Exploring New Synthetic Methodologies Using Organoboron Catalysts

Exploring New Synthetic Methodologies using Organoboron Catalysts

Tishaan Singh

A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Chemistry University of Toronto

Exploring New Synthetic Methodologies using Organoboron Catalysts

Tishaan Singh

Master of Science

Department of Chemistry University of Toronto

2014 Abstract Organic molecules as reaction catalysts (organocatalysts) has represented a major direction of research over the past 10–15 years. Organoboron compounds possess many advantageous features of organocatalysts, including their relatively low cost and toxicity, their high functional group tolerance and ease of structural modification. 2H-Chromenes have been studied extensively as a consequence of their widespread natural occurrence, diverse biological properties and photochromic behaviour. They have been employed as useful intermediates in the synthesis of many natural products, pharmaceuticals and photochromic ophthalmic plastic lenses.

Chapter 1 describes the optimization and initial substrate scope of an arylboronic acid-catalyzed synthesis of 2H-chromenes from the condensation of various phenols and aldehydes. Chapter 2 explores the utility of borinic acid catalysts in a Conia-Ene reaction. Finally, Chapter 3 discusses the synthesis of homobarrelenones, attractive building blocks for organic synthesis, via a Diels-

Alder cycloaddition reaction using catalytic boronic acids.

ii Acknowledgements

I would not be writing this thesis if not for all the people who helped me along this journey.

First and foremost, I would like to thank my supervisor, Mark Taylor, whose office door was almost always open to discuss chemistry or life. Thank you for all your guidance and I am grateful for the opportunity you have given me.

I would like to thank each and every member of the Taylor group. It is rare to find a group of coworkers that you genuinely love to work with. Waking up at 6:00 AM every morning and commuting 3 hours each day was worth it simply to work alongside all of you. Thomas, your wisdom and veteran presence in the lab was reassuring and your willingness to help and offer advice was greatly appreciated. Chris, thank you for all the fun times in the lab and I wish you all the best with your new job. Mike and Graham, thank you for making lunch the highlight of my day and I will miss nerding out with you guys. Thank you Elena for giving me a nickname that will remind me of my times in graduate school. Sanjay and Ross, thanks for obsessing over the

Jays with me (there's always next year). Kashif, I don't know how you were able to put up with me for a whole year. August was incredibly boring without you working beside me. Kyan, thank you your insight in chemistry and your eagerness to help. John, your cheerful mood always put a smile on my face. I would like to thank my fellow McMaster alumni Victoria. Days without our coffee break don't seem like complete days. Thank you all for laughing at my jokes and I hope we stay in touch for years to come.

And finally, but most importantly, thank you to my parents. Thank you for supporting my decisions. This thesis is yours as much as it is mine.

iii Table of Contents

Acknowledgements ...... iii

Table of Contents ...... iv

List of Tables ...... vi

List of Schemes ...... vii

List of Figures ...... ix

List of Appendices ...... x

List of Abbreviations ...... xi

Chapter 1 Arylboronic Acid-Catalyzed Synthesis of 2H-Chromenes ...... 1

1.1 Introduction ...... 1

1.1.1 General Introduction to 2H-Chromenes...... 1

1.1.2 Natural Occurrence and Biological Activities of 2H-Chromenes ...... 2

1.1.3 Photochromic Properties of 2H-Chromenes ...... 6

1.1.4 Synthesis of 2H-Chromenes ...... 9

1.1.5 Structure and Properties of Boronic Acids and Their Use as Reaction Promoters

and Catalysts ...... 12

1.1.6 Phenylboronic Acid-Mediated Synthesis of 2H-Chromenes ...... 16

1.2 Results and Discussion ...... 21

1.3 Conclusion ...... 37

1.4 Experimental ...... 38

1.4.1 General Experimental Procedures ...... 39

1.4.2 Characterization Data...... 39

iv Chapter 2 Boronic Acid-Catalyzed Conia-Ene Reaction ...... 45

2.1 Introduction ...... 45

2.1.1 Conia-Ene Reaction ...... 45

2.1.2 Structure and Properties of Borinic Acids ...... 49

2.2 Results and Discussion ...... 50

2.3 Conclusion ...... 56

2.4 Experimental ...... 57

2.4.1 General Experimental Procedures ...... 57

2.4.2 Characterization Data...... 59

Chapter 3 Synthesis of Homobarrelenones via Boronic Acid-Catalyzed Diels Alder

Cycloaddition ...... 63

3.1 Introduction ...... 63

3.1.1 Boronic Acids Acting as Brønsted Acids ...... 63

3.1.2 Applications of Boronic Acids in Diels-Alder Cycloadditions ...... 64

3.1.3 General Introduction to Homobarrelenones...... 66

3.2 Results and Discussion ...... 67

3.3 Conclusion ...... 75

3.4 Experimental ...... 76

3.4.1 General Experimental Procedures ...... 76

3.4.2 Characterization Data...... 77

Appendix A ...... 79

iv List of Tables

Table 1.1 Evaluation of organoboron catalysts and effects of Brønsted acid ...... 22

Table 1.2 Evaluation of Brønsted acids ...... 23

Table 1.3 Evaluation of solvents ...... 25

Table 1.4 Evaluation of electronically distinct arylboronic acids with 3-methoxyphenol ...... 26

Table 1.5 Evaluation of phenylboronic acid catalyst loading with 3,5-dimethoxyphenol ...... 27

Table 1.6 Evaluation of arylboronic acids with 1-naphthol ...... 28

Table 1.7 Scope of arylboronic acid-catalyzed condensation reaction of phenols and naphthols with α,β-unsaturated aldehydes ...... 31

Table 1.8 Attempted arylboronic acid-catalyzed synthesis of cannabinoids 1.60 ...... 34

Table 2.1 Evaluation of organoboron catalysts for the Conia-ene reaction of 2.12 ...... 51

Table 2.2 Evaluation of electronically distinct borinic acid catalysts ...... 53

Table 2.3 Evaluation of organoboron catalysts for the Conia-ene reaction of 2.13 ...... 55

Table 3.1 Exploring organoboron-catalyzed Diels-Alder cycloaddition of 3.4 and N- methylmaleimide...... 67

Table 3.2 Evaluation of organoboron catalysts in the Diels-Alder cycloaddition of 3.4 and N- methylmaleimide...... 69

Table 3.3 Evaluation of solvents ...... 71

Table 3.4 Optimized reaction conditions and evaluation of reaction concentration ...... 72

vi List of Schemes

Scheme 1.1 Biosynthetic pathway of 2H-chromenes ...... 2

Scheme 1.2 Proposed mechanism for the ring closure reaction to form 2H-chromenes ...... 3

Scheme 1.3 Mechanism of 2H-chromenes photochromism ...... 7

Scheme 1.4 Synthetic approaches to 2H-chromenes ...... 10

Scheme 1.5 Reactions of phenols with α,β-unsaturated aldehydes ...... 12

Scheme 1.6 Ionization equilibrium of boronic acids in water ...... 13

Scheme 1.7 Boronic acid-catalyzed Friedel-Crafts alkylation of benzylic alcohols ...... 14

Scheme 1.8 Phenylboronic acid-mediated Diels-Alder reaction ...... 15

Scheme 1.9 Phenylboronic acid-promoted ortho-alkylation of phenols with aldehydes ...... 15

Scheme 1.10 Phenylboronic acid-mediated synthesis of hexahydrocannabinoid products 1.36 ..17

Scheme 1.11 Reactions of benzodioxaborins as stable ortho-quinone methide precursors ...... 18

Scheme 1.12 General procedure for the phenylboronic acid-promoted preparation of substituted

2H-chromenes ...... 18

Scheme 1.13 Phenylboronic acid-mediated triple condensation reactions of phloroglucinol and unsaturated aldehydes ...... 19

Scheme 1.14 Phenylboronic acid-mediated synthesis of mollugin 1.38 ...... 20

Scheme 1.15 Phenylboronic acid-catalyzed synthesis of precocene I 1.7 ...... 22

Scheme 1.16 Attempted arylboronic acid-catalyzed chromenylation of phenol ...... 33

Scheme 1.17 Attempted arylboronic acid-catalyzed chromenylation of 4-bromophenol ...... 33

Scheme 1.18 Attempted arylboronic acid-catalyzed chromenylation of 3,5-dimethoxyphenol and crotonaldehyde ...... 34

vii Scheme 1.19 Proposed mechanism for the phenylboronic acid-catalyzed synthesis of precocene I

1.7...... 36

Scheme 2.1 General scheme representing ene reactions ...... 45

Scheme 2.2 Conia-ene reaction of activated carbonyl compounds ...... 47

Scheme 2.3 Conia-ene reaction of acetylenic dicarbonyl compounds catalyzed by 2.1 ...... 47

Scheme 2.4 Proposed mechanistic pathway of the Conia-ene reaction catalyzed by 2.1 ...... 48

Scheme 2.5 Conia-ene reaction of acetylenic dicarbonyl compounds catalyzed by 2.2 ...... 48

Scheme 2.6 Diphenylborinic acid-catalyzed aldol reaction of pyruvic acids ...... 50

Scheme 2.7 Formation of dioxoborolanones 2.7 ...... 50

Scheme 2.8 Synthesis of acetylenic dicarbonyl derivatives ...... 51

Scheme 2.9 Synthesis of electronically distinct arylborinic acids ...... 53

Scheme 3.1 Ionization equilibrium of heterocyclic boronic acid derivative 3.1 ...... 63

Scheme 3.2 Boronic acid-catalyzed Diels-Alder cycloaddition ...... 64

Scheme 3.3 Phenylboronic acid-mediated Diels-Alder reaction ...... 65

Scheme 3.4 Diels-Alder reaction of tropolone and N-methylmaleimide prompted by Et3N ...... 66

Scheme 3.5 Synthesis and structure of diphenylboryltropolonate 3.11 ...... 68

Scheme 3.6 Diels-Alder cycloaddition of 3.4 and trans-hex-3-en-2-one using catalyst 3.14 ...... 74

Scheme 3.7 Diels-Alder cycloaddition of 3.4 and butyl acrylate using catalyst 3.14 ...... 74

Scheme 3.8 Diels-Alder cycloaddition of 3.4 and dimethyl acetylenedicarboxylate using catalyst

3.14...... 75

viii List of Figures

Figure 1.1 2H-Chromene ring system ...... 1

Figure 1.2 Molecular structures of precocene I 1.7 and precocene II 1.8 ...... 4

Figure 1.3 Molecular structures of 2,2-dimethyl-2H-chromene natural products 1.9-1.14 ...... 5

Figure 1.4 Molecular structures of (+)-calanolide A 1.15 and (-)-calanolide B 1.16 ...... 6

Figure 1.5 Basic structures of pterocarpene 1.17 and cannabichromene 1.18 ...... 6

Figure 1.6 Molecular structures of furan-fused 2H-chromenes 1.21 and naphthopyran 1.22 ...... 9

Figure 1.7 Molecular structures of boronic acids 1.31 and boroxines 1.32 ...... 13

Figure 1.8 Proposed [3,3]-sigmatropic rearrangement pathway 1.33 and molecular structure of benzodioxaborine 1.34 ...... 16

Figure 2.1 Molecular structures of boronic acids 2.3, borinic acids 2.4, borinic anhydrides 2.5 and 2-ethanolamine borinates 2.6 ...... 49

Figure 3.1 Homobarrelenone skeleton 3.7 and molecular structure of barbaralone 3.8 ...... 66

ix List of Appendices

Appendix A 1H and 13C NMR Spectra...... 79

List of Abbreviations

°C degress Celsius

1H proton NMR

13C carbon 13 NMR

Ac acetyl

Ar aryl aq aqueous

Bn benzyl

Bu butyl

Bz benzoyl d doublet

DCM dichloromethane

DMF dimethylformamide

DMSO dimethyl sulfoxide

Equiv. equivalent

Et ethyl

EtOAc ethyl acetate

EWG electron-withdrawing group h hour(s)

HRMS high resolution mass spectrometry

Hz Hertz

J coupling constant (NMR spectrometry) m multiplet

xi 0

M molar

Me methyl

MHz megahertz mmol millimole(s)

NMR nuclear magnetic resonance

Nu nucleophile p pentet

Ph phenyl

PP pyrophosphate group ppm parts per million q quartet

R generic chemical group rpm revolutions per minute rt room temperature s singlet t triplet

THF tetrahydrofuran

xii 1

Chapter 1 Arylboronic Acid-Catalyzed Synthesis of 2H-Chromenes

1.1 Introduction

1.1.1 General Introduction to 2H-Chromenes

2H-Chromenes, also known as 2H-1-benzopyrans, are an important family of oxygen-containing heterocycles (Figure 1.1). These compounds are widely distributed in nature and almost every class of natural phenolic compounds includes members that feature a 2,2-dialkylchromene ring system.1

Figure 1.1 2H-Chromene ring system.

2H-Chromenes have been studied extensively as a consequence of their widespread natural occurrence and diverse biological properties. They have also been employed as useful intermediates in the synthesis of many natural products and medicinal agents.2 Moreover, the

1 Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.; Mitchenll, H. J. J. Am. Chem. Soc. 2000, 122, 9939.

