naphtho[1,2-c]chromene (164b) To a solution of 3c,4c,7-trimethoxy-8-methylisoflavanol 158b (250 mg, 0.76 mmol) in 20 mL of anhydrous DCM, was added diphenylethylene 127 (1.0 mL) and 5 drops of

BF3·OEt2. The reaction mixture was stirred overnight at r.t. It was quenched by the addition of Na2CO3 solution (15 mL, 20%) and extracted with DCM (20 mL). The organic layer was dried over anhydrous Na2SO4, and evaporated. Chromatography over silica

190 gel using DCM/light petroleum (50:50) eluted the title compound as a white solid (280 mg, -1 -1 76%). M.p. 194-196 °C; UV (MeOH): Omax 208 (H 229800 cm M ), 285 (16400) nm; IR (KBr): -1 Qmax 3447, 2931, 1610, 1514, 1492, 1463, 1442, 1312, 1248, 1220, 1119, 1065, 1033, 703 cm ; 1 H NMR (300 MHz, CDCl3): G 1.99 (s, 3H, CH3), 2.57 (dd, J = 3.3, 12.0 Hz, 1H, H11), 2.69 (dd, J = 3.3, 11.2 Hz, 1H, H10b), 3.13 (d, J = 12.0 Hz, 1H, H11), 3.17 (dt, J = 3.8, 11.2 Hz, 1H,

H4b), 3.42 (s, 3H, CH3O), 3.69 (s, 3H, CH3O), 3.82 (s, 3H, CH3O), 3.96 (d, J = 10.2 Hz, 1H, H5), 4.94 (dd, J = 3.8, 10.2 Hz, 1H, H5), 6.18 (s, 1H, H4), 6.32 (d, J = 8.7 Hz, 1H, H9), 6.74 (s, 1H, H1), 6.84 (d, J = 8.7 Hz, 1H, H10), 7.07-7.17 (m, 10H, ArH); 13C NMR (75.6 MHz,

CDCl3): G 8.6 (CH3), 34.2 (C10b), 40.5 (C4b), 42.6 (C11), 55.2 (C12), 56.0 (CH3O), 56.1

(CH3O), 56.2 (CH3O), 70.9 (C5), 102.7 (C9), 108.2 (C1), 113.9 (C7), 116.1 (C4), 118.6 (C10a), 122.0 (C10), 126.6 (ArCH), 126.7 (ArCH), 128.0 (C4a), 128.4 (ArCH), 129.8 (ArCH), 129.9 (ArCH), 135.2 (C12a), 147.6 (C2), 148.1 (C3), 148.8 (ArC), 149.9 (ArC), 153.2 (C6a), 157.5 + (C8); MS (TOF-ESI) m/z Calcd. for C33H32O4 (M + 1) 493.24. Found 493.12; Anal. Calcd. for

C33H32O4: C, 80.46; H, 6.55. Found: C, 80.67; H, 6.84.

(4bR,10bS)-12-(4-Chlorophenyl)-2,3,8-trimethoxy-7-methyl-12-phenyl-5,10b,11,12- tetrahydro-4bH-naphtho[1,2-c]chromene (164d) To a solution of 3c,4c,7-trimethoxy-8-methylisoflavanol 158b (250 mg, 0.76 mmol) in 20 mL of anhydrous DCM, was added 1-chloro-4-(1-phenylvinyl)benzene 168a (1.0 mL) and 5 drops of BF3·OEt2. The reaction mixture was stirred overnight at r.t. It was quenched by the addition of

Na2CO3 solution (15 mL, 20%) and extracted with DCM (20 mL). The organic layer was dried over anhydrous

Na2SO4, and evaporated. Chromatography over silica gel using DCM/light petroleum (50:50) eluted the title compound as a white solid (295 mg, 74%). M.p. 144-146 °C; UV (MeOH): Omax -1 -1 207 (H 150453 cm M ), 285 (9827) nm; IR (KBr): Qmax 3444, 2932, 1610, 1514, 1492, 1464, -1 1 1444, 1314, 1249, 1221, 1120, 1070, 1013, 702 cm ; H NMR (300 MHz, CDCl3): G 2.07 (s,

3H, CH3), 2.63 (dd, J = 3.2, 11.8 Hz, 1H, H11), 2.70 (dd, J = 3.2, 11.2 Hz, 1H, H10b), 3.19 (d, J

= 11.8 Hz, 1H, H11), 3.25 (dt, J = 3.8, 11.2 Hz, 1H, H4b), 3.54 (s, 3H, CH3O), 3.78 (s, 3H,

CH3O), 3.91 (s, 3H, CH3O), 4.03 (d, J = 10.3 Hz, 1H, H5), 5.01 (dd, J = 3.8, 10.3 Hz, 1H, H5), 6.23 (s, 1H, H4), 6.42 (d, J = 8.6 Hz, 1H, H9), 6.82 (s, 1H, H1), 6.91 (d, J = 8.6 Hz, 1H, H10), 13 7.09-7.18 (m, 9H, ArH); C NMR (75.6 MHz, CDCl3): G 8.1 (CH3), 33.6 (C10b), 39.9 (C4b),

42.3 (C11), 54.4 (C12), 55.6 (CH3O), 55.7 (CH3O), 55.8 (CH3O), 70.3 (C5), 102.2 (C9), 107.8

191 (C1), 113.4 (C7), 115.3 (C4), 117.8 (C10a), 121.5 (C10), 126.3 (ArCH), 127.6 (C4a), 127.9 (ArCH), 128.0 (ArCH), 129.0 (ArCH), 129.2 (ArCH), 131.9 (ArC), 134.1 (C12a), 147.2 (C2), 147.7 (C3), 148.0 (ArC), 148.8 (ArC), 152.6 (C6a), 157.1 (C8); MS (TOF-ESI) m/z Calcd. for + C33H31ClO4 (M + 1) 527.20. Found 527.01; Anal. Calcd. for C33H31ClO4: C, 75.20; H, 5.93. Found: C, 75.02; H, 6.17.

(4bR,10bS)-12-(4-Bromophenyl)-2,3,8-trimethoxy-7-methyl-12-phenyl-5,10b,11,12- tetrahydro-4bH-naphtho[1,2-c]chromene (164f) To a solution of 3c,4c,7-trimethoxy-8-methylisoflavanol 158b (250 mg, 0.76 mmol) in 20 mL of anhydrous DCM, was added 1-bromo-4-(1-phenylvinyl)benzene 168b (1.0 mL) and 5 drops of BF3·OEt2. The reaction mixture was stirred overnight at r.t. It was quenched by the addition of

Na2CO3 solution (15 mL, 20%) and extracted with DCM (20 mL). The organic layer was dried over anhydrous

Na2SO4, and evaporated. Chromatography over silica gel using DCM/light petroleum (50:50) eluted the title compound as a white solid (275 mg, 64%). M.p. 172-174 °C; UV (MeOH): Omax -1 -1 206 (H 310192 cm M ), 285 (19231) nm; IR (KBr): Qmax 3442, 2931, 1610, 1514, 1492, 1464, -1 1 1440, 1314, 1250, 1221, 1120, 1055, 1008, 703 cm ; H NMR (300 MHz, CDCl3): G 2.06 (s,

3H, CH3), 2.61 (dd, J = 2.8, 11.9 Hz, 1H, H11), 2.72 (dd, J = 2.8, 11.2 Hz, 1H, H10b), 3.16 (d, J

= 11.9 Hz, 1H, H11), 3.24 (dt, J = 3.6, 11.2 Hz, 1H, H4b), 3.54 (s, 3H, CH3O), 3.78 (s, 3H,

CH3O), 3.91 (s, 3H, CH3O), 4.02 (d, J = 10.3 Hz, 1H, H5), 5.01 (dd, J = 3.6, 10.3 Hz, 1H, H5), 6.22 (s, 1H, H4), 6.41 (d, J = 8.6 Hz, 1H, H9), 6.82 (s, 1H, H1), 6.90 (d, J = 8.6 Hz, 1H, H10), 13 7.02-7.43 (m, 9H, ArH); C NMR (75.6 MHz, CDCl3): G 8.1 (CH3), 33.6 (C10b), 39.9 (C4b),

42.2 (C11), 54.4 (C12), 55.5 (CH3O), 55.6 (CH3O), 55.7 (CH3O), 70.3 (C5), 102.2 (C9), 107.7 (C1), 113.4 (C7), 115.2 (ArCH), 115.4 (C4), 117.8 (C10a), 120.1 (ArC), 121.5 (C10), 126.3 (ArCH), 127.6 (C4a), 129.2 (ArCH), 131.0 (ArCH), 131.2 (ArCH), 134.1 (C12a), 146.9 (C2), 147.2 (C3), 148.6 (ArC), 148.7 (ArC), 152.6 (C6a), 157.0 (C8); MS (TOF-ESI) m/z Calcd. for + 79 79 C33H31BrO4 (M + 1) 571.15 (Br ). Found 571.01 (Br ); Anal. Calcd. for C33H31BrO4: C, 69.35; H, 5.47. Found: C, 69.61; H, 5.83.

192 (4bR,10bS)- 2,3,8-Trimethoxy-12-(4-methoxyphenyl)-7-methyl-12-phenyl-5,10b,11,12- tetrahydro-4bH-naphtho[1,2-c]chromene (164h) To a solution of 3c,4c,7-trimethoxy-8-methylisoflavanol 158b (250 mg, 0.76 mmol) in 20 mL of anhydrous DCM, was added 1-methoxy-4-(1-phenylvinyl)benzene 168c (0.5 g) and 5 drops of BF3·OEt2. The reaction mixture was stirred overnight at r.t. It was quenched by the addition of

Na2CO3 solution (15 mL, 20%) and extracted with DCM (20 mL). The organic layer was dried over anhydrous

Na2SO4, and evaporated. Chromatography over silica gel using DCM/light petroleum (50:50) eluted the title compound as a white solid (285 mg, 72%). M.p. 120-122 °C; UV (MeOH): Omax -1 -1 206 (H 53182 cm M ), 285 (4439) nm; IR (KBr): Qmax 3456, 2933, 1610, 1510, 1493, 1464, -1 1 1448, 1313, 1249, 1221, 1120, 1061, 1034, 703 cm ; H NMR (300 MHz, CDCl3): G 2.07 (s,

3H, CH3), 2.60 (dd, J = 3.1, 11.7 Hz, 1H, H11), 2.74 (dd, J = 3.1, 11.4 Hz, 1H, H10b), 3.15 (d, J

= 11.7 Hz, 1H, H11), 3.26 (dt, J = 3.8, 11.4 Hz, 1H, H4b), 3.50 (s, 3H, CH3O), 3.78 (s, 3H,

CH3O), 3.79 (s, 3H, CH3O), 3.91 (s, 3H, CH3O), 4.04 (d, J = 10.2 Hz, 1H, H5), 5.01 (dd, J = 3.8, 10.2 Hz, 1H, H5), 6.25 (s, 1H, H4), 6.41 (d, J = 8.6 Hz, 1H, H9), 6.83 (s, 1H, H1), 6.92 (d, J = 13 8.6 Hz, 1H, H10), 7.05-7.28 (m, 9H, ArH); C NMR (75.6 MHz, CDCl3): G 8.1 (CH3), 33.6

(C10b), 39.9 (C4b), 42.1 (C11), 54.1 (C12), 55.1 (CH3O), 55.5 (CH3O), 55.6 (CH3O), 55.7

(CH3O), 70.5 (C5), 102.2 (C9), 107.7 (C1), 113.1 (C7), 113.4 (ArCH), 115.5 (C4), 118.1 (C10a), 121.5 (C10), 126.1 (ArCH), 127.4 (C4a), 127.8 (ArCH), 129.2 (ArCH), 130.3 (ArCH), 135.1 (C12a), 147.1 (C2), 147.5 (C3), 149.5 (ArC), 149.6 (ArC), 152.6 (C6a), 157.0 (C8), 157.7 + (ArC); MS (TOF-ESI) m/z Calcd. for C34H34O5 (M + 1) 523.25. Found 523.16; Anal. Calcd. for

C34H34O5: C, 78.14; H, 6.56. Found: C, 78.29; H, 6.56.

(4bR,10bS)- 2,3,8-Trimethoxy-7-methyl-12-phenyl-12-p-tolyl-5,10b,11,12-tetrahydro-4bH- naphtho[1,2-c]chromene (164j) To a solution of 3c,4c,7-trimethoxy-8-methylisoflavanol 158b (250 mg, 0.76 mmol) in 20 mL of anhydrous DCM, was added 1-methyl-4-(1-phenylvinyl)benzene 168d (1.0 mL) and 5 drops of BF3·OEt2. The reaction mixture was stirred overnight at r.t. It was quenched by the addition of

Na2CO3 solution (15 mL, 20%) and extracted with DCM

(20 mL). The organic layer was dried over anhydrous Na2SO4, and evaporated. Chromatography

193 over silica gel using DCM/light petroleum (50:50) eluted the title compound as a white solid -1 -1 (270 mg, 71%). M.p. 128-130 °C; UV (MeOH): Omax 207 (H 280974 cm M ), 285 (17692) nm;

IR (KBr): Qmax 3452, 2931, 1611, 1513, 1493, 1464, 1444, 1314, 1249, 1221, 1120, 1072, 1028, -1 1 703 cm ; H NMR (300 MHz, CDCl3): G 2.07 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.63 (dd, J = 3.0, 11.8 Hz, 1H, H11), 2.75 (dd, J = 3.0, 11.3 Hz, 1H, H10b), 3.18 (d, J = 11.8 Hz, 1H, H11), 3.27

(dt, J = 3.8, 11.3 Hz, 1H, H4b), 3.55 (s, 3H, CH3O), 3.78 (s, 3H, CH3O), 3.90 (s, 3H, CH3O), 4.04 (d, J = 10.2 Hz, 1H, H5), 5.03 (dd, J = 3.8, 10.2 Hz, 1H, H5), 6.25 (s, 1H, H4), 6.40 (d, J = 8.5 Hz, 1H, H9), 6.81 (s, 1H, H1), 6.91 (d, J = 8.5 Hz, 1H, H10), 7.01-7.27 (m, 9H, ArH); 13C

NMR (75.6 MHz, CDCl3): G 8.1 (2 X CH3), 33.7 (C10b), 39.9 (C4b), 42.1 (C11), 54.3 (C12),

55.5 (CH3O), 55.6 (CH3O), 55.7 (CH3O), 70.5 (C5), 102.2 (C9), 107.6 (C1), 113.3 (C7), 115.5 (C4), 118.1 (C10a), 121.5 (C10), 126.1 (ArCH), 127.4 (C4a), 127.8 (ArCH), 128.5 (ArCH), 129.2 (ArCH), 129.3 (ArCH), 134.9 (C12a), 135.6 (ArC), 147.1 (C2), 147.5 (C3), 147.8 (ArC), + 149.5 (ArC), 152.6 (C6a), 156.9 (C8); MS (TOF-ESI) m/z Calcd. for C34H34O4 (M + 1) 507.25.

Found 507.18; Anal. Calcd. for C34H34O4: C, 80.60; H, 6.76. Found: C, 80.31; H, 6.46.

1-Chloro-4-(1-phenylvinyl)benzene (168a)212 To a solution of 4-chloroacetophenone 166a (2.65 ml, 16.5 mmol) in anhydrous ether (40 mL) was slowly added in drops, 3M solution in ether of phenylmagnesium bromide 165 (2.2 mL, 16.5 mmol) in an inert atmosphere of nitrogen. The solution was heated to reflux for 6 h. The reaction mixture was quenched by the addition of NH4Cl solution (200 mL, 20%) and the solution was extracted with diethyl ether (2 X 200 mL). The organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4 and evaporated. The crude product, 1-(4-chlorophenyl)-1-phenylethanol 167a obtained as yellow oil was used in the next step without any purification. The residue was dissolved in DCM (30 mL) followed by the addition of BF3·OEt2 (5 mL) and stirred at r.t. for 3 h. The reaction mixture was quenched by the addition of saturated NaHCO3 solution (30 mL).

The organic layer was collected, dried over anhydrous Na2SO4 and evaporated. Column chromatography over silica gel using 100% light petroleum eluted the title compound as a 1 colourless liquid (1.7 g, 49%). H NMR (300 MHz, CDCl3): G 5.56 and 5.58 (2s, 2H, CH2), 13 7.39-7.44 (m, 9H, ArH); C NMR (75.6 MHz, CDCl3): G 114.8 (CH2), 127.3 (C4c), 128.0 (C3, C5), 128.3 (C2c, C6c), 128.4 (C3c, C5c), 129.7 (C2, C6), 133.8 (C1), 140.1 (C4), 141.1 (C1c),

149.1 (C=CH2).

194 1-Bromo-4-(1-phenylvinyl)benzene (168b)126 To a solution of 4-bromoacetophenone 166b (3.0 g, 15.1 mmol) in anhydrous ether (40 mL) was slowly added in drops, 3M solution in ether of phenylmagnesium bromide 165 (2.0 mL, 15.1 mmol) in an inert atmosphere of nitrogen. The solution was heated to reflux for 6 h. The reaction mixture was quenched by the addition of NH4Cl solution (200 mL, 20%) and the solution was extracted with diethyl ether (2 X 200 mL). The organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4 and evaporated. The crude product, 1-(4-bromophenyl)-1-phenylethanol 167b obtained as yellow oil was used in the next step without any purification. The residue was dissolved in DCM (30 mL) followed by the addition of BF3·OEt2 (5 mL) and stirred at r.t. for 3 h. The reaction mixture was quenched by the addition of saturated NaHCO3 solution (30 mL).

The organic layer was collected, dried over anhydrous Na2SO4 and evaporated. Column chromatography over silica gel using 100% light petroleum eluted the title compound as a 1 colourless liquid (1.8 g, 47%). H NMR (300 MHz, CDCl3): G 5.56 and 5.59 (2 X d, J = 1.0 Hz,

2H, CH2), 7.32 (dd, J = 1.9, 6.6 Hz, 2H, H3, H5), 7.41-7.43 (m, 5H, H2c, H3c, H4c, H5c, H6c), 13 7.56 (dd, J = 1.9, 6.6 Hz, 2H, H2, H6); C NMR (75.6 MHz, CDCl3): G 114.9 (CH2), 122.0 (C1), 128.1 (C4c), 128.4 (C2c, C6c), 128.5 (C3c, C5c), 130.1 (C3, C5), 131.5 (C2, C6), 140.5

(C4), 141.1 (C1c), 149.2 (C=CH2).

1-Methoxy-4-(1-phenylvinyl)benzene (168c) To a solution of 4-methoxyacetophenone 166c (3.0 g, 20.0 mmol) in anhydrous ether (40 mL) was slowly added in drops, 3M solution in ether of phenylmagnesium bromide 165 (2.6 mL, 20.0 mmol) in an inert atmosphere of nitrogen. The solution was heated to reflux for 6 h. The reaction mixture was quenched by the addition of NH4Cl solution (200 mL, 20%) and the solution was extracted with diethyl ether (2 X 200 mL). The organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4 and evaporated. The crude product, 1-(4-methoxyphenyl)-1-phenylethanol 167c obtained as yellow oil was used in the next step without any purification. The residue was dissolved in DCM (30 mL) followed by the addition of BF3·OEt2 (5 mL) and stirred at r.t. for 3 h. The reaction mixture was quenched by the addition of saturated NaHCO3 solution (30 mL).

The organic layer was collected, dried over anhydrous Na2SO4 and evaporated. Column chromatography over silica gel using 100% light petroleum eluted the title compound as a white 213 1 solid (2.2 g, 52%). M.p. 68-70 °C, lit. 73-75 °C; H NMR (300 MHz, CDCl3): G 3.89 (s, 3H,

CH3O), 5.44 and 5.48 (2 X d, J = 1.1 Hz, 2H, CH2), 6.95 (dd, J = 1.9, 6.8 Hz, 2H, H2, H6), 7.28

195 (dd, J = 1.9, 6.8 Hz, 2H, H3, H5), 7.35-7.43 (m, 5H, H2c, H3c, H4c, H5c, H6c); 13C NMR (75.6

MHz, CDCl3): G 55.3 (CH3O), 113.0 (CH2), 113.6 (C2, C6), 127.7 (C4c), 128.2 (C2c, C6c), 128.4

(C3c, C5c), 129.5 (C3, C5), 134.0 (C4), 141.9 (C1c), 149.6 (C=CH2), 159.4 (C1).

1-Methyl-4-(1-phenylvinyl)benzene (168d)214 To a solution of 4-methylacetophenone 166d (3.0 g, 22.36 mmol) in anhydrous ether (40 mL) was slowly added in drops, 3M solution in ether of phenylmagnesium bromide 165 (2.9 mL, 22.36 mmol) in an inert atmosphere of nitrogen. The solution was heated to reflux for 6 h. The reaction mixture was quenched by the addition of NH4Cl solution (200 mL, 20%) and the solution was extracted with diethyl ether (2 X 200 mL). The organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4 and evaporated. The crude product, 1-phenyl-1-p-tolylethanol 167d obtained as yellow oil was used in the next step without any purification. The residue was dissolved in

DCM (30 mL) followed by the addition of BF3·OEt2 (5 mL) and stirred at r.t. for 3 h. The reaction mixture was quenched by the addition of saturated NaHCO3 solution (30 mL). The organic layer was collected, dried over anhydrous Na2SO4 and evaporated. Column chromatography over silica gel using 100% light petroleum eluted the title compound as a 1 colourless liquid (2.1 g, 48%). H NMR (300 MHz, CDCl3): G 2.61 (s, 3H, CH3), 5.67 and 5.70 13 (2 X d, J = 1.0 Hz, 2H, CH2), 7.36-7.63 (m, 9H, ArH); C NMR (75.6 MHz, CDCl3): G 21.5

(CH3), 113.9 (CH2), 127.9 (C4c), 128.4 (C2c, C6c), 128.5 (C3c, C5c), 128.6 (C2, C6), 129.2 (C3,

C5), 137.7 (C1), 138.9 (C4), 142.0 (C1c), 150.3 (C=CH2).

trans-3-(3-(3,4-Dimethoxyphenyl)-7-methoxychroman-4-yl)-1-methyl-1H-indole (172) To a stirred solution of 158a (200 mg, 0.63 mmol) and 1- methylindole 171 (0.095 mL, 0.76 mmol) in DCM (20 mL) was added BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of

NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (70:30) gave the title compound as an off-white solid (182 mg, 67%). M.p. 136-138 °C; UV (MeOH): Omax 204 (H -1 -1 295000 cm M ), 226 (156833), 281 (43333) nm; IR (KBr): Qmax 3387, 2932, 2900, 1620, 1504, -1 1 1464, 1265, 1161, 1135, 1039, 810, 747 cm ; H NMR (300 MHz, CDCl3): G 3.41 (ddd, J = 3.3,

196 7.6, 10.8 Hz, 1H, H3), 3.64 (s, 3H, NCH3), 3.66 (s, 3H, CH3O), 3.78 (s, 3H, CH3O), 3.81 (s, 3H,

CH3O), 4.21 (dd, J = 7.6, 10.8 Hz, 1H, H2), 4.37 (dd, J = 3.3, 10.8 Hz, 1H, H2), 4.42 (d, J = 7.6 Hz, 1H, H4), 6.38 (dd, J = 2.6, 8.5 Hz, 1H, H6), 6.48 (d, J = 2.6 Hz, 1H, H8), 6.52 (s, 1H, H2cc), 6.57 (d, J = 1.8 Hz, 1H, H2c), 6.68 (dd, J = 1.8, 8.3 Hz, 1H, H6c), 6.73 (d, J = 8.3 Hz, 1H, H5c), 6.88-7.20 (m, 3H, H5cc, H6cc, H7cc), 7.26 (d, J = 8.5 Hz, 1H, H5), 7.30-7.34 (m, 1H, H4cc); 13C

NMR (75.6 MHz, CDCl3): G 32.5 (NCH3), 39.3 (C4), 44.4 (C3), 55.2 (CH3O), 55.6 (CH3O),

55.7 (CH3O), 69.2 (C2), 100.9 (C8), 107.6 (C6), 109.2 (C7cc), 111.0 (C2c), 111.2 (C5c), 117.0 (C4a), 117.6 (C3cc), 118.7 (C5cc), 119.4 (C6c), 119.5 (C4cc), 121.4 (C6cc), 126.4 (C3cca), 128.3 (C5), 131.2 (C2cc), 134.1 (C7cca), 137.3 (C1c), 147.6 (C4c), 148.6 (C3c), 155.3 (C8a), 159.1 (C7); + MS (TOF-ESI) m/z Calcd. for C27H27NO4 (M + 1) 430.20. Found 430.14; Anal. Calcd. for

C27H27NO4: C, 75.50; H, 6.34; N, 3.26. Found: C, 75.55; H, 6.05; N, 3.39. trans-3-(4-Bromophenyl)-2-(3-(3,4-dimethoxyphenyl)-7-methoxy-8-methylchroman-4-yl)- 4,6-dimethoxy-1H-indole (173) To a stirred solution of 158b (200 mg, 0.61 mmol) and 3- (4c-bromophenyl)-4,6-dimethoxyindole 275 (241 mg,

0.73 mmol) in DCM (20 mL) was added BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (60:40) gave the title compound as a white solid (246 mg, 63%). M.p. 226-228 °C; UV (MeOH): Omax -1 -1 205 (H 266667 cm M ), 276 (27500) nm; IR (KBr): Qmax 3352, 2933, 2834, 1626, 1588, 1516, -1 1 1265, 1120, 1026, 810, 750 cm ; H NMR (300 MHz, CDCl3): G 2.14 (s, 3H, CH3), 3.20 (ddd, J

= 3.6, 10.9, 11.3 Hz, 1H, H3), 3.50 (s, 3H, CH3O), 3.63 (s, 3H, CH3O), 3.78 (s, 3H, CH3O), 3.80

(s, 3H, CH3O), 3.81 (s, 3H, CH3O), 4.13 (dd, J = 10.9, 11.3 Hz, 1H, H2), 4.37 (dd, J = 3.6, 10.9 Hz, 1H, H2), 4.42 (d, J = 10.9 Hz, 1H, H4), 6.11 (d, J = 2.0 Hz, 1H, H5cc), 6.15 (d, J = 2.0 Hz, 1H, H7cc), 6.30 (dd, J = 2.0, 8.3 Hz, 1H, H6c), 6.33 (d, J = 2.0 Hz, 1H, H2c), 6.40 (d, J = 8.6 Hz, 1H, H6), 6.55 (d, J = 8.3 Hz, 1H, H5c), 6.75 (d, J = 8.6 Hz, 1H, H5), 6.86 (s, 1H, NH), 7.32 (d, J

13 = 8.3 Hz, 2H, H2ccc, H6ccc), 7.55 (d, J = 8.3 Hz, 2H, H3ccc, H5ccc); C NMR (75.6 MHz, CDCl3):

G 8.2 (CH3), 40.5 (C4), 45.4 (C3), 54.9 (CH3O), 55.3 (CH3O), 55.5 (CH3O), 55.6 (CH3O), 55.8

(CH3O), 70.1 (C2), 86.8 (C5cc), 91.7 (C7cc), 103.6 (C6), 110.0 (C5), 111.5 (C2c), 113.7 (C5c), 197 116.0 (C4a), 116.6 (C3cc), 119.5 (C6c), 119.7 (C4ccc), 121.2 (C8), 126.8 (C3ccc, C5ccc), 131.6 (C3cca), 132.2 (C2ccc, C6ccc), 133.1 (C2cc), 134.5 (C1ccc), 137.0 (C7cca), 141.2 (C1c), 147.9 (C4c), 148.7 (C3c), 153.4 (C4cc), 154.2 (C6cc), 157.2 (C8a), 157.3 (C7); MS (TOF-ESI) m/z Calcd. for + 79 79 C35H34BrNO6 (M + 1) 644.17 (Br ). Found 644.24 (Br ); Anal. Calcd. for

C35H34BrNO6.0.2CH2Cl2: C, 63.91; H, 5.24; N, 2.12. Found: C, 64.12; H, 5.11; N, 2.40.

6-Hydroxyflavone (216a) The title compound was synthesized following general procedure 4 using 2c,5c-dihydroxyacetophenone 111a (3.0 g, 19.72 mmol), benzoyl chloride 214a (4.6 mL, 39.43 mmol) and K2CO3 (13.6 g, 98.59 mmol) and 6-hydroxyflavone 216a was obtained as a brown

215 1 solid (1.8 g, 38%). M.p. 228-230 °C, lit. 231-232 °C; H NMR (300 MHz, DMSO-d6): G 7.01 (s, 1H, H3), 7.32 (dd, J = 3.0, 9.0 Hz, 1H, H7), 7.38 (d, J = 3.0 Hz, 1H, H5), 7.62-7.66 (m, 3H, H3c, H4c, H5c), 7.71 (d, J = 9.0 Hz, 1H, H8), 8.14 (d, J = 8.6 Hz, 2H, H2c, H6c), 10.10 (s, 1H, 6

13 OH); C NMR (75.6 MHz, DMSO-d6): G 106.3 (C3), 107.8 (C5), 120.2 (C8), 123.5 (C7), 124.6 (C4a), 126.6 (C2c, C6c), 129.5 (C3c, C5c), 131.7 (C1c), 132.0 (C4c), 149.8 (C8a), 155.3 (C6), 162.6 (C2), 177.4 (C4).

