Synthesis of Benzofused-P-Indolequinones From

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2015-01-01 SynThesis of Benzofused-p-indolequinones from 1,4-naphthoquinone and selective N- Debenzylation by Dess-Martin Periodinane Quang Huynh Luu University of Texas at El Paso, [email protected]

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This is brought to you for free and open access by DigitalCommons@UTEP. It has been accepted for inclusion in Open Access Theses & Dissertations by an authorized administrator of DigitalCommons@UTEP. For more information, please contact [email protected]. SYNTHESIS OF BENZOFUSED-P-INDOLEQUINONES

FROM 1,4-NAPHTHOQUINONE AND SELECTIVE

N-DEBENZYLATION BY DESS-MARTIN PERIODINANE

QUANG HUYNH LUU

Department of Chemistry

APPROVED:

Katja Michael, Ph.D., Chair

Shizue Mito, Ph.D.

Carl Dirk, Ph.D.

Siddhartha Das, Ph.D.

Charles Ambler, Ph.D. Dean of the Graduate School

SYNTHESIS OF BENZOFUSED-P-INDOLEQUINONES FROM 1,4-NAPHTHOQUINONE AND SELECTIVE N-DEBENZYLATION BY DESS-MARTIN PERIODINANE

QUANG HUYNH LUU, B. ENG.

THESIS

Presented to the Faculty of the Graduate School of

The University of Texas at El Paso

in Partial Fulfillment

of the Requirements

for the Degree of

MASTER OF SCIENCE

Department of Chemistry

THE UNIVERSITY OF TEXAS AT EL PASO

August 2015 AKNOWLEDGEMENT

First and foremost, my special thanks go to my mentor, Dr. Shizue Mito, who not only gives me her full support, both academically and socially, but also inspires me to pursue my dream of becoming a professor. Working with her is a particularly precious experience.

It is also my pleasure and honor to have Dr. Michael, Dr. Dirk, and Dr. Das as my committee members. Their useful advices have kept me on the right track and helped me progressing with my research more than I could do by myself. Moreover, I owe my deep gratitude to Dr. Michael,

Dr. Villagrán, Dr. Pannell, and their labs for unconditionally supporting me during the hardest moments. Especially, the Department of Chemistry will always have my great appreciation for continuously providing me teaching assistantship and important equipments throughout my time at UTEP.

In addition, I would like to thank my talented undergraduate students, especially Jorge D.

Guerra, Cecilio M. Castañeda, and Jong Saunders (Baek). This thesis would not be possible without their enthusiastic contribution and hard work.

Finally, I am blessed to have my dear friends at UTEP, Dr. Kalagara and Karen Ventura, as well as my beloved family, who always believe in me and do not hesitate to provide me with the most convenient condition so that I can concentrate on my work.

Quang H. Luu

iii

TABLE OF CONTENTS

AKNOWLEDGEMENT ...... iii

TABLE OF CONTENTS ...... iv

LIST OF FIGURES ...... vi

LIST OF SCHEMES...... vii

LIST OF TABLES ...... x

ABBREVIATIONS ...... xi

CHAPTER 1: ULTRASOUND ASSISTED ONE-POT SYNTHESIS OF

BENZOFUSED-P-INDOLEQUINONES FROM 1,4-NAPHTHOQUINONE AND α-

AMINOACETALS ...... 1

1.1. Introduction ...... 1

1.1.1. Oxidation of indoles ...... 2

1.1.2. Cyclization of quinones ...... 6

1.1.3. Miscellaneous methods...... 13

1.2. Results and discussion ...... 15

1.3. Conclusion ...... 28

1.4. Experimental details and spectroscopic data ...... 29

References ...... 81

CHAPTER 2: SELECTIVE OXIDATIVE N-DEBENZYLATION OF TERTIARY AND

SECONDARY AMINES BY DESS-MARTIN PERIODINANE ...... 85

2.1. Introduction ...... 85

2.1.1. N-dealkylation using Cytochromes P-450 and other enzyme-derived species: ...... 85

2.1.2. N-Dealkylation using metal complexes: ...... 86

2.1.3. N-Dealkylation using non-metal reagents: ...... 92

2.2. Results and discussion: ...... 95

2.3. Conclusion:...... 103

2.4. Experimental procedure and spectral data ...... 104

References ...... 131

CHAPTER 3: SYNTHESIS OF PYRIDAZINEDIONES, QUINONE DIMERS, AND

POLYQUINONES ...... 133

3.1. Synthesis of pyridazinediones from alkynes and diformyl hydrazine: ...... 133

3.2. Synthesis of naphthoquinone dimers: ...... 138

3.3. Synthesis of polyquinones:...... 141

References ...... 146

CURRICULUM VITA...... 147

LIST OF FIGURES

Figure 1. 1. Natural products containing indolequinone structures ...... 2

Figure 1. 2. Medicinal compounds synthesized from indolequinone precursors ...... 2

Figure 2. 1. Compounds inert to N-debenzylation by CAN ...... 92

Figure 2. 2. Effect of substituent on acidity of H ...... 97

Figure 2. 3. Structures of DMP, IBX, and monoacetate iodinane 140 ...... 100

Figure 3. 1. Syn and anti conformation of 1,4-naphthoquinone dimer ...... 139

LIST OF SCHEMES

Scheme 1. 1. Synthesis of BE 10988 by Moody et al...... 4

Scheme 1. 2. Oxidation of indoles to indolequinones by dichromate reagent ...... 6

Scheme 1. 3. Yamashita’s utilization of Sonogashira coupling reaction in the synthesis of indolequinones ...... 9

Scheme 1. 4. Formation of indolequinones using Ce(IV) and Mn(III) ...... 10

Scheme 1. 5. Preparation of indolequinone precursor to marine alkaloid tsitsikammamine A by

Delfourne and co-workers...... 12

Scheme 1. 6. Indolequinones 55 synthesized by quinone–amine cyclization followed by dehydration ...... 13

Scheme 1. 7. Synthesis of indolequinone 57 from tryptamine and 2-methoxynaphthoquinone .. 13