2 Goujin, J. Y.; Zammattio, F.; Pagnoncelli, S.; Boursereau, Y.; Kirschleger, B. Synlett 2002, 322.

discovery of the photochromism of 2H-chromenes has sparked great interest in their industrial applicability in the field of photochromic ophthalmic plastic lenses.3

1.1.2 Natural Occurrence and Biological Activities of 2H-Chromenes

2H-Chromenes are constituents of a considerable number of natural phenolic compounds including flavanoids, coumarins, rotenoids, stilbenoids and chromene glycosides. The number of these types of compounds that are discovered increases every year. Surprisingly, studies on their biosynthetic pathways have been sparse.4 It is currently believed that essentially all natural 2,2- dialkylchromenes are derived in vivo by alkylation reactions of a phenol 1.2 or a related precursor with an allyl pyrophosphate 1.3 (Scheme 1.1).5

Scheme 1.1 Biosynthetic pathway of 2H-chromenes.

A variety of mechanisms have been proposed for the ring closure step.6 The most widely accepted hypothesis involves the abstraction of a hydride ion from the benzylic position of the

3 Becker, R. S.; Michl, J. J. Am. Chem. Soc. 1996, 88, 5931.

4 Crombie, L.; Redshaw, S. D.; Slack, D. A.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1983, 1411.

5 Merlini, L. Adv. Heterocycl. Chem. 1975, 18, 159.

6 See: ref 5 and references therein.

alkylated phenol 1.4 by a quinone-like enzyme cofactor (Scheme 1.2). The resulting ortho- quinone methide 1.6 undergoes an electrocyclization reaction to afford the 2H-chromene 1.5.

Scheme 1.2 Proposed mechanism for the ring closure reaction to form 2H-chromenes.

The basic structural framework of 2H-chromenes is a common feature in many tannins and polyphenols found in teas, fruits, vegetables and red wines, and these compounds have been increasingly important as a result of their reported health-promoting effects.7,8 The 2H-chromene core has also been found in many naturally-occurring pharmacological active compounds. These compounds have been found to have anti-depressant, anti-hypertensive as well as anti-ischaemic properties and their uses in treatment of diseases dates back thousands of years.9,10 New discoveries regarding the biological properties of this class of compounds continue to be reported and some important examples are discussed herein.

7 Doodeman, R.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett. 2000, 41, 5979.

8 Chang, S.; Grubb, R. H. J. Org. Chem. 1998, 63, 864.

9 Cruz-Almanza, R.; Perez-Flores, F.; Lemini, C.; Heterocycles 1994, 37, 759.

10 Kaye, P. T.; Nocanda, X. W. J. Chem. Soc., Perkin Trans.1 2002, 1318.

In 1976, Bowers and co-workers reported the discovery of the anti-juvenile hormones, precocene

I 1.7 and prococene II 1.8 (Figure 1.2). These compounds were obtained from the crude liquid extract of the bedding plant Ageratum houstonianum.11 These two simple 2H-chromene compounds induce precocious metamorphosis and sterilization in several insect orders. This discovery initiated a new area of research on environmentally benign and insect-specific pesticides.

Figure 1.2 Molecular structures of precocene I 1.7 and precocene II 1.8.

Other 2,2-dimethyl-2H-chromene compounds, such as seselin 1.9, xanthyletin 1.10 and acronycine 1.11, have been shown to exhibit anti-cancer activities (Figure 1.3).12,13 2,2-

Dimethyl-8-prenylchromene 1.12, 2,2-dimethylchromene-6-propenoic acid 1.13 and 2,2- dimethylchromene-6-carboxylic acid 1.14 were isolated from the methanolic extract of Brazilian propolis (Figure 1.4).14 The C8-prenylated 2H-chromene 1.12 exhibited potent in vitro cytotoxicity while the remaining two chromene carboxylic acids 1.13 and 1.14 were found to be inactive.

11 Bowers, W. S.; Ohta, T.; Cleere, J. S.; Marsella, P. A. Science 1976, 193, 542.

12 Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q. Angew. Chem. Int. Ed. 2000, 39, 734 and references therein.

13 Subburaj, K.; Trivedi, G. K. Bull. Chem. Soc. Jpn. 1999, 72, 259.

14 Banskota, A. H.; Tezuka, Y.; Prasain, J. K.; Matsushige, K.; Saiki, I.; Kadota, S. J. Nat. Prod. 1998, 61, 896.

Figure 1.3 Molecular structures of 2,2-dimethyl-2H-chromene natural products 1.9-1.14.

In 1992, eight new coumarin compounds with 2H-chromene ring systems were isolated by anti-

HIV bioassay guided fractionation of an extract of the tropical rainforest tree Calophyllym lanigerum var. austrocoriaceum.15 Of these compounds, (+)-calanolide A 1.15 and (-)-calanolide

B 1.16 showed potent activity against HIV-1 replication in human T-lymphoblastic cells (Figure

1.4). These discoveries have defined a new subclass of non-nucleoside HIV-1 reverse transcriptase inhibitors.16

15 Kashman, Y.; Gustafson, K. F.; Fuller, R. W.; Cardellina, J. H. II; McMahon, J. B.; Currens, M. J.; Buckheit, R. W. Jr.; Hughes, S. H.; Cragg, G. M.; Boyd, M. R. J. Med. Chem. 1992, 35, 2735.

16 McKee, T. C.; Fuller, R. W.; Covington, C. D.; Cardellina, J. H. II; Gulakowski, R. J.; Krepps, B. L.; McMahon, J. B.; Boyd, M. R. J. Nat. Prod. 1996, 59, 754.

Figure 1.4 Molecular structures of (+)-calanolide A 1.15 and (-)-calanolide B 1.16.

The 2H-chromene moiety has also been found in a large number of pterocarpenes 1.17 (Figure

1.5), which have been reported to possess anti-fungal, anti-tumor and potent activity against snake venom.17 Many cannabichromene compounds 1.18 have shown anti-bacterial activities against Gram-positive, Gram-negative and acid-fast bacteria (Figure 1.5).18

Figure 1.5 Basic structures of pterocarpene 1.17 and cannabichromene 1.18.

1.1.3 Photochromic Properties of 2H-Chromenes

The first account of photochromic 2H-chromenes was reported by Becker and Michl in 1966.3 It was found that the simple 2H-chromene 1.1 and over twenty-five analogues underwent

17 Murugesh, M. G.; Subburaj, K.; Trivedi, G. K.; Tetrahedron 1996, 52, 2217 and references therein.

18 Eisohly, H. N.; Turner, C. E.; Clark, A. M.; Eisohly, M. A.; J. Pharm. Sci. 1982, 71, 1319.

colourless to coloured conversion upon irradiation with UV light (Scheme 1.3). Gradual disappearance of the colour was observed as the temperature was increased. A mechanistic explanation for these transformations was proposed in which the 2H-chromene undergoes a reversible ring opening reaction on irradiation with UV light that leads to the open-form 1.19.

The molecule can then revert to the ring-closed form 1.1 via a thermal pathway. This mechanism was later confirmed by the reduction of the open-form 1.20 with lithium aluminium hydride at low temperature.19

Scheme 1.3 Mechanism of 2H-chromenes photochromism.

Research in the photochromic properties of 2H-chromenes has become increasingly active over the last couple of decades due to the industrial demand for materials that undergo variable optical absorption. The absorption maxima of the open-form of 2H-chromenes are usually in the range of 400-500 nm. This feature, together with good fatigue resistance, little temperature dependence and reasonable activation and fading rates, makes 2H-chromenes suitable to form mixtures that

19 Kolc, J.; Becker, R. S. J. Phys. Chem. 1976, 71, 4045.

produce photochromic systems with a neutral activated colour, as is required for the commercial viability of ophthalmic lenses. Extensive research has been carried out on the location and the nature of substituents on both rings of the 2H-chromenes in order to determine their influence on the photochromic properties. The results from these studies have been reviewed.20 Substituted derivatives were reported to be, in general, less photochromic than naphthopyrans that had the same substituents, and were found to be less fatigue resistant. Further improvement of photochromic properties could be achieved by annelation of the aromatic ring with heteroaromatic moieties and the addition of bulky substituents at the C2-position. The incorporation of phenyl groups at this position also allowed for extended conjugation.

A series of C5,C6-furan annelated 2H-chromene derivatives 1.21 have been prepared by Pozzo and co-workers for the study of their potential industrial applications (Figure 1.6).21 All of the compounds showed photochromic behaviour in toluene at room temperature. The electronic absorption spectra of the coloured-forms of these furan-fused 2H-chromene derivatives 1.21 extended over a much larger range of wavelengths than the corresponding naphthopyran 1.22.

The open-forms of C2-diphenyl compounds also exhibited a deeper colour and a bathochromic shift in the visible spectra than the corresponding monoaryl substituted compounds.

20 van Gemert, B. In Organic Photochromic and Thermochromic Compounds; Crano, J. C.; Guglielmetti, R., Eds.; Plenum Press; New York, 1999; Vol. 1, pp 111-140.

21 Pozzo, J.-L.; Samat, A.; Guglielmetti, R.; Lokshin, V.; Minkin, V. Can. J. Chem. 1996, 74, 1649.

Figure 1.6 Molecular structures of furan-fused 2H-chromenes 1.21 and naphthopyran 1.22.

1.1.4 Synthesis of 2H-Chromenes

The synthesis of 2H-chromenes has been an active area of research. Many procedures have been developed in the last few decades and new synthetic methods continue to be reported. In addition, the great commercial success of photochromic plastic ophthalmic lenses has generated interest in new synthetic 2H-chromenes that exhibit improved photochromic properties.20 The synthesis of 2H-chromenes has been reviewed and some of the important procedures as well as a selection of newly developed methods are summarized in Scheme 1.4.5,22

22 a) Hepworth, J. D. In Comprehensive Heterocycle Chemistry; Katrizky, A. R.; Rees, C. W.; Eds.; Pergamon Oress: Oxford, 1984; Vol. 3, pp 737-883. b) Levai, A.; Timar, T.; Sebok, P.; Eszenyi, T. Heterocycles 2000, 53, 1193.

Scheme 1.4 Synthetic approaches to 2H-chromenes.

These methods include a Claisen rearrangement of propargyl phenol ethers 1.23 (A),23 Pd- catalyzed ring closure of 2-isoprenyl phenols 1.24 (B),24 Ru-catalyzed ring closing metathesis of

2-styrenyl ethers 1.25 (C),25 catalytic Petasis reaction of salicylaldehyde 1.26 with vinylboronic acids 1.27 (D),26 6π-electrocyclic ring closure of the enols of vinylquinones 1.28 (E)27 and

23 Rao, U.; Balasubramanian, K. K. Tetrahedron Lett. 1983, 24, 5023.

24 Iyer, M.; Trivedi, G. R. Synth. Commun. 1990, 20, 1347.

25 a) Harrity, J. P. A.; La, D. S.; Cefalo, D. R.; Visser, M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 2343. b) Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63, 864. c) Wipf, P.; Weiner, W. S. J. Org. Chem. 1999, 64, 5321.

26 Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063.

27 Parker, K. A.; Mindt, T. L. Org. Lett. 2001, 3, 3875.

reactions of phenols 1.29 with α,β-unsaturated aldehydes 1.30 (F). The last approach (F) has been a popular method to prepare 2H-chromenes owing to its simple and commercially available starting materials (Scheme 1.5). In addition, this method complements the proposed biosynthetic pathway of 2H-chromenes (Scheme 1.2). Pyridine-promoted (G)28 and calcium hydroxide- mediated (H)29 reactions of phenols with unsaturated aldehydes have been reported, as well as reactions of titanium and magnesium salts of phenols with α,β-unsaturated aldehydes (I).30 An uncatalyzed, neutral, microwave-assisted method has also been developed (J).31 However, the phenylboronic acid-promoted condensation of phenols with α,β-unsaturated aldehydes (K) has been found to be a more convenient and mild method for the synthesis of 2H-chromenes with excellent regioselectivity, and will be the focus of the remaining chapter.32

28 Lamcharfi, E.; Menguy, L.; Zamarlik, H. Synth. Commun. 1993, 23, 3019.

29 Saimoto, H.; Yoshida, K.; Murakami, T.; Morimoto, M.; Sashiwa, H.; Shigemasa, Y. J. Org. Chem. 1996, 61, 6768.

30 Sartori, G.; Casiraghi, G.; Bolzoni, L.; Casnati, G. J. Org. Chem. 1979, 44, 803.

31 Adler, M. J.; Baldwin, S. W. Tetrahedron Lett. 2009, 50, 5075.

32 Chauder, B. A.; Lopes, C. C; Lopes, R. S. C; da Silva, A. J. M.; Snieckus, V. Synthesis 1998, 279.

Scheme 1.5 Reactions of phenols with α,β-unsaturated aldehydes.

1.1.5 Structure and Properties of Boronic Acids and Their Use as

Reaction Promoters and Catalysts

Boronic acids 1.31 are an attractive class of compounds due to their unique properties and reactivity as mild Lewis acids, coupled with their stability and ease of handling. In addition, due to their low toxicity and their ultimate degradation into boric acid, boronic acids can be regarded as environmentally-friendly ("green") compounds. They are solids under ambient conditions, and tend to exist as mixtures of oligomeric anhydrides, in particular the cyclic six-membered

boroxines 1.32 (Figure 1.7). In the past 5 years, impressive advances have been made in the use of boronic acids in molecular recognition, material science, and catalysis.33

Figure 1.7 Molecular structures of boronic acids 1.31 and boroxines 1.32.