4c-Chloro-6-hydroxyflavone (216b)216 The title compound was synthesized following general procedure 4 using 2c,5c-dihydroxyacetophenone 111a (3.0 g, 19.72 mmol), 4-chlorobenzoyl chloride 214b (5.1 mL, 39.43 mmol) and K2CO3 (13.6 g, 98.59 mmol) and 4c-chloro-6- hydroxyflavone 216b was obtained as a pale yellow solid (1.7 g, 32%). M.p. 256-258 °C; UV -1 -1 (MeOH): Omax 204 (H 44010 cm M ), 275 (40974), 306 (30490) nm; IR (KBr): Qmax 3447, 1641, -1 1 1621, 1596, 1492, 1475, 1360, 1095, 828 cm ; H NMR (300 MHz, DMSO-d6): G 6.91 (s, 1H, H3), 7.14-7.19 (m, 2H, H5, H7), 7.54 (d, J = 8.7 Hz, 1H, H8), 7.62 (d, J = 8.7 Hz, 2H, H2c, H6c),

13 8.08 (d, J = 8.7 Hz, 2H, H3c, H5c), 10.86 (s, 1H, 6 OH); C NMR (75.6 MHz, DMSO-d6): G 106.2 (C3), 107.8 (C5), 119.6 (C8), 124.8 (C4a), 124.9 (C7), 128.3 (C3c, C5c), 129.5 (C2c, C6c), 130.9 (C1c), 136.5 (C4c), 148.2 (C8a), 159.5 (C6), 160.8 (C2), 177.6 (C4).

198 6-Hydroxy-4c-methoxyflavone (216c) The title compound was synthesized following general procedure 4 using 2c,5c-dihydroxyacetophenone 111a (3.0 g, 19.72 mmol), 4-methoxybenzoyl chloride 214c (5.1 g,

29.58 mmol) and K2CO3 (13.6 g, 98.59 mmol) and 6- hydroxy-4c-methoxyflavone 216c was obtained as a yellow solid (1.8 g, 34%). M.p. 246-248 °C,

217 1 lit. 249 °C; H NMR (300 MHz, DMSO-d6): G 3.89 (s, 3H, CH3O), 6.90 (s, 1H, H3), 7.14 (d, J = 9.0 Hz, 2H, H3c, H5c), 7.28 (dd, J = 3.0, 8.7 Hz, 1H, H7), 7.37 (d, J = 3.0 Hz, 1H, H5), 7.67 (d, J = 8.7 Hz, 1H, H8), 8.07 (d, J = 9.0 Hz, 2H, H2c, H6c), 10.06 (s, 1H, 6 OH); 13C NMR (75.6

MHz, DMSO-d6): G 55.8 (CH3O), 104.8 (C3), 107.9 (C5), 114.9 (C3c, C5c), 120.1 (C8), 123.2 (C7), 123.8 (C1c), 124.5 (C4a), 128.4 (C2c, C6c), 149.6 (C8a), 155.1 (C6), 162.3 (C4c), 162.6 (C2), 177.2 (C4).

7-Hydroxyflavone (216d) The title compound was synthesized following general procedure 4 using 2c,4c-dihydroxyacetophenone 65 (3.0 g, 19.72 mmol), benzoyl chloride 214a (4.6 mL, 39.43 mmol) and K2CO3 (13.6 g, 98.59 mmol) and 7-hydroxyflavone 216d was obtained as a brown 218 1 solid (1.4 g, 30%). M.p. 234-236 °C, lit. 239 °C; H NMR (300 MHz, DMSO-d6): G 6.91 (s, 1H, H3), 6.94 (dd, J = 2.3, 8.7 Hz, 1H, H6), 7.01 (d, J = 2.3 Hz, 1H, H8), 7.55-7.60 (m, 3H, H3c, H4c, H5c), 7.89 (d, J = 8.7 Hz, 1H, H5), 8.07 (d, J = 8.3 Hz, 2H, H2c, H6c), 10.84 (s, 1H, 7 OH);

13 C NMR (75.6 MHz, DMSO-d6): G 102.9 (C8), 107.0 (C3), 115.5 (C6), 116.5 (C4a), 126.5 (C2c, C6c), 126.9 (C5), 129.5 (C3c, C5c), 131.7 (C1c), 131.9 (C4c), 157.9 (C8a), 162.3 (C2), 163.1 (C7), 176.8 (C4).

4c-Chloro-7-hydroxyflavone (216e) The title compound was synthesized following general procedure 4 using 2c,4c-dihydroxyacetophenone 65 (3.0 g, 19.72 mmol), 4-chlorobenzoyl chloride 214b (5.1 mL, 39.43 mmol) and K2CO3 (13.6 g, 98.59 mmol) and 4c-chloro-7- hydroxyflavone 216e was obtained as a pale pink solid (1.4 g, 219 1 26%). M.p. 274-276 °C, lit. 277-278 °C; H NMR (300 MHz, DMSO-d6): G 6.98 (s, 1H, H3), 6.99 (dd, J = 2.3, 8.7 Hz, 1H, H6), 7.06 (d, J = 2.3 Hz, 1H, H8), 7.68 (dd, J = 1.9, 6.8 Hz, 2H, H2c, H6c), 7.94 (d, J = 8.7 Hz, 1H, H5), 8.14 (dd, J = 1.9, 6.8 Hz, 2H, H3c, H5c), 10.05 (s, 1H, 7 199 13 OH); C NMR (75.6 MHz, DMSO-d6): G 102.9 (C8), 107.3 (C3), 115.5 (C6), 116.5 (C4a), 126.9 (C5), 128.3 (C3c, C5c), 129.5 (C2c, C6c), 130.0 (C1c), 136.5 (C4c), 157.8 (C8a), 163.2 (C2), 166.8 (C7), 176.7 (C4).

7-Hydroxy-4c-methoxyflavone (216f) The title compound was synthesized following general procedure 4 using 2c,4c-dihydroxyacetophenone 65 (3.0 g, 19.72 mmol), 4-methoxybenzoyl chloride 214c (5.1 g, 29.58 mmol) and K2CO3 (13.6 g, 98.59 mmol) and 7-hydroxy-4c- methoxyflavone 216f was obtained as a light brown solid 139a 1 (1.4 g, 27%). M.p. 264-266 °C, lit. 263-264 °C; H NMR (300 MHz, DMSO-d6): G 3.85 (s,

3H, CH3O), 6.79 (s, 1H, H3), 6.91 (dd, J = 2.3, 8.7 Hz, 1H, H6), 6.99 (d, J = 2.3 Hz, 1H, H8), 7.10 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.87 (d, J = 8.7 Hz, 1H, H5), 8.01 (d, J = 8.7 Hz, 2H, H2c,

13 H6c), 10.78 (s, 1H, 7 OH); C NMR (75.6 MHz, DMSO-d6): G 55.9 (CH3O), 102.9 (C8), 105.5 (C3), 114.9 (C3c, C5c), 115.2 (C6), 116.5 (C4a), 123.8 (C1c), 126.8 (C5), 128.3 (C2c, C6c), 157.8 (C4c), 162.3 (C8a), 162.4 (C2), 163.0 (C7), 176.7 (C4).

5-Hydroxyflavone (216g) The title compound was synthesized following general procedure 4 using 2c,6c-dihydroxyacetophenone 111b (3.0 g, 19.72 mmol), benzoyl chloride

214a (4.6 mL, 39.43 mmol) and K2CO3 (13.6 g, 98.59 mmol) and 5- hydroxyflavone 216g was obtained as a yellow solid (2.4 g, 52%). M.p. 220 1 152-154 °C, lit. 155-156 °C; H NMR (300 MHz, CDCl3): G 6.68 (s, 1H, H3), 6.74 (d, J = 8.3 Hz, 1H, H6), 6.93 (d, J = 8.3 Hz, 1H, H8), 7.37-7.54 (m, 5H, H2c, H3c, H4c, H5c, H6c), 7.84 (t, J

13 = 8.3 Hz, 1H, H7), 12.48 (s, 1H, 5 OH); C NMR (75.6 MHz, CDCl3): G 106.5 (C3), 107.5 (C8), 111.3 (C6), 111.9 (C4a), 126.8 (C2c, C6c), 128.9 (C4c), 129.5 (C3c, C5c), 131.6 (C1c), 135.8 (C7), 156.9 (C8a), 161.2 (C5), 165.0 (C2), 184.1 (C4).

2-Methyl-8-phenyl-2,3-dihydrochromeno[5,6-e][1,3]oxazin-10(1H)-one (219a) The title compound was prepared as described in general procedure 5 using 6-hydroxyflavone 216a (250 mg, 1.05 mmol), formaldehyde (0.36 mL, 37%, 12.59 mmol) and methylamine (0.073 mL, 24%, 2.1 mmol). The benzoxazine was obtained as a yellow solid (120 mg, 39%). M.p. 144-146 °C; UV (MeOH): Omax 200 -1 -1 204 (H 27751 cm M ), 273 (27862), 303 (16389) nm; IR (KBr): Qmax 3430, 3056, 2971, 2941, -1 1 1641, 1471, 1368, 1290, 1026, 939, 821, 771, 687 cm ; H NMR (300 MHz, DMSO-d6): G 2.47

(s, 3H, NCH3), 4.49 (s, 2H, ArCH2N), 4.79 (s, 2H, OCH2N), 6.89 (s, 1H, H3), 7.24 (d, J = 9.0 Hz, 1H, H7), 7.45 (d, J = 9.0 Hz, 1H, H8), 7.55-7.61 (m, 3H, H3c, H4c, H5c), 8.06 (d, J = 7.9 Hz,

13 2H, H2c, H6c); C NMR (75.6 MHz, DMSO-d6): G 36.8 (NCH3), 51.9 (ArCH2N), 83.1

(OCH2N), 107.6 (C3), 118.1 (C7), 119.3 (C5), 121.7 (C4a), 123.5 (C8), 126.5 (C2c, C6c), 129.5 (C3c, C5c), 131.3 (C1c), 132.0 (C4c), 150.9 (C8a), 151.7 (C6), 161.4 (C2), 179.8 (C4); MS (TOF- + ESI) m/z Calcd. for C18H15NO3 (M + 1) 294.11. Found 294.35; Anal. Calcd. for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C, 73.56; H, 5.00; N, 4.72.

2-Benzyl-8-phenyl-2,3-dihydrochromeno[5,6-e][1,3]oxazin-10(1H)-one (219b) The title compound was prepared as described in general procedure 5 using 6-hydroxyflavone 216a (250 mg, 1.05 mmol), formaldehyde (0.36 mL, 37%, 12.59 mmol) and benzyl amine (0.23 mL, 2.1 mmol). The benzoxazine was obtained as a brown solid (178 mg, 46%). M.p. 171-173 °C; UV (MeOH): -1 -1 Omax 205 (H 57137 cm M ), 276 (47383), 306 (23769) nm; IR

(KBr): Qmax 3429, 3055, 2968, 2948, 1638, 1467, 1369, 1283, -1 1 1029, 937, 823, 771, 691 cm ; H NMR (300 MHz, CDCl3): G 3.83 (s, 2H, NCH2Ph), 4.69 (s,

2H, ArCH2N), 4.76 (s, 2H, OCH2N), 6.61 (s, 1H, H3), 7.12 (d, J = 9.0 Hz, 1H, H7), 7.18-7.34 (m, 6H, H4c, H2cc, H3cc, H4cc, H5cc, H6cc), 7.43 (d, J = 9.0 Hz, 1H, H8), 7.49 (d, J = 7.9 Hz, 2H,

13 H3c, H5c), 7.82 (d, J = 7.9 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 51.3 (ArCH2N),

56.2 (NCH2Ph), 81.5 (OCH2N), 108.4 (C3), 117.8 (C7), 120.4 (C5), 122.4 (C4a), 123.7 (C8), 126.5 (C2c, C6c), 127.8 (C4cc), 128.9 (C3c, C5c), 129.4 (C2cc, C6cc), 129.6 (C3cc, C5cc), 131.8 (C4c), 132.0 (C1c), 138.4 (C1cc), 151.7 (C8a), 152.5 (C6), 162.3 (C2), 180.9 (C4); MS (TOF- + ESI) m/z Calcd. for C24H19NO3 (M + 1) 370.14. Found 370.08; Anal. Calcd. for

C24H19NO3.1/4EtOH: C, 77.25; H, 5.42; N, 3.68. Found: C, 77.29; H, 5.47; N, 3.81.

201 8-(4-Chlorophenyl)-2-methyl-2,3-dihydrochromeno[5,6-e][1,3]oxazin-10(1H)-one (219c) The title compound was prepared as described in general procedure 5 using 4c-chloro-6-hydroxyflavone 216b (200 mg, 0.73 mmol), formaldehyde (0.25 mL, 37%, 8.8 mmol) and methylamine (0.05 mL, 24%, 1.47 mmol). The benzoxazine was obtained as a white solid (90 mg, 38%). M.p. 188-190 °C; -1 -1 UV (MeOH): Omax 205 (H 43856 cm M ), 278 (49537), 306

(33193) nm; IR (KBr): Qmax 3448, 3074, 2975, 2945, 1633, 1473, 1409, 1321, 1094, 1012, 928, -1 1 836, 718 cm ; H NMR (300 MHz, DMSO-d6): G 2.48 (s, 3H, NCH3), 4.49 (s, 2H, ArCH2N),

4.80 (s, 2H, OCH2N), 6.94 (s, 1H, H3), 7.26 (d, J = 9.0 Hz, 1H, H7), 7.59 (d, J = 9.0 Hz, 1H, H8), 7.64 (d, J = 8.3 Hz, 2H, H2c, H6c), 8.10 (d, J = 8.3 Hz, 2H, H3c, H5c); 13C NMR (75.6 MHz,

DMSO-d6): G 39.7 (NCH3), 51.9 (ArCH2N), 83.1 (OCH2N), 107.9 (C3), 118.1 (C7), 119.3 (C5), 121.7 (C4a), 123.5 (C8), 128.3 (C3c, C5c), 129.5 (C2c, C6c), 130.2 (C1c), 136.8 (C4c), 151.0 + (C8a), 151.6 (C6), 160.2 (C2), 179.7 (C4); MS (TOF-ESI) m/z Calcd. for C18H14ClNO3 (M + 1)

328.07. Found 328.00; Anal. Calcd. for C18H14ClNO3: C, 65.96; H, 4.31; N, 4.27. Found: C, 65.79; H, 4.15; N, 4.23.

6-hydroxy -5-((methylamino)methyl)-2-phenyl-4H-chromen-4-one (223) To a solution of benzoxazine 219a (100 mg, 0.34 mmol) in ethanol (15 mL) was added 10 drops of formic acid and the mixture was stirred at r.t. for 24 h. The solvent was distilled off under vacuum and the residue was poured into ice-cold water. It was extracted with EtOAc (2 X 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum to give the title compound as a yellow solid (37 mg, 39%). M.p. 234-236 °C; UV -1 -1 (MeOH): Omax 210 (H 141972 cm M ), 278 (181408), 296 (149014) nm; IR (KBr): Qmax 3416, -1 1 3102, 1628, 1586, 1448, 1394, 1321, 1294, 819 cm ; H NMR (300 MHz, CDCl3): G 2.55 (s,

3H, NCH3), 4.53 (s, 2H, CH2), 6.91 (s, 1H, H3), 7.47 (d, J = 9.0 Hz, 1H, H7), 7.54-7.59 (m, 3H, H3c, H4c, H5c), 7.75 (d, J = 9.0 Hz, 1H, H8), 8.02 (d, J = 8.7 Hz, 2H, H2c, H6c); 13C NMR (75.6

MHz, CDCl3): G 32.9 (NCH3), 43.0 (CH2), 107.3 (C3), 113.9 (C4a), 121.8 (C8), 122.6 (C5), 123.4 (C7), 126.6 (C2c, C6c), 129.6 (C3c, C5c), 130.8 (C1c), 132.4 (C4c), 150.8 (C8a), 154.5 + (C6), 162.3 (C2), 180.1 (C4); MS (TOF-ESI) m/z Calcd. for C17H15NO3 (M + 1) 282.11. Found

282.08; Anal. Calcd. for C17H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.79; H, 5.45; N, 4.73.

202

6-Hydroxy-2-phenyl-5-(piperidin-1-ylmethyl)-4H-chromen-4-one (224a) To a solution of 6-hydroxyflavone 216a (250 mg, 1.05 mmol) in dioxan (10 mL) was added formaldehyde (0.36 mL, 12.59 mmol) and piperidine (0.21 mL, 2.1 mmol). The mixture was refluxed for 24 h. The solvent was distilled off under vacuum and the residue was poured into ice-cold water. A solid crushed out, which was filtered and air-dried to afford the Mannich base as a -1 -1 brown solid (137 mg, 39%). M.p. 162-164 °C; UV (MeOH): Omax 204 (H 45137 cm M ), 279

(44964) nm; IR (KBr): Qmax 3447, 3061, 2971, 2932, 1632, 1485, 1371, 1280, 1027, 923, 821, -1 1 768, 691 cm ; H NMR (300 MHz, CDCl3): G 1.57 (s, 6H, H3cc, H4cc, H5cc), 2.52 (s, 4H, H2cc,

H6cc), 4.62 (s, 2H, ArCH2N), 6.56 (s, 1H, H3), 7.04 (d, J = 9.0 Hz, 1H, H7), 7.28 (d, J = 9.0 Hz, 1H, H8), 7.37-7.79 (m, 5H, H2c, H3c, H4c, H5c, H6c), 10.65 (s, 1H, 6 OH); 13C NMR (75.6 MHz,

CDCl3): G 22.7 (C4cc), 24.7 (C3cc, C5cc), 52.7 (C2cc, C6cc), 56.8 (ArCH2N), 106.7 (C3), 117.2 (C5), 117.8 (C8), 121.3 (C4a), 122.2 (C7), 125.0 (C2c, C6c), 127.9 (C3c, C5c), 130.2 (C4c), 130.6

(C1c), 149.9 (C8a), 156.3 (C6), 160.2 (C2), 179.8 (C4); HRMS (ESI) m/z Calcd. for C21H21NO3 (M + 1)+ 336.1601. Found 336.1600.

6-Hydroxy-5-(morpholinomethyl)-2-phenyl-4H-chromen-4-one (224b) To a solution of 6-hydroxyflavone 216a (250 mg, 1.05 mmol) in dioxan (10 mL) was added formaldehyde (0.36 mL, 12.59 mmol) and morpholine (0.18 mL, 2.1 mmol). The mixture was refluxed for 24 h. The solvent was distilled off under vacuum and the residue was poured into ice-cold water. A solid crushed out, which was filtered and air-dried to afford the Mannich base as a light brown solid (131 mg, 37%). M.p. 156-158 °C; UV (MeOH):

-1 -1 Omax 204 (H 23060 cm M ), 277 (25225), 307 (12967) nm; IR (KBr): Qmax 3432, 3064, 2971, -1 1 2959, 1635, 1460, 1361, 1294, 1030, 928, 829, 773, 693 cm ; H NMR (300 MHz, CDCl3): G

2.60 (s, 4H, H2cc, H6cc), 3.70 (s, 4H, H3cc, H5cc), 4.70 (s, 2H, ArCH2N), 6.61 (s, 1H, H3), 7.09 (d, J = 9.0 Hz, 1H, H7), 7.35 (d, J = 9.0 Hz, 1H, H8), 7.42-7.82 (m, 5H, H2c, H3c, H4c, H5c, H6c);

13 C NMR (75.6 MHz, CDCl3): G 53.2 (C2cc, C6cc), 57.5 (ArCH2N), 67.1 (C3cc, C5cc), 108.3 (C3), 118.8 (C5), 119.1 (C8), 122.9 (C4a), 123.6 (C7), 126.5 (C2c, C6c), 129.4 (C3c, C5c), 131.8 (C4c), 132.0 (C1c), 151.8 (C8a), 156.9 (C6), 161.8 (C2), 181.2 (C4); HRMS (ESI) m/z Calcd. for + C20H19NO4 (M + 1) 338.1394. Found 338.1401. 203

5-((Dimethylamino)methyl)-6-hydroxy-2-phenyl-4H-chromen-4-one (226) To a solution of 6-hydroxyflavone 216a (250 mg, 1.05 mmol) in dioxan (10 mL) was added bis (dimethylamino)methane 225 (0.29 mL, 2.1 mmol) and the mixture refluxed for 9 h. The solvent was distilled off under vacuum and the residue was poured into ice- cold water. A solid crushed out, which was filtered and air-dried to afford the Mannich base as an off-white solid (140 mg, 45%). M.p. -1 -1 133-135 °C; UV (MeOH): Omax 204 (H 36740 cm M ), 278 (34244), 298 (26314) nm; IR (KBr): -1 1 Qmax 3435, 3061, 2976, 2954, 1641, 1497, 1370, 1289, 1022, 948, 824, 769, 687 cm ; H NMR

(300 MHz, CDCl3): G 2.34 (s, 6H, N(CH3)2), 4.68 (s, 2H, CH2N(CH3)2), 6.61 (s, 1H, H3), 7.10 (d, J = 9.0 Hz, 1H, H7), 7.35 (d, J = 9.0 Hz, 1H, H8), 7.43-7.82 (m, 5H, H2c, H3c, H4c, H5c,

13 H6c), 8.59 (s, 1H, 6 OH); C NMR (75.6 MHz, CDCl3): G 44.8 (N(CH3)2), 58.8 (CH2N(CH3)2), 108.3 (C3), 118.8 (C8), 119.6 (C5), 122.6 (C4a), 123.7 (C7), 126.5 (C2c, C6c), 129.4 (C3c, C5c), 131.7 (C4c), 132.1 (C1c), 151.5 (C8a), 157.8 (C6), 161.7 (C2), 181.3 (C4); HRMS (ESI) m/z + Calcd. for C18H17NO3 (M + 1) 296.1288. Found 296.1281.

(R)-2-((6-Hydroxy-4-oxo-2-phenyl-4H-chromen-5-yl)methylamino)-3-methylbutanoic acid (228a) The title compound was prepared as described in general procedure 5 using 6-hydroxyflavone 216a (250 mg, 1.05 mmol), formaldehyde (0.36 mL, 37%, 12.59 mmol) and L-valine (246 mg, 2.1 mmol). The Mannich base was obtained as an off-white solid

(166 mg, 43%). M.p. 257-259 °C; UV (1% CF3COOH/MeOH): -1 -1 Omax 206 (H 98751 cm M ), 277 (59290), 310 (44127) nm; IR

(KBr): Qmax 3428, 3059, 2967, 2943, 1626, 1449, 1399, 1269, -1 1 1029, 939, 820, 772, 687 cm ; H NMR (300 MHz, CDCl3: CF3COOH 7:3): G 0.99 (d, J = 6.8

Hz, 3H, CH3c), 1.04 (d, J = 6.8 Hz, 3H, CH3), 2.32-2.42 (m, 1H, CH(CH3)2), 3.91 (d, J = 4.5 Hz,

1H, NCH), 4.85-4.87 (m, 2H, ArCH2N), 7.12 (s, 1H, H3), 7.45 (d, J = 9.0 Hz, 1H, H7), 7.52- 7.59 (m, 3H, H3c, H4c, H5c), 7.63 (d, J = 9.0 Hz, 1H, H8), 7.86 (d, J = 7.9 Hz, 2H, H2c, H6c),

13 8.28 (s, 1H, 6 OH); C NMR (75.6 MHz, CDCl3: CF3COOH 7:3): G 17.6 (CH3), 17.8 (CH3′),

30.2 (CH(CH3)2), 43.9 (ArCH2N), 65.5 (NCH), 106.3 (C3), 116.6 (C8), 120.4 (C5), 122.1 (C4a), 123.3 (C7), 126.2 (C2c, C6c), 127.4 (C3c, C5c), 129.7 (C4c), 130.0 (C1c), 152.9 (C8a), 155.4 + (C6), 167.9 (C2), 176.8 (CO), 182.6 (C4); MS (TOF-ESI) m/z Calcd. for C21H21NO5 (M + 1) 204 368.15. Found 368.15; Anal. Calcd. for C21H21NO5.0.7H2O: C, 66.37; H, 5.94; N, 3.69. Found: C, 66.42; H, 5.84; N, 3.74.

2-((6-Hydroxy-4-oxo-2-phenyl-4H-chromen-5-yl)methylamino)propanoic acid (228b) The title compound was prepared as described in general procedure 5 using 6-hydroxyflavone 216a (250 mg, 1.05 mmol), formaldehyde (0.36 mL, 37%, 12.59 mmol) and DL-alanine (187 mg, 2.1 mmol). The Mannich base was obtained as an off-white solid (167 mg, 47%). M.p. 260-262 °C; UV (1% -1 -1 CF3COOH/MeOH): Omax 205 (H 86199 cm M ), 276 (60826), 308

(45068) nm; IR (KBr): Qmax 3433, 3054, 2988, 2969, 1633, 1449, 1329, 1261, 1057, 927, 818, -1 1 769, 682 cm ; H NMR (300 MHz, CDCl3: CF3COOH 7:3): G 1.73 (d, J = 7.2 Hz, 3H, CH3),

4.22-4.29 (m, 1H, NCH), 4.84-4.87 (m, 2H, ArCH2N), 7.09 (s, 1H, H3), 7.46 (d, J = 9.0 Hz, 1H, H7), 7.49-7.55 (m, 3H, H3c, H4c, H5c), 7.57 (d, J = 7.9 Hz, 2H, H2c, H6c), 7.89 (d, J = 9.0 Hz, 13 1H, H8), 7.92 (s, 1H, 6 OH), 7.97 (s, 1H, COOH); C NMR (75.6 MHz, CDCl3: CF3COOH

7:3): G 14.7 (CH3), 42.8 (ArCH2N), 56.5 (NCH), 106.3 (C3), 116.6 (C8), 120.4 (C5), 122.0 (C4a), 123.2 (C7), 126.2 (C4c), 127.4 (C2c, C6c), 129.7 (C1c), 130.0 (C3c, C5c), 152.9 (C8a),

155.1 (C6), 168.1 (C2), 173.7 (CO), 182.6 (C4); MS (TOF-ESI) m/z Calcd. for C19H17NO5 (M + + 1) 340.12. Found 340.10; Anal. Calcd. for C19H17NO5: C, 67.25; H, 5.05; N, 4.13. Found: C, 67.10; H, 5.24; N, 4.08.

(R)-2-((6-Hydroxy-4-oxo-2-phenyl-4H-chromen-5-yl)methylamino)-4-(methylthio)butanoic acid (228c) The title compound was prepared as described in general procedure 5 using 6-hydroxyflavone 216a (250 mg, 1.05 mmol), formaldehyde (0.36 mL, 37%, 12.59 mmol) and L- methionine (313 mg, 2.1 mmol). The Mannich base was obtained as an off-white solid (218 mg, 52%). M.p. 248-250 -1 - °C; UV (1% CF3COOH/MeOH): Omax 206 (H 70773 cm M 1 ), 276 (28907), 309 (21173) nm; IR (KBr): Qmax 3431, 3049, 2971, 2940, 1634, 1450, 1375, -1 1 1288, 1031, 926, 833, 772, 685 cm ; H NMR (300 MHz, CDCl3: CF3COOH 7:3): G 1.99 (s,

3H, SCH3), 2.22-2.38 (m, 2H, SCH2CH2), 2.65 (t, J = 6.4 Hz, 2H, SCH2), 4.28 (s, 1H, NCH),

4.91 (s, 2H, ArCH2N), 7.08 (s, 1H, H3), 7.47-7.61 (m, 4H, H7, H3c, H4c, H5c), 7.70 (d, J = 9.0 Hz, 1H, H8), 7.92 (d, J = 7.2 Hz, 2H, H2c, H6c), 8.24 (s, 1H, 6 OH), 8.37 (s, 1H, COOH); 13C 205 NMR (75.6 MHz, CDCl3: CF3COOH 7:3): G 15.0 (SCH3), 28.2 (SCH2), 30.3 (SCH2CH2), 43.4

(ArCH2N), 59.6 (NCH), 106.4 (C3), 116.8 (C8), 120.5 (C5), 122.3 (C4a), 123.1 (C7), 126.1 (C4c), 127.4 (C2c, C6c), 129.9 (C1c), 130.0 (C3c, C5c), 152.8 (C8a), 155.4 (C6), 167.4 (C2), + 176.2 (CO), 183.3 (C4); HRMS (ESI) m/z Calcd. for C21H21NO5S (M + 1) 400.1220. Found 400.1198.