Scheme 1. 8. Planned synthesis of isoquinolinoles 72...... 16

Scheme 1. 9. Alternate synthesis of 69a ...... 16

Scheme 1. 10. Planned Synthesis of heterocycles 75 ...... 17

Scheme 1. 11. Planned synthesis of indolequinone 80 ...... 18

Scheme 1. 12. Mechanism of indolequinone 82 formation ...... 21

Scheme 1. 13. General reaction for indolequinone synthetic methodology develoment...... 21

Scheme 1. 14. Formation of indolequinone 88a ...... 22

Scheme 1. 15. Synthesis of indolequinone 80 ...... 26

Scheme 1. 16. 1,4-benzoquinone as the starting material ...... 27

Scheme 1. 17. Plausible mechanism ...... 27

Scheme 1. 18. Treating 1,4-naphthoquinone with diethanol amine ...... 28

Scheme 1. 19. Extended application of the method ...... 29

vii

Scheme 2. 1. SET mechanism of P450-catalyzed N-dealkylation ...... 86

Scheme 2. 2. HAT mechanism of P450-catalyzed N-dealkylation ...... 86

Scheme 2. 3. Mechanism of DMA oxidation by copper dioxygen adduct ...... 86

Scheme 2. 4. In-situ generation of dibutylamine 105 for the synthesis of (E)--unsaturated amides 106 ...... 89

Scheme 2. 5. Mechanism of demethylation using ruthenium catalysts ...... 90

Scheme 2. 6. Mechanism of dealkylation using Pd catalyst ...... 90

Scheme 2. 7. Synthesis of Flutimide 127 by Sheo B. Singh ...... 92

Scheme 2. 8. Mechanism of N-debenzylation using DIAD 128 ...... 93

Scheme 2. 9. N-Debenzylation using NIS ...... 93

Scheme 2. 10. Treating intermediate 135 with DMP under heating condition ...... 95

Scheme 2. 11. Speculated mechanism of forming 80 by DMP ...... 97

Scheme 2. 12. Plausible mechanism of N-debenzylation by DMP...... 103

Scheme 2. 13. Synthesis of new analog of Wakayin derivative ...... 104

Scheme 3. 1. Planned synthesis of pyridazinediones 156 ...... 134

Scheme 3. 2. Revised planned synthesis of pyridazinediones 156 ...... 136

Scheme 3. 3. Calculated pathway of hydrogen abstraction from diformylhydrazine 155 by hydroxyl radicals ...... 137

Scheme 3. 4. Future synthesis of pyridazinediones ...... 138

Scheme 3. 5. Planned synthesis of substituted 1,4-naphthoquinone dimers ...... 140

Scheme 3. 6. Planned synthesis of polyquinones using photoacylation ...... 141

Scheme 3. 7. Synthesis of 165 from maleic anhydride 166 ...... 141

Scheme 3. 8. Revised planned synthesis of polyquinones ...... 143

viii

Scheme 3. 9. Preparation of 175a ...... 144

Scheme 3. 10. Preparation of 175b ...... 144

Scheme 3. 11. Preparation of compound 177 and future plan ...... 145

LIST OF TABLES

Table 1. 1. Oxidation of 67 by different reagents ...... 17

Table 1. 2. Reaction conditions for the amination of naphthoquinone ...... 18

Table 1. 3. List of the reaction conditions for deprotection of 77a...... 19

Table 1. 4. Screening of amine equivalents ...... 22

Table 1. 5. Formation of 88c in various solvents ...... 23

Table 1. 6. Reaction concentration and acid scope ...... 24

Table 1. 7. Synthesis of benzo[f]p-indolequinones 88 from 1,4-naphthoquinone and

aminoacetals 86 ...... 25

Table 2. 1. Solvent effect on formation of benzaldehyde from 139 ...... 98

Table 2. 2. Formation of benzaldehyde over the course of reaction ...... 99

Table 2. 3. Oxidative N-debenzylation of various amines ...... 100

Table 3. 1. Reaction conditions for Eq. 53 ...... 135

Table 3. 2. Reaction conditions for revised synthesis of pyridazinediones using metal reagents

...... 136

ABBREVIATIONS

Bn benzyl

CAN ceric ammonium nitrate

CYPs cytochromes P450

D day/days

DCE dichloroethane

DCM dichloromethane

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DIAD diisopropyl azodicarboxylate

DIBAL–H diisobutylaluminum hydride

DIPA diisopropylamine

DMA dimethylaniline

DMP Dess-Martin periodinane

DMSO dimethyl sulfoxide

EDG electron donating group equiv Equivalent(s)

EWG electron withdrawing group h hour(s)

HAT hydrogen atom transfer

HRMS high resolution mass spectrometry

IBX iodosobenzoic acid

IR infra-red min minute(s)

NIS N-iodosuccinimide

NMR nuclear magnetic resonance

PDC pyridinium dichromate

PG protecting group

PMB para-methoxybenzyl

PPA polyphosphoric acid

SAR structure-activity relationship

SET single electron transfer

TBAF tetrabutylammonium floride

TBDMS tert-butyldimethylsilyl

TEA triethylamine

TEOC 2-trimethylsilylethoxycarbonyl

THF tetrahydrofuran

TLC thin layer chromatography

TPAP tetra-n-propylammonium perruthenate

TPP tetraphenylporphyrin

Ts p-toluenesulfonyl

TsOH p-toluenesulfonic acid

TSPP tetra(p-sulfonatophenyl)porphyrin ttp tetrakis(4-methylphenyl)porphyrin

xii

CHAPTER 1: ULTRASOUND ASSISTED ONE-POT SYNTHESIS OF BENZOFUSED-P-INDOLEQUINONES FROM 1,4-NAPHTHOQUINONE AND α-AMINOACETALS

1.1. Introduction Indolequinones can be classified into two types of compounds based on their quinone structures: p-indolequinones and o-indolequinones. However, the applications of p- indolequinones are more dominant in synthetic organic chemistry since they constitute an important class of compounds that possess interesting properties. They have been reported to be powerful anticancer natural products such as Murrayaquinone A (1),1-5 Exiguamine A (2),6 BE

10988 (3),7 and dipyrrolobenzoquinone (+)-terreusinone (4)8 (Fig. 1). They are also key precursors for the synthesis of many useful medicinal compounds including Lymphostin (5),9

Discorhabdin C (6),10 E09 (7),11 or the marine alkaloid Tsitsikammamines A (8)12,13 (Fig. 2). In synthetic medicinal chemistry, they are usually referred to as effective prodrugs.14-17

Additionally, their cytotoxicities result from their unique structures; the structure-activity relationship (SAR) has been investigated in vivo and in vitro.18-20 Therefore, to advance the understanding of the mechanism of their biological activities, it is required to create a diverse library of indolequinones. This task has attracted synthetic chemists over the last few decades. In this section, a review of synthetic methodology development for p-indolequinones will be provided. The synthesis of related compounds such as carbazoles or cyclopropamitosenes can be found in our recent report21 and will not be included in this section. The methods were categorized into three general groups: oxidation of indoles, cyclization of quinones, and other methods.