By virtue of their deficient valence, boronic acids possess a vacant p-orbital. This characteristic confers them unique properties as mild Lewis acids. When coordinating with basic molecules, the resulting tetrahedral adducts acquire a carbon-like configuration. Thus, despite the presence of two hydroxyl groups, the acidic character of most boronic acids is not that of a Brønsted acid

(Equation 1.1, Scheme 1.6), but usually that of a Lewis acid (Equation 1.2, Scheme 1.6).33

Scheme 1.6 Ionization equilibrium of boronic acids in water.

33 Hall, D. G. In Boronic Acids - Preparation, Applications in Organic Synthesis; Hall, D. G., Eds.; Wiley-VCH; Weinheim, 2011; Vol. 2, pp 1-133.

By forming transient esters with alcohols, boronic acids have the capability to act as catalysts or templates for directed reactions.34 Applications of boronic acids in catalysis has been reviewed35 and they have been shown to catalyze aldol reactions,36 various cycloadditions of α,β-unsaturated carboxylic acids,37 transposition of allylic and proparglyic alcohols38 and Friedel-Crafts alkylation of benzylic alcohols (Scheme 1.7),39 to name a few.

Scheme 1.7 Boronic acid-catalyzed Friedel-Crafts alkylation of benzylic alcohols.

Boronic acids can also be employed to promote templating effects. Narasaka et al. demonstrated that phenylboronic acid can be employed to hold a diene and dienophile in such a way that the regiocontrol of a Diels-Alder reaction can be inverted.40 This templating strategy was elegantly

34 a) Ishihara, K.; Yamamoto, H. Eur. J. Org. Chem. 1999, 527. b) Georgiou, I.; Ilyashenko, G.; Whiting, A. Acc. Chem. Res. 2009, 42, 756.

35 Dimitrijevic, E.; Taylor, M. S. ACS Catal. 2013, 3, 945.

36 Aelvoet, K.; Batsanov, A. S.; Blatch, A. J.; Grosjean, C.; Patrick, L. G. F.; Smethurst, C. A.; Whiting, A. Angew. Chem. Int. Ed. 2008, 47, 768.

37 a) Zheng, H.; Hall, D. G. Chem. Eur. J. 2010, 16, 5454. b) Zheng, H.; Hall, D. G. Tetrahedron Lett. 2010, 51, 3561.

38 McCubbin, J. A.; Hosseini, H.; Krokhin, O. V. J. Org Chem. 2010, 75, 959.

39 Zheng, H.; Lejkowski, M.; Hall, D. G. Chemical Science 2011, 2, 1305.

40 Narasaka, K.; Shimada, G.; Osoda, K.; Iwasawa, N. Synthesis 1991, 1171.

exploited in the synthesis of a key intermediate in the total synthesis of taxol by Nicolaou et al.

(Scheme 1.8).41 By using a similar effect, phenols are ortho-alkylated with aldehydes through a proposed six-membered transition state where phenylboronic acid, used stoichiometrically, holds the two reactants in place (Scheme 1.9).42

Scheme 1.8 Phenylboronic acid-mediated Diels-Alder reaction.

Scheme 1.9 Phenylboronic acid-promoted ortho-alkylation of phenols with aldehydes.

41 Nicolaou, K. C.; Liu, J. J.; Yang, Z.; Ueno, H.; Sorensen, E. J.; Claiborne, C. F.; Guy, R. K.; Hwang, C.-K.; Nakada, M.; Nantermet, P. G. J. Am. Chem. Soc. 1995, 117, 634.

42 Nagata, W.; Okada, K.; Aoki, T. Synthesis 1979, 365.

1.1.6 Phenylboronic Acid-Mediated Synthesis of 2H-Chromenes

The ortho-alkylation of phenols with aldehydes promoted by phenylboronic acid was first reported in 1976.43 Full details were later presented by Nagata, who proposed a [3,3]-sigmatropic rearrangement pathway 1.33 and ultimately isolated benzodioxaborine 1.34 (Figure 1.8).44

Murphy and co-workers proposed that these benzodioxaborines could lead to transient ortho- quinone methides, if heated with an appropriate protic acid, and can be trapped by nucleophiles or dienophiles.45 They reported a one-pot annulation reaction of activated phenols with 3,7- dimethyloct-7-enal (citronellal) 1.35, phenylboronic acid and an excess of acetic acid to give hexahydrocannabinoid products 1.36 (Scheme 1.10).

Figure 1.8 Proposed [3,3]-sigmatropic rearrangement pathway 1.33 and molecular structure of benzodioxaborine 1.34.

43 Shiongo and Co. Ltd., Osaka, Japan, Ger. Pat. 2 545 338, 1976 (Chem. Abstr., 1976, 85, 32693.

44 Aoki, T.; Okada, K.; Nagata, W. Synthesis, 1976, 365.

45 Murphy, W. S.; Tuladhar, S. M.; Duffy, B. J. Chem. Soc. Perkin Trans. 1 1992, 605.

Scheme 1.10 Phenylboronic acid-mediated synthesis of hexahydrocannabinoid products 1.36.

Lau et al. took Murphy's approach one step further and reported the successful use of these benzodioxaborins as stable precursors of ortho-quinone methides in inter- and intramolecular cycloaddition reactions with different dienophiles to give various substituted chromans and several analogs of tetrahydrocannabinols, as well as their reactions with aryl and alkyl nucleophiles under Lewis acid conditions (Scheme 1.11).46 Later, they applied their methodology in the preparation of precocene I and II, and in a formal synthesis of robustadial A and B, natural products isolated as a Chinese herbal medicinal extract of Eucalyptus robusta leaves used in the treatment of malaria.47

46 Chambers, J. D.; Crawford, J.; Williams, H. W. R.; Dufresne, C.; Scheigetz, J.; Bernstein, M. A.; Lau, C. K. Can. J. Chem. 1992, 70, 1717.

47 Bissada, S.; Lau, C. K.; Bernstein, M. A.; Dufresne, C. Can. J. Chem. 1994, 72, 1866.

Scheme 1.11 Reactions of benzodioxaborins as stable ortho-quinone methide precursors.

A general phenylboronic acid-mediated procedure for the preparation of substituted 2H- chromenes by condensation of phenols with unsaturated aldehydes was developed by Snieckus and co-workers (Scheme 1.12).32 They demonstrated that electron-donating groups facilitated the reaction while electron-withdrawing substituents gave less satisfactory results, as expected on the basis of mechanistic considerations. Electron-donating groups would be able to stabilize the arenium ion from the Friedel-Crafts alkylation step by donating their electron density to the ring, whereas electron-withdrawing substituents would destabilize the arenium ion by removing electron density from the ring.

Scheme 1.12 General procedure for the phenylboronic acid-promoted preparation of substituted 2H-chromenes.

Wilson et al. described a remarkable phenylboronic acid-mediated triple condensation reaction of 1,3,5-trihydroxybenzene (phloroglucinol) with a series of α,β-unsaturated aldehydes to afford

C3-symmetric 2H-chromene derivatives 1.37 that resembled structural analogues of the natural product xyloketal A, which has been reported to be a potent inhibitor of acetylcholine esterase

(Scheme 1.13).48 Their initial reaction conditions used 25 mol% of phenylboronic acid, but a mixture of condensation products were observed. Increasing the amount of phenylboronic acid led to an increase in the amount of triple condensed product that was formed.

Scheme 1.13 Phenylboronic acid-mediated triple condensation reactions of phloroglucinol and unsaturated aldehydes.

A recent paper by Jahng and co-workers published a series of 6-deoxymollugins prepared by five steps from benzaldehyde and its derivatives using a phenylboronic acid-mediated chromenylation as a key step (Scheme 1.14).49 Mollugin (methyl 6-hydroxy-2,2-dimethyl-2H- benzeno[h]chromene-5-carboxylate) 1.38 is a strong inhibitor of tyrosinase originally isolated from the herbal medicine Rubiaceae family.

48 Pettigrew, J. D.; Cadieux, J. A.; So, S. S. S.; Wilson, P. D. Org. Lett. 2005, 7, 467. 49 Liang, J. L.; Javed, U.; Lee, S. H.; Park, J. G.; Jahng, Y. Arch. Pharm. Res. 2014, 37, 862.

Scheme 1.14 Phenylboronic acid-mediated synthesis of mollugin 1.38.

In all of the above examples, phenylboronic acid was used stoichiometrically, but mechanistically speaking, boronic acid should be regenerated over the course of this reaction. In other words, synthesis of 2H-chromenes using phenylboronic acid should be catalytic in boronic acid. Wilson and co-workers employed phenylboronic acid in catalytic amounts as low as 25 mol%, but observed incomplete reaction conversion and resorted to adding a stoichiometric amount of phenylboronic acid for their optimized conditions. Moreover, the reactivity and properties of boronic acids highly depend upon the nature of their single variable substituent directly bound to boron, but all of the examples in the literature only use simple phenylboronic acid. Organoboron compounds possess many of the advantageous features of organocatalysts, including their relatively low cost and toxicity as well as their high functional group tolerance.

Perhaps the most significant advantage of organocatalysts is their ability to undergo simple structural modifications, which enables empirical tuning of the various noncovalent interactions that determine enatio-, diasterio-, or regioselectivity.36 Tuning the steric and electronic nature of arylboronic acids may expand the scope of phenylboronic acid-mediated synthesis of 2H- chromenes and perhaps allow these reactions to proceed under milder conditions compared to literature procedures. This chapter will discuss our efforts in synthesizing various substituted 2H- chromenes and 2H-naphthopyrans via arylboronic acid-catalyzed condensation of various

phenols and naphthols with α,β-unsaturated aldehydes as well as explore the tunability of arylboronic acids to achieve milder reaction conditions.

1.2 Results and Discussion

Our initial reaction conditions mostly followed conditions already established in the literature.

Typically, they were performed with a slight excess of aldehyde, at least one equivalent of phenylboronic acid, either toluene or benzene with reaction concentrations ranging from 10-100 mM and heated at reflux with azeotropic removal of water using a Dean-Stark trap overnight.

However, there was no agreement within the literature regarding which Brønsted acid should be used and its stoichiometry. Some reports used a catalytic amount of Brønsted acid, whereas others used a large excess. To simplify our initial reaction conditions, Brønsted acid was omitted to minimize the amount of variables in the reaction. Our first attempt at a phenylboronic acid- catalyzed synthesis of precocene I 1.7 was successful with an NMR yield of 79% using 20 mol% of phenylboronic acid at 120 °C, albeit with only four turnovers of the catalyst (Scheme 1.15).

Nevertheless, this result was promising and agreed with our initial hypothesis that this reaction should be catalytic in phenylboronic acid. Our procedure also had a few minor modifications to conditions found in the literature including increasing the amount of aldehyde to two equivalents, using less solvent, thereby increasing the reaction concentration, and not utilizing a Dean-Stark apparatus to remove water from the reaction mixture. The latter change was mostly due to convenience in setting up the reaction.

a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5-trimethoxybenzene as a quantitative internal standard.

Scheme 1.15 Phenylboronic acid-catalyzed synthesis of precocene I 1.7.

With a working set of conditions in hand, the Brønsted acid was added in order to observe its effect on yield (Table 1.1). We started with adding a catalytic amount of propanoic acid (20 mol%) and observed a significant improvement in product yield (entry 4) compared to our initial reaction conditions at 100 °C (entry 2). Appropriate control reactions were carried out, with and without propanoic acid (entries 1 and 5), and no product was formed in either case.

Diphenylborinic acid was also screened as a potential organoboron catalyst for this reaction, but underperformed compared to phenylboronic acid (entry 3).

Table 1.1 Evaluation of organoboron catalysts and effects of Brønsted acid.

Entry Catalyst Brønsted Acid Yielda (%)

1 - - 0

2 - 33

Entry Catalyst Brønsted Acid Yielda (%)

3 - 9

4 77

5 - 0 a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5- trimethoxybenzene as a quantitative internal standard.

Surprisingly, there were only three Brønsted acids that appeared in the literature for this reaction: acetic acid, trichloroacetic acid, and propanoic acid. We decided to screen a number of Brønsted acids varying in structure and acidity (Table 1.2). Chloroacetic acid decreased product yield

(entry 2), whereas benzoic acid improved the yield (entry 3) compared to propanoic acid at 80 °C

(entry 1). Diphenylphosphinic acid gave the best yield, but minor decomposition of 3- methoxyphenol was observed (entry 5). Camphorsulfonic acid turned the reaction mixture into a black tar presumably full of polymeric side products from decomposition of the aldehyde (entry

6). A number of substituted benzoic acids, such as 3,4,5-trifluorobenzoic acid (entry 4), were screened, but no trend was observed in terms of structure or acidity and the yields were less than that of benzoic acid.

Table 1.2 Evaluation of Brønsted acids.

Entry Brønsted Acid Yielda (%)

1 23

2 12

3 35

4 19

5 39b

6 0b

a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5- trimethoxybenzene as a quantitative internal standard. b Decomposition of starting material was observed.

Solvent effects in the boronic acid-catalyzed chromenylation reaction were quite dramatic (Table

1.3). Polar, aprotic solvents, such as 1,4-dioxane (entry 2) and acetonitrile (entry 3), gave little to no product. 1,2-Dichloroethane increased product yield slightly (entry 4), but very non-polar solvents, such as cyclohexane (entry 5) and heptane (entry 6), significantly improved reactivity.