(R)-1-((6-Hydroxy-4-oxo-2-phenyl-4H-chromen-5-yl)methyl)pyrrolidine-2-carboxylic acid (228d) The title compound was prepared as described in general procedure 5 using 6-hydroxyflavone 216a (250 mg, 1.05 mmol), formaldehyde (0.36 mL, 37%, 12.59 mmol) and L-proline (242 mg, 2.1 mmol). The Mannich base was obtained as a brown solid

(142 mg, 37%). M.p. 218-220 °C; UV (1% CF3COOH/MeOH): -1 -1 Omax 207 (H 73185 cm M ), 247 (30745), 307 (49911) nm; IR

(KBr): Qmax 3410, 3064, 2970, 2950, 1641, 1447, 1375, 1292, -1 1 1030, 940, 826, 781, 690 cm ; H NMR (300 MHz, CDCl3: CF3COOH 7:3): G 2.13-2.44 (m,

2H, NCH2CH2CH2), 2.46-2.85 (m, 2H, NCH2CH2CH2), 3.53-3.58 (m, 1H, NCHaHbCH2), 3.92-

3.98 (m, 1H, NCHaHbCH2), 4.53-4.65 (m, 1H, NCH), 5.02-5.16 (m, 2H, ArCH2N), 7.48 (d, J = 9.0 Hz, 1H, H7), 7.73 (m, 4H, H3, H3c, H4c, H5c), 8.07 (d, J = 7.2 Hz, 2H, H2c, H6c), 8.46 (d, J

13 = 9.0 Hz, 1H, H8), 8.61 (s, 1H, 6 OH); C NMR (75.6 MHz, CDCl3: CF3COOH 7:3): G 23.2

(NCH2CH2CH2), 28.8 (NCH2CH2CH2), 48.9 (ArCH2N), 56.6 (NCH2CH2CH2), 68.3 (NCH), 103.3 (C3), 112.8 (C8), 116.5 (C5), 118.5 (C7), 120.3 (C4a), 127.8 (C2c, C6c), 129.0 (C1c), 130.4 (C3c, C5c), 130.5 (C4c), 155.8 (C8a), 157.8 (C6), 165.2 (C2), 171.9 (CO), 182.3 (C4); + HRMS (ESI) m/z Calcd. for C21H19NO5 (M + 1) 366.1343. Found 366.1344.

(R)-2-((2-(4-Chlorophenyl)-6-hydroxy-4-oxo-4H-chromen-5-yl)methylamino)-3- methylbutanoic acid (228e) The title compound was prepared as described in general procedure 5 using 4c-chloro-6-hydroxyflavone 216b (200 mg, 0.73 mmol), formaldehyde (0.25 mL, 37%, 8.8 mmol) and L- valine (172 mg, 1.47 mmol). The Mannich base was obtained as an off-white solid (100 mg, 34%). M.p. 260-262 °C; UV -1 -1 (1% CF3COOH/MeOH): Omax 207 (H 156718 cm M ), 281

(90703), 313 (73248) nm; IR (KBr): Qmax 3434, 3075, 2974, 2951, 1628, 1463, 1401, 1308, 206 -1 1 1095, 1012, 939, 844, 729 cm ; H NMR (300 MHz, CDCl3: CF3COOH 7:3): G 1.10 (d, J = 7.2

Hz, 3H, CH3c), 1.15 (d, J = 7.2 Hz, 3H, CH3), 2.47-2.53 (m, 1H, CH(CH3)2), 4.04 (s, 1H, NCH),

4.99 (s, 2H, ArCH2N), 7.23 (s, 1H, H3), 7.50 (d, J = 9.0 Hz, 1H, H7), 7.61 (d, J = 8.7 Hz, 2H, H2c, H6c), 7.83 (d, J = 9.0 Hz, 1H, H8), 7.98 (d, J = 8.7 Hz, 2H, H3c, H5c), 8.06 (s, 1H, 6 OH);

13 C NMR (75.6 MHz, CDCl3: CF3COOH 7:3): G 17.5 (CH3), 17.7 (CH3′), 30.3 (CH(CH3)2), 43.9

(ArCH2N), 65.5 (NCH), 106.4 (C3), 116.6 (C8), 120.4 (C5), 122.1 (C4a), 123.3 (C7), 128.1 (C1c), 128.6 (C3c, C5c), 130.4 (C2c, C6c), 140.9 (C4c), 152.8 (C8a), 155.5 (C6), 166.7 (C2), + 175.1 (CO), 182.7 (C4); MS (TOF-ESI) m/z Calcd. for C21H20ClNO5 (M + 1) 402.11. Found

402.09; Anal. Calcd. for C21H20ClNO5: C, 62.77; H, 5.02; N, 3.49. Found: C, 62.82; H, 4.86; N, 3.44.

2-((2-(4-Chlorophenyl)-6-hydroxy-4-oxo-4H-chromen-5-yl)methylamino)propanoic acid (228f) The title compound was prepared as described in general procedure 5 using 4c-chloro-6-hydroxyflavone 216b (200 mg, 0.73 mmol), formaldehyde (0.25 mL, 37%, 8.8 mmol) and DL-alanine (131 mg, 1.47 mmol). The Mannich base was obtained as an off-white solid (85 mg, 31%). M.p. 263-265 °C; -1 -1 UV (1% CF3COOH/MeOH): Omax 207 (H 34891 cm M ), 279

(40498), 311 (32050) nm; IR (KBr): Qmax 3449, 3072, 2974, 2940, 1629, 1495, 1411, 1328, -1 1 1092, 1014, 936, 827, 719 cm ; H NMR (300 MHz, CDCl3: CF3COOH 7:3): G 1.85 (d, J = 6.8

Hz, 3H, CH3), 4.37 (d, J = 3.4 Hz, 1H, NCH), 4.98 (s, 2H, ArCH2N), 7.17 (s, 1H, H3), 7.58 (d, J = 8.3 Hz, 2H, H2c, H6c), 7.81 (d, J = 8.3 Hz, 1H, H7), 7.96 (d, J = 8.3 Hz, 2H, H3c, H5c), 8.06

13 (d, J = 8.3 Hz, 1H, H8), 8.36 (s, 1H, 6 OH); C NMR (75.6 MHz, CDCl3: CF3COOH 7:3): G

14.7 (CH3), 42.7 (ArCH2N), 56.5 (NCH), 106.3 (C3), 116.7 (C8), 120.5 (C4a), 123.1 (C7), 126.2 (C5), 128.2 (C1c), 129.2 (C3c, C5c), 130.5 (C2c, C6c), 140.8 (C4c), 152.8 (C8a), 155.1 + (C6), 166.6 (C2), 178.4 (CO), 182.6 (C4); MS (TOF-ESI) m/z Calcd. for C19H16ClNO5 (M + 1)

374.08. Found 374.29; Anal. Calcd. for C19H16ClNO5: C, 61.05; H, 4.31; N, 3.75. Found: C, 61.32; H, 4.26; N, 4.04.

207 (R)-2-((2-(4-Chlorophenyl)-6-hydroxy-4-oxo-4H-chromen-5-yl)methylamino)-4- (methylthio)butanoic acid (228g) The title compound was prepared as described in general procedure 5 using 4c-chloro-6-hydroxyflavone 216b (200 mg, 0.73 mmol), formaldehyde (0.25 mL, 37%, 8.8 mmol) and L-methionine (219 mg, 1.47 mmol). The Mannich base was obtained as an off-white solid (140 mg, 44%). M.p. 240-242 °C; UV (1% -1 -1 CF3COOH/MeOH): Omax 207 (H 122884 cm M ), 281 (75148), 311 (60697) nm; IR (KBr): Qmax 3426, 3073, 2978, 2944, 1628, 1495, 1412, 1313, 1092, 1013, 930, 842, 719 cm-1; 1H NMR (300

MHz, CDCl3: CF3COOH 7:3): G 2.10 (s, 3H, SCH3), 2.38-2.43 (m, 2H, SCH2CH2), 2.74-2.78

(m, 2H, SCH2), 4.40 (s, 1H, NCH), 5.02 (s, 2H, ArCH2N), 7.19 (s, 1H, H3), 7.58 (d, J = 9.0 Hz, 1H, H7), 7.60 (d, J = 8.7 Hz, 2H, H2c, H6c), 7.82 (d, J = 9.0 Hz, 1H, H8), 7.97 (d, J = 8.7 Hz,

13 2H, H3c, H5c), 8.32 (s, 1H, 6 OH), 8.65 (s, 1H, COOH); C NMR (75.6 MHz, CDCl3:

CF3COOH 7:3): G 14.8 (SCH3), 27.8 (SCH2), 30.2 (SCH2CH2), 43.4 (ArCH2N), 59.6 (NCH), 106.4 (C3), 116.8 (C8), 120.6 (C4a), 123.3 (C7), 126.1 (C5), 128.2 (C1c), 128.6 (C3c, C5c), 130.3 (C2c, C6c), 140.7 (C4c), 152.8 (C8a), 155.4 (C6), 166.5 (C2), 172.0 (CO), 182.6 (C4); MS + (TOF-ESI) m/z Calcd. for C21H20ClNO5S (M + 1) 434.08. Found 434.07; Anal. Calcd. for

C21H20ClNO5S: C, 58.13; H, 4.65; N, 3.23. Found: C, 57.92; H, 4.40; N, 3.04.

(R)-2-((6-Hydroxy -2-(4-methoxyphenyl)-4-oxo-4H-chromen-5-yl)methylamino)-3- methylbutanoic acid (228h) The title compound was prepared as described in general procedure 5 using 6-hydroxy-4c-methoxyflavone 216c (200 mg, 0.75 mmol), formaldehyde (0.25 mL, 37%, 8.95 mmol) and L-valine (175 mg, 1.49 mmol). The Mannich base was obtained as an off-white solid (136 mg, 46%). M.p. 266-

268 °C; UV (1% CF3COOH/MeOH): Omax 207 (H 123700 -1 -1 cm M ), 282 (37678) nm; IR (KBr): Qmax 3434, 3075, 2974, 2951, 1628, 1512, 1425, 1308, -1 1 1095, 1012, 939, 844, 729 cm ; H NMR (300 MHz, CDCl3: CF3COOH 7:3): G 1.14 (d, J = 6.4

Hz, 3H, CH3c), 1.18 (d, J = 6.4 Hz, 3H, CH3), 2.52-2.55 (m, 1H, CH(CH3)2), 4.02 (s, 3H, CH3O),

4.11 (s, 1H, NCH), 5.07 (s, 2H, ArCH2N), 7.19 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.39 (s, 1H, H3), 7.68 (d, J = 9.0 Hz, 1H, H7), 7.90 (d, J = 9.0 Hz, 1H, H8), 7.99 (s, 1H, 6 OH), 8.10 (d, J = 8.7 13 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3: CF3COOH 7:3): G 17.1 (CH3), 17.4 (CH3′), 208 30.3 (CH(CH3)2), 44.1 (ArCH2N), 55.9 (CH3O), 65.6 (NCH), 104.0 (C3), 115.7 (C3c, C5c), 116.4 (C8), 120.2 (C5), 121.7 (C4a), 123.4 (C7), 126.4 (C1c), 130.1 (C2c, C6c), 152.9 (C8a), 155.7 (C6), 165.0 (C4c), 169.4 (C2), 172.1 (CO), 182.9 (C4); MS (TOF-ESI) m/z Calcd. for + C22H23NO6 (M + 1) 398.16. Found 398.14; Anal. Calcd. for C22H23NO6: C, 66.49; H, 5.83; N, 3.52. Found: C, 66.72; H, 5.60; N, 3.44.

9-Benzyl-2-phenyl-9,10-dihydrochromeno[8,7-e][1,3]oxazin-4(8H)-one (229a) The title compound was prepared as described in general procedure 5 using 7-hydroxyflavone 216d (250 mg, 1.05 mmol), formaldehyde (0.36 mL, 37%, 12.59 mmol) and benzyl amine (0.23 mL, 2.1 mmol). The benzoxazine was obtained as an off- white solid (160 mg, 41%). M.p. 147-149 °C; UV (MeOH): Omax -1 -1 208 (H 63404 cm M ), 309 (27355) nm; IR (KBr): Qmax 3451, 3060, 2916, 1639, 1494, 1433, 1408, 1376, 1355, 1081, 1025, -1 1 849 cm ; H NMR (300 MHz, CDCl3): G 3.88 (s, 2H, NCH2Ph), 4.26 (s, 2H, ArCH2N), 4.89 (s,

2H, OCH2N), 6.69 (s, 1H, H3), 6.84 (d, J = 9.0 Hz, 1H, H6), 7.27-7.31 (m, 5H, H2cc, H3cc, H4cc, H5cc, H6cc), 7.40-7.71 (m, 5H, H2c, H3c, H4c, H5c, H6c), 7.96 (d, J = 9.0 Hz, 1H, H5); 13C NMR

(75.6 MHz, CDCl3): G 45.7 (ArCH2N), 56.3 (NCH2Ph), 82.8 (OCH2N), 108.0 (C3), 108.2 (C8), 115.7 (C6), 117.9 (C4a), 125.1 (C5), 126.4 (C2c, C6c), 128.1 (C3cc, C5cc), 128.9 (C3c, C5c), 129.4 (C4c), 129.5 (C2cc, C6cc), 131.8 (C4cc), 132.3 (C1c), 137.9 (C1cc), 155.1 (C8a), 159.3 (C2), 162.9 + (C7), 178.4 (C4); MS (TOF-ESI) m/z Calcd. for C24H19NO3 (M + 1) 370.14. Found 370.10;

Anal. Calcd. for C24H19NO3: C, 78.03; H, 5.18; N, 3.79. Found: C, 77.82; H, 4.97; N, 4.04.

2-(4-Chlorophenyl)-9-methyl-9,10-dihydrochromeno[8,7-e][1,3]oxazin-4(8H)-one (229b) The title compound was prepared as described in general procedure 5 using 4c-chloro-7-hydroxyflavone 216e (200 mg, 0.73 mmol), formaldehyde (0.25 mL, 37%, 8.8 mmol) and methylamine (0.05 mL, 24%, 1.47 mmol). The benzoxazine was obtained as a yellow solid (96 mg, 40%). M.p. 145-147 °C; -1 -1 UV (MeOH): Omax 203 (H 62794 cm M ), 235 (42334) nm; IR (KBr): Qmax 3339, 3058, 2926, -1 1 1633, 1488, 1435, 1403, 1380, 1353, 1092, 1012, 842 cm ; H NMR (300 MHz, CDCl3): G 2.59

(s, 3H, NCH3), 4.17 (s, 2H, ArCH2N), 4.84 (s, 2H, OCH2N), 6.65 (s, 1H, H3), 6.80 (d, J = 8.7 Hz, 1H, H6), 7.41 (d, J = 8.6 Hz, 2H, H2c, H6c), 7.69 (d, J = 8.6 Hz, 2H, H3c, H5c), 7.90 (d, J =

13 8.7 Hz, 1H, H5); C NMR (75.6 MHz, CDCl3): G 39.2 (NCH3), 46.1 (ArCH2N), 83.4 (OCH2N),

209 106.5 (C8), 106.6 (C3), 114.3 (C6), 116.4 (C4a), 123.6 (C5), 126.2 (C3c, C5c), 128.4 (C2c, C6c), 129.3 (C1c), 136.7 (C4c), 153.6 (C8a), 157.5 (C2), 160.2 (C7), 176.7 (C4); MS (TOF-ESI) m/z + Calcd. for C18H14ClNO3 (M + 1) 328.07. Found 328.07; Anal. Calcd. for C18H14ClNO3: C, 65.96; H, 4.31; N, 4.27. Found: C, 65.71; H, 4.66; N, 4.51.

9-Benzyl-2-(4-chlorophenyl)-9,10-dihydrochromeno[8,7-e][1,3]oxazin-4(8H)-one (229c) The title compound was prepared as described in general procedure 5 using 4c-chloro-7-hydroxyflavone 216e (200 mg, 0.73 mmol), formaldehyde (0.25 mL, 37%, 8.8 mmol) and benzyl amine (0.16 mL, 1.47 mmol). The benzoxazine was obtained as a white solid (127 mg, 43%). M.p. 210-212 -1 -1 °C; UV (MeOH): Omax 211 (H 41243 cm M ), 260 (22806),

310 (19878) nm; IR (KBr): Qmax 3433, 3057, 2921, 1634, -1 1 1491, 1435, 1407, 1376, 1353, 1091, 1013, 831 cm ; H NMR (300 MHz, DMSO-d6): G 3.91 (s,

2H, NCH2Ph), 4.32 (s, 2H, ArCH2N), 4.99 (s, 2H, OCH2N), 6.96 (d, J = 9.0 Hz, 1H, H6), 6.98 (s, 1H, H3), 7.24-7.39 (m, 5H, H2cc, H3cc, H4cc, H5cc, H6cc), 7.60 (d, J = 8.7 Hz, 2H, H2c, H6c), 7.83 (d, J = 9.0 Hz, 1H, H5), 7.99 (d, J = 8.7 Hz, 2H, H3c, H5c); 13C NMR (75.6 MHz, DMSO- d6): G 55.2 (ArCH2N), 56.5 (NCH2Ph), 82.5 (OCH2N), 107.6 (C3), 108.8 (C8), 115.5 (C6), 117.1 (C4a), 127.2 (C4cc), 127.7 (C5), 128.3 (C1c), 128.7 (C3c, C5c), 128.9 (C2c, C6c), 129.2 (C2cc, C6cc), 129.6 (C3cc, C5cc), 136.8 (C4c), 138.3 (C1cc), 154.4 (C8a), 158.9 (C2), 160.9 (C7), 176.8 + (C4); MS (TOF-ESI) m/z Calcd. for C24H18ClNO3 (M + 1) 404.11. Found 404.06; Anal. Calcd. for C24H18ClNO3: C, 71.38; H, 4.49; N, 3.47. Found: C, 71.18; H, 4.48; N, 3.53.

2-(4-Methoxyphenyl)-9-methyl-9,10-dihydrochromeno[8,7-e][1,3]oxazin-4(8H)-one (229d) The title compound was prepared as described in general procedure 5 using 7-hydroxy-4c-methoxyflavone 216f (200 mg, 0.75 mmol), formaldehyde (0.25 mL, 37%, 8.95 mmol) and methylamine (0.05 mL, 24%, 1.49 mmol). The benzoxazine was obtained as a white solid (90 mg, 37%).

-1 -1 M.p. 267-269 °C; UV (MeOH): Omax 208 (H 48949 cm M ), 258 (26067), 323 (41029) nm; IR -1 1 (KBr): Qmax 3413, 3056, 2920, 1628, 1481, 1434, 1422, 1379, 1358, 1087, 1027, 823 cm ; H

NMR (300 MHz, CDCl3): G 2.59 (s, 3H, NCH3), 3.81 (s, 3H, CH3O), 4.18 (s, 2H, ArCH2N),

4.83 (s, 2H, OCH2N), 6.59 (s, 1H, H3), 6.78 (d, J = 8.6 Hz, 1H, H6), 6.94 (d, J = 9.0 Hz, 2H, H3c, H5c), 7.71 (d, J = 9.0 Hz, 2H, H2c, H6c), 7.90 (d, J = 8.6 Hz, 1H, H5); 13C NMR (75.6 MHz, 210 CDCl3): G 39.2 (NCH3), 46.2 (ArCH2N), 54.5 (CH3O), 83.3 (OCH2N), 105.0 (C3), 106.5 (C8), 113.5 (C6), 113.9 (C3c, C5c), 116.4 (C4a), 123.1 (C1c), 123.5 (C5), 126.6 (C2c, C6c), 153.6 (C8a), 157.2 (C4c), 161.3 (C2), 161.4 (C7), 176.9 (C4); MS (TOF-ESI) m/z Calcd. for + C19H17NO4 (M + 1) 324.12. Found 324.04; Anal. Calcd. for C19H17NO4: C, 70.58; H, 5.30; N, 4.33. Found: C, 70.82; H, 5.26; N, 4.04.

(S)-2-((2-(4-Chlorophenyl)-7-hydroxy-4-oxo-4H-chromen-8-yl)methylamino)-3- methylbutanoic acid (230a) The title compound was prepared as described in general procedure 5 using 4c-chloro-7-hydroxyflavone 216e (200 mg, 0.73 mmol), formaldehyde (0.25 mL, 37%, 8.8 mmol) and L- valine (172 mg, 1.47 mmol). The Mannich base was obtained as a white solid (83 mg, 28%). M.p. 242-244 °C; UV (1% -1 -1 CF3COOH/MeOH): Omax 213 (H 105948 cm M ), 258 (32699),

310 (57870) nm; IR (KBr): Qmax 3413, 3051, 2922, 1633, 1491, 1446, 1406, 1379, 1360, 1092, -1 1 1008, 836 cm ; H NMR (300 MHz, CDCl3: CF3COOH 7:3): G 1.14 (d, J = 6.8 Hz, 3H, CH3c),

1.22 (d, J = 6.8 Hz, 3H, CH3), 2.56-2.60 (m, 1H, CH(CH3)2), 4.19 (s, 1H, NCH), 4.97 (s, 2H,

ArCH2N), 7.38 (d, J = 9.0 Hz, 1H, H6), 7.51 (s, 1H, H3), 7.64 (d, J = 8.7 Hz, 2H, H2c, H6c), 7.97 (d, J = 8.7 Hz, 2H, H3c, H5c), 8.16 (s, 1H, 7 OH), 8.41 (d, J = 9.0 Hz, 1H, H5); 13C NMR

(75.6 MHz, CDCl3: CF3COOH 7:3): G 16.6 (CH3), 18.1 (CH3′), 30.4 (CH(CH3)2), 41.9

(ArCH2N), 66.6 (NCH), 103.9 (C3), 108.9 (C6), 112.6 (C8), 116.4 (C4a), 127.6 (C5), 128.9 (C3c, C5c), 130.4 (C1c), 130.7 (C2c, C6c), 142.6 (C4c), 157.3 (C8a), 164.3 (C7), 169.7 (C2), + 172.1 (CO), 183.8 (C4); MS (TOF-ESI) m/z Calcd. for C21H20ClNO5 (M + 1) 402.11. Found

402.10; Anal. Calcd. for C21H20ClNO5: C, 62.77; H, 5.02; N, 3.49. Found: C, 62.82; H, 5.06; N, 3.34.

(S)-2-((2-(4-Chlorophenyl)-7-hydroxy-4-oxo-4H-chromen-8-yl)methylamino)-4- (methylthio)butanoic acid (230b) The title compound was prepared as described in general procedure 5 using 4c-chloro-7-hydroxyflavone 216e (200 mg, 0.73 mmol), formaldehyde (0.25 mL, 37%, 8.8 mmol) and L-methionine (219 mg, 1.47 mmol). The Mannich base was obtained as a brown solid (95 mg, 30%). M.p. 225-227 °C; UV (1% 211 -1 -1 CF3COOH/MeOH): Omax 213 (H 164661 cm M ), 309 (47910) nm; IR (KBr): Qmax 3428, 3060, -1 1 2917, 1634, 1492, 1439, 1409, 1374, 1330, 1092, 1010, 829 cm ; H NMR (300 MHz, CDCl3:

CF3COOH 7:3): G 2.12 (s, 3H, SCH3), 2.52 (m, 2H, SCH2CH2), 2.84 (m, 2H, SCH2), 4.57 (m,

1H, NCH), 5.02 (m, 2H, ArCH2N), 7.41 (d, J = 9.4 Hz, 1H, H6), 7.55 (s, 1H, H3), 7.66 (d, J = 8.7 Hz, 2H, H2c, H6c), 8.01 (d, J = 8.7 Hz, 2H, H3c, H5c), 8.43 (d, J = 9.4 Hz, 1H, H5), 8.76 (s,

13 1H, 7 OH); C NMR (75.6 MHz, CDCl3: CF3COOH 7:3): G 14.5 (SCH3), 27.8 (SCH2), 29.9

(SCH2CH2), 41.3 (ArCH2N), 60.6 (NCH), 103.7 (C3), 108.9 (C6), 112.7 (C8), 116.4 (C4a), 127.5 (C5), 128.9 (C3c, C5c), 130.3 (C2c, C6c), 130.7 (C1c), 142.8 (C4c), 157.4 (C8a), 164.5 + (C7), 169.9 (C2), 178.2 (CO), 181.9 (C4); HRMS (ESI) m/z Calcd. for C21H20ClNO5S (M + 1) 434.0831. Found 434.0844.

2-(4-Chlorophenyl)-2,3-dihydroquinolin-4(1H)-one (261) L-proline (0.77 g, 30 mol%) was stirred in MeOH (30 mL) for 10 minutes, 2-aminoacetophenone 260 (2.68 mL, 22.19 mmol) and 4- chlorobenzaldehyde 67c (3.12 g, 22.19 mmol) were then added and the mixture was heated to reflux for 36 h. The reaction mixture was then brought to r.t. and left to stir for 3 h. The solid that precipitated from the reaction mixture was filtered and dried. The azaflavanone was obtained as a yellow 221 1 solid (2.8 g, 50%). M.p. 170-172 °C, lit. 168-170 °C; H NMR (300 MHz, acetone-d6): G 2.69- 2.89 (m, 2H, H3), 4.82-4.89 (m, 1H, H2), 6.24 (s, 1H, NH), 6.76 (ddd, J = 1.5, 7.0, 8.3 Hz, 1H, H6), 6.98 (dd, J = 1.5, 8.3 Hz, 1H, H8), 7.38 (ddd, J = 1.5, 7.0, 8.3 Hz, 1H, H7), 7.45 (d, J = 8.3 Hz, 2H, H3c, H5c), 7.59 (d, J = 8.3 Hz, 2H, H2c, H6c), 7.75 (dd, J = 1.5, 8.3 Hz, 1H, H5); 13C

NMR (75.6 MHz, DMSO-d6): G 45.4 (C3), 55.8 (C2), 116.7 (C8), 117.0 (C6), 118.1 (C4a), 126.7 (C5), 128.8 (C2c, C6c), 129.1 (C3c, C5c), 132.5 (C4c), 135.5 (C7), 141.1 (C1c), 152.7 (C8a), 192.6 (C4). cis-2-(4-Chlorophenyl)-1,2,3,4-tetrahydroquinolin-4-ol (262) To a solution of azaflavanone 261 (1.0 g, 3.88 mmol) in EtOH (25 mL), powdered NaBH4 (0.15 g, 3.88 mmol) was added in portions over 5 minutes. The reaction mixture was allowed to stir at r.t. for 4 h. The solvent was evaporated under reduced pressure, followed by the addition of ice (100 g). The reaction mixture was then quenched slowly by the addition of 10% AcOH to pH 5, and extracted with EtOAc (2 X 100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and evaporated to

212 yield the title compound as a white solid (0.96 g, 95%). M.p. 126-128 °C; UV (MeOH): Omax 192 -1 -1 (H 16400 cm M ), 208 (45000), 250 (16800) nm; IR (KBr): Qmax 3257, 2966, 2889, 1605, 1588, -1 1 1482, 1407, 1325, 1243, 1088, 1065, 1039, 1000, 802, 755 cm ; H NMR (300 MHz, CDCl3): G 2.07 (ddd, J = 10.2, 11.3, 13.3 Hz, 1H, H3), 2.40 (ddd, J = 2.6, 5.7, 13.3 Hz, 1H, H3), 4.59 (dd, J = 2.6, 11.3 Hz, 1H, H4), 5.08 (dd, J = 5.7, 10.2 Hz, 1H, H2), 6.57-7.12 (m, 4H, H5, H6, H7, H8), 7.28 (d, J = 8.6 Hz, 2H, H3c, H5c), 7.37 (d, J = 8.6 Hz, 2H, H2c, H6c); 13C NMR (75.6 MHz,

DMSO-d6): G 41.6 (C3), 54.5 (C2), 65.7 (C4), 114.0 (C8), 116.3 (C6), 125.4 (C4a), 126.7 (C7), 127.6 (C5), 128.7 (C2c, C6c), 128.8 (C3c, C5c), 131.8 (C4c), 143.7 (C1c), 145.2 (C8a); HRMS + (ESI) m/z Calcd. for C15H14ClNONa (M + Na) 282.0664. Found 282.0652.

trans-1-(2-(4-Chlorophenyl)-1,2,3,4-tetrahydroquinolin-4-yl)naphthalen-2-ol (263) To a stirred solution of azaflavanol 262 (250 mg, 0.96 mmol) and 2- naphthol 99 (166 mg, 1.16 mmol) in DCM (20 mL) was added

BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (50:50) gave the title compound as a white solid (230 mg, 62%). M.p. 141-143 °C; UV (MeOH): Omax 212 (H 105647 -1 -1 cm M ), 229 (132725) nm; IR (KBr): Qmax 3407, 1601, 1488, 1398, 1315, 1308, 1254, 1091, -1 1 1013, 816, 747 cm ; H NMR (300 MHz, CDCl3): G 2.15-2.41 (m, 2H, H3), 4.38 (s, 1H, NH), 4.51 (dd, J = 3.3, 10.3 Hz, 1H, H2), 4.80 (t, J = 3.0 Hz, 1H, H4), 6.61 (ddd, J = 1.1, 6.3, 7.4 Hz, 1H, H6), 6.68 (dd, J = 1.1, 7.4 Hz, 1H, H8), 6.98 (d, J = 8.9 Hz, 2H, H3c, H5c), 7.10 (ddd, J = 1.1, 6.3, 7.4 Hz, 1H, H7), 7.14 (d, J = 8.3 Hz, 1H, H3cc), 7.17 (dd, J = 1.1, 7.4 Hz, 1H, H5), 7.19 (dd, J = 1.0, 8.0 Hz, 1H, H5cc), 7.22 (ddd, J = 1.0, 6.9, 8.0 Hz, 1H, H6cc), 7.24 (d, J = 8.3 Hz, 1H, H4cc), 7.35 (ddd, J = 1.0, 6.9, 8.0 Hz, 1H, H7cc), 7.62 (d, J = 8.9 Hz, 2H, H2c, H6c), 7.72 (dd, J =

13 1.0, 8.0 Hz, 1H, H8cc); C NMR (75.6 MHz, CDCl3): G 32.8 (C4), 36.2 (C3), 53.0 (C2), 115.2 (C8), 118.7 (C6), 119.0 (C1cc), 120.3 (C3cc), 121.0 (C4a), 121.8 (C6cc), 123.3 (C8cc), 127.0 (C7cc), 127.8 (C2c, C6c), 128.8 (C3c, C5c), 128.9 (C4cc), 129.1 (C5cc), 129.2 (C7), 129.3 (C4cca), 129.7 (C5), 132.9 (C4c), 133.1 (C8cca), 142.8 (C1c), 144.5 (C8a), 152.9 (C2cc); MS (TOF-ESI) + m/z Calcd. for C25H20ClNO (M + 1) 386.13. Found 386.04; Anal. Calcd. for C25H20ClNO: C, 77.81; H, 5.22; N, 3.63. Found: C, 77.60; H, 5.46; N, 3.58.