Figure 1. 1. Natural products containing indolequinone structures

Figure 1. 2. Medicinal compounds synthesized from indolequinone precursors

1.1.1. Oxidation of indoles 1.1.1.1. Oxidation by Fremy’s salt

In methodology development of indolequinone synthesis, Fremy’s salt [K2NO(SO3)2] is considered to be the most powerful tool utilized. Moreover, the use of this salt accounts for the major portion to construct indolequinones in natural product syntheses and medicinal chemistry.

The oxidizing properties of Fremy’s salt as a single electron transfer agent have been investigated and well established.22 In general, two starting materials can be used to synthesize p- quinones by oxidation: phenol and aniline derivatives.22 Thus, Fremy’s salt has been readily applied to p-indolequinone synthesis using indoles as starting materials that have a hydroxyl or an amino group on the fused benzene ring.

Oxidation of indoles with hydroxyl groups

In the total synthesis of E09, the preparation of the key indolequinone 10 from 4- hydroxyindole 9 as a building block was accomplished by Fremy's salt oxidation (Eq. 1).11 The effect of phosphonate buffer condition on indoles oxidation by Fremy's salt was also investigated.23

This reaction condition was found to work well for the synthesis of precursor 12a for

Lymphostin (5) and 12b for exiguamines (Eq. 2)9,24 as well as precursors 14 for Discorhabdin C

(6) (Eq. 3).10,25,26 The same oxidation condition was also utilized in the synthesis of BE 10988

(3) (Scheme 1.1).7,27

Scheme 1. 1. Synthesis of BE 10988 by Moody et al.

The oxidation of hydroxyindoles 17, which have a formyl group at the para-position to the hydroxyl group, gave p-indolequinones 18 as the products, accompanied by loss of the formyl group (Eq. 4).28

Oxidation of indoles with amino groups

Similarly to a hydroxyl group, the indole derivatives bearing an amino group at the 4- or 7- position were readily oxidized by Fremy’s salt. The phosphonate buffer was also required to obtain indolequinones from indoles in acceptable yields.16,18-20,29-33 In a particular case, indolequinone 20a was obtained quantitatively from 19a (Eq. 5).34 Additionally, this method tolerated a silyl protecting group, thus indolequinone 20b was obtained from 19b in 79% yield

(Eq. 5).35

1.1.1.2. Oxidation by other metal reagents

In addition to Fremy’s salt, many other oxidation methods were also investigated and applied to the preparation of indolequinones. Ceric ammonium nitrate (CAN) has been most frequently used in organic synthesis as an oxidant. Indolequinones 22 was obtained in good yields by using

CAN in acetonitrile/water (Eq. 6).36-39 On the other hand, the use of acetic acid in water for the

CAN oxidation of 3-substituted indoles gave low yields of indolequinones.40 Furthermore, other solvent systems and additives were also found to be effective for oxidation. When tetrabutylammonium hydrogen sulfate was used in combination with CAN in dichloromethane for the oxidation of 4,6,7-trimethoxyindoles, indole-4,7-diones was selectively formed.41,42

A cobalt(II) complex with the salen ligand, commonly known as salcomine, also exhibits interesting oxidizing properties. This reagent was, therefore, appreciably explored for the conversion of indoles into indolequinones 18b and 23 (Eq. 7).43-45

The combination of dichromate salts and sulfuric acid is well-known as a strong oxidizing agent. When applied to indolequinones synthesis, it was found to be quite useful although the availability of unprotected hydroxyl groups is required for oxidation (Scheme 1.2).46,47

Scheme 1. 2. Oxidation of indoles to indolequinones by dichromate reagent

The reaction with aluminum chloride for hydrolysis followed by iron chloride for oxidation was another method that readily oxidized the dimethoxyindoles 27c and 27d to indolequinones

28c and 28d, respectively (Eq. 8).48

Dess–Martin Periodinane (DMP) is also useful since it can be used in mild reaction conditions.

Being one of the experts in using DMP, Nicolaou et al. developed a remarkable methodology to prepare quinones, including indolequinone 30 from 29 (Eq. 9).49

1.1.2. Cyclization of quinones Although the conventional methods of oxidation of indoles to indolequinones have been predominantly employed in the past few decades, these methods still have some drawbacks. One of them is the formation of o-indolequinones as byproducts.48,50-52 Additionally, the starting materials, indole precursors for p-indolequinones, are usually required to have a hydroxyl or an

6 amino group at the 4-, or 7-position. Effectively introducing these functional groups into indoles is laborious work requiring long synthetic routes. Therefore, alternative pathways have been sought to simplify the synthesis. One of the most successful synthetic pathways is the direct cyclization of quinone derivatives. This approach can avoid the oxidation step, which sometimes is problematic in regioselectivity and functional group tolerance.

The synthesis of indolequinones from quinones has been under development since the late

1970’s. The majority of these methods use transition metals such as palladium, copper, gold, and silver to mediate or catalyze the annulation of quinones with enamines, alkynes, or aniline derivatives. Other metals such as manganese and cerium, on the other hand, provide the cyclization of quinones through a different mechanism – oxidative free radical reactions. There are also some methods without using transition metals for cyclization; bases, acids, heat, and UV light were used instead and were proven to be as efficient as metal reagents.