Table 1.3 Evaluation of solvents.

Entry Solvent Yielda (%)

1 Toluene 35

2 1,4-Dioxane 0

3 Acetonitrile 4

4 1,2-Dichloroethane 43

5 Cyclohexane >95

6 Heptane >95 a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5- trimethoxybenzene as a quantitative internal standard.

Our evaluation of Brønsted acids and solvents allowed us to considerably improve upon our initial reaction conditions. Using 20 mol% of benzoic acid and cyclohexane as our solvent, along with PhB(OH)2 as catalyst (20 mol%), we were able to fully convert starting material into product at 80 °C. Next, a number of electronically distinct arylboronic acids were screened to explore their tunability in an effort to achieve even milder reaction conditions. More than 30 different arylboronic acids were evaluated with varying steric and electronic properties and a

representative sample is presented in Table 1.4. The general trend we observed was that the

Lewis acidity of the arylboronic acid must be tuned to the reactivity of the phenol. Otherwise, decomposition of the phenol occurs. For example, for activated phenols bearing a single methoxy group at the meta position, such as 3-methoxyphenol, phenylboronic acid was the only catalyst that gave high yields with no starting material decomposition (entry 1). Alkyl- or phenyl-substituted arylboronic acids, such as 3,5-dimethylphenylboronic acid 1.39, were not as soluble as phenylboronic acid in cyclohexane and lower yields were observed (entry 2).

Arylboronic acids with electron-donating substituents, such as 4-methoxyphenylboronic acid

1.40, consistently gave little to no product (entry 3). This result shifted our focus to more Lewis acidic arylboronic acids with electron-withdrawing groups. 4-(Trifluoromethyl)phenylboronic acid 1.41 significantly increased product yield, although there was a considerable amount of starting material decomposition (entry 4). With more Lewis acidic arylboronic acids, more decomposition was observed (entry 5).

Table 1.4 Evaluation of electronically distinct arylboronic acids with 3-methoxyphenol.

a Entry ArB(OH)2 Yield (%)

1 39

a Entry ArB(OH)2 Yield (%)

2 27

3 8

4 71b

5 34b

a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5- trimethoxybenzene as a quantitative internal standard. b Decomposition of starting material was observed.

With doubly activated phenols bearing methoxy groups at both meta positions, such as 3,5- dimethoxyphenol, even phenylboronic acid led to starting material decomposition (Table 1.5).

Lowering the catalyst loading to 5 mol% resulted in no observable side reactions (entry 3).

Table 1.5 Evaluation of phenylboronic acid catalyst loading with 3,5-dimethoxyphenol.

Entry Catalyst Loading (mol%) Yielda (%)

1 15 69b

2 10 62b

3 5 35 a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5- trimethoxybenzene as a quantitative internal standard. b Decomposition of starting material was observed.

With unactivated naphthols, no decomposition was observed, even with very Lewis acidic arylboronic acids, such as 3,5-bis(trifluoromethyl)phenylboronic acid 1.42 (Table 1.6). As a result, the reaction went to completion at 60 °C with catalyst 1.42 (entry 3).

Table 1.6 Evaluation of arylboronic acids with 1-naphthol.

a Entry ArB(OH)2 Yield (%)

1 25

2 32

a Entry ArB(OH)2 Yield (%)

3 >95

a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5- trimethoxybenzene as a quantitative internal standard.

Variation of both the phenol and aldehyde components revealed that this method is useful for the preparation of a broad range of 2H-chromenes and 2H-naphthopyrans (Table 1.7). Our optimized reaction conditions involved catalytic amounts of arylboronic acid and benzoic acid, two equivalents of aldehyde and heptane solvent at 60–100 °C depending on the substrate. The reaction was also performed under ambient atmosphere and did not require the azeotropic removal of water via a Dean-Stark apparatus. Instead, the amount of water present may be critical to the reaction. The addition of 4 Å molecular sieves completely shut down the reaction and adding MgSO4 as a drying agent resulted in decreased yields. There was also no reaction with the addition of 10 mol% of water. From a mechanistic standpoint, we hypothesize that water may play a role in catalyst turnover. This phenomenon was reported by Hall and co- workers for boronic acid-catalyzed cycloaddition reactions wherein substoichiometric amount of water generated by condensation of the boronic acid with a carboxylic acid was necessary to ensure catalyst turnover.76 Overall, the yields were quite comparable, and in some cases better, to literature reported yields. Entry 5 showcases a phenylboronic acid-catalyzed triple condensation reaction of phloroglucinol and 3-methyl-2-butenal with only 20 mol% of catalyst (6.7 mol% for each step). The reason why such a low catalyst loading was required for this reaction was the resulting product after each step would be more reactive than the starting material and require

less catalyst as the reaction proceeds. Product 1.46 represented an example of a deactivated phenol bearing a methoxy group at the para position (entry 6). At this position, the methoxy group cannot aid in the Friedel-Crafts alkylation through resonance and instead hinders the reaction inductively by removing electron density from the aromatic ring. 4-Methoxyphenol did not decompose in the presence of strongly Lewis acidic arylboronic acids, such as catalyst 1.42, and the yield was further improved by substituting benzoic acid with 10 mol% of diphenylphosphinic acid. It is also worth mentioning that phenols with methoxy groups at the meta and para positions, such as 3,4-dimethoxyphenol (entry 2) and 3,4-(methylenedioxy)phenol

(entry 3) are sufficiently activated to undergo phenylboronic acid-catalyzed chromenylation with unsaturated aldehydes, although the reaction temperature had to be increased compared to 3- methoxyphenol (entry 1). 1-Naphthol was more reactive than 2-naphthol with complete conversion to product 1.47 at 60 °C (entry 7), whereas the corresponding reaction with 2- naphthol only went to completion at 80 °C (entry 8). Following the trend observed for unactivated naphthols, 3,5-dimethylphenol was compatible with catalyst 1.42 and product 1.49 was isolated in 91%. Snieckus and co-workers performed the same reaction with stoichiometric amounts of phenylboronic acid and only reported a 65% yield. This methodology can also be applied to the synthesis of photochromic 2H-chromenes (entries 10 and 11). trans-

Cinnamaldehyde was sensitive to decomposition, which limited its reaction partner to 3,5- dimethoxyphenol since only 5 mol% of phenylboronic acid was required for the reaction to proceed. This reaction was also compatible with α,β-unsaturated aldehydes with a single alkyl substituent at the β position (entry 12).

Table 1.7 Scope of arylboronic acid-catalyzed condensation reaction of phenols and naphthols with α,β-unsaturated aldehydes.

a Entry ArOH RCHO ArB(OH)2 Product Yield (%)

1 94

2 92

3 90

4 97b

5 85c

6 76d

a Entry ArOH RCHO ArB(OH)2 Product Yield (%)

7 93

8 94

9 91

10 89

11 81b

12 82

a Isolated yield (0.5 mmol scale) of pure product by flash column chromatography. b Reaction performed with 5 mol% of phenylboronic acid. c Reaction performed with 6.0 equiv. of 3- methyl-2-butenal. d Reaction performed with 10 mol% of diphenylphosphinic acid in place of benzoic acid.

While the arylboronic acid-catalyzed condensation reaction of phenols and naphthols with α,β- unsaturated aldehydes had a broad substrate scope, there were still quite a few limitations to this methodology. Reactions with phenol gave little to no product and significant starting material

decomposition (Scheme 1.16). Deactivated phenols bearing an electron-withdrawing group at the para position, such as 4-bromophenol, resulted in minor product formation, even with catalyst

1.42 (Scheme 1.17). trans-2-Butenal was also sensitive to decomposition, similar to trans- cinnamaldehyde, and even with 3,5-dimethoxyphenol and 5 mol% of phenylboronic acid, decomposition was still observed (Scheme 1.18).

a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5-trimethoxybenzene as a quantitative internal standard. Decomposition of starting material was observed.

Scheme 1.16 Attempted arylboronic acid-catalyzed chromenylation of phenol.

a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5-trimethoxybenzene as a quantitative internal standard.

Scheme 1.17 Attempted arylboronic acid-catalyzed chromenylation of 4-bromophenol.

a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5-trimethoxybenzene as a quantitative internal standard. Decomposition of starting material was observed.

Scheme 1.18 Attempted arylboronic acid-catalyzed chromenylation of 3,5-dimethoxyphenol and crotonaldehyde.

Similar to Murphy et al. and Lau and co-workers, we attempted an arylboronic acid-catalyzed synthesis of cannabinoids 1.60 using (S)-(-)-citronellal. The reaction would involve a Friedel-

Craft alkylation followed by a Diels-Alder reaction with the resulting ortho-quinone methide. No product was observed with 3-methoxyphenol (entry 1) or the more activated 3,5- dimethoxyphenol (entry 2). Using a more Lewis acidic catalyst 1.42 resulted in minor product formation (entry 3).

Table 1.8 Attempted arylboronic acid-catalyzed synthesis of cannabinoids 1.60.

a Entry ArOH ArB(OH)2 Product Yield (%)

1 0

a Entry ArOH ArB(OH)2 Product Yield (%)

2 0b

3 8

a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5- trimethoxybenzene as a quantitative internal standard. bReaction performed with 5 mol% of phenylboronic acid.

We suggest the following mechanism for the phenylboronic acid-catalyzed synthesis of precocene I 1.7 (Scheme 1.19). 3-Methoxyphenol condenses with phenylboronic acid to form boronic ester 1.53. 3-Methyl-2-butenal is then activated by the boronic acid and subsequent

Friedel-Crafts hydroxyalkylation via intermediate 1.54 leads to benzodioxaborine 1.56 with loss of water. Benzoic acid may play a role at this step by complexing with boron to form intermediate 1.57 and allowing the following reactions to turn over more efficiently. Cyclization of the ortho-alkylated phenol 1.58 via an SN2'-type reaction would lead directly to precocene I

1.7 (Path A). Alternatively, 1,4-elimination may lead to the ortho-quinone methide 1.59, which affords 1.7 on 6π-electrocyclic ring closure (Path B). In any case, phenylboronic acid is regenerated for the catalytic cycle.

Scheme 1.19 Proposed mechanism for the phenylboronic acid-catalyzed synthesis of precocene I 1.7.

1.3 Conclusion

An arylboronic acid-catalyzed condensation of phenols and naphthols with α,β-unsaturated aldehydes to synthesize 2H-chromenes and 2H-naphthopyrans was developed. Reaction conditions were mild and yields varied from good to excellent. The tunability of arylboronic acids was explored for this reaction and the general trend observed was the Lewis acidity of the organocatalyst must be tuned to the reactivity of the phenol. Future work involves expanding our initial substrate scope, focusing on examples that utilize catalysts other than phenyboronic acid.

1.4 Experimental

General: Reactions were carried out without effort to exclude air or moisture, unless otherwise indicated. Stainless steel syringes were used to transfer air- and moisture-sensitive liquids. Flash chromatography was carried out using neutral silica gel (Silicycle).

Materials: All reagents and solvents were purchased from Sigma Aldrich or Alfa Aesar and used without further purification. Toluene and acetonitrile were purified by passing through two columns of activated alumina under nitrogen (Innovative Technology Inc.). Nuclear magnetic resonance (NMR) solvents were purchased from Cambridge Isotope Laboratories.

Diphenylborinic acid was prepared from 2-aminoethyl diphenylborinate according to literature procedure.50

1 13 Instrumentation: H and C NMR spectra were recorded in CDCl3 or benzene-d6 using either a

Bruker Avance III 400 MHz, Varian Mercury 400 MHz or Agilent 500 MHz spectrometer. 1H

NMR are reported in parts per million (ppm) relative to tetramethylsilane and referenced to residual protium in the solvent. Spectral features are tabulated in the following order: chemical shift (δ, ppm); multiplicity (s-singlet, d-doublet, t-triplet, q-quartet, m-complex multiplet); number of protons; coupling constants (J, Hz). High-resolution mass spectra (HRMS) were obtained on a VS 70-250S (double focusing) mass spectrometer at 70 eV.

50 Lee, D.; Newman, S. G.; Taylor, M. S. Org. Lett. 2009, 23, 5486.

1.4.1 General Experimental Procedures

General Procedure A: Evaluation of Organoboron Catalyst, Brønsted Acid, Solvent, and

Arylboronic Acid Effects on Boronic Acid-Catalyzed Condensation Reaction

To a 2-dram vial equipped with a magnetic stirring bar were added phenol (0.2 mmol), arylboronic acid (5-20 mol%), Brønsted acid (20 mol%), 3-methyl-2-butenal (0.4 mmol) and solvent (1 mL). The vial was capped in ambient atmosphere and stirred at 400 rpm at 60 - 120

°C. After 17 hours, the mixture was diluted with toluene (0.5 mL) and 1,3,5-trimethoxybenzene

(10.0 mg, 0.0595 mmol) was added as a quantitative internal standard. An aliquot of the mixture

1 was concentrated in vacuo, diluted with benzene-d6 and analyzed by H NMR.