213 trans-2-(2-(4-Chlorophenyl)-1,2,3,4-tetrahydroquinolin-4-yl)naphthalen-1-ol (265) To a stirred solution of azaflavanol 262 (250 mg, 0.96 mmol) and 1- naphthol 264 (166 mg, 1.16 mmol) in DCM (20 mL) was added

BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (50:50) gave the title compound as a white solid (115 mg, 31%). M.p. 158-160 °C; UV (MeOH): Omax 211 (H 64597 -1 -1 cm M ), 239 (38000), 306 (9500) nm; IR (KBr): Qmax 3395, 1599, 1487, 1380, 1315, 1271, -1 1 1090, 1013, 764 cm ; H NMR (300 MHz, CDCl3): G 2.24-2.37 (m, 2H, H3), 4.11 (s, 1H, NH), 4.24 (dd, J = 3.0, 10.5 Hz, 1H, H2), 4.90 (t, J = 3.0 Hz, 1H, H4), 6.65-8.30 (m, 14H, ArH); 13C

NMR (75.6 MHz, CDCl3): G 37.6 (C4), 37.8 (C3), 51.5 (C2), 107.7 (C8), 114.1 (C6), 117.7 (C7), 122.3 (C4a), 122.5 (C4cc), 123.0 (C3cc), 124.7 (C2cc), 124.9 (C6cc), 126.7 (C7cc), 127.5 (C8cc), 127.7 (C5cc), 128.1 (C2c, C6c), 128.5 (C3c, C5c), 130.8 (C5), 131.7 (C4c), 132.9 (C8cca),

135.0 (C4cca), 142.5 (C1c), 145.1 (C8a), 150.1 (C1cc); MS (TOF-ESI) m/z Calcd. for C25H20ClNO + (M + 1) 386.13. Found 386.08; Anal. Calcd. for C25H20ClNO: C, 77.81; H, 5.22; N, 3.63. Found: C, 77.55; H, 5.19; N, 3.91. trans-2-(2-(4-Chlorophenyl)-1,2,3,4-tetrahydroquinolin-4-yl)-3,5-dimethoxyphenol (267) To a stirred solution of azaflavanol 262 (300 mg, 1.16 mmol) and 3,5-dimethoxyphenol 266 (214 mg, 1.39 mmol) in DCM (20 mL) was added BF3·OEt2 (10 drops). The mixture was stirred at r.t. for

12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (60:40) gave the title compound as a white solid (110 mg, 24%). M.p. -1 -1 112-114 °C; UV (MeOH): Omax 208 (H 65794 cm M ) nm; IR (KBr): Qmax 3423, 2934, 1607, -1 1 1488, 1388, 1313, 1208, 1147, 1093, 1012, 820, 749 cm ; H NMR (300 MHz, CDCl3): G 2.13-

2.31 (m, 2H, H3), 3.75 (s, 3H, CH3O), 3.80 (s, 3H, CH3O), 4.37 (s, 1H, NH), 4.52 (dd, J = 3.6, 10.0 Hz, 1H, H2), 4.57 (t, J = 3.0 Hz, 1H, H4), 6.06 (d, J = 2.4 Hz, 1H, H3cc), 6.15 (d, J = 2.4

214 Hz, 1H, H5cc), 6.71 (dd, J = 1.0, 7.6 Hz, 1H, H8), 6.75 (ddd, J = 1.0, 6.4, 7.6 Hz, 1H, H6), 7.09 (dd, J = 1.0, 7.6 Hz, 1H, H5), 7.16 (ddd, J = 1.0, 6.4, 7.6 Hz, 1H, H7), 7.28 (d, J = 8.6 Hz, 2H, 13 H3c, H5c), 7.31 (d, J = 8.6 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 30.9 (C4), 37.2

(C3), 53.5 (C2), 55.7 (CH3O), 56.1 (CH3O), 92.1 (C5cc), 95.2 (C3cc), 111.9 (C1cc), 115.3 (C8), 118.8 (C6), 120.3 (C4a), 127.9 (C7), 128.3 (C2c, C6c), 129.0 (C3c, C5c), 130.2 (C5), 133.3 (C4c), 143.4 (C1c), 144.9 (C8a), 156.9 (C2cc), 158.9 (C6cc), 160.3 (C4cc); MS (TOF-ESI) m/z Calcd. for + C23H22ClNO3 (M + 1) 396.14. Found 396.04; Anal. Calcd. for C23H22ClNO3.1/2EtOH: C, 68.81; H, 6.02; N, 3.34. Found: C, 68.78; H, 6.09; N, 3.36.

4, 6-Dimethoxy-2,3-diphenyl-1H-indole (270) A mixture of 3,5-dimethoxyaniline 268 (2.0 g, 13.0 mmol) and benzoin 269 (2.8 g, 13.0 mmol) was heated at 125 °C for 1.5 h. The mixture was cooled to r.t., aniline (0.4 mL, 4.3 mmol) and acetic acid (8.0 mL) were added and the heating was continued further at 125 °C for 4 h. The mixture was cooled to r.t. and filtered. The product was washed with MeOH and dried (2.7 g, 63%). M.p. 240-242 °C, lit.222 1 240-241 °C; H NMR (300 MHz, CDCl3): G 3.65 (s, 3H, CH3O), 3.85 (s, 3H, CH3O), 6.20 (d, J = 2.0 Hz, 1H, H5), 6.65 (d, J = 2.0 Hz, 1H, H7), 7.25-7.40 (m, 10H, ArH).

1-(4-Bromophenyl)-2-(3,5-dimethoxyphenylamino)ethanone (272) A mixture of 3,5-dimethoxyaniline 268 (4.1 g, 26.76 mmol), 4-bromophenacylbromide 271 (7.5 g, 27.0 mmol), sodium bicarbonate (2.6 g, 31.0 mmol) and absolute EtOH (75 mL) was refluxed for 1.5 h. The reaction mixture was cooled to r.t. and stirred for 1 h. The product was filtered, washed with chilled MeOH (20 mL) and dried (8.9 g, 95%). M.p. 133-135 °C, lit.222 134-135 °C; 1H NMR

(300 MHz, CDCl3): G 3.78 (s, 6H, CH3O), 4.52 (s, 2H, CH2), 5.90-5.95 (m, 3H, H2c, H4c, H6c), 7.60-7.95 (m, 4H, H2, H3, H5, H6).

215 N-[2-(4-Bromophenyl)-2-oxoethyl]-N-(3,5-dimethoxyphenyl)acetamide (273)164 A mixture of acetophenone 272 (10.0 g, 28.55 mmol) and

Ac2O (20 mL) was heated at 50 °C for 1 h. Water (100 mL) was added and the mixture was stirred overnight at r.t. The precipitated product was filtered, washed with water and dried (10.0 g, 89%). M.p. 113-114 °C; 1H NMR (300 MHz,

CDCl3): G 2.00 (s, 3H, CH3CO), 3.76 (s, 6H, CH3O), 4.98 (s, 2H, CH2), 6.40 (t, J = 2.3 Hz, 1H, H4c), 6.50 (d, J = 2.3 Hz, 2H, H2c, H6c), 7.56 (d, J = 8.7 Hz, 2H, H2, H6), 7.78 (d, J = 8.7 Hz, 2H, H3, H5).

1-Acetyl-3-(4c-bromophenyl)-4,6-dimethoxyindole (274) A mixture of ketone 273 (10.0 g, 25.5 mmol) and TFA (25 mL) was refluxed under an argon atmosphere for 2 h. The reaction mixture was cooled to r.t. and then poured into ice-cold water (200 mL). The precipitated product was filtered, washed with cold water and air- dried (9.0 g, 94%). M.p. 156-158 °C, lit.164 156-158 °C; 1H NMR (300

MHz, CDCl3): G 2.62 (s, 3H, CH3CO), 3.74 (s, 3H, CH3O), 3.89 (s,

3H, CH3O), 6.40 (d, J = 1.8 Hz, 1H, H5), 7.14 (s, 1H, H2), 7.41 (d, J = 8.7 Hz, 2H, H2c, H6c), 7.49 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.76 (d, J = 1.8 Hz, 1H, H7).

3-(4c-Bromophenyl)-4,6-dimethoxyindole (275) To a suspension of acetylindole 274 (4.5 g, 12.0 mmol) in MeOH (70 mL) was added KOH (2.5 g, 44.6 mmol). The mixture was stirred at ambient temperature for 1 h and then poured into ice-water (200 mL). The precipitated product was filtered, washed with water and dried (3.0 g, 75%). M.p. 175-178 °C, lit.222 180-181 °C; 1H NMR (300

MHz, CDCl3): G 3.79 (s, 3H, CH3O), 3.84 (s, 3H, CH3O), 6.25 (d, J = 1.9 Hz, 1H, H5), 6.48 (d, J = 1.9 Hz, 1H, H7), 7.00 (d, J = 2.6 Hz, 1H, H2), 7.46 (s, 4H, H2c, H3c, H5c, H6c), 8.13 (br, 1H, NH).

216 4c,7-Dimethoxyisoflav-3-ene (276) To a mixture of phenoxodiol 138 (480 mg, 2.0 mmol),

K2CO3 (414 mg, 3.0 mmol) and DMF (10 mL) was added MeI (2 mL). The mixture was refluxed for 12 h, cooled to r.t. and then poured into crushed ice. The resulting solid was filtered, washed with water and air-dried. The title compound was obtained as a white solid 211 -1 -1 (500 mg, 93%). M.p. 155-158 °C, lit. 159-161 °C; UV (MeOH): Omax 211 (H 31027 cm M ), 1 249 (19926), 333 (32348) nm; H NMR (300 MHz, CDCl3): G 3.78 (s, 3H, CH3O), 3.80 (s, 3H,

CH3O), 5.10 (s, 2H, H2), 6.44 (d, J = 2.3 Hz, 1H, H8), 6.47 (dd, J = 2.3, 7.9 Hz, 1H, H6), 6.67 (s, 1H, H4), 6.91 (d, J = 9.1 Hz, 2H, H3c, H5c), 6.98 (d, J = 7.9 Hz, 1H, H5), 7.35 (d, J = 9.1 Hz,

13 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 55.2 (CH3O), 55.3 (CH3O), 67.2 (C2), 101.3 (C8), 107.2 (C6), 114.0 (C3c, C5c), 116.3 (C4a), 118.0 (C4), 125.8 (C2c, C6c), 127.3 (C5), 128.3 (C3), 129.5 (C1c), 154.2 (C8a), 159.2 (C4c), 160.3 (C7). trans-2-(4-Chlorophenyl)-4-(furan-2-yl)-1,2,3,4-tetrahydroquinoline (278) To a stirred solution of azaflavanol 262 (300 mg, 1.16 mmol) and furan 277 (0.1 mL, 1.39 mmol) in DCM (20 mL) was added

BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (25:75) gave the title compound as -1 -1 an off-white solid (89 mg, 25%). M.p. 96-98 °C; UV (MeOH): Omax 204 (H 79843 cm M ), 248

(26747) nm; IR (KBr): Qmax 3398, 1604, 1478, 1340, 1307, 1252, 1165, 1090, 1011, 816, 731 -1 1 cm ; H NMR (300 MHz, CDCl3): G 1.98-2.04 (m, 1H, H3), 2.27 (dt, J = 3.0, 13.0 Hz, 1H, H3), 3.92 (s, 1H, NH), 4.04 (t, J = 4.0 Hz, 1H, H4), 4.19 (dd, J = 3.0, 10.5 Hz, 1H, H2), 5.72 (d, J = 3.0 Hz, 1H, H3cc), 6.17 (dd, J = 1.9, 3.0 Hz, 1H, H4cc), 6.47 (dd, J = 1.0, 7.6 Hz, 1H, H8), 6.57 (ddd, J = 1.0, 6.6, 7.6 Hz, 1H, H6), 6.94 (ddd, J = 1.0, 6.6, 7.6 Hz, 1H, H7), 6.99 (d, J = 1.9 Hz, 1H, H5cc), 7.17 (dd, J = 1.0, 7.6 Hz, 1H, H5), 7.19 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.23 (d, J = 8.7

13 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 36.1 (C3), 36.5 (C4), 52.6 (C2), 107.8 (C3cc), 110.6 (C4cc), 115.0 (C8), 118.0 (C6), 120.3 (C4a), 128.4 (C7), 128.6 (C2c, C6c), 129.2 (C3c, C5c), 130.9 (C5), 133.6 (C4c), 142.0 (C5cc), 143.1 (C1c), 144.9 (C8a), 159.1 (C2cc); MS

217 + (TOF-ESI) m/z Calcd. for C19H16ClNO (M + 1) 310.10. Found 310.03; Anal. Calcd. for

C19H16ClNO.0.2CH2Cl2: C, 70.57; H, 5.06; N, 4.29. Found: C, 70.34; H, 5.27; N, 4.14.

trans-2-(4-Chlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1,2,3,4-tetrahydroquinoline (279) To a stirred solution of azaflavanol 262 (300 mg, 1.16 mmol) and 1- methylindole 171 (0.18 mL, 1.39 mmol) in DCM (20 mL) was added

BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (75:25) gave a solid, which was recrystallized from EtOH to yield the title compound as white crystals (276 mg, 64%). M.p. 152- -1 -1 154 °C; UV (MeOH): Omax 206 (H 77418 cm M ), 223 (74903), 293 (13873) nm; IR (KBr): Qmax 3398, 1605, 1481, 1340, 1311, 1256, 1238, 1084, 1013, 814, 734 cm-1; 1H NMR (300 MHz,

CDCl3): G 2.07-2.16 (m, 1H, H3), 2.27 (dt, J = 3.0, 12.8 Hz, 1H, H3), 3.59 (s, 3H, NCH3), 3.96 (s, 1H, NH), 4.21 (dd, J = 3.0, 10.3 Hz, 1H, H2), 4.36 (t, J = 4.0 Hz, 1H, H4), 6.32 (s, 1H, H2cc), 6.55 (ddd, J = 1.0, 6.3, 7.3 Hz, 1H, H6), 6.59 (dd, J = 1.0, 7.3 Hz, 1H, H8), 6.96 (dd, J = 1.0, 7.3 Hz, 1H, H5), 7.00 (ddd, J = 1.0, 6.3, 7.3 Hz, 1H, H7), 7.14-7.51 (m, 8H, H2c, H3c, H5c, H6c,

13 H4cc, H5cc, H6cc, H7cc); C NMR (75.6 MHz, CDCl3): G 33.1 (NCH3), 34.1 (C4), 37.9 (C3), 52.2 (C2), 110.0 (C8), 114.6 (C6), 117.8 (C7cc), 119.3 (C5cc), 119.5 (C4cc), 121.2 (C3cc), 122.1 (C6cc), 123.3 (C4a), 126.8 (C3cca), 127.8 (C2cc), 128.7 (C2c, C6c), 129.0 (C7), 129.1 (C3c, C5c), 131.0 (C5), 133.4 (C1c), 137.8 (C7cca), 143.4 (C4c), 145.0 (C8a); MS (TOF-ESI) m/z Calcd. for + C24H21ClN2 (M + 1) 373.15. Found 373.09; Anal. Calcd. for C24H21ClN2: C, 77.30; H, 5.68; N, 7.51. Found: C, 77.31; H, 5.86; N, 7.68. trans-2-(4-Chlorophenyl)-4-(2-phenyl-1H-indol-3-yl)-1,2,3,4-tetrahydroquinoline (281) To a stirred solution of azaflavanol 262 (300 mg, 1.16 mmol) and 2-phenylindole 280 (268 mg, 1.39 mmol) in DCM (20 mL) was added BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under

218 vacuum. Chromatography over silica gel using DCM/light petroleum (70:30) gave the title compound as a white solid (337 mg, 67%). M.p. 174-176 °C; UV (MeOH): Omax 208 (H 59764 -1 -1 cm M ), 239 (33153), 304 (21653) nm; IR (KBr): Qmax 3410, 3364, 1603, 1487, 1309, 1293, -1 1 1094, 1012, 833, 749 cm ; H NMR (300 MHz, CDCl3): G 2.09-2.16 (m, 1H, H3), 2.58-2.68 (m, 1H, H3), 4.20 (dd, J = 3.6, 10.3 Hz, 1H, H2), 4.31 (s, 1H, NH), 4.67 (t, J = 4.0 Hz, 1H, H4), 6.40 (ddd, J = 1.1, 6.4, 7.4 Hz, 1H, H6), 6.58 (dd, J = 1.1, 7.4 Hz, 1H, H8), 6.66 (dd, J = 1.1, 7.4 Hz, 1H, H5), 6.86 (ddd, J = 1.1, 6.4, 7.4 Hz, 1H, H7), 6.92-7.29 (m, 13H, H2c, H3c, H5c, H6c, H4cc, H5cc, H6cc, H7cc, H2ccc, H3ccc, H4ccc, H5ccc, H6ccc), 7.93 (s, 1H, NH); 13C NMR (75.6 MHz,

CDCl3): G 30.5 (C4), 37.4 (C3), 54.0 (C2), 111.3 (C8), 113.7 (C7cc), 115.6 (C4a), 117.4 (C6), 118.2 (C3cc), 119.5 (C4cc), 121.6 (C5cc), 122.4 (C6cc), 123.7 (C2cc), 127.6 (C7), 128.0 (C2ccc, C6ccc), 128.2 (C4ccc), 128.5 (C2c, C6c), 128.9 (C3c, C5c), 129.0 (C3ccc, C5ccc), 129.8 (C5), 133.0 (C3cca), 133.2 (C4c), 136.0 (C1ccc), 136.7 (C7cca), 144.0 (C1c), 144.7 (C8a); MS (TOF-ESI) m/z + Calcd. for C29H23ClN2 (M + 1) 435.16. Found 435.03; Anal. Calcd. for C29H23ClN2.1/4CH2Cl2: C, 77.01; H, 5.19; N, 6.14. Found: C, 77.15; H, 5.19; N, 6.01.

trans-4-(3-(4-Bromophenyl)-4,6-dimethoxy-1H-indol-2-yl)- 2-(4-chlorophenyl)-1,2,3,4- tetrahydroquinoline (282) To a stirred solution of azaflavanol 262 (300 mg, 1.16 mmol) and 3-(4c-bromophenyl)-4,6-dimethoxyindole 275 (460 mg, 1.39 mmol) in DCM (20 mL) was added

BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (75:25) gave the title compound as an off-white solid -1 -1 (312 mg, 47%). M.p. 142-144 °C; UV (MeOH): Omax 206 (H 96977 cm M ), 223 (88953), 306 -1 1 (20023) nm; IR (KBr): Qmax 3415, 1625, 1588, 1486, 1213, 1150, 1129, 1012, 824, 750 cm ; H

NMR (300 MHz, CDCl3): G 2.02-2.17 (m, 2H, H3), 3.71 (s, 3H, CH3O), 3.80 (s, 3H, CH3O), 4.20 (s, 1H, NH), 4.29 (t, J = 3.0 Hz, 1H, H4), 4.44 (dd, J = 3.3, 10.0 Hz, 1H, H2), 6.23 (d, J = 1.9 Hz, 1H, H5cc), 6.36 (d, J = 1.9 Hz, 1H, H7cc), 6.62-6.67 (m, 2H, H6, H8), 6.87 (dd, J = 1.0, 7.5 Hz, 1H, H5), 7.12 (ddd, J = 1.1, 6.4, 7.5 Hz, 1H, H7), 7.18 (d, J = 8.5 Hz, 2H, H3c, H5c), 7.24 (d, J = 8.5 Hz, 2H, H2c, H6c), 7.27 (d, J = 8.6 Hz, 2H, H2ccc, H6ccc), 7.40 (d, J = 8.6 Hz, 2H, 219 13 H3ccc, H5ccc), 7.78 (s, 1H, NH); C NMR (75.6 MHz, CDCl3): G 32.5 (C4), 37.6 (C3), 52.9 (C2),

55.2 (CH3O), 55.7 (CH3O), 86.8 (C5cc), 92.2 (C7cc), 111.7 (C4a), 113.2 (C3cc), 114.3 (C8), 117.7 (C6), 119.9 (C3cca), 120.5 (C4ccc), 127.7 (C7), 128.3 (C3ccc, C5ccc), 128.8 (C2c, C6c), 130.0 (C3c, C5c), 130.4 (C2ccc, C6ccc), 132.3 (C5), 133.2 (C4c), 134.8 (C2cc), 136.0 (C1ccc), 136.7 (C7cca), 142.5 (C1c), 144.2 (C8a), 154.5 (C4cc), 157.3 (C6cc); MS (TOF-ESI) m/z Calcd. for + 79 79 C31H26BrClN2O2 (M + 1) 573.09 (Br ). Found 572.99 (Br ); Anal. Calcd. for C31H26BrClN2O2: C, 64.88; H, 4.57; N, 4.88. Found: C, 64.71; H, 4.63; N, 4.83. trans-2-(4-Chlorophenyl)-4-(4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)-1,2,3,4- tetrahydroquinoline (283) To a stirred solution of azaflavanol 262 (300 mg, 1.16 mmol) and 4,6-dimethoxy-2,3-diphenylindole 270 (456 mg, 1.39 mmol) in DCM (20 mL) was added BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of

NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (65:35) gave the title compound as a white solid (416 mg, 63%). M.p. 160-162 °C; UV (MeOH): Omax 206 (H 72583 -1 -1 cm M ), 250 (33396), 320 (15104) nm; IR (KBr): Qmax 3433, 1601, 1480, 1347, 1260, 1152, -1 1 1100, 1013, 823, 753 cm ; H NMR (300 MHz, CDCl3): G 2.06-2.30 (m, 2H, H3), 3.80 (s, 3H,

CH3O), 3.86 (s, 3H, CH3O), 4.17 (s, 1H, NH), 4.45 (dd, J = 2.6, 11.3 Hz, 1H, H2), 5.10 (t, J = 3.8 Hz, 1H, H4), 6.24 (s, 1H, H5cc), 7.01-7.22 (m, 14H, H5, H6, H7, H8, ArH), 7.23 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.29 (d, J = 8.7 Hz, 2H, H2c, H6c), 7.62 (s, 1H, NH); 13C NMR* (75.6 MHz,

CDCl3): G 32.0 (C4), 39.2 (C3), 53.4 (C2), 55.9 (CH3O), 57.4 (CH3O), 90.0 (C5cc), 109.2 (C7cc), 114.2 (C8), 118.7 (C6), 119.6 (C4a), 127.0 (C7), 127.6 (ArCH), 127.7 (ArCH), 128.6 (C2c, C6c), 128.7 (ArCH), 128.8 (ArCH), 128.9 (C3c, C5c), 129.1 (ArCH), 129.2 (ArCH), 130.7 (C5), 131.9 (ArC), 132.4 (C3cca), 133.2 (C4c), 133.7 (C2cc), 135.4 (ArC), 136.8 (C3cc), 137.5 (C7cca), 142.3

(C1c), 144.9 (C4cc), 146.0 (C8a), 154.1 (C6cc); MS (TOF-ESI) m/z Calcd. for C37H31ClN2O2 (M + + 1) 571.22. Found 571.06; Anal. Calcd. for C37H31ClN2O2: C, 77.81; H, 5.47; N, 4.91. Found: C, 77.71; H, 5.63; N, 4.83. *Additional peaks are due to atropisomers.

220 trans-2-(4-Chlorophenyl)-4-(7-methoxy-3-(4-methoxyphenyl)-2H-chromen-6-yl)-1,2,3,4- tetrahydroquinoline (284) To a stirred solution of azaflavanol 262 (300 mg, 1.16 mmol) and 4c,7-dimethoxyisoflav-3-ene 276 (372 mg, 1.39 mmol) in DCM (20 mL) was added BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous

Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (75:25) gave the title compound as a white solid (118 mg, 20%). M.p. 194-196 °C;

-1 -1 UV (MeOH): Omax 206 (H 33366 cm M ), 252 (16656), 339 (12269) nm; IR (KBr): Qmax 3389, 1615, 1514, 1496, 1250, 1160, 1127, 1107, 1035, 1013, 818, 748 cm-1; 1H NMR (300 MHz,

CDCl3): G 2.09-2.13 (m, 2H, H3), 3.80 (s, 3H, CH3O), 3.82 (s, 3H, CH3O), 4.20 (s, 1H, NH), 4.24 (dd, J = 2.6, 8.3 Hz, 1H, H2), 4.46 (t, J = 3.8 Hz, 1H, H4), 5.10 (s, 2H, H2cc), 6.41 (s, 1H, H8cc), 6.47 (s, 1H, H5cc), 6.56 (s, 1H, H4cc), 6.65 (ddd, J = 1.0, 6.3, 7.4 Hz, 1H, H6), 6.68 (dd, J = 1.0, 7.4 Hz, 1H, H8), 6.87 (d, J = 8.9 Hz, 2H, H3ccc, H5ccc), 6.92 (dd, J = 1.0, 7.4 Hz, 1H, H5), 7.09 (ddd, J = 1.0, 6.3, 7.4 Hz, 1H, H7), 7.25 (d, J = 8.9 Hz, 2H, H2ccc, H6ccc), 7.27 (d, J = 8.9

13 Hz, 2H, H3c, H5c), 7.30 (d, J = 8.9 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 35.4

(C4), 37.1 (C3), 51.6 (C2), 55.3 (CH3O), 55.5 (CH3O), 67.3 (C2cc), 98.7 (C8cc), 114.1 (C3ccc, C5ccc), 114.1 (C8), 115.1 (C4cca), 117.6 (C6), 118.4 (C4a), 122.3 (C6cc), 125.7 (C2c, C6c), 127.4 (C5cc), 127.9 (C7), 128.3 (C2ccc, C6ccc), 128.6 (C3c, C5c), 128.8 (C4cc), 129.6 (C3cc), 130.7 (C5), 132.9 (C4c), 133.0 (C1ccc), 143.0 (C1c), 145.2 (C8a), 152.6 (C8cca), 156.8 (C7cc), 159.1 (C4ccc); + MS (TOF-ESI) m/z Calcd. for C32H28ClNO3 (M + 1) 510.18. Found 510.07; Anal. Calcd. for

C32H28ClNO3: C, 75.36; H, 5.53; N, 2.75. Found: C, 75.19; H, 5.81; N, 2.71.

221 trans-2-(4-Chlorophenyl)-4-(4-chlorophenylthio)-1,2,3,4-tetrahydroquinoline (287) To a stirred solution of azaflavanol 262 (300 mg, 1.16 mmol) and 4-chlorothiophenol 285 (200 mg, 1.39 mmol) in DCM (20 mL) was added BF3·OEt2 (10 drops). The mixture was stirred at r.t. for

12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM

(25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (40:60) gave the title compound as a white crystalline solid (325 mg, 73%). M.p. 118-120 °C; UV (MeOH): Omax 204 -1 -1 (H 84804 cm M ), 259 (29732), 313 (9795) nm; IR (KBr): Qmax 3381, 1603, 1476, 1337, 1315, -1 1 1255, 1093, 1013, 821, 808, 754 cm ; H NMR (300 MHz, CDCl3): G 1.95-2.07 (m, 2H, H3), 4.02 (s, 1H, NH), 4.42 (t, J = 3.0 Hz, 1H, H4), 4.75 (dd, J = 4.5, 9.7 Hz, 1H, H2), 6.48 (dd, J = 1.0, 7.6 Hz, 1H, H8), 6.60 (ddd, J = 1.0, 6.4, 7.6 Hz, 1H, H6), 6.99 (ddd, J = 1.0, 6.4, 7.6 Hz, 1H, H7), 7.12 (dd, J = 1.0, 7.6 Hz, 1H, H5), 7.18 (d, J = 8.6 Hz, 2H, H2cc, H6cc), 7.21 (d, J = 8.6 Hz, 2H, H3cc, H5cc), 7.24 (d, J = 8.5 Hz, 2H, H3c, H5c), 7.31 (d, J = 8.5 Hz, 2H, H2c, H6c); 13C

NMR (75.6 MHz, CDCl3): G 36.2 (C3), 46.1 (C4), 51.2 (C2), 114.9 (C8), 117.7 (C6), 118.4 (C4a), 128.2 (C2c, C6c), 128.8 (C3c, C5c), 128.9 (C3cc, C5cc), 129.3 (C7), 130.8 (C5), 133.4 (C4cc), 133.5 (C4c), 133.7 (C1cc), 133.8 (C2cc, C6cc), 141.9 (C1c), 144.7 (C8a); MS (TOF-ESI) + m/z Calcd. for C21H17Cl2NS (M + 1) 386.05. Found 385.99; Anal. Calcd. for C21H17Cl2NS: C, 65.29; H, 4.44; N, 3.63. Found: C, 65.22; H, 4.41; N, 3.59. trans-2-(4-Chlorophenyl)-4-(4-methoxyphenylthio)-1,2,3,4-tetrahydroquinoline (288) To a stirred solution of azaflavanol 262 (300 mg, 1.16 mmol) and 4-methoxythiophenol 286 (0.17 mL, 1.39 mmol) in DCM (20 mL) was added BF3·OEt2 (10 drops). The mixture was stirred at r.t. for

12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM

(25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (40:60) gave the title compound as a white crystalline solid (313 mg, 71%). M.p. 113-115 °C; UV (MeOH): Omax 204 -1 -1 (H 85869 cm M ), 236 (48415), 311 (9746) nm; IR (KBr): Qmax 3369, 1606, 1590, 1490, 1287, -1 1 1247, 1085, 1030, 826, 753 cm ; H NMR (300 MHz, CDCl3): G 1.93-1.98 (m, 2H, H3), 3.72 (s,

222 3H, CH3O), 4.01 (s, 1H, NH), 4.28 (t, J = 3.0 Hz, 1H, H4), 4.81 (dd, J = 4.5, 9.7 Hz, 1H, H2), 6.48 (dd, J = 1.0, 7.5 Hz, 1H, H8), 6.60 (ddd, J = 1.0, 6.3, 7.5 Hz, 1H, H6), 6.79 (d, J = 8.7 Hz, 2H, H2cc, H6cc), 6.98 (ddd, J = 1.0, 6.3, 7.5 Hz, 1H, H7), 7.12 (dd, J = 1.0, 7.5 Hz, 1H, H5), 7.24 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.29 (d, J = 8.7 Hz, 2H, H2c, H6c), 7.37 (d, J = 8.7 Hz, 2H, H3cc,

13 H5cc); C NMR (75.6 MHz, CDCl3): G 35.9 (C3), 47.2 (C4), 51.1 (C2), 55.4 (CH3O), 114.7 (C3cc, C5cc), 114.8 (C8), 117.5 (C6), 119.2 (C4a), 125.3 (C1cc), 128.2 (C2c, C6c), 128.6 (C7), 128.8 (C3c, C5c), 130.8 (C5), 133.3 (C4c), 135.9 (C2cc, C6cc), 142.3 (C1c), 144.6 (C8a), 159.8

+ (C4cc); MS (TOF-ESI) m/z Calcd. for C22H20ClNOS (M + 1) 382.10. Found 382.06; Anal.