1.1.2.1. Metal mediated and catalyzed cyclization

Hegedus et al. reported the palladium-catalyzed synthesis of indolequinone 32 from allylaminoquinone 31 (Eq.10),53,54 as well as indolequinones 34 from N-allylbromoquinone 33

(Eq. 11).55

Beside palladium, copper has been prominent among the many metals used for the cyclization of quinones. The copper-catalyzed annulation of bromoquinones and enamines has been

56,57 investigated using Cu(OAc)2·H2O (Eq. 12). The detailed mechanism was also studied and quinone was proved to act as an electrophile toward enamines. Instead of Cu(OAc)2·H2O, this electrophilic attack can also be assisted by AcOH/NaOAc or NaOH,58,59 pyridine,60 and triethyl amine.61

Moreover, the preparation of indolequinones via Sonogashira coupling/cyclization cascade reaction in one-pot has been developed by Yamashita recently. A proposed detailed mechanism is shown in Scheme 1.3.62 The cyclization step from 38 to 39 can be accomplished by using

63 catalytic amount of KOH in mesitylene as solvent, or equimolar quantity of K2CO3 in acetonitrile.64

Scheme 1. 3. Yamashita’s utilization of Sonogashira coupling reaction in the synthesis of

indolequinones

Even though it seems that palladium and copper dominate in the catalyzed and mediated reactions for the quinone cyclization, there is still room for method development using other metals. Mn, Ce, Au, and Ag have been reported to achieve this cyclization effectively. With a similar mechanism, gold and silver were also proved to be promising catalysts for the annulation of 2-bromo-1,4-naphthoquinone 40 and enamines 41 (Eq. 13).65

Chuang et al. took a different approach to the synthesis of indolequinones involving both the use of metals and a radical reaction pathway (Scheme 1.4).66,67 However, due to the nature of radical reactions, factors including low regioselectivity and byproduct formation were observed.

A mechanistic explanation for this drawback has also been provided in Scheme 1.4. Velu et al. further developed Chuang’s method by investigating additional substrates including quinones68 and applied this methodology successfully to the total syntheses of bispyrroloquinone69,70

Zyzzyanone A71 and Calothrixin A and B.72

Scheme 1. 4. Formation of indolequinones using Ce(IV) and Mn(III)

1.1.2.2. Metal-free cyclization

Some other research also integrated p-quinones as starting materials for the synthesis of p- indolequinones in metal-free conditions. The cyclization products were alternatively obtained with the use of heat, UV light, acids, and bases.

The formation of indolequinones by thermal decomposition of azidoquinones was first reported by Moore et al. in 1969.73 Under heating in benzene, the intramolecular reaction afforded indolequinones 44 in good yields from 43 (Eq. 14).74,75 Later, it was found that the intermolecular [2+3]-photocycloaddition between 2-aminonaphthoquinone 45 and alkenes 46 also afforded p-indolequinones 47 (Eq. 15).76

Other studies also utilized acids to build indolequinone structures. In the total synthesis of the marine alkaloid Tsitsikammamine A (8), Delfourne and co-workers have been successful in producing indolequinone moieties by reacting an amino ethanol derivative 49 and a quinone derivative 48 (Scheme 1.5).12,13 The use of triflouroacetic acid furnished the ring closure product

51 from 50. Then, manganese dioxide was required to convert dihydroindolequinones 51 into indolequinones 52. The treatment of quinones 53 with primary amine 54 in methanol followed by addition of 2N HCl resulted in moderate to good yields of indolequinones 55 (Scheme 1.6).77

Treatment with 2N HCl can be replaced by addition of CH2N2 or applying heat.

Scheme 1. 5. Preparation of indolequinone precursor to marine alkaloid tsitsikammamine A by

Delfourne and co-workers

Scheme 1. 6. Indolequinones 55 synthesized by quinone–amine cyclization followed by dehydration

Another interesting result was obtained by Zhang et al.78 The reaction of 2- methoxynaphthoquinone and tryptamine followed by treatment with DDQ and acetic acid resulted in a good yield of indolequinone 57 (Scheme 1.7).78

Scheme 1. 7. Synthesis of indolequinone 57 from tryptamine and 2-methoxynaphthoquinone

The isomerization of o-quinones to p-quinones has been also well established and was therefore used as a tool to synthesize p-indolequinone from o-indolequinones. 0.1N HCl aq. facilitated this isomerization.79

1.1.3. Miscellaneous methods

Besides the oxidation of indoles and cyclization of quinones, there are other notable synthetic methods utilizing a variety of starting materials and catalysts to prepare p-indolequinones.

Friedel-Crafts type cyclization gave indolequinones using different reagents such as phosphorus pentoxide (Eq. 16),80 anhydrous aluminum chloride (Eq. 16),81 polyphosphoric acid

(PPA) (Eq. 17).82

The thermolysis of cyclobutenones was also proved to be a useful tool as it generated p- indolequinones in acceptable to good yields (Eq. 18).83,84

Regarding using dehydrogenation for indolequinone synthesis, Malesani’s work is a prime example of the trend. They proved that elemental selenium, MnO2, DDQ, and chloranil could not dehydrogenate their compound 64 to form 65. On the other hand, heating of 64 for prolonged reaction time at 250 oC in the presence of palladium on activated carbon in benzene enabled formation of indolequinone 65, which was separated from the reaction mixture by vacuum sublimation (Eq. 19).85 However, the yield of 65 was not reported in this work.

These special methods can avoid the problem in functional groups toleration found in oxidation of indoles. One disadvantage is that they still involve the synthesis of starting materials through many steps and cannot be generalized in many cases. Therefore, among all three methods, cyclization of quinones seems to be the most efficient for further development among all. However, this approach requires heavy metals as catalysts or reagents. Moreover, the great majority of them only describe quinones as electrophiles in cyclization. There were only three examples that aminoquinones intramolecularly attacks a carboxylic carbon,86,87 an alcoholic,12 or a carbonyl carbon.88 Although they did not mention the mechanism, it seems that aminoquinones worked as nucleophiles. In addition, these reactions either required multi-step12 or proceeded with only one specific substrate along with laborious syntheses of starting materials12,88 or resulted in low yields12,86-88 and in a case, it was reported to be unable to reproduce.89 Thus, we sought to develop a synthesis of p-indolequinones utilizing the nucleophilicity of aminoquinones from 1,4-naphthoquinone and -aminoacetals. The results of this new synthetic methodology development with a detailed mechanism are discussed in the following section.