General Procedure B: Arylboronic Acid-Catalyzed Condensation Reaction (Preparative

Scale)

To a screw cap Pyrex® tube equipped with a magnetic stirring bar were added phenol (0.5 mmol), arylboronic acid (5-20 mol%), benzoic acid (20 mol%), aldehyde (1.0 mmol) and heptane (2.5 mL). The tube was capped in ambient atmosphere and stirred at 400 rpm at 60 - 100

°C. After 17 hours, the mixture was concentrated in vacuo and the resulting crude material was purified by silica gel chromatography.

1.4.2 Characterization Data

7-Methoxy-2,2-dimethyl-2H-chromene (1.7)

Synthesized according to general procedure B, from 3-methoxyphenol and

3-methyl-2-butenal using 20 mol% phenylboronic acid at 80 °C. Purified

using 0.5-1% EtOAc/pentane (5% EtOAc/pentane: Rf = 0.7), 94% yield, pale yellow oil. Spectral

32 1 data were in agreement with previous reports. H NMR (500 MHz, CDCl3): δ 6.88 (dd, J =

8.2, 0.3 Hz, 1H), 6.40 (dd, J = 8.2, 2.5 Hz, 1H), 6.38 – 6.37 (m, 1H), 6.27 (ddd, J = 9.8, 0.7, 0.3

Hz, 1H), 5.47 (dd, J = 9.8, 0.3 Hz, 1H), 3.77 (s, 3H), 1.42 (s, 6H). 13C NMR (125 MHz,

CDCl3): δ 160.8, 154.3, 128.0, 127.0, 122.0, 114.8, 106.8, 102.1, 76.5, 55.4, 28.2.

6,7-Dimethoxy-2,2-dimethyl-2H-chromene (1.8)

Synthesized according to general procedure B, from 3,4-dimethoxyphenol

and 3-methyl-2-butenal using 20 mol% phenylboronic acid at 100 °C.

Purified using DCM (DCM: Rf = 0.6), 92% yield, pale yellow oil. Spectral

32 1 data were in agreement with previous reports. H NMR (400 MHz, CDCl3): δ 6.53 (s, 1H),

6.41 (s, 1H), 6.24 (d, J = 9.7 Hz, 1H), 5.48 (d, J = 9.7 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 1.41 (s,

13 6H). C NMR (100 MHz, CDCl3): δ 149.8, 147.4, 143.2, 128.4, 122.1, 113.2, 109.9, 101.2,

76.1, 56.7, 56.1, 27.8.

2,2-Dimethyl-6,7-methylenedioxy-2H-chromene (1.43)

Synthesized according to general procedure B, from 3,4-

(methylenedioxy)phenol and 3-methyl-2-butenal using 20 mol%

phenylboronic acid at 100 °C. Purified using 0.5-1% EtOAc/pentane (5%

EtOAc/pentane: Rf = 0.7), 90% yield, pale yellow oil. Spectral data were in agreement with

32 1 previous reports. H NMR (400 MHz, CDCl3): δ 6.47 (s, 1H), 6.38 (s, 1H), 6.19 (d, J = 9.7

13 Hz, 1H), 5.87 (s, 2H), 5.47 (d, J = 9.7 Hz, 1H), 1.39 (s, 6H). C NMR (100 MHz, CDCl3): δ

148.4, 147.7, 141.5, 128.3, 122.4, 114.4, 105.8, 101.0, 99.2, 76.2, 27.6.

5,7-Dimethoxy-2,2-dimethyl-2H-chromene (1.44)

Synthesized according to general procedure B, from 3,5-dimethoxyphenol

and 3-methyl-2-butenal using 5 mol% phenylboronic acid at 100 °C.

Purified using 1-2% EtOAc/pentane (5% EtOAc/pentane: Rf = 0.5), 97% yield, pale yellow oil. Spectral data were in agreement with previous reports.51 1H NMR (500

MHz, CDCl3): δ 6.58 (dd, J = 9.9, 0.7 Hz, 1H), 6.03 (dd, J = 2.3, 0.7 Hz, 1H), 6.01 (d, J = 2.3

Hz, 1H), 5.42 (d, J = 9.9 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 1.41 (s, 6H). 13C NMR (125 MHz,

CDCl3): δ 161.1, 156.3, 154.8, 126.0, 116.8, 104.3, 94.1, 91.6, 76.4, 55.7, 55.5, 27.9.

2,2,6,6,10,10-Hexamethyl-2H,6H,10H-dipyrano[6,5-f,6',5'-h]chromene (1.45)

Synthesized according to general procedure B, from 1,3,5-

trihydroxylbenzene and 3-methyl-2-butenal (3.0 mmol) using 20 mol%

phenylboronic acid at 100 °C. Purified using 0.5-1% EtOAc/pentane (5%

EtOAc/pentane: Rf = 0.8), 85% yield, pale yellow solid. Spectral data were

48 1 in agreement with previous reports. H NMR (400 MHz, CDCl3): δ 6.59

13 (d, J = 9.9 Hz, 3H), 5.42 (d, J = 9.9 Hz, 3H), 1.41 (s, 18H). C NMR (100 MHz, CDCl3): δ

149.3, 126.0, 117.0, 103.6, 76.6, 28.1. HRMS (DART, m/z): Calculated for C21H25O3

[(M+H)+]: 325.1793. Found: 325.1804.

6-Methoxy-2,2-dimethyl-2H-chromene (1.46)

Synthesized according to general procedure B, from 4-methoxyphenol and

3-methyl-2-butenal using 20 mol% 3,5-bis(trifluoromethyl)phenylboronic

51 Haro, T.; Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512.

acid and 10 mol% diphenylphosphinic acid at 100 °C. Purified using 0.5-1% EtOAc/pentane (5%

EtOAc/pentane: Rf = 0.7), 76% yield, pale yellow oil. Spectral data were in agreement with

x 1 previous reports. H NMR (400 MHz, CDCl3): δ 6.71 (d, J = 8.7 Hz, 1H), 6.66 (dd, J = 8.7, 2.9

Hz, 1H), 6.55 (d, J = 2.8 Hz, 1H), 6.28 (d, J = 9.8 Hz, 1H), 5.64 (d, J = 9.8 Hz, 1H), 3.75 (s, 3H),

13 1.41 (s, 6H). C NMR (100 MHz, CDCl3): δ 153.9, 146.9, 131.9, 122.5, 122.0, 116.9, 114.3,

111.6, 75.9, 55.9, 27.8.

2,2-Dimethyl-2H-naphtho[1,2-b]pyran (1.47)

Synthesized according to general procedure B, from 1-naphthol and 3-methyl-

2-butenal using 20 mol% 3,5-bis(trifluoromethyl)phenylboronic acid at 60 °C.

Purified using 0.5-1% EtOAc/pentane (5% EtOAc/pentane: Rf = 0.8), 93% yield, pale yellow oil. Spectral data were in agreement with previous reports.52 1H NMR (400

MHz, CDCl3): δ 8.24 – 8.18 (m, 1H), 7.76 – 7.70 (m, 1H), 7.47 – 7.39 (m, 2H), 7.34 (d, J = 8.3

Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.45 (d, J = 9.7 Hz, 1H), 5.64 (d, J = 9.7 Hz, 1H), 1.53 (s, 6H).

13 C NMR (100 MHz, CDCl3): δ 148.4, 134.6, 129.4, 127.7, 126.2, 125.3, 125.2, 124.6, 122.9,

122.1, 119.9, 115.5, 76.9, 28.1.

2,2-Dimethyl-2H-naphtho[2,1-b]pyran (1.48)

Synthesized according to general procedure B, from 2-naphthol and 3-methyl-

2-butenal using 20 mol% 3,5-bis(trifluoromethyl)phenylboronic acid at 80 °C.

Purified using 0.5-1% EtOAc/pentane (5% EtOAc/pentane: Rf = 0.8), 94% yield, pale yellow oil. Spectral data were in agreement with previous reports.32 1H NMR (500

MHz, CDCl3): δ 7.96 – 7.93 (m, 1H), 7.75 – 7.73 (m, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.47 (ddd, J

52 Zeng, H.; Ju, J.; Hua, R. Tetrahedron Lett. 2011, 52, 3926.

= 8.4, 6.8, 1.3 Hz, 1H), 7.33 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 7.06 (dd, J = 8.8, 0.7 Hz, 1H), 7.03

13 (d, J = 9.9 Hz, 1H), 5.72 (dd, J = 9.9, 0.3 Hz, 1H), 1.49 (s, 6H). C NMR (125 MHz, CDCl3): δ

151.1, 130.0, 129.5, 129.4, 129.3, 128.6, 126.6, 123.5, 121.4, 118.6, 118.4, 113.9, 76.2, 27.7.

2,2,5,7-Tetramethyl-2H-chromene (1.49)

Synthesized according to general procedure B, from 3,5-dimethylphenol and

3-methyl-2-butenal using 20 mol% 3,5-bis(trifluoromethyl)phenylboronic acid

at 100 °C. Purified using 0.5-1% EtOAc/pentane (5% EtOAc/pentane: Rf =

0.8), 91% yield, pale yellow oil. Spectral data were in agreement with previous reports.32 1H

NMR (500 MHz, CDCl3): δ 6.52 (tt, J = 1.4, 0.7 Hz, 1H), 6.49 – 6.46 (m, 2H), 5.58 (d, J = 10.0

13 Hz, 1H), 2.25 (s, 3H), 2.23 (s, 3H), 1.41 (s, 6H). C NMR (125 MHz, CDCl3): δ 153.0, 138.8,

133.8, 129.6, 123.4, 119.4, 117.3, 115.0, 75.4, 27.9, 21.5, 18.5.

7-Methoxy-2,2-diphenyl-2H-chromene (1.50)

Synthesized according to general procedure B, from 3-methylphenol and

β-phenylcinnamaldehyde using 20 mol% phenylboronic acid at 100 °C.

Purified using 0.5-1% EtOAc/pentane (5% EtOAc/pentane: Rf = 0.7),

1 89% yield, yellow viscous oil. H NMR (400 MHz, CDCl3): δ 7.45 – 7.41 (m, 4H), 7.35 – 7.29

(m, 4H), 7.28 – 7.23 (m, 2H), 6.91 (d, J = 8.3 Hz, 1H), 6.57 (d, J = 9.8 Hz, 1H), 6.51 (d, J = 2.4

Hz, 1H), 6.40 (dd, J = 8.3, 2.5 Hz, 1H), 6.02 (d, J = 9.8 Hz, 1H), 3.76 (s, 3H). 13C NMR (100

MHz, CDCl3): δ 161.1, 153.9, 145.2, 128.2, 127.6, 127.4, 127.2, 126.1, 123.1, 114.6, 107.2,

+ 102.3, 83.0, 55.5. HRMS (DART, m/z): Calculated for C22H19O2 [(M+H) ]: 315.1387. Found:

315.1385.

5,7-Dimethoxy-flav-3-ene (1.51)

Synthesized according to general procedure B, from 3,5-

dimethoxyphenol and trans-cinnamaldehyde using 5 mol%

phenylboronic acid at 100 °C. Purified using 1-2% EtOAc/pentane (5%

EtOAc/pentane: Rf = 0.5), 81% yield, yellow viscous oil. Spectral data were in agreement with

53 1 previous reports. H NMR (400 MHz, CDCl3): δ 7.49 – 7.44 (m, 2H), 7.40 – 7.29 (m, 3H),

6.81 (ddd, J = 10.0, 1.9, 0.6 Hz, 1H), 6.06 (d, J = 2.2 Hz, 1H), 6.03 (d, J = 2.3 Hz, 1H), 5.83 (dd,

J = 3.4, 1.9 Hz, 1H), 5.62 (dd, J = 9.9, 3.5 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 3H). HRMS (DART,

+ m/z): Calculated for C17H17O3 [(M+H) ]: 269.1174. Found: 269.1178.

7-Methoxy-2-propyl-2H-chromene (1.52)

Synthesized according to general procedure B, from 3-methoxyphenol

and trans-3-hexen-2-al using 20 mol% phenylboronic acid at 100 °C.

Purified using 0.5-1% EtOAc/pentane (5% EtOAc/pentane: Rf = 0.7), 82% yield, pale yellow oil.

1 H NMR (400 MHz, CDCl3): δ 6.86 (d, J = 8.2 Hz, 1H), 6.40 (dd, J = 8.2, 2.5 Hz, 1H), 6.37 (d,

J = 2.5 Hz, 1H), 6.34 (dd, J = 9.9, 1.4 Hz, 1H), 5.54 (dd, J = 9.8, 3.3 Hz, 1H), 4.83 (dddd, J =

6.8, 5.0, 3.4, 1.7 Hz, 1H), 3.77 (s, 3H), 1.83 – 1.74 (m, 1H), 1.68 – 1.40 (m, 3H), 0.96 (t, J = 7.3

13 Hz, 3H). C NMR (100 MHz, CDCl3): δ 160.7, 155.0, 127.2, 123.6, 123.2, 115.5, 106.8, 102.0,

+ 75.2, 55.4, 37.7, 18.2, 14.1. HRMS (DART, m/z): Calculated for C13H17O2 [(M+H) ]:

205.1234. Found: 205.1228.

53 Pouget, C.; Fagnere, C.; Basly, J.-P.; Leveque, H.; Chulia, A.-J. Tetrahedron 2000, 56, 6047.

Chapter 2 Borinic Acid-Catalyzed Conia-Ene Reaction

2.1 Introduction

2.1.1 Conia-Ene Reaction

An ene reaction can be broadly classified as the reaction of an alkene bearing an allylic hydrogen

(the ene) with a double or triple bond, known as the enophile (Scheme 2.1).54 These reactions are accompanied by migration of the double bond and a 1,5-hydrogen shift. The ene reaction can be used to build up a wide range of functionalized products and a particularly appealing feature of this reaction is that it is potentially 100% atom efficient.