Calcd. for C22H20ClNOS: C, 69.19; H, 5.28; N, 3.67. Found: C, 69.23; H, 5.22; N, 3.61.

N-(3,5-Dimethoxyphenyl)-2,2,2-trifluoroacetamide (289) To a solution of 3,5-dimethoxyaniline 268 (5.00 g, 32.0 mmol) in anhydrous DCM (50 mL) was added drop wise anhydrous triethylamine (6.85 mL, 48.9 mmol) followed by TFAA (6.91 mL, 48.9 mmol) in an ice bath. The reaction mixture was stirred at r.t. for 2 h. It was treated with ice water, extracted in DCM (3 x 20 mL) and concentrated under reduced pressure to give a crude solid, which was recrystallised in DCM to yield the title compound as a white solid (6.6 g, 82%). M.p. 101-102 °C, lit.165 M.p. 94-96 °C; 1H NMR (300

MHz, CDCl3): G 3.78 (s, 6H, CH3O), 6.33 (t, J = 2.1 Hz, 1H, H4), 6.78 (d, J = 2.1 Hz, 2H, H2, H6), 7.95 (br s, 1H, NH).

N-(2-Acetyl-3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (290) and N- (4-Acetyl-3,5- dimethoxyphenyl)-2,2,2-trifluoroacetamide (291) To a solution of N-(3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide 289 (5.0 g, 20.1 mmol) in DCE (20 mL) in an ice bath in an inert atmosphere of nitrogen was added stannic chloride (4.7 mL, 40.0 mmol) and chilled acetyl chloride (1.45 mL, 20.0 mmol). The reaction mixture was stirred at r.t. for 3 h, quenched with water (50 mL), extracted with DCM (3 x 20 mL) and the organic phase washed with 10% HCl (3 x 20 mL) and dried over anhydrous

Na2SO4, concentrated under reduced pressure and purified by column chromatography over silica gel using 100% DCM to yield fraction 1, the title compound 290 as a white solid (2.8 g, 165 1 49%). M.p. 119-120 °C (from EtOH), lit. M.p. 74-76 °C; H NMR (300 MHz, CDCl3): G 2.61

(s, 2H, CH3CO), 3.88 (s, 3H, CH3O), 3.90 (s, 3H, CH3O), 6.31 (d, J = 2.3 Hz, 1H, H4), 7.90 (d, J = 2.3 Hz, 1H, H6), 13.30 (br s, 1H, NH).

223 Fraction 2 yielded the title compound 291 as a white solid (1.5 g, 26%). M.p. 153-155 °C (from MeOH), lit.165 M.p. 155-157 °C; 1H

NMR (300 MHz, CDCl3): G 2.46 (s, 3H, CH3CO), 3.77 (s, 6H,

CH3O), 6.81 (s, 2H, H2, H6), 8.21 (br s, 1H, NH).

2-Amino-4,6-dimethoxyacetophenone (292)165 A mixture of N-(2-acetyl-3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide

290 (1.9 g, 6.99 mmol) and K2CO3 (1.6 g, 11.86 mmol) in MeOH (40 mL) was heated under reflux for 3 h. The reaction mixture was extracted with DCM (3 x 10 mL), and the organic phase washed with water (3 x 10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound as a white solid (1.0 g, 49%). M.p. 105-107 °C (from MeOH); 1H NMR (300 MHz,

CDCl3): G 2.53 (s, 3H, CH3CO), 3.77 (s, 3H, CH3O), 3.81 (s, 3H, CH3O), 5.73 (d, J = 2.3 Hz, 13 1H, H3), 5.77 (d, J = 2.3 Hz, 1H, H5); C NMR (75.6 MHz, CDCl3): G 33.7 (CH3CO), 55.1

(CH3O), 55.2 (CH3O), 88.2 (C5), 97.5 (C1), 105.7 (C3), 153.4 (C2), 163.4 (C6), 163.9 (C4), 200.1 (CO).

2-Amino-4c-chloro-4,6-dimethoxychalcone (294) To a solution of 2-amino-4,6-dimethoxyacetophenone 292 (2.0 g, 10.24 mmol) in EtOH (50 mL) was added 4- chlorobenzaldehyde 67c (1.44 g, 10.24 mmol). This was followed by slow addition of crushed NaOH pellets (1.0 g, 25.61 mmol). The reaction mixture was stirred for 12 h at r.t., poured into ice (100 g) and acidified using conc. HCl to pH 3. The solid so obtained was filtered and air-dried. Recrystallization from EtOH gave the title compound as yellow crystals (2.4 g, 74%). M.p. 106- -1 -1 108 °C; UV (MeOH): Omax 202 (H 60540 cm M ), 223 (65504), 312 (43558) nm; IR (KBr): Qmax -1 1 3447, 1609, 1585, 1213, 1165, 1144, 822 cm ; H NMR (300 MHz, DMSO-d6): G 3.76 (s, 3H,

CH3O), 3.83 (s, 3H, CH3O), 5.86 (d, J = 1.9 Hz, 1H, H3c), 5.99 (d, J = 1.9 Hz, 1H, H5c), 7.43 (d,

J = 15.3 Hz, 1H, HD), 7.52 (d, J = 15.3 Hz, 1H, HE), 7.58 (d, J = 8.6 Hz, 2H, H3, H5), 7.71 (d, J 13 = 8.6 Hz, 2H, H2, H6); C NMR (75.6 MHz, DMSO-d6): G 55.4 (CH3O), 56.1 (CH3O), 88.3

(C5c), 92.3 (C3c), 105.9 (C1c), 127.8 (CD), 129.3 (C3, C5), 130.0 (C2, C6), 131.5 (CE), 134.3 (C1), 134.8 (C4), 153.9 (C2c), 162.7 (C6c), 164.2 (C4c), 190.0 (CO); MS (TOF-ESI) m/z Calcd. + for C17H16ClNO3 (M + 1) 318.09. Found 318.04; Anal. Calcd. for C17H16ClNO3: C, 64.26; H, 5.08; N, 4.41. Found: C, 64.15; H, 5.19; N, 4.21.

224 2-(4-Chlorophenyl)-5,7-dimethoxy-2,3-dihydroquinolin-4(1H)-one (293) A mixture of aminochalcone 294 (1.0 g, 3.15 mmol) and

ZnCl2 (0.64 g, 4.72 mmol) in anhydrous CH3CN (50 mL) was refluxed for 36 h. The reaction mixture was concentrated under vacuum to 20 mL, diluted with water (100 mL) and extracted with EtOAc (2 X 100 mL). The organic layers were collected and washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using 100% chloroform eluted the title compound 293 as a yellow solid (680 mg, 68%). M.p. 94-96 °C; UV (MeOH): Omax 202 -1 -1 (H 37669 cm M ), 221 (33988), 241 (28896), 290 (15521), 348 (5276) nm; IR (KBr): Qmax 3291, -1 1 2935, 1607, 1524, 1471, 1267, 1216, 1163, 1140, 1013, 828 cm ; H NMR (300 MHz, CDCl3):

G 2.59-2.80 (m, 2H, H3), 3.78 (s, 3H, CH3O), 3.84 (s, 3H, CH3O), 4.60-4.66 (m, 1H, H2), 4.67 (s, 1H, NH), 5.78 (d, J = 2.2 Hz, 1H, H8), 5.84 (d, J = 2.2 Hz, 1H, H6), 7.32 (s, 4H, H2c, H3c,

13 H5c, H6c); C NMR (75.6 MHz, CDCl3): G 47.4 (C3), 55.2 (CH3O), 55.8 (CH3O), 57.0 (C2), 90.0 (C8), 90.8 (C6), 104.0 (C4a), 127.8 (C2c, C6c), 129.0 (C3c, C5c), 133.9 (C4c), 140.0 (C1c),

154.8 (C8a), 163.0 (C5), 165.4 (C7), 190.0 (C4); MS (TOF-ESI) m/z Calcd. for C17H16ClNO3 + (M + 1) 318.09. Found 318.04; Anal. Calcd. for C17H16ClNO3: C, 64.26; H, 5.08; N, 4.41. Found: C, 64.15; H, 5.19; N, 4.21. cis-2-(4-Chlorophenyl)-5,7-dimethoxy-1,2,3,4-tetrahydroquinolin-4-ol (295) To a solution of azaflavanone 293 (1.0 g, 3.15 mmol) in

EtOH (25 mL), powdered NaBH4 (0.12 g, 3.15 mmol) was added in portions over 15 minutes. The reaction mixture was allowed to stir at r.t. for 4 h. The solvent was evaporated under reduced pressure, followed by the addition of ice (100 g). The reaction mixture was then quenched slowly by the addition of 10% AcOH to pH 5, and extracted with EtOAc (2 X 100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and evaporated to yield the title compound as a white solid (785 mg, -1 -1 78%). M.p. 64-66 °C; UV (MeOH): Omax 212 (H 65786 cm M ), 258 (41824), 343 (14905) nm;

IR (KBr): Qmax 3450, 2930, 2833, 1620, 1494, 1338, 1239, 1206, 1161, 1138, 1089, 1012, 859, -1 1 826 cm ; H NMR (300 MHz, CDCl3): G 2.13 (ddd, J = 9.0, 10.9, 13.4 Hz, 1H, H3), 2.34 (ddd,

J = 2.7, 6.9, 13.4 Hz, 1H, H3), 3.73 (s, 3H, CH3O), 3.83 (s, 3H, CH3O), 4.36 (dd, J = 2.7, 10.9 Hz, 1H, H4), 5.19 (dd, J = 6.9, 9.0 Hz, 1H, H2), 5.77 (d, J = 2.2 Hz, 1H, H8), 5.92 (d, J = 2.2 Hz, 1H, H6), 7.30 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.38 (d, J = 8.7 Hz, 2H, H2c, H6c); 13C NMR

225 (75.6 MHz, CDCl3): G 39.4 (C3), 54.9 (C2), 55.1 (CH3O), 55.4 (CH3O), 64.0 (C4), 89.3 (C6), 91.9 (C8), 105.6 (C4a), 128.0 (C2c, C6c), 128.7 (C3c, C5c), 133.2 (C4c), 141.7 (C1c), 146.4 (C8a), + 159.7 (C7), 160.5 (C5); HRMS (ESI) m/z Calcd. for C17H18ClNO3Na (M + Na) 342.0875. Found 342.0863.

2-(4-Chlorophenyl)-5,7-dimethoxy-1,2,3,4-tetrahydroquinoline (301), 2-(4-Chlorophenyl)- 5,7-dimethoxyquinoline (300) and trans-1-(2-(4-Chlorophenyl)-5,7-dimethoxy-1,2,3,4- tetrahydroquinolin-4-yl)naphthalen-2-ol (296) To a stirred solution of azaflavanol 295 (250 mg, 0.78 mmol) and 2-naphthol 99 (140 mg, 0.94 mmol) in DCM (20 mL) was added BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum gave three fractions.

Fraction 1 eluted using DCM/light petroleum (20:80) gave 301 as a colourless sticky residue (45 mg, 19%). 1H NMR

(300 MHz, CDCl3): G 1.87-2.13 (m, 2H, H3), 2.55-2.70 (m,

2H, H4), 3.75 (s, 3H, CH3O), 3.78 (s, 3H, CH3O), 4.01 (s, 1H, NH), 4.34 (dd, J = 2.2, 9.4 Hz, 1H, H2), 5.79 (d, J = 2.3 Hz, 1H, H8), 5.91 (d, J = 2.3 Hz, 1H, H6), 7.31 (s, 4H, H2c, H3c, H5c, H6c); 13C NMR (75.6 MHz,

CDCl3): G 19.6 (C4), 30.9 (C3), 55.1 (CH3O), 55.2 (CH3O), 55.3 (C2), 88.4 (C6), 91.4 (C8), 101.8 (C4a), 127.8 (C2c, C6c), 128.6 (C3c, C5c), 133.0 (C4c), 143.1 (C1c), 145.6 (C8a), 158.6 + (C7), 159.4 (C5); MS (TOF-ESI) m/z Calcd. for C17H18ClNO2 (M + 1) 304.11. Found 304.07;

Anal. Calcd. for C17H18ClNO2: C, 67.21; H, 5.97; N, 4.61. Found: C, 67.49; H, 5.79; N, 4.71.

Fraction 2 eluted using DCM/light petroleum (50:50) gave 4c- chloro-5,7-dimethoxyquinoline 300 as a white crystalline solid

(56 mg, 24%). M.p. 116-118 °C; UV (MeOH): Omax 204 (H 82726 cm-1M-1), 283 (65822), 342 (31480), 382 (19890) nm; -1 IR (KBr): Qmax 3395, 1630, 1599, 1416, 1233, 1115, 810 cm ; 1 H NMR (300 MHz, CDCl3): G 3.96 (s, 3H, CH3O), 3.98 (s, 3H, CH3O), 6.51 (d, J = 2.2 Hz, 1H, H6), 7.07 (d, J = 2.2 Hz, 1H, H8), 7.47 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.64 (d, J = 8.7 Hz, 1H, H3), 8.08 (d, J = 8.7 Hz, 2H, H2c, H6c), 8.48 (d, J = 8.7 Hz, 1H, H4); 13C NMR (75.6 MHz,

226 CDCl3): G 55.6 (CH3O), 55.7 (CH3O), 98.0 (C6), 99.8 (C8), 115.4 (C3), 115.6 (C4a), 128.7 (C2c, C6c), 128.8 (C3c, C5c), 131.5 (C4), 135.2 (C4c), 138.2 (C1c), 150.3 (C8a), 155.9 (C2), 156.6 + (C7), 161.5 (C5); MS (TOF-ESI) m/z Calcd. for C17H14ClNO2 (M + 1) 300.08. Found 300.01;

Anal. Calcd. for C17H14ClNO2: C, 68.12; H, 4.71; N, 4.67. Found: C, 68.29; H, 4.59; N, 4.71.

Fraction 3 eluted using DCM/light petroleum (75:25) gave the title compound 296 as a white solid (112 mg, 32%). M.p. -1 -1 214-216 °C; UV (MeOH): Omax 206 (H 192720 cm M ), 227

(259320), 280 (43120) nm; IR (KBr): Qmax 3382, 1620, 1594, -1 1 1478, 1212, 1167, 819 cm ; H NMR (300 MHz, CDCl3): G

2.18-2.30 (m, 2H, H3), 3.96 (s, 3H, CH3O), 3.98 (s, 3H,

CH3O), 4.36 (s, 1H, NH), 5.09 (t, J = 4.0 Hz, 1H, H4), 5.93 (dd, J = 2.3, 10.0 Hz, 1H, H2), 6.50 (d, J = 2.2 Hz, 1H, H8), 6.53 (d, J = 2.2 Hz, 1H, H6), 7.21-7.49 (m, 4H, H3cc, H4cc, H6cc, H7cc), 7.65 (d, J = 8.7 Hz, 2H, H3c, H5c), 8.07 (d, J = 8.7 Hz, 2H, H2c, H6c), 8.09 (d, J = 8.6 Hz, 1H,

13 H5cc), 8.48 (d, J = 8.6 Hz, 1H, H8cc); C NMR (75.6 MHz, CDCl3): G 29.9 (C4), 38.7 (C3), 52.5

(C2), 55.2 (CH3O), 55.7 (CH3O), 89.3 (C6), 91.7 (C8), 105.0 (C4a), 118.2 (C1cc), 120.8 (C3cc), 123.0 (C6cc), 123.9 (C8cc), 127.0 (C7cc), 128.0 (C5cc), 128.7 (C4cc), 128.9 (C2c, C6c), 129.0 (C4cca), 129.8 (C3c, C5c), 132.0 (C4c), 133.1 (C8cca), 142.1 (C1c), 146.5 (C8a), 153.9 (C2cc), + 157.2 (C5), 158.3 (C7); MS (TOF-ESI) m/z Calcd. for C27H24ClNO3 (M + 1) 446.15. Found

446.05; Anal. Calcd. for C27H24ClNO3: C, 72.72; H, 5.42; N, 3.14. Found: C, 72.55; H, 5.59; N, 3.03. trans-2-(2-(4-Chlorophenyl)-5,7-dimethoxy-1,2,3,4-tetrahydroquinolin-4-yl)-3,5- dimethoxyphenol (297) To a stirred solution of azaflavanol 295 (250 mg, 0.78 mmol) and 3,5-dimethoxyphenol 266 (145 mg, 0.94 mmol) in DCM (20 mL) was added BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (70:30) gave the title compound as -1 -1 a white solid (143 mg, 41%). M.p. 174-176 °C; UV (MeOH): Omax 206 (H 190820 cm M ), 279

227 -1 1 (18667) nm; IR (KBr): Qmax 3388, 1616, 1587, 1467, 1208, 1152, 820 cm ; H NMR (300 MHz,

CDCl3): G 2.19-2.34 (m, 2H, H3), 3.66 (s, 3H, CH3O), 3.75 (s, 3H, CH3O), 3.78 (s, 3H, CH3O),

3.90 (s, 3H, CH3O), 4.31 (s, 1H, NH), 4.43 (dd, J = 3.3, 10.3 Hz, 1H, H2), 4.51 (t, J = 4.0 Hz, 1H, H4), 5.85 (d, J = 2.2 Hz, 1H, H8), 5.92 (d, J = 2.2 Hz, 1H, H6), 5.96 (d, J = 2.4 Hz, 1H, H3cc), 6.10 (d, J = 2.4 Hz, 1H, H5cc), 7.27 (s, 4H, H2c, H3c, H5c, H6c); 13C NMR (75.6 MHz,

CDCl3): G 27.5 (C4), 38.8 (C3), 52.6 (C2), 55.0 (CH3O), 55.1 (CH3O), 55.6 (2 X CH3O), 89.2 (C6), 91.4 (C8), 91.6 (C5cc), 94.6 (C3cc), 105.3 (C4a), 111.5 (C1cc), 128.1 (C2c, C6c), 128.6 (C3c, C5c), 133.0 (C4c), 142.3 (C1c), 146.0 (C8a), 157.1 (C2cc), 158.1 (C5), 159.1 (C7), 160.0 (C6cc),

+ 161.2 (C4cc); MS (TOF-ESI) m/z Calcd. for C25H26ClNO5 (M + 1) 456.16. Found 456.09; Anal.

Calcd. for C25H26ClNO5: C, 65.86; H, 5.75; N, 3.07. Found: C, 66.15; H, 5.99; N, 3.01. trans-2-(4-Chlorophenyl)-5,7-dimethoxy-4-(2-phenyl-1H-indol-3-yl)-1,2,3,4- tetrahydroquinoline (298) To a stirred solution of azaflavanol 295 (250 mg, 0.78 mmol) and 2-phenylindole 280 (181 mg, 0.94 mmol) in

DCM (20 mL) was added BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (70:30) gave the title compound as a white solid (178 mg, 46%). M.p. -1 -1 158-160 °C; UV (MeOH): Omax 209 (H 99348 cm M ), 221 (110260), 303 (29696) nm; IR -1 1 (KBr): Qmax 3394, 1613, 1588, 1488, 1202, 1153, 814 cm ; H NMR (300 MHz, CDCl3): G 1.98-

2.14 (m, 2H, H3), 3.53 (s, 3H, CH3O), 3.78 (s, 3H, CH3O), 4.19 (s, 1H, NH), 4.50 (dd, J = 3.3, 10.1 Hz, 1H, H2), 4.79 (t, J = 3.0 Hz, 1H, H4), 5.82 (d, J = 2.3 Hz, 1H, H8), 5.98 (d, J = 2.3 Hz, 13 1H, H6), 6.93-7.59 (m, 13H, ArH), 7.98 (s, 1H, NH); C NMR (75.6 MHz, CDCl3): G 28.0

(C4), 31.5 (C3), 52.6 (C2), 55.1 (CH3O), 55.3 (CH3O), 88.6 (C6), 91.1 (C8), 103.6 (C4a), 110.5 (Ar), 118.4 (Ar), 119.4 (Ar), 119.8 (Ar), 121.3 (Ar), 123.2 (Ar), 127.5 (Ar), 128.2 (Ar), 128.5 (Ar), 128.6 (Ar), 128.8 (Ar), 129.0 (Ar), 132.8 (Ar), 133.8 (Ar), 135.6 (Ar), 142.9 (Ar), 145.7 + (C8a), 159.3 (C5), 159.9 (C7); MS (TOF-ESI) m/z Calcd. for C31H27ClN2O2 (M + 1) 495.18.

Found 495.06; Anal. Calcd. for C31H27ClN2O2: C, 75.22; H, 5.50; N, 5.66. Found: C, 75.12; H, 5.80; N, 5.87.

228 trans-2-(4-Chlorophenyl)-4-(furan-2-yl)-5,7-dimethoxy-1,2,3,4-tetrahydroquinoline (299) To a stirred solution of azaflavanol 295 (250 mg, 0.78 mmol) and furan 277 (0.07 mL, 0.94 mmol) in DCM (20 mL) was added BF3·OEt2 (10 drops). The mixture was stirred at r.t. for 12 h and then quenched by the addition of

NaHCO3 solution (25 mL, 25%). The mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with DCM (25 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum. Chromatography over silica gel using DCM/light petroleum (70:30) gave the title compound as a white solid (95 mg, 33%). M.p. 64- -1 -1 66 °C; UV (MeOH): Omax 221 (H 71866 cm M ), 255 (12463) nm; IR (KBr): Qmax 3388, 1613, -1 1 1588, 1479, 1202, 1156, 805 cm ; H NMR (300 MHz, CDCl3): G 1.91-2.32 (m, 2H, H3), 3.70

(s, 3H, CH3O), 3.77 (s, 3H, CH3O), 4.03 (s, 1H, NH), 4.18 (t, J = 4.0 Hz, 1H, H4), 4.37 (dd, J = 3.3, 10.3 Hz, 1H, H2), 5.85 (d, J = 2.3 Hz, 1H, H8), 5.92 (d, J = 2.3 Hz, 1H, H6), 5.99-6.27 (m, 13 2H, H3cc, H4cc), 7.29-7.34 (m, 5H, H2c, H3c, H5c, H6c, H5cc); C NMR (75.6 MHz, CDCl3): G

28.3 (C4), 33.4 (C3), 49.4 (C2), 52.7 (CH3O), 53.0 (CH3O), 86.3 (C6), 88.9 (C8), 98.7 (C4a), 104.0 (C3cc), 107.6 (C4cc), 125.7 (C2c, C6c), 126.2 (C3c, C5c), 130.7 (C4c), 138.4 (C5cc), 140.1 (C1c), 143.2 (C8a), 156.3 (C2cc), 156.7 (C5), 157.8 (C7); MS (TOF-ESI) m/z Calcd. for + C21H20ClNO3 (M + 1) 370.12. Found 370.03; Anal. Calcd. for C21H20ClNO3: C, 68.20; H, 5.45; N, 3.79. Found: C, 68.15; H, 5.19; N, 4.01.

2-(4-Chlorophenyl)quinoline (303) To a solution of azaflavanol 262 (250 mg, 0.96 mmol) in DCM (20 mL) was added 10 drops of BF3·OEt2 and the mixture stirred at r.t. for 4 h. The reaction mixture was quenched by the addition of saturated solution of NaHCO3 (20 mL). The organic layer was collected, dried over anhydrous Na2SO4 and evaporated. The residue so obtained was purified by column chromatography over silica gel to elute the title compound using DCM/light petroleum (40:60) as a white crystalline solid (162 mg, 70%). M.p. 106-108 °C, lit.223 110-111 °C; 1H

NMR (300 MHz, CDCl3): G 7.40 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.46 (ddd, J = 1.5, 6.8, 8.0 Hz, 1H, H6), 7.64 (ddd, J = 1.5, 6.8, 8.0 Hz, 1H, H7), 7.71 (dd, J = 1.5, 8.0 Hz, 1H, H8), 7.74 (d, J = 8.7 Hz, 1H, H3), 8.03 (dd, J = 1.5, 8.0 Hz, 1H, H5), 8.07 (d, J = 8.7 Hz, 2H, H2c, H6c), 8.12 (d, J

13 = 8.7 Hz, 1H, H4); C NMR (75.6 MHz, CDCl3): G 118.5 (C3), 126.5 (C8), 127.2 (C4a), 127.5 (C6), 128.8 (C2c, C6c), 129.0 (C3c, C5c), 129.7 (C5), 129.8 (C7), 135.6 (C4c), 136.9 (C4), 138.1 (C1c), 148.3 (C8a), 156.0 (C2). 229 2-(4-Chlorophenyl)-1,2,3,4-tetrahydroquinoline (304)224 To a solution of 2-(4-chlorophenyl)quinoline 303 (100 mg, 0.42 mmol) in anhydrous THF (10 mL), was added slowly LAH (15.8 mg, 0.42 mmol) and the mixture was refluxed for 10 h. The reaction mixture was cooled to r.t., quenched by the addition of 10 drops of 1N NaOH, and extracted with EtOAc (2 X 20 mL). The organic layers were collected, washed with brine (15 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to yield the 1 title compound as an off-white solid (62 mg, 61%). H NMR (300 MHz, CDCl3): G 1.89-2.97 (m, 4H, H3, H4), 4.01 (s, 1H, NH), 4.41-4.45 (m, 1H, H2), 6.55 (dd, J = 1.0, 7.3 Hz, 1H, H8), 6.67 (ddd, J = 1.0, 6.4, 7.3 Hz, 1H, H6), 7.01 (dd, J = 1.0, 7.3 Hz, 1H, H5), 7.05 (ddd, J = 1.0, 6.4, 7.3 Hz, 1H, H7), 7.32 (d, J = 8.6 Hz, 2H, H3c, H5c), 7.38 (d, J = 8.6 Hz, 2H, H2c, H6c); 13C

NMR (75.6 MHz, CDCl3): G 26.1 (C4), 40.0 (C3), 55.6 (C2), 114.1 (C8), 117.4 (C6), 120.8 (C4a), 127.0 (C7), 127.9 (C2c, C6c), 128.7 (C3c, C5c), 129.3 (C5), 133.0 (C4c), 143.4 (C1c), 144.4 (C8a).

2-(4-Chlorophenyl)-4-phenyl-1,2,3,4-tetrahydroquinolin-4-ol (305) To a solution of azaflavanone 261 (500 mg, 1.6 mmol) in anhydrous THF (25 mL), was added slowly phenylmagnesium bromide (0.2 mL, 1.6 mmol) in an inert atmosphere of nitrogen. The reaction mixture was refluxed for 18 h. It was quenched by the addition of NH4Cl solution (20 mL, 20%) and extracted with EtOAc (2 X 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude product was purified by column chromatography over silica gel using DCM/light petroleum (80:20) as eluent to give the title compound as a yellow solid (153 mg, -1 -1 29%). M.p. 62-64 °C; UV (MeOH): Omax 207 (H 71076 cm M ), 252 (24176) nm; IR (KBr): Qmax -1 1 3377, 1661, 1609, 1489, 1313, 1256, 1089, 1014, 752 cm ; H NMR (300 MHz, CDCl3): G 2.37-2.41 (m, 2H, H3), 4.05 (s, 1H, NH), 4.17 (dd, J = 5.4, 9.4 Hz, 1H, H2), 6.63 (dd, J = 1.0, 8.0 Hz, 1H, H8), 6.77 (ddd, J = 1.0, 6.8, 8.0 Hz, 1H, H6), 7.14 (dd, J = 1.0, 8.0 Hz, 1H, H5), 7.18 (ddd, J = 1.0, 6.8, 8.0 Hz, 1H, H7), 7.21-7.31 (m, 9H, H2c, H3c, H5c, H6c, H2cc, H3cc, H4cc,

13 H5cc, H6cc); C NMR (75.6 MHz, CDCl3): G 48.9 (C3), 54.3 (C2), 74.9 (C4), 114.4 (C8), 118.5 (C6), 126.2 (C4a), 127.3 (C7), 127.8 (C2cc, C6cc), 127.9 (C2c, C6c), 128.4 (C4cc), 128.5 (C3cc, C5cc), 129.2 (C3c, C5c), 129.4 (C5), 133.8 (C4c), 142.1 (C1c), 144.7 (C1cc), 148.4 (C8a); MS

230 + (TOF-ESI) m/z Calcd. for C21H18ClNONa (M + Na) 358.10. Found 358.03; Anal. Calcd. for

C21H18ClNO.1/4CH2Cl2: C, 71.48; H, 5.22; N, 3.92. Found: C, 71.49; H, 5.35; N, 3.68.