1.2. Results and discussion

Our initial attempt of utilizing 1,4-naphthoquinone 66 in bioactive compounds synthesis was to synthesize heterocycles such as isoquinolinoles 72 (Scheme 1.8). The key compound 67 was obtained from the photo-Friedel–Craft reaction using sunlight as reported previously by our group.90 However, reductive amination of 67 with amino acetaldehyde dimethyl acetal 68 and NaBH4 in methanol did not give the desired product

69. It might be due to the failure in imine formation prior to reduction by NaBH4.

Therefore, an alternative pathway was designed to obtained 69 using sunlight reaction

15 between quinones and imines (Scheme 1.9). We hypothesized that hydrogen abstraction from imines could happen similarly as in the case of aldehydes. This alternative approach also turned out ineffective.

Scheme 1. 8. Planned synthesis of isoquinolinoles 72

Scheme 1. 9. Alternate synthesis of 69a

Simultaneously, synthesis of another type of nitrogen-containing heterocycles was attempted as illustrated in Scheme 1.10. Oxidation of 67 by different reagents successfully gave 74 in good yields (Eq. 20 and Table 1.1). However, the cyclization step to synthesize 75 with a diamine did not happen for all the R group of 74 even in the presence of a dehydrating agent such as molecular sieves and Na2SO4 or with catalysts including FeCl3 and acetic acid. Instead, the formation of an amination product was

16 observed (Eq. 21). This amination reaction was in agreement with the reported results

91 using CeCl3•7H2O as the catalyst.

Scheme 1. 10. Planned Synthesis of heterocycles 75

Table 1. 1. Oxidation of 67 by different reagents R reagents Solvents Yield of 74 (%)

C6H5 CAN CH3CN/H2O quant.

C6H5 Ag2O MeOH 80

CH3 CAN CH3CN/H2O quant.

C11H23 CAN CH3CN/H2O 88

C11H23 Ag2O MeOH 78

This oxidative amination reaction91 was then utilized to synthesize a rare heterocycle compound, indole-3-one 79, which has been neglected from biological activity screening as well as synthetic methodology development. Compound 79 can also serve as the precursor for the bioactive indolequinone 80. The planned synthesis pathway is illustrated in Scheme 1.11.

Scheme 1. 11. Planned synthesis of indolequinone 80

The initial amination step was carried out using both ethanol and acetonitrile with and without

CeCl3•7H2O as the catalyst. It was found that in the presence of catalyst, after stirring at room temperature for 24 hours in acetonitrile, 77 was obtained quantitatively (Eq. 22 and Table 1.2).

Table 1. 2. Reaction conditions for the amination of naphthoquinone Products Solvents Catalyst (5 mol%) Yield (%)

77a CH3CN CeCl3•7H2O quant.

77a CH3CN – 80

a 77a EtOH CeCl3•7H2O –

b 77b CH3CN CeCl3•7H2O quant.

77c CH3CN CeCl3•7H2O quant. a1,4-naphthoquinone cannot be dissolved completely in ethanol and created a cloudy solution. No reaction happened. bRegiochemistry and regioselectivity of compound 77b was not determined.

The second step of the synthesis involved deprotection of the acetal protecting group. This task was reported to be accomplished by using aqueous acidic condition.92 However, in our case, many attempts using different acid catalysts did not give desired product 78 (Eq. 23 and Table

1.3).

Table 1. 3. List of the reaction conditions for deprotection of 77a Reagents/Catalysts Conditions

1N HCl MeOH/H2O, reflux

10% AcOH MeOH/H2O, rt to reflux

10% AcOH CH3CN/H2O, rt to reflux

TsOH•H2O (10 mol%) CH3CN/H2O, rt to reflux

CF3COOH (10 mol%) CHCl3/H2O, rt to reflux

TsOH•H2O (5 mol%) Acetone/H2O, rt to reflux

2.5M AcOH aq. THF, reflux

CAN/K2CO3 CH3CN/H2O

The failure of these reactions can be attributed to the presence of the basic N–H in the molecule of 77a. To address this problem, a more stable protection group for N–H was planned to be introduced before the hydrolysis of dimethyl acetal. The common tosyl protective group was first chosen. However, the reaction between 77a and TsCl in pyridine did not proceed to 81

(Eq. 24, condition 1). Changing pyridine to a stronger base such as NaH or using allyl protection as an alternate also could not afford 81 (Eq. 24, condition 2 and 3. Interestingly, when 77a was treated with triethylamine and triflouroacetic anhydride in wet THF, indolequinone 82 was obtained in 30% yield (Eq. 25).

We hypothesized that the reaction involved intermediates 83 to 85; and an intramolecular nucleophilic attack of quinone to the in-situ generated carbonyl group played the key role in cyclization step (Scheme 1.12). The desired indolequinone was then formed in one reaction without having to go through indole-3-one 79 as planned in Scheme 1.11. Thus, we further investigated and developed this reaction to a synthetic methodology for benzofused-p- indolequinones. The general reaction is shown in Scheme 1.13.

Scheme 1. 12. Mechanism of indolequinone 82 formation

Scheme 1. 13. General reaction for indolequinone synthetic methodology develoment

When aminoacetal 68 was replaced by a secondary amine 86a (R = Bn) (Eq. 26), the amination reaction did not complete, and 58% of 1,4-naphthoquinone was recovered. 100% conversion of naphthoquinone was accomplished when the reaction was carried out in dry acetonitrile using 10 equivalents of amine 86a with the assistance of ultrasound (Eq. 26). The formation of aminoquinone 87a was confirmed by crude 1H NMR. However, the product 87a could not be isolated by column chromatography with silica gel or alumina since an N- debenzylation happened as reported.93 Thus, the synthesis of indolequinones was then investigated further in one-pot, as shown in Scheme 1.14. Ten equivalents of 86a was added to a

1 mL of 1M solution of 1,4-naphthoquinone in dry acetonitrile in the presence of 5 mol% of

CeCl3·7H2O at room temperature, and the mixture was placed in a sonicator for 24 h. The mixture was then diluted by additional 1 mL of acetonitrile and treated with 1 mL of 1M H2SO4 aq. at 70 oC for 24 h. The corresponding benzofused-p-indolequinone 88a (R = Bn) was obtained in 77% yield after column chromatography (Scheme 1.14). In one-pot manner, it was also found that 10 equivalents of the amines are required to achieve a good yield of indolequinone (Eq. 27 and Table 1.4).