Scheme 2.1 General scheme representing ene reactions.

The Conia-ene reaction is a carbon-carbon bond-forming reaction in which the enol tautomer of an activated carbonyl compound undergoes an ene-type reaction with an alkene or alkyne enophile (Scheme 2.2).54 The carbocyclization of 1,3-dicarbonyl compounds pendent to alkyne functionality, first discovered by Eglinton and Whiting55 and then developed by Conia and

54 Clarke, M. L.; France, M. B. Tetrahedron 2008, 64, 9003.

55 Eglinton, G.; Whiting, M. C. J. Chem. Soc. 1953, 3052.

Perchec,56 has received much attention in recent years.57 The reaction allows the formation of cyclopentanes bearing a methylene substituent adjacent to the newly formed quaternary centre and can be conducted under thermal conditions,56 strong mineral acid,58 base,55 or metal ion catalysis.59 However, the application of the ene carbocyclization of acetylenic dicarbonyl compounds in organic synthesis is limited due to the harsh experimental conditions that are often required. Recently, the use of transition metal catalysis has allowed a notable improvement to the reaction conditions. Several metal catalysts such as Zn,60 In,61 Cu,62 Au,63 Ag-Cu,64 Ni,65 and

Co66 can promote the Conia-ene reaction under mild conditions and with a broader scope of substrates. These discoveries have also allowed the possibility of developing enantioselective versions of the Conia-ene reaction, and several research groups have worked towards this goal.67

56 Conia, J. M.; Perchec, P. L. Synthesis, 1975, 1.

57 Fisk, J. S.; Tepe, J. J. J. Am. Chem. Soc. 2007, 129, 3058.

58 Boaventura, M. A.; Drouin, J.; Conia, J. M. Synthesis, 1983, 801.

59 Deng, C. L.; Song, R. J.; Guo, S. M.; Wang, Z. Q.; Li, J. H. Org. Lett. 2007, 9, 5111.

60 Hess, W.; Burton, J. W. Adv. Synth. Catal. 2011, 353, 2966.

61 Hu, B.; Ren, J.; Wang, Z. W. Tetrahedron, 2011, 67, 763.

62 Montel, S.; Bouyssi, D.; Balme, G. Adv. Synth. Catal. 2010, 352, 2315.

63 Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526.

64 Deng, C.-L.; Zou, T.; Wang, Z. Q.; Song, R. J.; Li, J. H.; Yang, D. Org. Lett. 2009, 74, 412.

65 Gao, Q.; Zheng, B. F.; Li, J. H.; Yang, D. Org. Lett. 2005, 7, 2185.

66 Renaud, J. L.; Aubert, C.; Malacria, M. Tetrahedron 1999, 55, 5113.

67 a) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168. b) Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 9140. c) Matsuzawa, A.; Mashiko, T.; Kumagai, N.; Shibasaki, M. Angew. Chem. Int. Ed. 2011, 50, 7616.

Scheme 2.2 Conia-ene reaction of activated carbonyl compounds.

Dixon and co-workers discovered a transition-metal-free method for the Conia-ene reaction of acetylenic dicarbonyl compounds using arylboronic acid catalysts (Scheme 2.3).68 Under optimized conditions, carbocyclizations of 1,3-dicarbonyl compounds bearing pendant alkynyl groups were achieved using 5 mol% of 3-nitrophenylboronic acid 2.1 in refluxing toluene. On the basis of deuterium labeling studies that indicated a syn-addition to the alkyne, the authors proposed a catalyst-promoted enolization of the β-ketoester, which underwent concerted ene cyclization (Scheme 2.4, path A). A mechanism involving the intermediacy of a boron enolate can also be envisioned (path B).35

Scheme 2.3 Conia-ene reaction of acetylenic dicarbonyl compounds catalyzed by 2.1.

68 Li, M.; Yang, T.; Dixon, D. J. Chem. Commun. 2010, 46, 2191.

Scheme 2.4 Proposed mechanistic pathway of the Conia-ene reaction catalyzed by 2.1.

Following the work by Dixon, Shibata et al. reported a Conia-ene carbocyclization of 1,3- dicarbonyl compounds using 3,5-bis(pentafluorosulfanyl)phenylboronic acid 2.2 (Scheme 2.5).69

Compared to catalyst 2.1, 2.2 performed slightly better in a non-polar solvents, such as toluene and Solkane®365mfc (1,1,1,3,3-pentafluorobutane).

Scheme 2.5 Conia-ene reaction of acetylenic dicarbonyl compounds catalyzed by 2.2.

69 Yang, Y.-D.; Lu, X.; Tokunaga, E.; Shibata, N. J. Fluorine Chem. 2012, 143, 204.

2.1.2 Structure and Properties of Borinic Acids

Borinic acids 2.4 differ from boronic acids 2.3 by the presence of two boron-carbon bonds and a single boron-oxygen bond, and display distinct steric and electronic properties (Figure 2.1).70

Borinic acids can also exist as a mixture of its anhydride 2.5. Since free borinic acids are unstable and prone to oxidation, they are usually stored as the ethanolamine salt 2.6.33

Figure 2.1 Molecular structures of boronic acids 2.3, borinic acids 2.4, borinic anhydrides 2.5 and 2-ethanolamine borinates 2.6.

Taylor and co-workers demonstrated that borinic acids were efficient catalysts for the direct aldol reaction of pyruvic acids and aldehydes in aqueous suspension at room temperature

(Scheme 2.6).50 Underlying this process was the stabilization of the enol tautomer of pyruvic acids by organoboron compounds to furnish dioxoborolanones 2.7 (Scheme 2.7). Such reactions were first observed almost a century ago and form the basis of methods for the quantitative analysis of pyruvic acids.71 The use of borinic rather than boronic acid catalysts was an important consideration, with the former providing direct access to the tetracoordinate adducts that were proposed to serve as activated nucleophiles.

70 Chudzinski, M. G.; Chi, Y.; Taylor, M. S. Aust. J. Chem. 2011, 64, 1466. 71 Boeseken, J.; Niks, A. Recl. Trav. Chim. Pays-Bas 1940, 59, 1062.

Scheme 2.6 Diphenylborinic acid-catalyzed aldol reaction of pyruvic acids.

Scheme 2.7 Formation of dioxoborolanones 2.7.

We hypothesized that borinic acids would be able to form more nucleophilic boron enolates of acetylenic dicarbonyl compounds than boronic acids and serve as better organocatalysts for the

Conia-ene reaction. This chapter will discuss our efforts in developing a method to catalyze the

Conia-ene reaction of activated acetylenic dicarbonyl compounds using borinic acids in hopes to achieve milder reaction conditions and possibly work towards designing chiral organoboron catalysts for asymmetric versions of this reaction.

2.2 Results and Discussion

We initiated our studies by first synthesizing the acetylenic dicarbonyl compounds starting from acetoacetic esters and 5-chloro-1-pentyne following a modified procedure reported by Procter et al.72 and Martin and co-workers (Scheme 2.8).73 The products were isolated as a mixture of their

72 Sautier, B.; Lyons, S. E.; Webb, M. R.; Procter, D. J. Org. Lett. 2012, 14, 146.

keto and enol form. They existed mostly (80–90%) in their keto form at room temperature, as can be seen by their 1H NMR spectra (see Appendix A).

Scheme 2.8 Synthesis of acetylenic dicarbonyl derivatives.

Diphenylborinic acid was prepared from 2-aminoethyl diphenylborinate according to literature procedure.50 Hydrolysis of the ethanolamine adduct under acidic conditions gave a white solid, presumably a mixture of the free diphenylborinic acid and its anhydride. Our initial reaction conditions followed the reported conditions by Dixon and Shibata and our first attempt at a borinic acid-catalyzed Conia-ene reaction of 2.12 (Table 2.1, entry 3) was comparable in yield to catalyst 2.1 used by Dixon (entry 2). The background reaction with no catalyst was also consistent with the control reaction performed by Shibata (entry 1).

Table 2.1 Evaluation of organoboron catalysts for the Conia-ene reaction of 2.12.

73 Perez-Hernandez, N.; Febles, M.; Perez, C.; Perez, R.; Rodriguez, M. L.; Foces-Foces, C.; Martin, J. D. J. Org. Chem. 2006, 71, 1139.

Entry Catalyst Yielda (%)

1 - 23

2 >95

3 >95

a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5- trimethoxybenzene as a quantitative internal standard.

Due to the promising reactivity of diphenylborinic acid 2.8, several electronically distinct arylborinic acids were then tested under these conditions (Table 2.2). These were synthesized according to a modified procedure reported by Kobayashi et al.,74 involving lithium-halogen exchange between an aryl halide and sec-butyllithium, followed by a quench with tributylborate to form the crude borinic acid (Scheme 2.9). Since free borinic acids are unstable and prone to oxidation, these were stored as the ethanolamine salt, which required stirring the borinic acid with 2-ethanolamine in toluene at 50 °C overnight.

74 Mori, Y.; Kobayashi, J.; Manabe, K.; Kobayashi, S. Tetrahedron 2002, 58, 8263.

Scheme 2.9 Synthesis of electronically distinct arylborinic acids.

It was found that at a lower temperatures, diphenylborinic acid 2.8 (entry 3) underperformed compared to 3-nitrophenylboronic acid 2.1 (entry 2). Electron-donating substituents on the diarylborinic acid decreased product yield (entry 4), whereas electron-withdrawing substituents improved the reactivity of the catalyst. Catalyst 2.10 gave comparable yields to 2.1 (entry 5) and catalyst 2.11 resulted in greater product yield than 2.1. The trend of increasing Lewis acidity of the arylborinic acids resulting in greater product yield may be explained by the greater nucleophilicity of the boron enolate tetracoordinate adduct.

Table 2.2 Evaluation of electronically distinct borinic acid catalysts.

Entry Catalyst Yielda (%)

1 - 5

2 68

3 36

4 8

5 67

6 88

a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5- trimethoxybenzene as a quantitative internal standard.

The same reaction conditions were applied to the acetylenic dicarbonyl derivative 2.13 and surprisingly, catalyst 2.11 resulted in the same product yield as diphenylborinic acid 2.8. In general, our results were inconsistent and difficult to reproduce, which made it challenging to interpret our data. Typically, a fresh batch of borinic acid was prepared from its ethanolamine salt before performing a set of experiments due to the limited shelf life of free borinic acids.

Also, due to the difficulty of purifying the acetylenic dicarbonyl derivatives, Synthesis of 2.12 and 2.14 was also performed in small batches instead of a single large scale synthesis. With this in mind, it was difficult to compare the results of our data when the batch of starting material and catalyst varied from one experiment to another.

Table 2.3 Evaluation of organoboron catalysts for the Conia-ene reaction of 2.13.

Entry Catalyst Yielda (%)

1 - 0

2 72

3 32

4 38

a Yield (0.2 mmol scale) as determined by 1H NMR of crude reaction with 1,3,5- trimethoxybenzene as a quantitative internal standard.

2.3 Conclusion

A borinic acid-catalyzed Conia-ene reaction of activated acetylenic 1,3-dicarbonyl compounds was explored. While initially our results were promising with the use of diphenylborinic acid, we discovered that our results were inconsistent and difficult to reproduce. Efforts to fully understand this reaction would involve utilizing a single batch of starting material and fresh borinic acids to minimize potential decomposition and investigating possible promoters or inhibitors of this reaction that may come about from borinic acid decomposition.

2.4 Experimental

Materials: All reagents and solvents were purchased from Sigma Aldrich or Alfa Aesar and used without further purification. THF, toluene and diethyl ether were purified by passing through two columns of activated alumina under nitrogen (Innovative Technology Inc.). Nuclear magnetic resonance (NMR) solvents were purchased from Cambridge Isotope Laboratories.

1 Instrumentation: H spectra were recorded in CDCl3 or DMSO-d6 using either a Bruker Avance

III 400 MHz or Varian Mercury 400 MHz. 1H NMR are reported in parts per million (ppm) relative to tetramethylsilane and referenced to residual protium in the solvent. Spectral features are tabulated in the following order: chemical shift (δ, ppm); multiplicity (s-singlet, d-doublet, t- triplet, q-quartet, p-pentet, m-complex multiplet); number of protons; coupling constants (J, Hz).

1.4.1 General Experimental Procedures

General Procedure A: Synthesis of Arylboronic Acid Catalysts

To a 2-dram vial equipped with a magnetic stirring bar were added 2-aminoethyl diarylborinate

(0.4 mmol), acetone (0.2 mL) and methanol (0.2 mL). To the resulting solution was added

HCl(aq) (1 M, 0.5 mL). The vial was capped in ambient atmosphere and stirred at 400 rpm at room temperature. After 1 hour, the mixture was diluted with diethyl ether, washed with water and extracted several times with diethyl ether. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo.