2-(4-Chlorophenyl)-4-phenylquinoline (307) To a solution of 2-(4-chlorophenyl)-4-phenyl-1,2,3,4- tetrahydroquinolin-4-ol 305 (200 mg, 0.6 mmol) in DCM (20 mL) was added 5 drops of BF3·OEt2 and the mixture stirred at r.t. for 4 h. The reaction mixture was quenched by the addition of saturated solution of NaHCO3 (20 mL). The organic layer was collected, dried over anhydrous Na2SO4 and evaporated. The residue so obtained was purified by column chromatography using DCM/light petroleum (50:50) that eluted the title compound as a white crystalline solid (147 mg, 78%). M.p. 108-110 °C, lit.225 106-108 °C; 1H

NMR (300 MHz, CDCl3): G 7.46 (ddd, J = 1.5, 7.3, 8.4 Hz, 1H, H6), 7.51 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.52-7.57 (m, 5H, H2cc, H3cc, H4cc, H5cc, H6cc), 7.74 (ddd, J = 1.5, 7.3, 8.4 Hz, 1H, H7), 7.78 (s, 1H, H3), 7.91 (dd, J = 1.5, 8.4 Hz, 1H, H8), 8.16 (d, J = 8.7 Hz, 2H, H2c, H6c),

13 8.23 (dd, J = 1.5, 8.4 Hz, 1H, H5); C NMR (75.6 MHz, CDCl3): G 118.9 (C3), 125.7 (C5), 125.9 (C4a), 126.6 (C6), 128.5 (C2cc, C6cc), 128.7 (C2c, C6c), 129.0 (C3cc, C5cc), 129.6 (C3c, C5c), 129.6 (C4cc), 129.7 (C7), 130.1 (C8), 135.6 (C4c), 138.1 (C1c), 138.3 (C1cc), 148.8 (C8a), 149.4 (C4), 155.5 (C2).

1-(2-(4-Chlorophenyl)-3,4-dihydroquinolin-4-yl)naphthalen-2-ol (323) To a solution of 263 (200 mg, 0.52 mmol) in anhydrous THF (20 mL), DDQ (353 mg, 1.56 mmol) was added in small portions over 10 minutes in an inert atmosphere of nitrogen. The reaction mixture was refluxed for 48 h. The solvent was removed partially under vacuum and water (25 mL) was added to it. It was then extracted with EtOAc (2 X 25 mL). The organic layer was washed with brine

(10 mL) and dried over anhydrous Na2SO4. Chromatography over silica gel using DCM/light petroleum (60:40) eluted the title compound as a white solid (140 mg, 70%). M.p. 186-188 °C; -1 -1 UV (MeOH): Omax 204 (H 19743 cm M ), 229 (29250) nm; IR (KBr): Qmax 3414, 1622, 1483, -1 1 1392, 1260, 1232, 1090, 1078, 1029, 1010, 812, 743 cm ; H NMR (300 MHz, CDCl3): G 2.29- 2.46 (m, 2H, H3), 4.82 (t, J = 2.8 Hz, 1H, H4), 5.08 (s, 1H, NH), 6.60 (dd, J = 1.0, 7.4 Hz, 1H, H8), 6.72 (ddd, J = 1.0, 6.4, 7.4 Hz, 1H, H7), 7.00 (ddd, J = 1.0, 6.4, 7.4 Hz, 1H, H6), 7.23 (d, J = 8.9 Hz, 1H, H3cc), 7.36 (ddd, J = 1.0, 7.2, 8.0 Hz, 1H, H6cc), 7.44 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.55 (dd, J = 1.0, 7.4 Hz, 1H, H5), 7.58 (ddd, J = 1.0, 7.2, 8.0 Hz, 1H, H7cc), 7.61 (dd, J = 1.0, 231 8.0 Hz, 1H, H5cc), 7.64 (d, J = 8.9 Hz, 1H, H4cc), 7.77 (d, J = 8.7 Hz, 2H, H2c, H6c), 8.34 (dd, J =

13 1.0, 8.0 Hz, 1H, H8cc); C NMR (75.6 MHz, CDCl3): G 29.8 (C4), 33.2 (C3), 112.6 (C3cc), 117.0 (C1cc), 117.3 (C8), 117.9 (C8cc), 121.0 (C6cc), 122.2 (C7cc), 123.8 (C4cca), 125.5 (C6), 126.2 (C7), 126.3 (C5cc), 126.5 (C4cc), 127.1 (C2c, C6c), 127.6 (C5), 127.8 (C3c, C5c), 128.4 (C8cca), 130.5 (C1c), 133.4 (C4c), 136.2 (C4a), 140.0 (C8a), 141.0 (C2), 153.2 (C2cc); MS (TOF-ESI) m/z + Calcd. for C25H18ClNO (M + 1) 384.12. Found 384.04; Anal. Calcd. for C25H18ClNO: C, 78.22; H, 4.73; N, 3.65. Found: C, 78.07; H, 4.83; N, 3.66.

1-(2-(4-Chlorophenyl)quinolin-4-yl)naphthalen-2-ol (324) To a solution of 263 (200 mg, 0.52 mmol) in AcOH (10 mL) was added iodine (132 mg, 0.52 mmol) and potassium acetate (102 mg, 1.04 mmol). The mixture was stirred at r.t. for 7 days. The reaction mixture was poured into ice (100 g) and washed with Na2S2O3 solution (3 X 50 mL, 25%) to remove the unreacted iodine from the reaction mixture. A brown solid crushed out which was filtered and air-dried. Purification of the crude product over silica gel using 100% DCM eluted the title compound as a white solid (48 mg, 24%). M.p. 254-256 °C; UV (MeOH): Omax 228 (H 162785 -1 -1 cm M ), 263 (87677), 326 (24923) nm; IR (KBr): Qmax 3416, 1620, 1596, 1545, 1495, 1194, -1 1 1143, 1322, 1288, 1130, 1099, 1013, 819, 745 cm ; H NMR (300 MHz, DMSO-d6): G 7.03 (dd, J = 1.0, 7.0 Hz, 1H, H8), 7.20 (ddd, J = 1.5, 6.2, 7.0 Hz, 1H, H6cc), 7.26 (ddd, J = 1.5, 6.2, 7.0 Hz, 1H, H7cc), 7.32 (dd, J = 1.5, 7.0 Hz, 1H, H5cc), 7.34-7.37 (m, 2H, H5, H6), 7.50 (d, J = 8.7 Hz, 2H, H3c, H5c), 7.68-7.73 (m, 1H, H7), 7.83 (dd, J = 1.5, 7.0 Hz, 1H, H8cc), 7.88 (d, J = 8.4 Hz, 1H, H3cc), 7.95 (s, 1H, H3), 8.16 (d, J = 8.4 Hz, 1H, H4cc), 8.28 (d, J = 8.7 Hz, 2H, H2c,

13 H6c), 9.52 (s, 1H, 2cc OH); C NMR (75.6 MHz, DMSO-d6): G 103.2 (C3), 116.7 (C4a), 118.6 (C3cc), 122.9 (C6cc), 124.1 (C5), 126.1 (C1cc), 126.5 (C8cc), 126.7 (C7cc), 127.4 (C6), 128.1 (C4cca), 128.2 (C5cc), 128.9 (C3c, C5c), 129.1 (C2c, C6c), 129.8 (C7), 129.9 (C4cc), 130.0 (C8), 133.6 (C4c), 135.0 (C8cca), 137.9 (C1c), 145.5 (C8a), 148.5 (C4), 152.7 (C2), 155.0 (C2cc); MS + (TOF-ESI) m/z Calcd. for C25H16ClNO (M + 1) 382.10. Found 382.10; Anal. Calcd. for

C25H16ClNO: C, 78.63; H, 4.22; N, 3.67. Found: C, 78.42; H, 4.33; N, 3.46.

232 2-(2-(4-Chlorophenyl)quinolin-4-yl)naphthalene-1-ol (325) To a solution of 265 (100 mg, 0.26 mmol) in AcOH (10 mL) was added iodine (66 mg, 0.26 mmol) and potassium acetate (51 mg, 0.52 mmol). The mixture was stirred at r.t. for 7 days. The reaction mixture was poured into ice (100 g) and washed with Na2S2O3 solution (3 X 50 mL, 25%) to remove the unreacted iodine from the reaction mixture. A brown solid crushed out which was filtered and air-dried. Purification of the crude product over silica gel using DCM/light petroleum (75:25) eluted the title compound as a white solid (19 mg, 19%). M.p. 79- -1 -1 81 °C; UV (MeOH): Omax 204 (H 79792 cm M ), 230 (79514), 294 (20486) nm; IR (KBr): Qmax 3430, 1616, 1590, 1550, 1487, 1322, 1291, 1150, 1102, 1019, 820, 746 cm-1; 1H NMR (300

MHz, CDCl3): G 6.98 (dd, J = 1.0, 7.3 Hz, 1H, H8), 7.17 (ddd, J = 1.0, 6.3, 7.2 Hz, 1H, H6cc), 7.22 (ddd, J = 1.0, 6.3, 7.2 Hz, 1H, H7cc), 7.32 (dd, J = 1.0, 7.2 Hz, 1H, H5cc), 7.39 (dd, J = 1.0, 7.3 Hz, 1H, H5), 7.43 (ddd, J = 1.0, 6.4, 7.3 Hz, 1H, H6), 7.49 (d, J = 8.6 Hz, 2H, H3c, H5c), 7.67 (ddd, J = 1.0, 6.4, 7.3 Hz, 1H, H7), 7.83 (dd, J = 1.0, 7.2 Hz, 1H, H8cc), 7.99 (d, J = 8.3 Hz, 1H, H3cc), 8.16 (s, 1H, H3), 8.24 (d, J = 8.3 Hz, 1H, H4cc), 8.39 (d, J = 8.6 Hz, 2H, H2c, H6c),

13 10.12 (s, 1H, 1cc OH); C NMR (75.6 MHz, CDCl3): G 102.1 (C3), 117.8 (C4a), 119.9 (C3cc), 123.1 (C6cc), 124.9 (C5), 125.8 (C2cc), 126.0 (C8cc), 127.1 (C7cc), 127.9 (C6), 128.6 (C4cca), 128.8 (C5cc), 129.0 (C3c, C5c), 129.4 (C2c, C6c), 129.5 (C7), 129.7 (C4cc), 130.9 (C8), 134.1 (C4c), 135.9 (C8cca), 138.9 (C1c), 145.9 (C8a), 149.2 (C4), 152.9 (C2), 154.8 (C1cc); MS (TOF- + ESI) m/z Calcd. for C25H16ClNO (M + 1) 382.10. Found 382.13; Anal. Calcd. for

C25H16ClNO.0.15CH2Cl2: C, 76.55; H, 4.16; N, 3.55. Found: C, 76.80; H, 4.44; N, 3.85.

2-(2-(4-Chlorophenyl)quinolin-4-yl)-3,5-dimethoxyphenol (326) To a solution of 267 (200 mg, 0.51 mmol) in AcOH (10 mL) was added iodine (128 mg, 0.51 mmol) and potassium acetate (99 mg, 1.02 mmol). The mixture was stirred at r.t. for 7 days. The reaction mixture was poured into ice (100 g) and washed with Na2S2O3 solution (3 X 50 mL, 25%) to remove the unreacted iodine from the reaction mixture. A brown solid crushed out which was filtered and air-dried. Purification of the crude product over silica gel using DCM/light petroleum (80:20) eluted the title compound as a white solid (44 mg, 22%). M.p. 98- -1 -1 100 °C; UV (MeOH): Omax 207 (H 77976 cm M ), 261 (84286), 323 (20119) nm; IR (KBr): Qmax 3416, 1620, 1589, 1553, 1487, 1318, 1286, 1127, 1091, 1011, 818, 752 cm-1; 1H NMR (300

233 MHz, CDCl3): G 3.81 (s, 3H, CH3O), 3.84 (s, 3H, CH3O), 6.45 (d, J = 2.3 Hz, 1H, H3cc), 6.91 (d, J = 2.3 Hz, 1H, H5cc), 7.34 (ddd, J = 1.5, 5.4, 7.0 Hz, 1H, H6), 7.41 (ddd, J = 1.5, 5.4, 7.0 Hz, 1H, H7), 7.48 (d, J = 8.5 Hz, 2H, H3c, H5c), 7.80 (dd, J = 1.5, 7.0 Hz, 1H, H8), 7.99 (dd, J = 1.5, 7.0 Hz, 1H, H5), 8.15 (s, 1H, H3), 8.32 (d, J = 8.5 Hz, 2H, H2c, H6c); 13C NMR (75.6 MHz,

CDCl3): G 55.2 (CH3O), 55.9 (CH3O), 92.7 (C5cc), 95.3 (C3cc), 103.8 (C3), 109.9 (C1cc), 117.3 (C4a), 124.1 (C5), 126.9 (C6), 128.9 (C7), 129.3 (C2c, C6c), 129.7 (C3c, C5c), 131.1 (C8), 133.6 (C4c), 138.4 (C1c), 144.8 (C8a), 148.8 (C4), 152.4 (C2), 157.4 (C2cc), 159.3 (C6cc), 161.3 (C4cc); + MS (TOF-ESI) m/z Calcd. for C23H18ClNO3 (M + 1) 392.11. Found 392.10; Anal. Calcd. for

C23H18ClNO3: C, 70.50; H, 4.63; N, 3.57. Found: C, 70.40; H, 4.41; N, 3.40.

2-(4-Chlorophenyl)-4-(furan-2-yl)quinoline (327) To a solution of 278 (150 mg, 0.48 mmol) in AcOH (10 mL) was added iodine (123 mg, 0.48 mmol) and potassium acetate (95 mg, 0.96 mmol). The mixture was stirred at r.t. for 7 days. The reaction mixture was poured into ice (100 g) and washed with Na2S2O3 solution (3 X 50 mL, 25%) to remove the unreacted iodine from the reaction mixture. A brown solid crushed out which was filtered and air-dried. Purification of the crude product over silica gel using DCM/light petroleum (70:30) eluted the title compound as a white solid (30 mg, 20%). M.p. 78-80 °C; UV (MeOH): Omax 204 -1 -1 (H 41709 cm M ), 266 (30171), 332 (14017) nm; IR (KBr): Qmax 3411, 1610, 1586, 1544, 1493, -1 1 1323, 1297, 1143, 1091, 1027, 831, 733 cm ; H NMR (300 MHz, CDCl3): G 6.66 (dd, J = 1.8, 3.5 Hz, 1H, H4cc), 7.03 (d, J = 3.5 Hz, 1H, H3cc), 7.50 (dd, J = 1.0, 6.7 Hz, 1H, H8), 7.58 (ddd, J = 1.0, 5.5, 6.7 Hz, 1H, H6), 7.67 (ddd, J = 1.0, 5.5, 6.7 Hz, 1H, H7), 7.72 (d, J = 8.6 Hz, 2H, H3c, H5c), 7.80 (d, J = 1.8 Hz, 1H, H5cc), 8.08 (s, 1H, H3), 8.16 (dd, J = 1.0, 6.7 Hz, 1H, H5),

13 8.34 (d, J = 8.6 Hz, 2H, H2c, H6c); C NMR (75.6 MHz, CDCl3): G 102.9 (C3), 107.1 (C4cc), 112.6 (C3cc), 117.8 (C4a), 123.8 (C5), 126.9 (C6), 128.9 (C2c, C6c), 129.7 (C3c, C5c), 130.0 (C7), 131.9 (C8), 132.9 (C4c), 137.9 (C1c), 142.8 (C5cc), 145.9 (C8a), 148.7 (C4), 153.2 (C2),

+ 158.3 (C2cc); MS (TOF-ESI) m/z Calcd. for C19H12ClNO (M + 1) 306.07. Found 306.10; Anal.

Calcd. for C19H12ClNO: C, 74.64; H, 3.96; N, 4.58. Found: C, 74.49; H, 4.10; N, 4.46.

234

CHAPTER 8

REFERENCES

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247 APPENDIX CRYSTAL STRUCTURE DATA A1. Introduction Don Craig and Mohan Bhadbhade at the University of New South Wales, Sydney, obtained the X-ray crystallography data shown in the appendix.

Structure determination: Reflection data were measured with an Enraf-Nonius CAD-4 diffractometer in 2/T scan mode using nickel filtered copper radiation (O 1.5418 Å). Reflections with I>3V(I) were considered observed. The structures were determined by direct phasing and Fourier methods. Hydrogen atoms were included in calculated positions and were assigned thermal parameters equal to those of the atom to which they were bonded. Positional and anisotropic thermal parameters for the non-hydrogen atoms were refined using full matrix 2 2 least squares. Reflection weights used were 1/V (Fo), with V(Fo) being derived from V (Io) = [V (Io) 2 1/2 2 2 1/2 +(0.04Io) ] . The weighted residual is defined as Rw = (6w' /6wFo ) . Atomic scattering factors and anomalous dispersion parameters were from International Tables for X-ray crystallography. 1 Structure solutions were performed by SIR922 and refinements used RAELS. 3 ORTEP II4 running on Macintosh was used for the structural diagrams.

1. Ibres, J. A. and Hamilton, W. C. (Eds). Intern atioanal tables for X-ray Crystallography Vol. 4, Kynoch Press, Birmingham, 1974. 2. Altomare, A. Burla, M. C., Camalli, M., Cascar ano, G., Giacovazzo, C., Guagliardi, A., Polidori, G., J. Appl. Cryst., 1994, 27, 435. 3. Rae, A. D. Comprehensive constrained least sq uares refinement program, University of New South Wales, 1989. 4. Johnson, C. K., ‘ORTEP-II’, Oak Ridge National Laboratory, Tennessee, U. S. A., 1976.

A2. 4c-Bromo-7-methoxyflavene (73b)

EXPERIMENTAL DETAILS

Crystal data

Chemical formula C16H13BrO2

Mr 317.17

Crystal system, space Monoclinic, P21/c group Temperature (K) 150 a, b, c (Å) 12.8071 (3), 8.6945 (3), 11.5190 (3) E (°) 93.424 (1) V (Å3) 1280.37 (6) Z 4 248 Radiation type Mo KD P (mm-1) 3.20 Crystal size (mm) 0.38 × 0.16 × 0.08 Data collection

Tmin, Tmax 0.376, 0.784 No. of measured, 17719, 3734, 2888 independent and observed [I > 2V (I)] reflections

Rint 0.056 Refinement R[F2 > 2V (F2)], 0.030, 0.075, 1.11 wR(F2), S No. of reflections 3734 No. of parameters 174 No. of restraints 0 H-atom treatment H-atom parameters constrained -3 '²max, '²min (e Å ) 0.39, -0.38

ATOMIC COORDINATES AND DISPLACEMENT PARAMETERS

Br1 0.646703(14) 0.11852(2) 0.266203(17) 0.02650(8) O2 0.04204(11) 0.64747(15) 0.22968(12) 0.0258(3) O1 0.17061(9) 0.24024(14) -0.00178(11) 0.0212(3) C9 0.15980(13) 0.3952(2) 0.01753(16) 0.0187(4) C6 0.23949(14) 0.4476(2) -0.16590(17) 0.0231(4) H6 0.2500 0.5159 -0.2285 0.028 C8 0.25674(13) 0.1946(2) -0.07260(16) 0.0205(4) H8 0.2389 0.0909 -0.1058 0.025 C1 0.10896(13) 0.4374(2) 0.11598(16) 0.0192(4) H1 0.0871 0.3618 0.1689 0.023 C7 0.26813(14) 0.3010(2) -0.17280(16) 0.0236(4) H7 0.2960 0.2637 -0.2420 0.028 C5 0.19204(13) 0.5031(2) -0.06198(16) 0.0195(4) C2 0.09075(14) 0.5928(2) 0.13532(16) 0.0201(4) C4 0.17264(14) 0.6579(2) -0.03984(17) 0.0226(4) H4 0.1941 0.7336 -0.0929 0.027 C3 0.12280(14) 0.7033(2) 0.05773(17) 0.0232(4) H3 0.1105 0.8092 0.0717 0.028 C10 0.00597(15) 0.5371(2) 0.30954(16) 0.0251(4) H10A -0.0399 0.4630 0.2677 0.038 H10B -0.0329 0.5896 0.3687 0.038 H10C 0.0660 0.4830 0.3472 0.038 C12 0.42986(14) 0.2914(2) 0.01874(17) 0.0221(4) H12 0.4212 0.3832 -0.0256 0.027 C15 0.45768(14) 0.0214(2) 0.14517(16) 0.0213(4) H15 0.4681 -0.0717 0.1875 0.026 C14 0.52872(14) 0.1406(2) 0.15886(16) 0.0196(4) C11 0.35541(13) 0.1757(2) 0.00609(15) 0.0188(4) 249 C13 0.51709(14) 0.2744(2) 0.09568(17) 0.0230(4) H13 0.5678 0.3539 0.1044 0.028 C16 0.37121(14) 0.0402(2) 0.06872(16) 0.0206(4) H16 0.3218 -0.0409 0.0588 0.025

Br1 0.02587(11) 0.02811(12) 0.02500(11) 0.00222(8) -.00292(7) 0.00450(8) O2 0.0340(8) 0.0203(7) 0.0243(7) -0.0028(5) 0.0119(6) 0.0008(6) O1 0.0194(6) 0.0198(7) 0.0251(7) -0.0031(5) 0.0070(5) -0.0006(5) C9 0.0145(8) 0.0203(9) 0.0211(9) -0.0027(7) -0.0009(7) 0.0001(7) C6 0.0180(9) 0.0318(11) 0.0196(9) 0.0017(8) 0.0023(7) -0.0002(8) C8 0.0186(8) 0.0199(9) 0.0232(10) -0.0069(7) 0.0039(7) 0.0014(7) C1 0.0163(8) 0.0215(9) 0.0200(9) 0.0023(7) 0.0014(7) -0.0021(7) C7 0.0202(9) 0.0334(11) 0.0174(9) -0.0042(8) 0.0013(7) 0.0005(8) C5 0.0151(8) 0.0245(10) 0.0189(9) 0.0008(7) 0.0004(7) 0.0004(7) C2 0.0178(8) 0.0236(10) 0.0191(9) -0.0030(7) 0.0016(7) -0.0012(7) C4 0.0219(9) 0.0228(10) 0.0231(10) 0.0053(8) 0.0024(7) -0.0006(7) C3 0.0237(9) 0.0194(10) 0.0267(10) -0.0013(8) 0.0032(8) 0.0010(7) C10 0.0270(10) 0.0269(11) 0.0217(10) 0.0017(8) 0.0053(8) 0.0040(8) C12 0.0244(9) 0.0152(9) 0.0265(10) 0.0019(7) -0.0011(8) 0.0002(7) C15 0.0261(9) 0.0189(9) 0.0199(9) 0.0016(7) 0.0087(7) 0.0011(7) C14 0.0201(8) 0.0205(9) 0.0185(9) -0.0015(7) 0.0025(7) 0.0038(7) C11 0.0199(8) 0.0199(8) 0.0171(9) -0.0050(7) 0.0054(7) 0.0014(7) C13 0.0233(9) 0.0173(9) 0.0278(10) -0.0007(7) -0.0026(8) -0.0017(7) C16 0.0236(9) 0.0188(9) 0.0203(9) -0.0023(7) 0.0094(7) -0.0023(7)

SELECTED GEOMETRIC PARAMETERS

BOND LENGTHS Br1—C14 1.9042 (18) C10—H10A 0.9800 C1—C2 1.391 (3) C10—H10B 0.9800 C1—H1 0.9500 C10—H10C 0.9800 C2—C3 1.391 (3) C11—C16 1.390 (3) C3—H3 0.9500 C12—C11 1.388 (3) C4—C3 1.383 (3) C12—C13 1.392 (3) C4—H4 0.9500 C12—H12 0.9500 C5—C4 1.394 (3) C13—H13 0.9500 C6—C5 1.457 (3) C14—C13 1.375 (3) C6—C7 1.330 (3) C15—C14 1.382 (3) C6—H6 0.9500 C15—C16 1.383 (3) C7—H7 0.9500 C15—H15 0.9500 C8—C7 1.493 (3) C16—H16 0.9500 C8—C11 1.520 (3) O1—C8 1.465 (2) C8—H8 1.0000 O1—C9 1.374 (2) C9—C1 1.390 (3) O2—C2 1.370 (2) C9—C5 1.391 (3) O2—C10 1.425 (2)

250 BOND ANGLES C2—O2—C10 117.32 (14) C5—C4—H4 119.3 C9—O1—C8 116.26 (13) C4—C3—C2 119.56 (18) O1—C9—C1 116.61 (16) C4—C3—H3 120.2 O1—C9—C5 121.21 (16) C2—C3—H3 120.2 C1—C9—C5 122.04 (17) O2—C10—H10A 109.5 C7—C6—C5 119.79 (18) O2—C10—H10B 109.5 C7—C6—H6 120.1 H10A—C10—H10B 109.5 C5—C6—H6 120.1 O2—C10—H10C 109.5 O1—C8—C7 111.96 (14) H10A—C10—H10C 109.5 O1—C8—C11 108.90 (14) H10B—C10—H10C 109.5 C7—C8—C11 114.32 (15) C11—C12—C13 120.66 (18) O1—C8—H8 107.1 C11—C12—H12 119.7 C7—C8—H8 107.1 C13—C12—H12 119.7 C11—C8—H8 107.1 C14—C15—C16 118.73 (18) C9—C1—C2 118.58 (17) C14—C15—H15 120.6 C9—C1—H1 120.7 C16—C15—H15 120.6 C2—C1—H1 120.7 C13—C14—C15 121.61 (18) C6—C7—C8 120.50 (17) C13—C14—Br1 119.06 (14) C6—C7—H7 119.7 C15—C14—Br1 119.32 (14) C8—C7—H7 119.7 C12—C11—C16 118.83 (17) C9—C5—C4 117.87 (17) C12—C11—C8 121.74 (17) C9—C5—C6 118.17 (17) C16—C11—C8 119.43 (16) C4—C5—C6 123.90 (17) C14—C13—C12 118.98 (17) O2—C2—C1 123.56 (17) C14—C13—H13 120.5 O2—C2—C3 115.83 (16) C12—C13—H13 120.5 C1—C2—C3 120.61 (17) C15—C16—C11 121.13 (17) C3—C4—C5 121.33 (17) C15—C16—H16 119.4 C3—C4—H4 119.3 C11—C16—H16 119.4

A3. 2,3,5-Trimethoxy-6-(3-p-tolylallyl)phenol (83c) EXPERIMENTAL DETAILS

Crystal data

Chemical formula C19H22O4

Mr 314.37 Crystal system, space Triclinic, P¯1 group Temperature (K) 293

251 a, b, c (Å) 7.3258 (8), 8.8857 (15), 13.9345 (15) D, E, J (°) 99.933 (10), 104.973 (8), 91.401 (10) V (Å3) 860.9 (2) Z 2 Radiation type Mo KD P (mm-1) 0.08 Crystal size (mm) 0.18 × 0.12 × 0.11 Data collection

Tmin, Tmax 0.985, 0.991 No. of measured, 3013, 3013, 1546 independent and observed [I > 2V(I)] reflections

Rint 0.0000 Refinement R[F2 > 2V(F2)], 0.059, 0.178, 0.92 wR(F2), S No. of reflections 3013 No. of parameters 213 No. of restraints 0 H-atom treatment H-atom parameters constrained -3 '²max, '²min (e Å ) 0.38, -0.16