Scheme 1. 14. Formation of indolequinone 88a

Table 1. 4. Screening of amine equivalents Equivalent of amine 86b 2 5 10

Yield of 88b (%) 19 43 87

To develop the one-pot reaction, the amination step and deprotection-cyclization steps should work in the same solvent system. Since the deprotection of the acetal requires the presence of water for the formation of aldehyde, some water-miscible solvents were examined, such as acetonitrile, ethanol, THF, and nitromethane (Eq. 28 and Table 1.5). The reaction in acetonitrile gave the best result, and the use of THF and ethanol resulted in low yield of 88c. The low yield in ethanol is due to the effect of this solvent on the equilibrium of forming aldehyde. In addition, the better result in acetonitlile than THF can be attributed to the miscibility with water.

Nitromethane suppressed the reaction because of its amine sensitizing activity.94

Table 1. 5. Formation of 88c in various solvents Solvent CH3CN THF EtOH CH3NO2

Yield of 88c (%) 81 50 47 –

Since the miscibility with water seems to have some effects on the reaction, the additional amount of acetonitrile in the cyclization step was also investigated (Eq. 29 and Table 1.6, entries

1-5). The addition of 1 mL of CH3CN in the second step, which resulted in total amount of 2 mL of CH3CN, gave the best result (88%, entry 3). Without the addition of CH3CN, a significant drop of the product yield was observed (38%, entry 2). When the reaction was run under neat condition, only a trace amount of product was obtained (entry 1). The dilution of the reaction mixture with more than 1 mL also resulted in lower yields (entries 4, 5). In the cyclization step,

23 acid is essential to form aldehyde as an electrophile. Thus, the effect of acid was also investigated. Ten equivalents of acids were used to assure the excess amount of amine was neutralized and did not hinder the cyclization. Sulfuric acid showed good activity while

TsOH·H2O or HCl did not (Table 1.6, entries 2,6,7).

Table 1. 6. Reaction concentration and acid scope Entry Addition of CH3CN (x mL) Acid Yield of 88d (%)

a 1 0 H2SO4 Trace

2 0 H2SO4 38

3 1 H2SO4 88

4 2 H2SO4 66

5 3 H2SO4 66

6 1 TsOH•H2O 63

7 1 HCl 16 a Reaction was run under neat condition. No solvent was used in both steps.

More examples of benzo[f]p-indolequinones prepared by using this optimized one-pot process are summarized in Table 1.7 and Eq. 30. Amines 86a–l were synthesized by reductive amination of 68 and aldehydes while 86m–p were obtained by substitution reaction of 2- chloroacetaldehyde dimethyl acetal and allylamine or aniline derivatives. The use of ultrasound in the amination step gave higher yields (entries 3, 5, 10). The electron donating groups on benzene ring resulted in better yields of the products 88 compared to other groups (entries 2, 4–

7). Interestingly, the halogen substituents also affect the reaction yields in a positive way (entries

3, 10, 11). The amine with an allyl substituent was found to be quite unstable under heating condition. Consequently, the indolequinone 88m was afforded in a low yield (entry 13). In case of alkyl amine, the amination step did not proceed well, and no cyclization product formed (entry

12). When aromatic amines were used, the amination was completed, but the cyclization step did not take place even with the electron-donating group on the benzene ring (entries 15–17). We believe that the nitrogen atom was deactivated due to the conjugation of the aromatic system.

Table 1. 7. Synthesis of benzo[f]p-indolequinones 88 from 1,4-naphthoquinone and - aminoacetals 86 Entry Amines R Products Yield (%)a

1 86a 88a C6H5CH2 77 2 86b 88b 4-CH3OC6H4CH2 87 3 86c 88c 4-ClC6H4CH2 81 (61) 4 86d 88d 3-CH3OC6H4CH2 88 5 86e 88e 4-CH3C6H4CH2 80 (49) 6 86f 88f 2-CH3C6H4CH2 80 7 86g 88g 2-HOC6H4CH2 83 8 86h 88h C6H5C≡CCH2 45 9 86i 88i 1-Naph-CH2 70

10 86j 88j 4-BrC6H4CH2 74 (67) 11 86k 88k 4-FC6H4CH2 82 12 86l 88l (CH3)2CH –

13 86m 88m c CH2=CHCH2 25 14 86n 88n 4-CH3OC6H5 – 15 86o 88o 4-CH3C6H5 – 16 86p 88p C6H5 – a All reactions were carried out with 66 (0.1 mmol), 86 (1 mmol), and CeCl3·7H2O (5 mol%) in CH3CN (1 mL), then CH3CN (1mL) and 1M H2SO4 aq (1 mL) were added. bYields without ultrasound in the amination step are given in parentheses. c42% of 66 was recovered.

When the primary amine, amino acetaldehyde dimethyl acetal 68, was used, the product 80 was not obtained under the optimized condition. This can be attributed to the acid-base reaction of the aminoquinone 77a and sulfuric acid, and the resulted salt cannot cyclize and led to the failure of the reaction. When the cyclization step was carried out under reflux condition in dichloroethane (DCE) in the presence of triethylamine and trifluoroacetic anhydride,95 product

80 was obtained in 35% yield without isolation of 77a (Scheme 1.15).

Scheme 1. 15. Synthesis of indolequinone 80

In the case when 1,4-naphthoquinone was replaced by 1,4-benzoquinone, the amination step

26 with 86d proceeded to 87q in 100% conversion. However, as indicated by crude product 1H

NMR, acidification of the reaction mixture only resulted in the formation of a stable aldehyde intermediate, which did not cyclize to 88q under the optimized conditions (Scheme 1.16). We believed that without the benzofused ring, the quinone moiety was not electrophilic enough to attack the carbonyl group to furnish 88q.

Scheme 1. 16. 1,4-benzoquinone as the starting material

We proposed a mechanism including the formation of an aldehyde intermediate followed by nucleophilic attack by aminoquinone (Scheme 1.17). The subsequent dehydration furnishes p- indolequinones.

Scheme 1. 17. Plausible mechanism

To further confirm the aldehyde intermediate, an experiment with 1,4-naphthoquinone 66 and

1.5 equivalents of diethanolamine was carried out (Scheme 1.18). We speculated that the amination followed by oxidation by Dess-Martin Periodinane generates the corresponding aldehyde. This reaction resulted in 49% yield of product 91 suggesting that the aldehyde 90 is the intermediate.