General Procedure B: Synthesis of 1,3-Dicarbonyl Compounds

To a 10 mL round bottom flask equipped with a magnetic stirring bar were added sodium hydride (2.2 mmol) and potassium iodide (2.2 mmol). The flask was then sealed with a septum and purged with argon. Anhydrous THF (1 mL) and DMF (1 mL) were added to the flask, followed by acetoacetate ester (2.0 mmol) and 5-chloro-1-pentyne (3.0 mmol). The resulting mixture was stirred at 400 rpm at 100 °C. After 17 hours, the mixture was diluted with ethyl acetate and washed with water several times. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography.

General Procedure C: Evaluation of Borinic Acid-Catalyzed Conia-Ene Reaction

To a screw cap Pyrex® tube equipped with a magnetic stirring bar was added organoboron catalyst (5 mol%). The flask was then sealed with a septum and purged with argon. 1,3-

Dicarbonyl compound (0.2 mmol) was dissolved in anhydrous toluene (5 mL) and added to the tube. The resulting mixture was stirred at 400 rpm at 100 - 120 °C. After 17 hours, 1,3,5- trimethoxybenzene (10.0 mg, 0.0595 mmol) was added as a quantitative internal standard. An

1 aliquot of the mixture was concentrated in vacuo, diluted with CDCl3 and analyzed by H NMR.

General Procedure D: Synthesis of 2-Aminoethyl Arylborinate Precatalysts

To a 25 mL round bottom flask equipped with a magnetic stirring bar was added substituted bromobenzene (1 mmol). The flask was then sealed with a septum and purged with argon.

Anhydrous diethyl ether (4 mL) was added to the flask, followed by sec-butyllithium (1.4 M in cyclohexane, 1 mmol) and tributylborate (0.34 mmol) at -78 °C. The resulting mixture was

stirred at 400 rpm at room temperature. After 17 hours, the mixture was quenched with water.

The ether layer was washed with 1 M HCl(aq), water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude borinic acid was transferred to a 25 mL round bottom flask equipped with a magnetic stirring bar, followed by toluene (8 mL) and 2-ethanolamine (0.46 mmol). The resulting mixture was stirred at 400 rpm at 50 °C. After 17 hours, the mixture was concentrated in vacuo and washed with DCM/pentane mixture.

2.4.2 Characterization Data

Diphenylborinic acid (2.8)

Synthesized according to general procedure A, from 2-aminoethyl

diphenylborinate, 84% yield, white solid. Spectral data were in agreement with

50 1 previous reports. H NMR (400 MHz, DMSO-d6): δ 7.66 (dd, J = 7.9, 1.4

11 Hz, 4H), 7.49 – 7.43 (m, 2H), 7.43 – 7.37 (m, 4H). B NMR (128 MHz, DMSO-d6): δ 45.4.

Benzyl 2-acetylhept-6-ynoate (2.12)

Synthesized according to general procedure B, from benzyl acetoacetate.

Purified using 5% EtOAc/pentane (10% EtOAc/pentane Rf = 0.4), 70% yield,

pale yellow oil. Spectral data were in agreement with previous reports.72 1H

NMR (400 MHz, CDCl3): δ 7.35 (m, 5H), 5.18 (d, J = 1.9 Hz, 2H), 3.49 (t, J =

7.4 Hz, 1H), 2.24 – 2.19 (m, 2H), 2.18 (s, 3H), 2.03 – 1.93 (m, 3H), 1.56 – 1.48 (m, 2H).

Ethyl 2-acetylhept-6-ynoate (2.13)

Synthesized according to general procedure B, from ethyl acetoacetate. Purified

using 5% EtOAc/pentane (10% EtOAc/pentane Rf = 0.4), 60% yield, pale yellow

oil. Spectral data were in agreement with previous reports.72 1H NMR (400

MHz, CDCl3): δ 4.20 (q, J = 7.1, 2H), 3.43 (t, J = 7.4 Hz, 1H), 2.25 – 2.20 (m,

5H), 2.00 – 1.93 (m, 3H), 1.52 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).

Benzyl 1-acetyl-2-methylenecyclopentane-1-carboxylate (2.14)

Synthesized according to general procedure C, from benzyl 2-acetylhept-6-

ynoate and 3-nitrophenylboronic acid. Purified using 5% EtOAc/pentane (10%

EtOAc/pentane Rf = 0.5), 94% yield, pale yellow oil. Spectral data were in

68 1 agreement with previous reports. H NMR (400 MHz, CDCl3): δ 7.39 – 7.29 (m, 5H), 5.28 (t,

J = 2.1 Hz, 1H), 5.21 (t, J = 2.3 Hz, 1H), 5.18 (s, 2H), 2.52 – 2.37 (m, 3H), 2.21 (m, 1H), 2.18 (s,

3H), 1.79 – 1.65 (m, 2H).

Ethyl 1-acetyl-2-methylenecyclopentane-1-carboxylate (2.15)

Synthesized according to general procedure C, from ethyl benzyl-2-acetylhept-6-

ynoate and 3-nitrophenylboronic acid. Purified using 5% EtOAc/pentane (10%

EtOAc/pentane Rf = 0.5), 93% yield, pale yellow oil. Spectral data were in

68 1 agreement with previous reports. H NMR (400 MHz, CDCl3): δ 5.29 (t, J = 2.1 Hz, 1H), 5.24

(t, J = 2.3 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 2.42 (m, 3H), 2.22 (s, 3H), 2.20 – 2.14 (m, 1H),

1.79 – 1.64 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H).

2-Aminoethyl bis(4-methoxyphenyl)borinate

Synthesized according to general procedure D, from 4-

bromoanisole. Spectral data were in agreement with previous

74 1 reports. H NMR (400 MHz, DMSO-d6): δ 7.26 (d, J = 8.4 Hz,

4H), 6.71 (d, J = 8.4 Hz, 4H), 5.87 (s, 2H), 3.73 (t, J = 6.5 Hz,

11 2H), 3.67 (s, 6H), 2.80 (p, J = 6.1 Hz, 2H). B NMR (128 MHz, DMSO-d6): δ 5.3.

2-Aminoethyl bis(4-fluorophenyl)borinate

Synthesized according to general procedure D, from 1-bromo-4-

fluorobenzene. Spectral data were in agreement with previous reports.74

1 H NMR (400 MHz, DMSO-d6): δ 7.41 – 7.32 (m, 4H), 6.97 – 6.89 (m,

4H), 6.08 (s, 2H), 3.76 (t, J = 6.5 Hz, 2H), 2.83 (p, J = 6.2 Hz, 2H). 11B

NMR (128 MHz, DMSO-d6): δ 4.7.

2-Aminoethyl bis(3,5-di(trifluoromethyl)phenyl)borinate

Synthesized according to general procedure D, from 1,3-

bis(trifluoromethyl)-5-bromobenzene. Spectral data were in

agreement with previous reports.74 1H NMR (400 MHz, DMSO-

d6): δ 8.03 (s, 4H), 7.78 (s, 2H), 6.59 (s, 2H), 3.84 (t, J = 6.4 Hz,

11 2H), 2.98 – 2.88 (m, 2H). B NMR (128 MHz, DMSO-d6): δ 3.6.

Bis(4-methoxyphenyl)borinic acid (2.9)

Synthesized according to general procedure A, from 2-aminoethyl

bis(4-methoxyphenyl)borinate. Spectral data were in agreement

74 1 with previous reports. H NMR (400 MHz, CDCl3): δ 7.77 (d, J

11 = 8.6 Hz, 4H), 6.98 (d, J = 8.6 Hz, 4H), 3.87 (s, 6H). B NMR (128 MHz, CDCl3): δ 44.5.

Bis(4-fluorophenyl)borinic acid (2.10)

Synthesized according to general procedure A, from 2-aminoethyl bis(4-

fluorophenyl)borinate. Spectral data were in agreement with previous

74 1 reports. H NMR (400 MHz, CDCl3): δ 7.80 (m, 4H), 7.21 – 7.14 (m,

11 5H). B NMR (128 MHz, CDCl3): δ 45.2.

Bis(3,5-di(trifluoromethyl)phenyl)borinic acid (2.11)

Synthesized according to general procedure A, from 2-Aminoethyl

bis(3,5-di(trifluoromethyl)phenyl)borinate. Spectral data were in

74 1 agreement with previous reports. H NMR (400 MHz, CDCl3): δ

11 8.17 (s, 4H), 8.08 (s, 2H). B NMR (128 MHz, CDCl3): δ 44.3.

Chapter 3 Synthesis of Homobarrelenones via Boronic Acid- Catalyzed Diels-Alder Cycloaddition

3.1 Introduction

3.1.1 Boronic Acids Acting as Brønsted Acids

Boronic acids display Brønsted acidity only in exceptional cases where the formation of a tetrahedral boronate adduct is highly unfavorable. For example, coordination of hydroxide ion to boron in heterocyclic boronic acid derivative 3.1, to form 3.2, would break the partial aromatic character of the central ring (Scheme 3.1).33 Based on 11B NMR and UV spectroscopic evidence, it was suggested that 3.1 acts as a Brønsted acid in water and forms conjugate base 3.3 through direct proton transfer.75

Scheme 3.1 Ionization equilibrium of heterocyclic boronic acid derivative 3.1.

75 Dewar, M. J. S.; Jones, R. J. Am. Chem. Soc. 1967, 89, 2408.

3.1.2 Applications of Boronic Acids in Diels-Alder Cycloadditions

Acyloxyboron intermediates generated from α,β-unsaturated carboxylic acids display enhanced reactivity as dienophiles, thus providing a unique mode of cycloaddition catalysts.35 The group of Hall disclosed that 2-iodophenylboronic acid gave rise to high levels of rate acceleration for cycloadditions of acrylic acids with 2,3-dimethylbutadiene, cyclopentadiene, or furan (Scheme

3.2).76

Scheme 3.2 Boronic acid-catalyzed Diels-Alder cycloaddition.

As mentioned in Chapter 1, boronic acids can also be employed to promote templating effects in cycloaddition reactions. Narasaka et al. demonstrated that phenylboronic acid can be employed to hold a diene and dienophile in such a way that the regiocontrol of a Diels-Alder reaction can be inverted.40 This templating strategy was elegantly exploited in the synthesis of a key intermediate in the total synthesis of taxol by Nicolaou et al. (Scheme 3.3).41

76 Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem. Int. Ed. 2008, 47, 2876.

Scheme 3.3 Phenylboronic acid-mediated Diels-Alder reaction.

Tropone and α-tropolone 3.4 are non-benzenoid aromatic compounds whose properties and reactivities are well documented.77 In particular, Diels-Alder and other types of cycloaddition reactions of non-benzenoid aromatic compounds including tropolones were of great interest in early molecular orbital studies, and have been studied since the 1950s.78 However, synthetic applications of Diels-Alder reactions of tropones and tropolones have been limited due to their lower reactivity of these dienes, which can be explained by their aromatic character and electron- deficient nature.79 Okamura et al. found that tropolone reacted with various electron-deficient dienophiles in the presence of Et3N or silica gel at room temperature to give the corresponding homobarrelenone cycloadducts as a mixture of endo and exo isomers (Scheme 3.4).80

77 Pauson, P. L. Chem. Rev. 1955, 55, 9. b) Pietra, F. Chem. Rev. 1973, 73, 293.

78 Dewar, M. J. S.; Angew. Chem. 1971, 83, 859. b) Woodward, R. B.; Hoffmann, R. Angew. Chem. Int. Engl. 1969, 8, 781.

79 a) Brecht, R.; Haenel, F.; Seitz, G.; Frenzen, G.; Pilz, A.; Guenard, D. Eur. J. Org. Chem. 1998, 2451. b) Dahnke, K. R.; Paquette, L. A. J. Org. Chem. 1994, 59, 885. c) Funk, R. L.; Bolton, G. L. J. Am. Chem. Soc. 1986, 108, 4655. d) Ishar, M. P. S.; Gandhi, R. P. Tetrahedron 1993, 49, 6729. e) Ito, K.; Noro, Y.; Saito, K.; Takahashi, K. Bull. Chem. Soc. Jpn. 1990, 63, 2573. f) Sasaki, T.; Kanematsu, K.; Hayakawa, K. J. Chem. Soc., Perkin Trans. 1 1951, 1972. g) Uyehara, T.; Furuta, T.; Kabasawa, Y.; Yamada, J. I.; Kato, T. J. Chem. Soc., Chem. Commun. 1986, 539.

80 Okamura, H.; Iiji, H.; Hamada, T.; Iwagawa, T.; Furuno, H. Tetrahedron 2009, 65, 10709.

Scheme 3.4 Diels-Alder reaction of tropolone and N-methylmaleimide prompted by Et3N.

3.1.3 General Introduction to Homobarrelenones

Compounds possessing the homobarrelenone (bicyclo[3.2.2]nona-3,6,8-triene) skeleton 3.7 continue to attract attention since they are important precursors for a wide range of theoretically interesting reactive intermediates81 and provide access to a number of unique polycyclic molecules such as barbaralone 3.8 which exhibit fluxional behaviour (Figure 3.1).82 They are also attractive building blocks for organic synthesis.80

Figure 3.1 Homobarrelenone skeleton 3.7 and molecular structure of barbaralone 3.8.

It was hypothesized that an organoboron catalysts should be able to bind to the carbonyl and α- hydroxy of tropolone, similar to Scheme 3.3, and increase the reactivity of this diene. This

81 a) Grutzner, J. B.; Winstein, S. J. Am. Chem. Soc. 1972, 94¸2200. b) Freeman, P. K.; Swenson, K. E. J. Org Chem. 1982, 47, 2040.