ATOMIC COORDINATES AND DISPLACEMENT PARAMETERS O1 0.2218(3) -0.0095(2) 0.36892(16) 0.0733(6) H1 0.3218 -0.0407 0.3978 0.110 O2 0.4079(3) 0.1097(2) 0.56678(15) 0.0695(6) O3 0.4125(3) 0.4117(2) 0.63830(14) 0.0709(6) O4 0.0431(3) 0.4759(3) 0.30690(16) 0.0725(6) C1 0.2980(4) 0.2579(4) 0.0341(2) 0.0677(9) C2 0.4708(5) 0.1925(4) 0.0537(2) 0.0775(9) H2 0.5034 0.1398 0.1071 0.093 C3 0.5945(5) 0.2040(4) -0.0042(3) 0.0799(10) H3 0.7100 0.1603 0.0116 0.096 C4 0.5522(5) 0.2782(4) -0.0848(2) 0.0763(10) C6 0.2582(5) 0.3366(4) -0.0449(2) 0.0847(10) H6 0.1456 0.3848 -0.0587 0.102 C8 0.1613(4) 0.2491(4) 0.0947(2) 0.0707(9) H8 0.0590 0.3095 0.0819 0.085 C9 0.1669(4) 0.1660(4) 0.1648(2) 0.0684(9) H9 0.2646 0.1008 0.1756 0.082 C10 0.0307(4) 0.1659(4) 0.2292(2) 0.0675(9) H10A -0.0753 0.2248 0.2042 0.081 H10B -0.0184 0.0617 0.2242 0.081 C11 0.1246(4) 0.2331(4) 0.3379(2) 0.0552(7) C12 0.2206(4) 0.1441(3) 0.4044(2) 0.0563(7) 252 C13 0.3136(4) 0.2055(4) 0.5040(2) 0.0567(7) C14 0.3175(4) 0.3617(3) 0.5394(2) 0.0534(7) C15 0.2262(4) 0.4541(3) 0.4748(2) 0.0577(8) H15 0.2274 0.5590 0.4975 0.069 C16 0.1328(4) 0.3898(4) 0.3757(2) 0.0565(7) C17 0.2985(6) 0.0492(5) 0.6256(3) 0.1015(13) H17A 0.2788 0.1303 0.6763 0.152 H17B 0.3656 -0.0282 0.6575 0.152 H17C 0.1783 0.0052 0.5821 0.152 C18 0.4224(4) 0.5725(4) 0.6773(2) 0.0780(10) H18A 0.4705 0.6282 0.6348 0.117 H18B 0.5052 0.5944 0.7446 0.117 H18C 0.2981 0.6028 0.6788 0.117 C19 0.0723(5) 0.6374(4) 0.3350(2) 0.0767(10) H19A 0.0192 0.6717 0.3905 0.115 H19B 0.0118 0.6834 0.2786 0.115 H19C 0.2057 0.6665 0.3549 0.115 C7 0.6895(5) 0.2912(5) -0.1475(3) 0.0953(12) H7A 0.7585 0.3897 -0.1257 0.143 H7B 0.6211 0.2797 -0.2174 0.143 H7C 0.7765 0.2123 -0.1393 0.143 C5 0.3809(5) 0.3457(5) -0.1041(3) 0.0895(11) H5 0.3485 0.3979 -0.1578 0.107

O1 0.0714(14) 0.0696(16) 0.0737(15) 0.0054(12) 0.0152(11) 0.0075(11) O2 0.0649(13) 0.0860(15) 0.0656(13) 0.0242(11) 0.0234(11) 0.0190(11) O3 0.0659(13) 0.0876(17) 0.0530(13) 0.0053(11) 0.0099(10) 0.0051(11) O4 0.0627(13) 0.0773(16) 0.0768(14) 0.0272(12) 0.0084(11) 0.0088(11) C1 0.0566(19) 0.090(2) 0.0525(18) 0.0078(17) 0.0124(15) -0.0048(17) C2 0.072(2) 0.099(3) 0.060(2) 0.0144(18) 0.0151(17) 0.0060(19) C3 0.063(2) 0.106(3) 0.068(2) 0.011(2) 0.0166(18) 0.0035(18) C4 0.065(2) 0.107(3) 0.0521(19) 0.0081(18) 0.0130(16) -0.0091(19) C6 0.064(2) 0.129(3) 0.065(2) 0.034(2) 0.0126(17) 0.005(2) C8 0.0540(18) 0.096(3) 0.0585(19) 0.0144(18) 0.0094(15) -0.0004(17) C9 0.0671(19) 0.084(2) 0.0515(18) 0.0061(17) 0.0163(15) 0.0009(16) C10 0.0593(19) 0.081(2) 0.0590(19) 0.0103(16) 0.0124(15) -0.0053(16) C11 0.0419(15) 0.073(2) 0.0536(17) 0.0160(16) 0.0148(13) 0.0014(14) C12 0.0510(16) 0.060(2) 0.0619(19) 0.0082(16) 0.0241(15) 0.0024(14) C13 0.0453(16) 0.072(2) 0.0579(18) 0.0217(16) 0.0156(14) 0.0131(14) C14 0.0428(15) 0.069(2) 0.0528(18) 0.0099(16) 0.0215(13) 0.0057(14) C15 0.0481(16) 0.065(2) 0.0637(19) 0.0127(16) 0.0209(15) 0.0071(14) C16 0.0449(16) 0.069(2) 0.0601(19) 0.0171(17) 0.0193(14) 0.0025(14) C17 0.101(3) 0.137(3) 0.089(3) 0.049(3) 0.047(2) 0.017(2) C18 0.069(2) 0.092(3) 0.065(2) -0.0122(19) 0.0240(16) -0.0117(18) C19 0.074(2) 0.078(3) 0.089(2) 0.0358(19) 0.0282(18) 0.0174(17) C7 0.077(2) 0.133(3) 0.078(2) 0.016(2) 0.028(2) -0.006(2) C5 0.071(2) 0.138(3) 0.067(2) 0.041(2) 0.0180(18) 0.002(2)

253

SELECTED GEOMETRIC PARAMETERS

BOND LENGTHS O1—C12 1.370 (3) C10—C11 1.502 (4) O1—H1 0.8200 C10—H10A 0.9700 O2—C13 1.393 (3) C10—H10B 0.9700 O2—C17 1.440 (4) C11—C12 1.386 (4) O3—C14 1.363 (3) C11—C16 1.395 (4) O3—C18 1.431 (3) C12—C13 1.385 (4) O4—C16 1.374 (3) C13—C14 1.387 (4) O4—C19 1.416 (3) C14—C15 1.380 (4) C1—C6 1.376 (4) C15—C16 1.386 (4) C1—C2 1.388 (4) C15—H15 0.9300 C1—C8 1.476 (4) C17—H17A 0.9600 C2—C3 1.373 (4) C17—H17B 0.9600 C2—H2 0.9300 C17—H17C 0.9600 C3—C4 1.370 (4) C18—H18A 0.9600 C3—H3 0.9300 C18—H18B 0.9600 C4—C5 1.387 (5) C18—H18C 0.9600 C4—C7 1.507 (4) C19—H19A 0.9600 C6—C5 1.378 (5) C19—H19B 0.9600 C6—H6 0.9300 C19—H19C 0.9600 C8—C9 1.316 (4) C7—H7A 0.9600 C8—H8 0.9300 C7—H7B 0.9600 C9—C10 1.505 (4) C7—H7C 0.9600 C9—H9 0.9300 C5—H5 0.9300 BOND ANGLES C12—O1—H1 109.5 C12—C13—O2 119.3 (3) C13—O2—C17 115.1 (2) C14—C13—O2 120.6 (3) C14—O3—C18 117.6 (2) O3—C14—C15 124.8 (3) C16—O4—C19 117.8 (2) O3—C14—C13 115.9 (3) C6—C1—C2 116.9 (3) C15—C14—C13 119.2 (3) C6—C1—C8 119.9 (3) C14—C15—C16 119.6 (3) C2—C1—C8 123.1 (3) C14—C15—H15 120.2 C3—C2—C1 121.3 (3) C16—C15—H15 120.2 C3—C2—H2 119.3 O4—C16—C15 122.5 (3) C1—C2—H2 119.3 O4—C16—C11 114.9 (3) C4—C3—C2 121.7 (3) C15—C16—C11 122.6 (3)

254 C4—C3—H3 119.1 O2—C17—H17A 109.5 C2—C3—H3 119.1 O2—C17—H17B 109.5 C3—C4—C5 117.3 (3) H17A—C17—H17B 109.5 C3—C4—C7 121.3 (3) O2—C17—H17C 109.5 C5—C4—C7 121.3 (3) H17A—C17—H17C 109.5 C1—C6—C5 121.7 (3) H17B—C17—H17C 109.5 C1—C6—H6 119.1 O3—C18—H18A 109.5 C5—C6—H6 119.1 O3—C18—H18B 109.5 C9—C8—C1 127.7 (3) H18A—C18—H18B 109.5 C9—C8—H8 116.1 O3—C18—H18C 109.5 C1—C8—H8 116.1 H18A—C18—H18C 109.5 C8—C9—C10 126.4 (3) H18B—C18—H18C 109.5 C8—C9—H9 116.8 O4—C19—H19A 109.5 C10—C9—H9 116.8 O4—C19—H19B 109.5 C11—C10—C9 111.4 (2) H19A—C19—H19B 109.5 C11—C10—H10A 109.3 O4—C19—H19C 109.5 C9—C10—H10A 109.3 H19A—C19—H19C 109.5 C11—C10—H10B 109.3 H19B—C19—H19C 109.5 C9—C10—H10B 109.3 C4—C7—H7A 109.5 H10A—C10—H10B 108.0 C4—C7—H7B 109.5 C12—C11—C16 116.2 (3) H7A—C7—H7B 109.5 C12—C11—C10 121.6 (3) C4—C7—H7C 109.5 C16—C11—C10 122.0 (3) H7A—C7—H7C 109.5 O1—C12—C13 119.9 (3) H7B—C7—H7C 109.5 O1—C12—C11 117.9 (3) C6—C5—C4 121.0 (3) C13—C12—C11 122.2 (3) C6—C5—H5 119.5 C12—C13—C14 120.1 (3) C4—C5—H5 119.5

A4. 6a, 12a-Dihydro-1,3,4,8,10,11-hexamethoxy-6-(4c-methoxyphenyl)-7-[(1E)-2-(4cc- methoxyphenylethenyl)]-6H,7H-[1]benzopyrano[4,3-b][1]benzopyran (85c) EXPERIMENTAL DETAILS Crystal data

Chemical formula C38H40O10

Mr 656.70 Crystal system, space Monoclinic, C2/c group Temperature (K) 150 a, b, c (Å) 35.5891 (12), 9.6315 (3), 24.3878 (9) E (°) 127.021 (3) 255 V (Å3) 6674.4 (4) Z 8 Radiation type Mo KD P (mm-1) 0.09 Crystal size (mm) 0.48 × 0.07 × 0.05 Data collection

Tmin, Tmax 0.957, 0.996 No. of measured, 43978, 5856, 4115 independent and observed [I > 2V (I)] reflections

Rint 0.088 Refinement R[F2 > 2V (F2)], 0.054, 0.151, 1.02 wR(F2), S No. of reflections 5856 No. of parameters 572 No. of restraints 0 H-atom treatment H atoms treated by a mixture of independent and constrained refinement 2 2 2 w = 1/[V (Fo ) + (0.0692P) + 10.8288P] 2 2 where P = (Fo + 2Fc )/3 -3 '²max, '²min (e Å ) 1.07, -0.50

ATOMIC COORDINATES AND DISPLACEMENT PARAMETERS

O1 0.18544(6) 0.52280(18) 0.40516(8) 0.0262(4) O2 0.09255(6) 0.72081(17) 0.25786(8) 0.0249(4) O3 0.04810(6) 0.77724(19) 0.33110(9) 0.0297(4) O4 0.18179(8) 0.7486(2) 0.57193(9) 0.0433(6) O5 0.22502(6) 0.5785(2) 0.53682(9) 0.0350(5) O6 0.05699(8) 0.9105(2) 0.05545(10) 0.0431(6) O7 0.07436(7) 0.94069(18) 0.17842(10) 0.0327(5) O8 0.06984(7) 0.40963(18) 0.08938(9) 0.0322(5) O9 -0.15963(7) 0.0908(2) 0.07132(10) 0.0392(5) O10 0.29018(8) 0.1666(3) 0.32190(12) 0.0536(6) C1 0.07538(9) 0.8099(3) 0.15587(13) 0.0257(6) C2 0.06566(10) 0.7912(3) 0.09225(13) 0.0294(6) C3 0.06413(10) 0.6584(3) 0.06828(14) 0.0300(6) C4 0.07147(9) 0.5450(3) 0.10861(13) 0.0250(6) C5 0.08123(8) 0.5595(3) 0.17302(12) 0.0218(6) C6 0.08298(9) 0.6934(3) 0.19557(12) 0.0227(6) C7 0.09041(9) 0.6043(3) 0.29420(13) 0.0226(6) C8 0.11438(9) 0.4773(3) 0.29133(12) 0.0222(6) C9 0.08979(9) 0.4337(3) 0.21623(12) 0.0224(6) C10 0.16657(9) 0.5141(3) 0.33287(12) 0.0239(6) C11 0.16013(9) 0.6049(3) 0.41847(13) 0.0249(6)

256 C12 0.18189(9) 0.6375(3) 0.48722(13) 0.0280(6) C13 0.11481(9) 0.6510(3) 0.36660(12) 0.0224(6) C14 0.15812(10) 0.7216(3) 0.50334(13) 0.0296(6) C15 0.11355(10) 0.7731(3) 0.45252(14) 0.0292(6) C16 0.09224(9) 0.7353(3) 0.38492(13) 0.0250(6) C17 0.01753(11) 0.8286(3) 0.34607(16) 0.0325(7) C18 0.16333(15) 0.8507(5) 0.59174(19) 0.0553(10) C19 0.26345(11) 0.6726(4) 0.57880(17) 0.0556(10) H19A 0.2619 0.7469 0.5501 0.083 H19B 0.2933 0.6224 0.6012 0.083 H19C 0.2614 0.7129 0.6138 0.083 C20 0.20394(11) 0.1194(4) 0.00705(17) 0.0465(8) C22 0.04104(17) 0.8960(4) 0.01349(18) 0.0498(9) C23 0.05932(12) 0.3847(3) 0.02405(15) 0.0353(7) C24 0.04560(9) 0.3539(3) 0.19211(13) 0.0243(6) C25 0.00164(9) 0.3978(3) 0.15129(13) 0.0239(6) C26 -0.04072(9) 0.3206(3) 0.13070(12) 0.0235(6) C27 -0.08530(9) 0.3696(3) 0.07925(13) 0.0274(6) C28 0.03826(10) 0.1935(3) 0.16113(14) 0.0285(6) C29 0.12578(10) 0.2956(3) 0.05691(14) 0.0288(6) C30 -0.12223(9) 0.1715(3) 0.08796(13) 0.0286(6) C31 0.07811(10) 0.1215(3) 0.14123(14) 0.0304(6) C32 0.20605(10) 0.2814(3) 0.35356(15) 0.0335(7) C33 0.23699(11) 0.1949(3) 0.35278(16) 0.0393(7) C34 0.25892(10) 0.2426(3) 0.32542(15) 0.0373(7) C35 0.24978(12) 0.3747(3) 0.29853(16) 0.0416(8) C36 0.21985(10) 0.4614(3) 0.30076(15) 0.0350(7) C37 0.30873(15) 0.0432(5) 0.3621(2) 0.0577(11) C38 0.19773(9) 0.4157(3) 0.32911(12) 0.0255(6) H24 0.0529(10) 0.263(3) 0.2145(14) 0.033(8) H25 -0.0038(9) 0.492(3) 0.1329(14) 0.031(7) H28 -0.0061(10) 0.157(3) 0.2001(14) 0.031(7) H29 -0.1530(10) 0.331(3) 0.0231(15) 0.029(7) H36 0.2133(10) 0.556(3) 0.2816(15) 0.039(8) H35 0.2674(12) 0.408(3) 0.2843(17) 0.055(10) H33 0.2429(11) 0.104(3) 0.3712(16) 0.046(9) H3 0.0575(9) 0.641(3) 0.0240(15) 0.032(7) H181 0.1312(14) 0.820(4) 0.5782(19) 0.067(11) H182 0.1868(12) 0.859(4) 0.640(2) 0.057(10) H183 0.1608(14) 0.950(4) 0.570(2) 0.079(13) H231 0.0549(11) 0.283(4) 0.0178(16) 0.050(9) H232 0.0310(11) 0.435(3) -0.0126(16) 0.035(8) H233 0.0863(10) 0.419(3) 0.0233(14) 0.031(7) H31 -0.0791(11) 0.035(3) 0.1596(16) 0.050(9) H9 0.1106(9) 0.366(3) 0.2153(13) 0.024(7) H7 0.0566(9) 0.585(2) 0.2713(12) 0.015(6) H8 0.1102(9) 0.400(3) 0.3137(13) 0.025(7) H32 0.1919(11) 0.249(3) 0.3744(16) 0.044(9) H221 0.0144(12) 0.833(4) -0.0390(17) 0.046(10) H222 0.0338(12) 0.984(4) -0.0306(18) 0.055(10) H223 0.0668(13) 0.857(4) -0.0133(17) 0.052(10) H201 -0.2274(12) 0.044(3) 0.0027(17) 0.053(9) H202 -0.2022(13) 0.114(4) -0.035(2) 0.068(11) H203 -0.2128(12) 0.212(4) 0.0090(17) 0.051(10) H171 0.0151(11) 0.758(3) 0.3721(17) 0.050(9) 257 H172 0.0296(10) 0.924(3) 0.3713(15) 0.038(8) H173 -0.0148(11) 0.845(3) 0.2980(15) 0.034(7) H371 0.2816(17) -0.029(5) 0.342(2) 0.094(16) H372 0.3305(12) 0.003(3) 0.3526(16) 0.050(9) H373 0.3233(13) 0.062(4) 0.408(2) 0.063(11) H27 -0.0885(10) 0.457(3) 0.0584(14) 0.031(7) H15 0.0979(11) 0.833(3) 0.4630(16) 0.044(9) H10 0.1698(8) 0.609(3) 0.3189(12) 0.020(6) C99 0.11858(15) 1.0090(4) 0.2194(3) 0.0916(17) H99A 0.1426 0.9444 0.2540 0.137 H99B 0.1165 1.0890 0.2423 0.137 H99C 0.1272 1.0408 0.1901 0.137

O1 0.0228(9) 0.0340(10) 0.0192(9) 0.0013(8) 0.0114(8) 0.0009(8) O2 0.0343(10) 0.0241(9) 0.0211(9) 0.0020(7) 0.0193(8) 0.0019(8) O3 0.0316(11) 0.0338(10) 0.0272(10) -0.0010(8) 0.0196(9) 0.0049(8) O4 0.0523(14) 0.0519(13) 0.0216(10) -0.0102(9) 0.0201(10) -0.0079(10) O5 0.0269(10) 0.0433(12) 0.0224(10) -0.0012(8) 0.0082(9) -0.0068(9) O6 0.0755(16) 0.0330(11) 0.0353(11) 0.0127(9) 0.0411(12) 0.0133(11) O7 0.0468(12) 0.0233(10) 0.0353(11) 0.0025(8) 0.0286(10) 0.0053(9) O8 0.0476(12) 0.0286(10) 0.0274(10) -0.0039(8) 0.0264(10) -0.0009(9) O9 0.0251(11) 0.0459(12) 0.0421(12) -0.0066(9) 0.0178(10) -0.0068(9) O10 0.0590(15) 0.0650(15) 0.0583(14) 0.0122(12) 0.0468(13) 0.0251(12) C1 0.0314(15) 0.0237(14) 0.0286(14) 0.0046(11) 0.0215(12) 0.0054(11) C2 0.0350(16) 0.0303(15) 0.0297(15) 0.0073(12) 0.0231(13) 0.0057(12) C3 0.0371(16) 0.0365(16) 0.0234(14) 0.0033(12) 0.0219(13) 0.0042(13) C4 0.0247(14) 0.0275(14) 0.0256(13) -0.0016(11) 0.0167(12) 0.0003(11) C5 0.0193(13) 0.0258(14) 0.0214(13) 0.0006(10) 0.0128(11) -0.0005(10) C6 0.0201(13) 0.0286(14) 0.0212(13) 0.0008(11) 0.0135(11) 0.0012(11) C7 0.0247(14) 0.0235(13) 0.0219(13) 0.0024(10) 0.0152(12) -0.0012(11) C8 0.0242(14) 0.0237(13) 0.0214(13) 0.0026(11) 0.0152(11) -0.0004(11) C9 0.0232(14) 0.0214(13) 0.0225(13) 0.0011(10) 0.0137(11) 0.0018(11) C10 0.0244(14) 0.0278(14) 0.0190(13) 0.0026(11) 0.0127(11) -0.0007(11) C11 0.0281(14) 0.0250(14) 0.0241(13) 0.0004(11) 0.0170(12) -0.0060(11) C12 0.0267(14) 0.0321(15) 0.0221(13) 0.0017(11) 0.0131(12) -0.0064(12) C13 0.0246(14) 0.0230(13) 0.0208(13) 0.0007(10) 0.0144(11) -0.0040(11) C14 0.0363(16) 0.0331(15) 0.0210(13) -0.0048(11) 0.0181(13) -0.0118(13) C15 0.0386(17) 0.0278(15) 0.0309(15) -0.0050(12) 0.0261(14) -0.0064(13) C16 0.0287(15) 0.0253(14) 0.0233(13) 0.0006(11) 0.0169(12) -0.0031(11) C17 0.0344(17) 0.0359(17) 0.0372(17) -0.0037(14) 0.0268(15) -0.0017(14) C18 0.053(2) 0.077(3) 0.037(2) -0.0291(19) 0.0270(18) -0.018(2) C19 0.0379(19) 0.066(2) 0.0361(18) 0.0058(16) 0.0080(15) -0.0211(17) C20 0.0262(17) 0.067(3) 0.0377(18) -0.0107(17) 0.0149(15) -0.0067(17) C22 0.082(3) 0.044(2) 0.0386(19) 0.0154(17) 0.044(2) 0.014(2) C23 0.0448(19) 0.0397(18) 0.0244(15) -0.0081(13) 0.0223(15) -0.0035(15) C24 0.0292(15) 0.0196(13) 0.0238(13) 0.0016(11) 0.0158(12) -0.0002(11) C25 0.0283(15) 0.0215(14) 0.0209(13) -0.0004(11) 0.0143(12) -0.0004(11) C26 0.0248(14) 0.0258(14) 0.0192(12) -0.0026(10) 0.0129(11) 0.0020(11) C27 0.0313(16) 0.0272(15) 0.0259(14) 0.0013(12) 0.0183(13) 0.0055(12) C28 0.0221(15) 0.0320(15) 0.0246(14) 0.0021(12) 0.0104(12) 0.0002(12) C29 0.0204(15) 0.0370(16) 0.0249(14) 0.0000(12) 0.0114(13) 0.0079(12) C30 0.0268(15) 0.0336(15) 0.0288(14) -0.0087(12) 0.0184(13) -0.0033(12) C31 0.0302(16) 0.0273(15) 0.0325(15) 0.0005(12) 0.0182(13) -0.0021(12) C32 0.0339(16) 0.0398(17) 0.0325(15) 0.0090(13) 0.0230(14) 0.0070(13) C33 0.0444(19) 0.0417(18) 0.0391(17) 0.0134(14) 0.0290(15) 0.0140(15) 258 C34 0.0339(17) 0.0493(19) 0.0340(16) 0.0020(14) 0.0233(14) 0.0097(14) C35 0.0446(19) 0.050(2) 0.0484(19) 0.0035(15) 0.0378(17) 0.0005(16) C36 0.0384(17) 0.0370(17) 0.0389(17) 0.0060(13) 0.0283(15) 0.0025(14) C37 0.054(2) 0.079(3) 0.042(2) 0.013(2) 0.0291(19) 0.033(2) C38 0.0181(13) 0.0323(15) 0.0219(13) 0.0004(11) 0.0097(11) -0.0005(11) C99 0.073(3) 0.044(2) 0.133(4) -0.044(3) 0.049(3) -0.014(2)

SELECTED GEOMETRIC PARAMETERS

BOND LENGTHS O1—C11 1.376 (3) C17—H173 1.05 (3) O1—C10 1.463 (3) C18—H181 1.02 (4) O2—C6 1.368 (3) C18—H182 0.95 (4) O2—C7 1.460 (3) C18—H183 1.07 (4) O3—C16 1.368 (3) C19—H19A 0.9800 O3—C17 1.428 (3) C19—H19B 0.9800 O4—C14 1.371 (3) C19—H19C 0.9800 O4—C18 1.419 (4) C20—H201 1.06 (3) O5—C12 1.381 (3) C20—H202 1.05 (4) O5—C19 1.433 (4) C20—H203 0.96 (4) O6—C2 1.375 (3) C22—H221 0.97 (3) O6—C22 1.421 (4) C22—H222 0.91 (4) O7—C1 1.384 (3) C22—H223 0.99 (4) O7—C99 1.419 (4) C23—H231 0.99 (3) O8—C4 1.375 (3) C23—H232 0.98 (3) O8—C23 1.420 (3) C23—H233 1.02 (3) O9—C30 1.374 (3) C24—C25 1.320 (4) O9—C20 1.429 (4) C24—H24 0.98 (3) O10—C34 1.377 (3) C25—C26 1.472 (4) O10—C37 1.425 (4) C25—H25 0.98 (3) C1—C2 1.383 (4) C26—C27 1.385 (4) C1—C6 1.398 (4) C26—C28 1.407 (4) C2—C3 1.393 (4) C27—C29 1.391 (4) C3—C4 1.386 (4) C27—H27 0.95 (3) C3—H3 0.97 (3) C28—C31 1.378 (4) C4—C5 1.397 (3) C28—H28 1.01 (3) C5—C6 1.388 (4) C29—C30 1.379 (4) C5—C9 1.512 (3) C29—H29 0.88 (3) C7—C13 1.493 (3) C30—C31 1.389 (4) C7—C8 1.517 (4) C31—H31 0.96 (3) C7—H7 0.99 (3) C32—C38 1.380 (4) 259 C8—C10 1.528 (4) C32—C33 1.390 (4) C8—C9 1.538 (3) C32—H32 0.96 (3) C8—H8 0.99 (3) C33—C34 1.375 (4) C9—C24 1.515 (4) C33—H33 0.95 (3) C9—H9 1.00 (3) C34—C35 1.378 (4) C10—C38 1.503 (4) C35—C36 1.380 (4) C10—H10 1.01 (3) C35—H35 0.94 (3) C11—C13 1.394 (4) C36—C38 1.395 (4) C11—C12 1.395 (4) C36—H36 0.99 (3) C12—C14 1.388 (4) C37—H371 1.04 (5) C13—C16 1.392 (4) C37—H372 1.01 (3) C14—C15 1.390 (4) C37—H373 0.93 (4) C15—C16 1.385 (4) C99—H99A 0.9800 C15—H15 0.93 (3) C99—H99B 0.9800 C17—H171 0.97 (3) C99—H99C 0.9800 C17—H172 1.05 (3) BOND ANGLES C11—O1—C10 115.22 (18) H181—C18—H183 111 (3) C6—O2—C7 117.17 (18) H182—C18—H183 106 (3) C16—O3—C17 117.9 (2) O5—C19—H19A 109.5 C14—O4—C18 118.5 (3) O5—C19—H19B 109.5 C12—O5—C19 116.4 (2) H19A—C19—H19B 109.5 C2—O6—C22 117.6 (2) O5—C19—H19C 109.5 C1—O7—C99 114.7 (2) H19A—C19—H19C 109.5 C4—O8—C23 118.1 (2) H19B—C19—H19C 109.5 C30—O9—C20 116.6 (2) O9—C20—H201 105.0 (18) C34—O10—C37 117.2 (3) O9—C20—H202 112 (2) C2—C1—O7 121.1 (2) H201—C20—H202 111 (3) C2—C1—C6 119.0 (2) O9—C20—H203 108 (2) O7—C1—C6 119.7 (2) H201—C20—H203 112 (3) O6—C2—C1 115.4 (2) H202—C20—H203 108 (3) O6—C2—C3 123.8 (2) O6—C22—H221 111.1 (19) C1—C2—C3 120.7 (2) O6—C22—H222 105 (2) C4—C3—C2 118.9 (2) H221—C22—H222 113 (3) C4—C3—H3 117.9 (16) O6—C22—H223 109 (2) C2—C3—H3 123.2 (16) H221—C22—H223 108 (3) O8—C4—C3 123.7 (2) H222—C22—H223 111 (3) O8—C4—C5 114.2 (2) O8—C23—H231 104.5 (19)

260 C3—C4—C5 122.2 (2) O8—C23—H232 111.7 (17) C6—C5—C4 117.4 (2) H231—C23—H232 112 (3) C6—C5—C9 121.7 (2) O8—C23—H233 110.5 (15) C4—C5—C9 120.9 (2) H231—C23—H233 112 (2) O2—C6—C5 122.8 (2) H232—C23—H233 107 (2) O2—C6—C1 115.4 (2) C25—C24—C9 127.8 (2) C5—C6—C1 121.8 (2) C25—C24—H24 120.3 (17) O2—C7—C13 106.27 (19) C9—C24—H24 111.7 (17) O2—C7—C8 110.83 (19) C24—C25—C26 126.9 (2) C13—C7—C8 110.8 (2) C24—C25—H25 117.3 (16) O2—C7—H7 107.0 (13) C26—C25—H25 115.7 (16) C13—C7—H7 111.6 (14) C27—C26—C28 116.6 (2) C8—C7—H7 110.2 (14) C27—C26—C25 121.1 (2) C7—C8—C10 105.9 (2) C28—C26—C25 122.3 (2) C7—C8—C9 110.0 (2) C26—C27—C29 122.1 (3) C10—C8—C9 116.5 (2) C26—C27—H27 119.2 (17) C7—C8—H8 107.9 (15) C29—C27—H27 118.6 (17) C10—C8—H8 109.7 (15) C31—C28—C26 121.9 (3) C9—C8—H8 106.6 (15) C31—C28—H28 119.8 (15) C5—C9—C24 114.2 (2) C26—C28—H28 118.3 (15) C5—C9—C8 110.1 (2) C30—C29—C27 119.9 (3) C24—C9—C8 108.3 (2) C30—C29—H29 122.5 (18) C5—C9—H9 110.3 (15) C27—C29—H29 117.7 (18) C24—C9—H9 105.9 (15) O9—C30—C29 125.1 (2) C8—C9—H9 107.9 (15) O9—C30—C31 115.4 (2) O1—C10—C38 106.80 (19) C29—C30—C31 119.5 (3) O1—C10—C8 107.76 (19) C28—C31—C30 119.9 (3) C38—C10—C8 117.4 (2) C28—C31—H31 126 (2) O1—C10—H10 107.0 (14) C30—C31—H31 114 (2) C38—C10—H10 108.3 (14) C38—C32—C33 121.4 (3) C8—C10—H10 109.2 (14) C38—C32—H32 119.4 (19) O1—C11—C13 122.2 (2) C33—C32—H32 119.1 (19) O1—C11—C12 116.4 (2) C34—C33—C32 119.5 (3) C13—C11—C12 121.4 (2) C34—C33—H33 121 (2) O5—C12—C14 122.5 (2) C32—C33—H33 120 (2) O5—C12—C11 118.7 (2) C33—C34—O10 124.7 (3) C14—C12—C11 118.7 (2) C33—C34—C35 119.9 (3) C16—C13—C11 118.1 (2) O10—C34—C35 115.4 (3)