Scheme 1. 18. Treating 1,4-naphthoquinone with diethanol amine

Additionally, the deprotection with acid was stopped after 5 hours, and the reaction mixture was extracted with ice-cold deuterated chloroform (Eq. 31). 1H NMR spectrum of the mixture showed a characteristic aldehyde signal at 9.97 ppm indicating the aldehyde as an intermediate.

1.3. Conclusion A method was developed to synthesize benzo[f]p-indolequinones in one-pot from 1,4- naphthoquinone and -aminoacetals. The use of easily synthesized -aminoacetals eliminates undesired laborious work for the synthesis of starting materials. The mechanism was studied and an aldehyde intermediate was proved. Our method provides an effective, inexpensive, and

28 convenient way to synthesize p-indolequinones.

Moreover, the method is not only limited to the synthesis of p-indolequinones. We believe that it can be extended to other heterocycles such as quinolinones when -aminoacetals are used, or carbazole alkaloid analogs with cyclic aminoacetals as starting materials (Scheme 1.19).

Scheme 1. 19. Extended application of the method

1.4. Experimental details and spectroscopic data

Equipments and materials:

All reactions were carried out using oven-dried glassware. All dry solvents (THF, CH3CN), if stated, were dried and degassed using a Pure Process Technology solvent purification system prior to being used. 200 proof Ethanol was purchased from EMD. All other solvents, if not stated as dry, were purchased and used without further purification. Thin Layer Chromatography (TLC) was performed on EMD silica gel 60 F254; chromatogram was visualized with UV light (254 and

360 nm). Flash column chromatography was performed on Sorbtech silica gel 60 (ASTM 230–

400 mesh). 1H and 13C NMR was recorded at 600 MHz (Jeol 600 MHz NMR spectrometer).

High resolution mass spectra (HRMS) were obtained on an ESI-TOF-MS. Infra-red (IR) spectroscopy was performed on a Perkin-Elmer Spectrum 100.

Commercial reagents were purchased from Sigma-Aldrich, Alfa Aesar, Acros Organics and were used without further purification.

1.4.1. Synthesis of α-aminoacetals 86a–p

1.4.1.1. Synthesis of α-aminoacetals 86a-l

General methods:

A solution of amino acetaldehyde dimethyl acetal 68 (10. 514 g, 1.081 mL, 10 mmol), purchased from Alfa Aesa, and an aldehyde (10 mmol) in dry ethanol was placed in a round bottom flask and stirred for 12 h. To that solution, sodium borohydride powder (0.567 g, 15 mmol) was added at 0 oC slowly over 5 minutes. the solution was then warmed to room temperature. After stirring for 4 h, the reaction was quenched with 3 drops of water and the mixture was filtered through a pad of celite. The solvent was evaporated under reduced pressure, the residue was extracted with 100 mL of ethyl ether and washed with 100 mL of water. The organic layer was dried over MgSO4 anhydrous. Ethyl ether was then evaporated and the resulted viscous liquid was purified by flash column chromatography (SiO2; 4:1 then 3:1 and finally 1:1 hexanes/ethyl acetate).

2-(Benzylamino)acetaldehyde dimethyl acetal (86a) from benzaldehyde and 68

Compound 86a was obtained as a colorless liquid in 95.0 % yield (1.854 g). 1H NMR (600

MHz, Chloroform-d) δ 7.39 – 7.20 (m, 5H, Ar), 4.48 (t, J = 5.5 Hz, 1H, CH(OCH3)2), 3.80 (s,

2H, C6H5CH2NH), 3.36 (s, 6H, OCH3), 2.74 (d, J = 5.5 Hz, 2H, (CH3O)2CHCH2), 1.53 (s, 1H,

NH). 13C NMR (151 MHz, Chloroform-d) δ 140.14 , 128.43 , 128.15 , 127.00 , 103.92 , 53.94 ,

53.92 , 50.53 .

2-(4-methoxybenzylamino)acetaldehyde dimethyl acetal (86b) from 4-methoxy benzaldehyde and 68

Compound 86b was obtained as a colorless liquid in 89.0 % yield (2.004 g). 1H NMR (600 MHz,

Chloroform-d) δ 7.22 (d, J = 8.6 Hz, 2H, Ar), 6.85 (d, J = 9.8 Hz, 2H, Ar), 4.47 (t, J = 5.5 Hz,

1H, CH(OCH3)2), 3.77 (s, 3H, C6H4OCH3), 3.73 (s, 2H, C6H4CH2 ), 3.35 (s, 6H, CH(OCH3)2),

13 2.72 (d, J = 5.5 Hz, 2H, (OCH3)2CHCH2NH), 1.60 (s, 1H, NH). C NMR (151 MHz,

Chloroform-d) δ 158.71 , 132.29 , 129.38 , 113.82 , 103.94 , 55.26 , 53.95 , 53.34 , 50.45 .

2-(4-chlorobenzylamino)acetaldehyde dimethyl acetal (86c) from 4-chloro benzaldehyde and 68

Compound 86c was obtained as a colorless liquid in 80.4 % yield (1.842 g). 1H NMR (600 MHz,

Chloroform-d) δ 7.30 – 7.23 (m, 4H, Ar), 4.47 (t, J = 5.5 Hz, 1H, CH(OCH3)2), 3.76 (s, 2H,

C6H4CH2), 3.36 (s, 6H, CH(OCH3)2), 2.72 (d, J = 5.5 Hz, 2H, (OCH3)2CHCH2), 1.54 (s, 1H,

NH). 13C NMR (151 MHz, Chloroform-d) δ 138.66 , 132.61 , 129.45 , 128.48 , 103.85 , 53.97 ,

53.10 , 50.43 .

2-(3-methoxybenzylamino)acetaldehyde dimethyl acetal (86d) from 3-methoxy benzaldehyde and 68

Compound 86d was obtained as a colorless liquid in 85.9 % yield (1.934 g). 1H NMR (600 MHz,

Chloroform-d) δ 7.27 – 7.20 (m, 1H, Ar), 6.93 – 6.86 (m, 2H, Ar), 6.82 – 6.76 (m, 1H, Ar), 4.49

(t, 1H, CH(OCH3)2), 3.80 (s, 3H, C6H4OCH3), 3.78 (s, 2H, C6H4CH2) 3.36 (s, 6H, CH(OCH3)2),

13 2.75 (d, J = 5.5 Hz, 2H, (OCH3)2CHCH2), 1.55 (s, 1H, NH). C NMR (151 MHz, Chloroform-d)

δ 159.79 , 141.85 , 129.44 , 120.46 , 113.58 , 112.55 , 103.94 , 55.22 , 53.99 , 53.89 , 50.54 .