82 Barborak, J. C.; Chari, S.; Schleyer, P. v. R. J. Am. Chem. Soc. 1971, 93, 5275.

chapter will discuss the synthesis of homobarrelenones via a boronic acid-catalyzed Diels-Alder cycloaddition of tropolone and electron-deficient dienophiles.

3.2 Results and Discussion

The organoboron-catalyzed Diels-Alder cycloaddition of tropolone and N-methylmaleimide was first attempted using the conditions reported by Okamura and co-workers. There was no product formation at room temperature in DCM after 48 h. We decided to drastically change the reaction conditions to those that we are more familiar with, specifically toluene at elevated temperatures.

We were able to observe some reactivity with diphenylborinic acid 3.9 in toluene at 100 °C

(Table 3.1, entry 2). However, the background reaction without catalyst was close in yield to the catalyzed reaction (entry 1). Phenylboronic acid 3.10 resulted in a yield lower than the control, suggesting that it may hinder the Diels-Alder cycloaddition reaction (entry 3).

Table 3.1 Exploring organoboron-catalyzed Diels-Alder cycloaddition of 3.4 and N- methylmaleimide.

Entry Catalyst Yielda (%) endo : exo Ratioa

1 - 33 3.5 : 1.0

Entry Catalyst Yielda (%) endo : exo Ratioa

2 47 1.1 : 1.0

3 26 2.2 : 1.0 a Yield (0.1 mmol scale) as determined by 1H NMR of crude reaction with mesitylene as a quantitative internal standard.

Interestingly, when an equivalent of diphenylborinic acid was used, there was no product formation. Instead, a yellow-green solid was formed from colourless starting material. The solid was isolated and determined to be diphenylboryltropolonate 3.11 (Scheme 3.5). This species has been studied before for its interesting physical properties due to its high dipole moment.13 The boron tropolonate is fully delocalized, whereby the positive charge is delocalized in the tropylium ring, while both oxygen atoms carry the negative charge 3.12.

Scheme 3.5 Synthesis and structure of diphenylboryltropolonate 3.11.

Both borinic acid 3.9 and boronic acid 3.10 were not attractive organoboron catalysts for the

Diels-Alder cycloaddition reaction of tropolone 3.4 and N-methylmaleimide. Nevertheless, a variety of electronically distinct arylborinic and arylboronic acids were screened and the results

are summarized in Table 1.2. Catalysts 3.13, 3.14 and 3.15 were previously synthesized by our group and were available to be screened without the need to synthesize them from commercially available starting material.14,15 Also, the solvent was changed to acetonitrile from the results of a short solvent screen and the temperature was decreased to 80 °C to compare reaction yields more effectively. The reaction with diphenylborinic acid 3.9 (entry 2) was comparable in yield to the background reaction (entry 1) with approximately 20 mol% of tropolone 3.4 converted to diphenylboryltropolonate 3.11. Catalyst 3.13 decreased product yield, similar to phenylboronic acid 3.10, but a 3:1 endo:exo ratio was observed (entry 3). Catalyst 3.14 significantly improved product yield compared to the control reaction and other arylboronic acid catalysts (entry 4).

Also, decreasing catalyst loading to 5 mol% did not lower the yield to any appreciable amount.

Catalyst 3.15 resulted in no product formation. Benzoxaborole 3.16 was synthesized from the reduction of 2-formylphenylboronic acid and subsequent intramolecular condensation, following the procedure by Sporzynski et al.16 One reason why catalyst 3.14 demonstrated greater reactivity than all other organoboron catalysts screened (shown and not shown) is it may be acting as a Brønsted acid (Scheme 3.1).

Table 3.2 Evaluation of organoboron catalysts in the Diels-Alder cycloaddition of 3.4 and N- methylmaleimide.

Entry Catalyst Yielda (%) endo : exo Ratioa

1 - 31 1.2 : 1.0

2 33 1.0 : 1.2

3 21 3.0 : 1.0

4 71 1.0 : 1.6

5 66b 1.0 : 1.5

6 0 -

7 35 1.2 : 1.0

a Yield (0.1 mmol scale) as determined by 1H NMR of crude reaction with mesitylene as a quantitative internal standard. b Reaction performed with 5 mol% of catalyst.

A more extensive solvent screen was performed and the results were quite dramatic (Table 3.3).

Non-polar solvents, such as toluene, resulted in lower product yield (entry 2). Polar, aprotic solvents increased product yield with 1,4-dioxane considerably improving the yield of the reaction (entry 6).

Table 3.3 Evaluation of solvents.

Entry Solvent Yielda (%) endo : exo Ratioa

1 Acetonitrile 66 1.0 : 1.5

2 Toluene 23 1.0 : 1.5

3 EtOAc 48 1.0 : 1.5

4 DMF 46 1.1 : 1.0

5 DMSO 70 1.0 : 1.2

Entry Solvent Yielda (%) endo : exo Ratioa

6 1,4-Dioxane >95 1.0 : 1.9

7 THF 9b 1.0 : 1.0 a Yield (0.1 mmol scale) as determined by 1H NMR of crude reaction with mesitylene as a quantitative internal standard. b Reaction performed at 60 °C.

Our evaluation of organoboron catalysts and solvents have allowed us to considerably improve upon our initial reaction conditions (Table 3.4). Using 10 mol% of catalyst 3.14 and 1,4-dioxane as our solvent, we were able to fully convert starting material 3.4 into products 3.5 and 3.6 at 80

°C (entry 2). However, the background reaction was still present (entry 1). Next, we decided to evaluate reaction concentration since the Diels-Alder reaction is a bimolecular reaction.

Increasing the reaction concentration by 10-fold resulted in a 78% conversion of starting material into product at room temperature (entry 4). Without catalyst, 30% of product was formed (entry

3).

Table 3.4 Optimized reaction conditions and evaluation of reaction concentration.

Entry Reaction Concentration (M) Yielda (%) endo : exo Ratioa

1 0.1 33b 1.0 : 1.0

2 0.1 >95 1.0 : 1.9

3 1.0 30b,c 2.3 : 1.0

4 1.0 78c 2.2 : 1.0 a Yield (0.1 mmol scale) as determined by 1H NMR of crude reaction with mesitylene as a quantitative internal standard.b Reaction performed without catalyst 3.14. c Reaction performed at room temperature.

N-methylmaleimide is quite a reactive dienophile. Less electron-deficient dienophiles were explored to evaluate the substrate scope of this reaction. Diels-Alder cycloaddition of tropolone with trans-hex-3-en-2-one using catalyst 3.14 gave no product, even at 1.0 M reaction concentration and 70 h (Scheme 3.16). Butyl acrylate resulted in minor product formation after

70 h with a reaction concentration of 1.0 M (Scheme 3.17). Dimethyl acetylenedicarboxylate gave fair yields of product 3.21 (3.18). Overall, the substrate scope was disappointing and the reaction conditions were quite harsh compared to those reported by the group of Okamura.

Scheme 3.6 Diels-Alder cycloaddition of 3.4 and trans-hex-3-en-2-one using catalyst 3.14.

a Yield (0.1 mmol scale) as determined by 1H NMR of crude reaction with mesitylene as a quantitative internal standard.

Scheme 3.7 Diels-Alder cycloaddition of 3.4 and butyl acrylate using catalyst 3.14.

a Yield (0.1 mmol scale) as determined by 1H NMR of crude reaction with mesitylene as a quantitative internal standard.

Scheme 3.8 Diels-Alder cycloaddition of 3.4 and dimethyl acetylenedicarboxylate using catalyst 3.14.

3.3 Conclusion

Synthesis of homobarrelenones via a boronic acid-catalyzed Diels-Alder cycloaddition of tropolone and electron-deficient dienophiles was investigated. A novel organocatalyst dibenzo[c,e][1,2]oxaborinin-6-ol was shown to catalyze this reaction. Further investigation is required to determine whether this catalyst is acting as a Lewis acid or Brønsted acid.

3.4 Experimental

Materials: All reagents and solvents were purchased from Sigma Aldrich or Alfa Aesar and used without further purification. THF, toluene and acetonitrile were purified by passing through two columns of activated alumina under nitrogen (Innovative Technology Inc.). Nuclear magnetic resonance (NMR) solvents were purchased from Cambridge Isotope Laboratories.

1 13 Instrumentation: H and C spectra were recorded in CDCl3, benzene-d6, CD3CN or DMSO-d6 using either a Bruker Avance III 400 MHz or Varian Mercury 400 MHz. 1H NMR are reported in parts per million (ppm) relative to tetramethylsilane and referenced to residual protium in the solvent. Spectral features are tabulated in the following order: chemical shift (δ, ppm); multiplicity (s-singlet, d-doublet, t-triplet, q-quartet, p-pentet, m-complex multiplet); number of protons; coupling constants (J, Hz).

1.4.1 General Experimental Procedures

General Procedure A: Evaluation of Organoboron-Catalyzed Diels-Alder Reaction of α-

Tropolone and Dienophiles

To a 2-dram vial equipped with a magnetic stirring bar were added α-tropolone (0.1 mmol), dienophile (0.12 mml), organoboron catalyst (10 mol%) and solvent (1 mL). The vial was capped in ambient atmosphere and stirred at 400 rpm at 25 - 100 °C. After 17 hours, Mesitylene

(10.0 mg, 0.0595 mmol) was added as a quantitative internal standard. An aliquot of the mixture

1 was concentrated in vacuo, diluted with CDCl3 and analyzed by H NMR.

General Procedure B: Synthesis of Diphenylboryltropolonate

To a 2-dram vial equipped with a magnetic stirring bar were added α-tropolone (0.1 mmol), diphenylborinic acid (0.1 mmol) and acetone (1 mL). The vial was capped in ambient atmosphere and stirred at 400 rpm at room temperature. After 1 hour, the mixture was concentrated in vacuo and the resulting crude material was purified by silica gel chromatography.

General Procedure C: Synthesis of 1,3-Dihydro-1-hydroxy-2,1-benzoxaborole

To a 10 mL round bottom flask were added 2-formylphenylboronic acid (0.5 mmol) and sodium borohydride (0.5 mmol). The flask was then sealed with a septum and purged with argon.

Methanol (2.5 mL) was added to the flask. The resulting mixture was stirred at 400 rpm at room temperature. After 17 hours, the mixture was poured into ice-water (2 mL). 1.5 M H2SO4(aq) (0.5 mL) was added, precipitate was filtered off and dried in vacuo.

1.4.2 Characterization Data

3.5 and 3.6 (as a mixture)

Synthesized according to general procedure A, from N-methylmaleimide, 10-

hydroxy-9,10-oxabora-phenanthrene and anhydrous 1,4-dioxane at 80 °C. 97%

yield, pale yellow oil. Spectral data were in agreement with previous reports.80

1 H NMR for x (400 MHz, CDCl3): δ 7.32 (dd, J = 11.0, 8.7 Hz, 1H), 6.38

(dd, J = 8.8, 7.2 Hz, 1H), 6.11 – 5.95 (m, 2H), 4.93 (s, 1H), 4.04 – 3.95 (m, 1H), 3.33 (m, 1H),

1 3.06 (d, J = 8.4 Hz, 1H), 2.99 (s, 3H),. H NMR for y (400 MHz, CDCl3): δ 7.02 (dd, J = 11.2,

8.4 Hz, 2H), 6.53 (dd, J = 8.7, 7.3 Hz, 2H), 6.11 – 5.95 (m, 2H), 4.83 (s, 1H), 4.04 – 3.95 (m,

1H), 3.47 (d, J = 9.6 Hz, 1H), 3.33 (m, 1H), 2.90 (s, 3H).

Diphenylboryltropolonate (3.11)

Synthesized according to general procedure B. Purified using DCM

1 (DCM: Rf = 0.9), 96% yield, yellow-green solid. H NMR (400 MHz,

Benzene-d6): δ 7.98 – 7.92 (m, 4H), 7.44 – 7.37 (m, 4H), 7.31 – 7.25 (m,

2H), 6.66 (dd, J = 11.0, 0.7 Hz, 2H), 6.34 (dd, J = 11.0, 10.0 Hz, 2H), 5.99

13 (t, J = 9.9 Hz, 1H). C NMR (100 MHz, CD3CN): δ 176.6, 145.7, 132.3, 132.2, 128.2, 127.5,

+ 125.0, 118.3. HRMS (DART, m/z): Calculated for C19H19BNO2 [(M+NH4) ]: 304.1519. Found:

304.1509.

1,3-Dihydro-1-hydroxy-2,1-benzoxaborole (3.16)

Synthesized according to general procedure C. 42% yield, pale white solid.

Spectral data were in agreement with previous reports.83 1H NMR (400 MHz,

DMSO-d6): δ 7.72 (d, J = 7.3 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 7.39 (d, J = 7.6

11 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 4.97 (s, 2H). B NMR (128 MHz, DMSO-d6): δ 32.3.

83 Adamczyk-Wozniak, A.; Cyranski, M. K.; Jakubczyk, M.; Klimentowska, P.; Koll, A.; Kolodziejczak, J.; Pojmaj, G.; Zubrowska, A.; Zukowska, G. Z.; Sporzynski, A. J. Phys. Chem. A 2010, 114, 2324.

Appendix A: 1H and 13C NMR Spectra