261 C16—C13—C7 121.2 (2) C34—C35—C36 120.4 (3) C11—C13—C7 120.6 (2) C34—C35—H35 118 (2) O4—C14—C12 115.1 (2) C36—C35—H35 121 (2) O4—C14—C15 123.6 (3) C35—C36—C38 120.6 (3) C12—C14—C15 121.2 (2) C35—C36—H36 120.6 (18) C16—C15—C14 118.7 (3) C38—C36—H36 118.9 (17) C16—C15—H15 119.7 (19) O10—C37—H371 109 (2) C14—C15—H15 121.5 (19) O10—C37—H372 105.2 (18) O3—C16—C15 123.7 (2) H371—C37—H372 105 (3) O3—C16—C13 114.6 (2) O10—C37—H373 111 (2) C15—C16—C13 121.8 (2) H371—C37—H373 112 (3) O3—C17—H171 108.0 (19) H372—C37—H373 114 (3) O3—C17—H172 110.5 (16) C32—C38—C36 118.1 (3) H171—C17—H172 113 (2) C32—C38—C10 122.6 (2) O3—C17—H173 104.8 (15) C36—C38—C10 119.3 (2) H171—C17—H173 111 (2) O7—C99—H99A 109.5 H172—C17—H173 108 (2) O7—C99—H99B 109.5 O4—C18—H181 110 (2) H99A—C99—H99B 109.5 O4—C18—H182 104 (2) O7—C99—H99C 109.5 H181—C18—H182 114 (3) H99A—C99—H99C 109.5 O4—C18—H183 112 (2) H99B—C99—H99C 109.5

A5. (E)-5a-(4cc-Bromophenyl)-11-(4c-bromostyryl)- 2,9-dimethoxy-5a,11,11a,12- tetrahydrochromeno[2,3-b]chromene (115b) EXPERIMENTAL DETAILS

Crystal data

Chemical formula C32H26Br2O4

Mr 634.35

Crystal system, space Monoclinic, P21/c group Temperature (K) 293 a, b, c (Å) 11.584 (4), 11.099 (2), 23.573 (7) E (°) 115.21 (2) V (Å3) 2742.1 (13) Z 4 Radiation type Mo KD P (mm-1) 2.99 Crystal size (mm) 0.18 × 0.12 × 0.11

262 Data collection

Tmin, Tmax 0.615, 0.734 No. of measured, 4792, 4792, 2107 independent and observed [I > 2V (I)] reflections

Rint 0.0000 Refinement R[F2 > 2V (F2)], 0.057, 0.157, 0.71 wR(F2), S No. of reflections 4792 No. of parameters 345 No. of restraints 0 H-atom treatment H atoms treated by a mixture of independent and constrained refinement -3 '²max, '²min (e Å ) 0.28, -0.35

ATOMIC COORDINATES AND DISPLACEMENT PARAMETERS Br1 0.32606(8) 0.86037(9) 0.38182(5) 0.0933(4) O1 0.1512(4) 1.1343(3) 0.33055(19) 0.0413(10) O2 0.2277(4) 1.1305(3) 0.43646(19) 0.0453(10) O4 0.0586(5) 0.9599(5) 0.0969(2) 0.0793(15) C1 0.1719(5) 1.0567(5) 0.3824(3) 0.0399(15) C2 0.3507(5) 1.1690(5) 0.4520(3) 0.0397(15) C3 0.3891(6) 1.2727(5) 0.4871(3) 0.0499(17) H3 0.3325 1.3125 0.4991 0.060 C5 0.5936(6) 1.2574(6) 0.4867(3) 0.0467(17) C6 0.5556(5) 1.1522(5) 0.4524(3) 0.0441(16) H6 0.6133 1.1112 0.4415 0.053 C7 0.4333(5) 1.1062(5) 0.4338(3) 0.0365(15) C8 0.3902(5) 0.9976(5) 0.3930(3) 0.0407(15) H8A 0.4522 0.9337 0.4114 0.049 H8B 0.3878 1.0164 0.3523 0.049 C9 0.2580(5) 0.9518(5) 0.3838(3) 0.0365(15) H9 0.2695 0.9007 0.4198 0.044 C10 0.1917(5) 0.8769(5) 0.3243(3) 0.0390(15) H10 0.1160 0.8404 0.3257 0.047 C11 0.1461(5) 0.9589(5) 0.2669(3) 0.0358(14) C12 0.1206(6) 0.9164(5) 0.2071(3) 0.0503(17) H12 0.1268 0.8344 0.2009 0.060 C13 0.0866(6) 0.9941(6) 0.1573(3) 0.0515(17) C14 0.0786(6) 1.1168(6) 0.1660(3) 0.0572(19) H14 0.0576 1.1699 0.1325 0.069 C15 0.1019(6) 1.1588(5) 0.2242(3) 0.0488(17) H15 0.0960 1.2411 0.2300 0.059 C16 0.1340(5) 1.0823(5) 0.2751(3) 0.0378(15) C17 0.0466(5) 1.0134(5) 0.3809(3) 0.0381(14) C18 -0.0693(6) 1.0345(5) 0.3323(3) 0.0473(17) 263 H18 -0.0731 1.0802 0.2985 0.057 C19 -0.1816(6) 0.9900(6) 0.3317(3) 0.0529(18) H19 -0.2596 1.0047 0.2979 0.064 C24 0.2748(5) 0.7764(5) 0.3207(3) 0.0380(14) H24 0.3404 0.7961 0.3095 0.046 C25 0.2617(6) 0.6612(5) 0.3323(3) 0.0423(15) H25 0.1935 0.6423 0.3417 0.051 C26 0.3436(5) 0.5608(5) 0.3319(3) 0.0360(14) C27 0.4595(6) 0.5766(5) 0.3295(3) 0.0514(18) H27 0.4909 0.6545 0.3318 0.062 Br2 0.57862(9) 0.23502(7) 0.31121(5) 0.0889(4) C20 -0.1750(6) 0.9239(6) 0.3822(3) 0.0488(17) C22 0.0490(6) 0.9485(6) 0.4318(3) 0.0494(17) H22 0.1267 0.9353 0.4661 0.059 C21 -0.0615(6) 0.9031(6) 0.4328(3) 0.0526(18) H21 -0.0586 0.8595 0.4671 0.063 C4 0.5104(7) 1.3185(6) 0.5048(3) 0.0562(18) H4 0.5357 1.3888 0.5284 0.067 O3 0.7185(4) 1.2927(4) 0.5024(2) 0.0731(15) C23 0.7468(7) 1.4157(6) 0.5097(4) 0.082(3) H23A 0.6973 1.4568 0.4711 0.123 H23B 0.8360 1.4273 0.5208 0.123 H23C 0.7266 1.4474 0.5423 0.123 C32 0.0388(10) 0.8357(8) 0.0812(4) 0.107(3) H32A 0.1140 0.7912 0.1069 0.160 H32B 0.0209 0.8251 0.0379 0.160 H32C -0.0321 0.8069 0.0884 0.160 C30 0.3722(6) 0.3461(5) 0.3259(3) 0.0522(17) H30 0.3434 0.2677 0.3253 0.063 C29 0.4834(6) 0.3677(5) 0.3213(3) 0.0474(17) C31 0.3031(6) 0.4428(5) 0.3316(3) 0.0485(17) H31 0.2275 0.4288 0.3353 0.058 C28 0.5305(6) 0.4823(6) 0.3239(3) 0.0573(18) H28 0.6080 0.4954 0.3218 0.069

Br1 0.0691(6) 0.1080(7) 0.1251(8) -0.0185(6) 0.0627(6) -0.0306(5) O1 0.045(2) 0.036(2) 0.043(3) 0.006(2) 0.019(2) 0.005(2) O2 0.037(2) 0.046(2) 0.050(3) -0.014(2) 0.016(2) -0.004(2) O4 0.111(4) 0.070(4) 0.051(3) -0.001(3) 0.028(3) -0.005(3) C1 0.037(3) 0.043(4) 0.040(4) 0.001(3) 0.017(3) 0.008(3) C2 0.034(4) 0.033(3) 0.049(4) 0.000(3) 0.015(3) -0.002(3) C3 0.057(4) 0.039(4) 0.050(4) 0.004(3) 0.020(4) 0.000(3) C5 0.032(4) 0.043(4) 0.042(4) 0.000(3) -0.006(3) -0.012(3) C6 0.036(4) 0.042(4) 0.043(4) 0.003(3) 0.006(3) 0.004(3) C7 0.036(4) 0.034(3) 0.034(4) -0.004(3) 0.010(3) -0.005(3) C8 0.032(3) 0.036(3) 0.051(4) -0.006(3) 0.015(3) 0.002(3) C9 0.037(3) 0.026(3) 0.039(4) 0.000(3) 0.010(3) -0.004(3) C10 0.029(3) 0.032(3) 0.054(4) 0.001(3) 0.015(3) 0.000(3) C11 0.038(3) 0.033(3) 0.035(4) -0.002(3) 0.015(3) -0.004(3) C12 0.059(4) 0.034(4) 0.054(5) 0.000(4) 0.019(4) -0.005(3) C13 0.057(4) 0.059(5) 0.033(4) -0.002(4) 0.014(4) -0.006(4) C14 0.072(5) 0.046(5) 0.047(5) 0.018(4) 0.020(4) 0.001(4) C15 0.049(4) 0.032(4) 0.061(5) 0.008(4) 0.018(4) 0.001(3) C16 0.024(3) 0.039(4) 0.042(4) 0.011(3) 0.006(3) 0.002(3) C17 0.030(3) 0.044(4) 0.034(4) 0.000(3) 0.008(3) 0.004(3) 264 C18 0.041(4) 0.049(4) 0.054(5) 0.007(3) 0.022(4) 0.003(3) C19 0.036(4) 0.066(5) 0.053(5) -0.008(4) 0.016(4) 0.003(3) C24 0.034(3) 0.034(3) 0.042(4) -0.001(3) 0.012(3) -0.002(3) C25 0.043(4) 0.042(4) 0.044(4) -0.001(3) 0.020(3) -0.002(3) C26 0.038(4) 0.030(3) 0.036(4) 0.002(3) 0.012(3) 0.003(3) C27 0.045(4) 0.033(4) 0.074(5) 0.002(3) 0.023(4) 0.001(3) Br2 0.1267(8) 0.0592(5) 0.1080(7) 0.0106(5) 0.0762(6) 0.0376(5) C20 0.042(4) 0.053(4) 0.055(5) -0.012(4) 0.023(4) -0.006(3) C22 0.037(4) 0.053(4) 0.049(5) 0.003(4) 0.010(3) 0.007(3) C21 0.062(5) 0.046(4) 0.059(5) 0.001(3) 0.035(4) -0.006(3) C4 0.063(5) 0.042(4) 0.049(4) -0.005(3) 0.009(4) -0.004(4) O3 0.046(3) 0.054(3) 0.099(4) -0.003(3) 0.010(3) -0.014(2) C23 0.081(6) 0.066(5) 0.092(7) 0.008(5) 0.030(5) -0.028(5) C32 0.177(10) 0.085(7) 0.046(5) -0.026(5) 0.036(6) -0.027(7) C30 0.069(5) 0.029(4) 0.063(5) 0.002(3) 0.032(4) 0.001(3) C29 0.066(5) 0.038(4) 0.044(4) -0.002(3) 0.029(4) 0.017(4) C31 0.053(4) 0.036(4) 0.058(5) 0.005(3) 0.025(4) 0.003(3) C28 0.052(4) 0.056(5) 0.074(5) 0.007(4) 0.037(4) 0.003(4)

SELECTED GEOMETRIC PARAMETERS

BOND LENGTHS Br1—C20 1.883 (6) C11—C16 1.398 (8) O1—C16 1.365 (7) C12—C13 1.373 (8) O1—C1 1.429 (7) C13—C14 1.386 (9) O2—C2 1.380 (6) C14—C15 1.364 (9) O2—C1 1.418 (7) C15—C16 1.383 (8) O4—C13 1.373 (7) C17—C18 1.364 (8) O4—C32 1.419 (9) C17—C22 1.390 (8) C1—C17 1.515 (8) C18—C19 1.385 (8) C1—C9 1.524 (7) C19—C20 1.372 (9) C2—C3 1.376 (8) C24—C25 1.331 (8) C2—C7 1.392 (8) C25—C26 1.467 (8) C3—C4 1.381 (9) C26—C27 1.379 (8) C5—C6 1.381 (8) C26—C31 1.390 (8) C5—C4 1.387 (9) C27—C28 1.372 (8) C5—O3 1.389 (7) Br2—C29 1.914 (6) C6—C7 1.390 (7) C20—C21 1.368 (8) C7—C8 1.488 (7) C22—C21 1.384 (8) C8—C9 1.539 (7) O3—C23 1.397 (8) C9—C10 1.528 (8) C30—C29 1.359 (8) C10—C24 1.498 (7) C30—C31 1.379 (8) C10—C11 1.525 (8) C29—C28 1.375 (8) C11—C12 1.395 (8) 265 BOND ANGLES C16—O1—C1 117.9 (4) O4—C13—C14 115.2 (6) C2—O2—C1 116.2 (4) C12—C13—C14 120.2 (6) C13—O4—C32 118.6 (6) C15—C14—C13 119.2 (6) O2—C1—O1 105.5 (4) C14—C15—C16 121.8 (6) O2—C1—C17 105.6 (4) O1—C16—C15 116.5 (5) O1—C1—C17 111.2 (5) O1—C16—C11 124.3 (5) O2—C1—C9 112.2 (5) C15—C16—C11 119.2 (6) O1—C1—C9 110.5 (5) C18—C17—C22 117.7 (5) C17—C1—C9 111.6 (5) C18—C17—C1 123.7 (5) C3—C2—O2 116.9 (5) C22—C17—C1 118.6 (5) C3—C2—C7 121.0 (6) C17—C18—C19 122.1 (6) O2—C2—C7 122.1 (5) C20—C19—C18 118.5 (6) C2—C3—C4 121.1 (6) C25—C24—C10 124.8 (6) C6—C5—C4 120.3 (6) C24—C25—C26 126.7 (6) C6—C5—O3 115.5 (6) C27—C26—C31 116.9 (5) C4—C5—O3 124.2 (6) C27—C26—C25 123.2 (5) C5—C6—C7 121.6 (6) C31—C26—C25 119.8 (5) C6—C7—C2 117.5 (5) C28—C27—C26 122.7 (6) C6—C7—C8 121.2 (5) C21—C20—C19 121.6 (6) C2—C7—C8 121.3 (5) C21—C20—Br1 119.1 (5) C7—C8—C9 113.5 (5) C19—C20—Br1 119.3 (5) C1—C9—C10 109.1 (5) C21—C22—C17 121.6 (6) C1—C9—C8 110.7 (4) C20—C21—C22 118.5 (6) C10—C9—C8 112.9 (5) C3—C4—C5 118.5 (6) C24—C10—C11 112.5 (5) C5—O3—C23 118.1 (5) C24—C10—C9 111.9 (5) C29—C30—C31 118.7 (6) C11—C10—C9 109.8 (4) C30—C29—C28 122.1 (6) C12—C11—C16 118.6 (5) C30—C29—Br2 119.4 (5) C12—C11—C10 122.6 (5) C28—C29—Br2 118.6 (5) C16—C11—C10 118.7 (5) C30—C31—C26 121.6 (6) C13—C12—C11 120.9 (6) C27—C28—C29 117.8 (6) O4—C13—C12 124.6 (6)

266 A6. (2S, 4S)-2-(4-Chlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1,2,3,4-tetrahydroquinoline (279) EXPERIMENTAL DETAILS

Crystal data

Chemical formula C24H21ClN2

Mr 372.88 Crystal system, space Triclinic, P¯1 group Temperature (K) 150 a, b, c (Å) 7.0842 (3), 9.8987 (5), 14.7206 (8) D, E, J (°) 75.526 (2), 87.110 (2), 70.732 (2) V (Å3) 942.94 (8) Z 2 Radiation type Mo KD P (mm-1) 0.21 Crystal size (mm) 0.25 × 0.18 × 0.06 Data collection

Tmin, Tmax 0.948, 0.987 No. of measured, 13667, 3958, 3475 independent and observed [I > 2V (I)] reflections

Rint 0.049 Refinement R[F2 > 2V (F2)], 0.039, 0.107, 1.04 wR(F2), S No. of reflections 3958 No. of parameters 246 No. of restraints 0 H-atom treatment Riding -3 '²max, '²min (e Å ) 0.53, -0.52

ATOMIC COORDINATES AND DISPLACEMENT PARAMETERS Cl1 0.98698(6) -0.12273(4) 0.41963(3) 0.03589(14) N1 0.13073(19) 0.88881(13) 0.12785(9) 0.0252(3) N2 0.08230(18) 0.39360(14) 0.37260(8) 0.0245(3) H3N 0.1091 0.3249 0.4257 0.029 C1 0.2090(2) 0.83235(16) 0.05277(10) 0.0245(3) C2 0.3152(2) 0.88589(18) 0.02257(12) 0.0318(4) H2 0.3462 0.9737 -0.0272 0.038 C3 0.3730(3) 0.8063(2) 0.08970(12) 0.0380(4) H3 0.4446 0.8403 -0.1417 0.046 267 C4 0.3287(3) 0.6765(2) 0.08298(12) 0.0360(4) H4 0.3718 0.6237 -0.1301 0.043 C5 0.2236(2) 0.62406(17) 0.00912(11) 0.0283(3) H5 0.1943 0.5358 -0.0051 0.034 C6 0.1605(2) 0.70290(16) 0.06006(10) 0.0223(3) C7 0.0465(2) 0.68366(15) 0.14308(10) 0.0210(3) C8 0.0327(2) 0.79877(15) 0.18130(10) 0.0233(3) H8 -0.0352 0.8146 0.2370 0.028 C9 0.1474(3) 1.02108(17) 0.14713(12) 0.0331(4) H9A 0.2873 1.0048 0.1629 0.050 H9B 0.0642 1.0443 0.2000 0.050 H9C 0.1021 1.1036 0.0915 0.050 C10 -0.0333(2) 0.55707(15) 0.17983(10) 0.0214(3) H10 -0.1130 0.5514 0.1276 0.026 C11 -0.1710(2) 0.57970(15) 0.26089(10) 0.0209(3) C12 -0.3665(2) 0.67668(16) 0.24507(11) 0.0257(3) H12 -0.4129 0.7287 0.1825 0.031 C13 -0.4958(2) 0.69971(16) 0.31791(12) 0.0281(3) H13 -0.6289 0.7661 0.3054 0.034 C14 -0.4279(2) 0.62443(16) 0.40934(11) 0.0268(3) H14 -0.5139 0.6411 0.4599 0.032 C15 -0.2360(2) 0.52553(16) 0.42711(10) 0.0239(3) H15 -0.1920 0.4736 0.4899 0.029 C16 -0.1052(2) 0.50060(15) 0.35394(10) 0.0209(3) C17 0.2341(2) 0.39751(15) 0.30214(10) 0.0219(3) H17 0.2705 0.4885 0.2970 0.026 C18 0.1390(2) 0.40931(15) 0.20856(10) 0.0232(3) H18A 0.0871 0.3262 0.2144 0.028 H18B 0.2408 0.4036 0.1598 0.028 C19 0.4195(2) 0.26463(15) 0.33170(10) 0.0217(3) C20 0.4140(2) 0.12085(17) 0.35731(12) 0.0319(4) H20 0.2893 0.1044 0.3567 0.038 C21 0.5875(3) 0.00131(17) 0.38363(12) 0.0332(4) H21 0.5827 -0.0966 0.4007 0.040 C22 0.7676(2) 0.02681(16) 0.38459(10) 0.0251(3) C23 0.7778(2) 0.16793(17) 0.35985(11) 0.0261(3) H23 0.9026 0.1840 0.3609 0.031 C24 0.6031(2) 0.28572(16) 0.33345(10) 0.0237(3) H24 0.6090 0.3833 0.3161 0.028

Cl1 0.0355(2) 0.0300(2) 0.0303(2) -.00528(16) -.00387(16) 0.00380(17) N1 0.0292(7) 0.0228(6) 0.0243(7) -0.0029(5) -0.0013(5) -0.0114(5) N2 0.0237(6) 0.0285(6) 0.0175(6) -0.0009(5) 0.0005(5) -0.0070(5) C1 0.0221(7) 0.0257(7) 0.0221(7) -0.0005(6) -0.0026(6) -0.0066(6) C2 0.0277(8) 0.0329(8) 0.0309(9) 0.0036(7) 0.0002(6) -0.0134(7) C3 0.0328(9) 0.0446(10) 0.0288(9) 0.0022(7) 0.0099(7) -0.0123(8) C4 0.0368(9) 0.0409(9) 0.0240(8) -0.0072(7) 0.0075(7) -0.0064(7) C5 0.0313(8) 0.0292(8) 0.0218(8) -0.0046(6) 0.0021(6) -0.0079(7) C6 0.0217(7) 0.0233(7) 0.0180(7) -0.0001(5) -0.0019(5) -0.0056(6) C7 0.0219(7) 0.0224(7) 0.0170(7) -0.0017(5) -0.0019(5) -0.0068(6) C8 0.0253(7) 0.0239(7) 0.0194(7) -0.0022(6) -0.0003(6) -0.0087(6) C9 0.0414(9) 0.0251(8) 0.0354(9) -0.0045(7) -0.0052(7) -0.0155(7) C10 0.0249(7) 0.0229(7) 0.0177(7) -0.0042(5) 0.0000(5) -0.0102(6) C11 0.0236(7) 0.0217(7) 0.0204(7) -0.0045(5) 0.0012(6) -0.0119(6) C12 0.0269(7) 0.0235(7) 0.0257(8) -0.0015(6) -0.0025(6) -0.0100(6) 268 C13 0.0221(7) 0.0236(7) 0.0372(9) -0.0064(6) 0.0023(6) -0.0067(6) C14 0.0273(8) 0.0258(7) 0.0310(8) -0.0090(6) 0.0090(6) -0.0133(6) C15 0.0288(8) 0.0247(7) 0.0208(7) -0.0040(6) 0.0030(6) -0.0136(6) C16 0.0217(7) 0.0210(7) 0.0230(7) -0.0054(6) 0.0003(5) -0.0110(6) C17 0.0225(7) 0.0209(7) 0.0240(7) -0.0047(6) 0.0021(6) -0.0102(6) C18 0.0274(7) 0.0219(7) 0.0210(7) -0.0054(6) 0.0038(6) -0.0095(6) C19 0.0236(7) 0.0219(7) 0.0205(7) -0.0050(5) 0.0008(5) -0.0087(6) C20 0.0278(8) 0.0264(8) 0.0438(10) -0.0046(7) -0.0021(7) -0.0142(6) C21 0.0388(9) 0.0207(7) 0.0401(9) -0.0037(7) -0.0028(7) -0.0120(7) C22 0.0284(8) 0.0237(7) 0.0185(7) -0.0049(6) -0.0013(6) -0.0023(6) C23 0.0220(7) 0.0302(8) 0.0256(8) -0.0040(6) 0.0007(6) -0.0099(6) C24 0.0266(7) 0.0222(7) 0.0238(7) -0.0034(6) 0.0010(6) -0.0118(6)

SELECTED GEOMETRIC PARAMETERS

BOND LENGTHS Cl1—C22 1.7476 (15) C10—H10 1.0000 N1—C1 1.373 (2) C11—C12 1.392 (2) N1—C8 1.3780 (18) C11—C16 1.412 (2) N1—C9 1.4492 (19) C12—C13 1.388 (2) N2—C16 1.3873 (18) C12—H12 0.9500 N2—C17 1.4593 (18) C13—C14 1.388 (2) N2—H3N 0.8800 C13—H13 0.9500 C1—C2 1.401 (2) C14—C15 1.380 (2) C1—C6 1.411 (2) C14—H14 0.9500 C2—C3 1.379 (3) C15—C16 1.401 (2) C2—H2 0.9500 C15—H15 0.9500 C3—C4 1.399 (3) C17—C19 1.5083 (19) C3—H3 0.9500 C17—C18 1.525 (2) C4—C5 1.377 (2) C17—H17 1.0000 C4—H4 0.9500 C18—H18A 0.9900 C5—C6 1.402 (2) C18—H18B 0.9900 C5—H5 0.9500 C19—C24 1.3862 (19) C6—C7 1.4378 (19) C19—C20 1.391 (2) C7—C8 1.366 (2) C20—C21 1.386 (2) C7—C10 1.5101 (18) C20—H20 0.9500 C8—H8 0.9500 C21—C22 1.381 (2) C9—H9A 0.9800 C21—H21 0.9500 C9—H9B 0.9800 C22—C23 1.378 (2) C9—H9C 0.9800 C23—C24 1.383 (2) C10—C11 1.5159 (19) C23—H23 0.9500 C10—C18 1.540 (2) C24—H24 0.9500

269 BOND ANGLES C1—N1—C8 108.32 (12) C13—C12—C11 121.99 (14) C1—N1—C9 125.75 (13) C13—C12—H12 119.0 C8—N1—C9 125.93 (13) C11—C12—H12 119.0 C16—N2—C17 118.52 (12) C14—C13—C12 119.05 (14) C16—N2—H3N 120.7 C14—C13—H13 120.5 C17—N2—H3N 120.7 C12—C13—H13 120.5 N1—C1—C2 130.18 (14) C15—C14—C13 120.31 (14) N1—C1—C6 107.97 (12) C15—C14—H14 119.8 C2—C1—C6 121.83 (14) C13—C14—H14 119.8 C3—C2—C1 117.42 (15) C14—C15—C16 120.99 (14) C3—C2—H2 121.3 C14—C15—H15 119.5 C1—C2—H2 121.3 C16—C15—H15 119.5 C2—C3—C4 121.56 (15) N2—C16—C15 120.06 (13) C2—C3—H3 119.2 N2—C16—C11 120.71 (13) C4—C3—H3 119.2 C15—C16—C11 119.13 (13) C5—C4—C3 121.06 (16) N2—C17—C19 110.20 (11) C5—C4—H4 119.5 N2—C17—C18 107.20 (11) C3—C4—H4 119.5 C19—C17—C18 113.98 (12) C4—C5—C6 119.02 (15) N2—C17—H17 108.4 C4—C5—H5 120.5 C19—C17—H17 108.4 C6—C5—H5 120.5 C18—C17—H17 108.4 C5—C6—C1 119.09 (13) C17—C18—C10 109.57 (11) C5—C6—C7 133.89 (13) C17—C18—H18A 109.8 C1—C6—C7 107.01 (12) C10—C18—H18A 109.8 C8—C7—C6 106.11 (12) C17—C18—H18B 109.8 C8—C7—C10 128.39 (13) C10—C18—H18B 109.8 C6—C7—C10 125.48 (12) H18A—C18—H18B 108.2 C7—C8—N1 110.59 (13) C24—C19—C20 118.37 (14) C7—C8—H8 124.7 C24—C19—C17 119.03 (12) N1—C8—H8 124.7 C20—C19—C17 122.60 (13) N1—C9—H9A 109.5 C21—C20—C19 121.01 (14) N1—C9—H9B 109.5 C21—C20—H20 119.5 H9A—C9—H9B 109.5 C19—C20—H20 119.5 N1—C9—H9C 109.5 C22—C21—C20 118.91 (14) H9A—C9—H9C 109.5 C22—C21—H21 120.5 H9B—C9—H9C 109.5 C20—C21—H21 120.5 C7—C10—C11 112.45 (11) C23—C22—C21 121.43 (14)

270 C7—C10—C18 110.91 (11) C23—C22—Cl1 119.17 (12) C11—C10—C18 110.37 (11) C21—C22—Cl1 119.39 (12) C7—C10—H10 107.6 C22—C23—C24 118.79 (13) C11—C10—H10 107.6 C22—C23—H23 120.6 C18—C10—H10 107.6 C24—C23—H23 120.6 C12—C11—C16 118.49 (13) C23—C24—C19 121.48 (13) C12—C11—C10 120.74 (13) C23—C24—H24 119.3 C16—C11—C10 120.75 (13) C19—C24—H24 119.3

271

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