2-(4-methylbenzylamino)acetaldehyde dimethyl acetal (86e) from 4-methyl benzaldehyde and 68

Compound 86e was obtained as a colorless liquid in 96.5 % yield (2.018 g). 1H NMR (600 MHz,

Chloroform-d) δ 7.19 (d, J = 8.0 Hz, 2H, Ar), 7.11 (d, J = 8.0 Hz, 2H, Ar), 4.47 (t, J = 5.5 Hz,

1H, CH(OCH3)2), 3.75 (s, 2H, C6H4CH2), 3.34 (s, 6H, CH(OCH3)2), 2.73 (d, J = 5.6 Hz, 2H,

13 (OCH3)2CHCH2), 2.31 (s, 3H, C6H4CH3), 1.56 (s, 1H, NH). C NMR (151 MHz, Chloroform-d)

δ 137.03 , 136.45 , 129.04 , 128.06 , 103.86 , 53.84 , 53.58 , 50.41 , 21.04 .

2-(2-methylbenzylamino)acetaldehyde dimethyl acetal (86f) from 2-methyl benzaldehyde and 68

Compound 86f was obtained as a colorless liquid in 64.5 % yield (1.348 g). 1H NMR (600 MHz,

Chloroform-d) δ 7.20 (td, J = 7.5, 3.4 Hz, 1H, Ar), 7.15 – 7.02 (m, 3H, Ar), 4.49 (t, J = 5.5 Hz,

1H, CH(OCH3)2), 3.76 (s, 2H, C6H4CH2), 3.36 (s, 6H, CH(OCH3)2), 2.74 (d, J = 5.5 Hz, 2H,

13 (OCH3)2CHCH2), 2.33 (s, 3H, C6H4CH3), 1.48 (s, 1H, NH). C NMR (151 MHz, Chloroform-d)

δ 140.04 , 137.97 , 128.91 , 128.29 , 127.71 , 125.17 , 103.89 , 53.92 , 53.89 , 50.57 , 21.37 .

2-(2-hydroxybenzylamino)acetaldehyde dimethyl acetal (86g) from salicylaldehyde and 68

Compound 86g was obtained as a colorless liquid in 43.6 % yield (0.921 g). 1H NMR (600 MHz,

Chloroform-d) δ 7.17 (td, J = 8.0, 1.7 Hz, 1H, Ar), 6.98 (dd, J = 7.5, 1.6 Hz, 1H, Ar), 6.83 (dd, J

= 8.1, 1.1 Hz, 1H, Ar), 6.78 (td, J = 7.4, 1.2 Hz, 1H, Ar), 4.49 (t, J = 5.4 Hz, 1H, CH(OCH3)2),

13 4.00 (s, 2H, C6H4CH2), 3.39 (s, 6H, CH(OCH3)2), 2.78 (d, J = 5.5 Hz, 2H, (OCH3)2CHCH2). C

NMR (151 MHz, Chloroform-d) δ 158.21 , 128.89 , 128.49 , 122.39 , 119.16 , 116.48 , 103.20 ,

54.34 , 52.60 , 49.73 .

2-(3-phenylprop-2-ynyl-1-amino)acetaldehyde dimethyl acetal (86h) from phenyl propargyl aldehyde and 68

Compound 86h was obtained as a colorless liquid in 80.0 % yield (1.754 g). 1H NMR (600 MHz,

Chloroform-d) δ 7.45 – 7.38 (m, 2H, Ar), 7.29 (dt, J = 4.4, 2.0 Hz, 3H, Ar), 4.53 (t, J = 5.5 Hz,

1H, CH(OCH3)2), 3.67 (s, 2H, C≡CCH2), 3.40 (s, 6H, CH(OCH3)2), 2.90 (d, J = 5.5 Hz, 2H,

13 (OCH3)2CHCH2), 1.45 (s, 1H, NH). C NMR (151 MHz, Chloroform-d) δ 131.63 , 128.24 ,

128.04 , 123.15 , 103.79 , 87.35 , 83.64 , 53.91 , 49.93 , 39.05 .

2-(1-Naphthylmethyleneamino)acetaldehyde dimethyl acetal (86i) from 1- naphthylaldehyde and 68

Compound 86i was obtained as a colorless liquid in 86.0 % yield (2.110 g). 1H NMR (600 MHz,

Chloroform-d) δ 8.15 (d, J = 8.4 Hz, 1H, Ar), 7.88 (d, J = 8.1 Hz, 1H, Ar), 7.79 (d, J = 8.1 Hz,

1H, Ar), 7.55 (t, J = 7.1 Hz, 1H, Ar), 7.53 – 7.46 (m, 2H, Ar), 7.44 (t, J = 7.5 Hz, 1H, Ar), 4.54

(t, J = 5.5 Hz, 1H, CH(OCH3)2), 4.27 (s, 2H, ArCH2NH), 3.38 (s, 6H, CH(OCH3)2), 1.66 (s, 1H,

NH). 13C NMR (151 MHz, Chloroform-d) δ 135.70 , 133.85 , 131.76 , 128.67 , 127.76 , 126.05 ,

126.01 , 125.58 , 125.35 , 123.63 , 103.85 , 53.84 , 51.49 , 50.95 .

2-(4-bromobenzylamino)acetaldehyde dimethyl acetal (86j) from 4-bromo benzaldehyde and 68

Compound 86j was obtained as a colorless liquid in 88.4 % yield (2.423 g). 1H NMR (600 MHz,

Chloroform-d) δ 7.42 (d, J = 8.4 Hz, 2H, Ar), 7.19 (d, J = 8.4 Hz, 2H, Ar), 4.47 (t, J = 5.5 Hz,

1H, CH(OCH3)2), 3.74 (s, 2H, C6H4CH2), 3.36 (s, 6H, CH(OCH3)2), 2.71 (d, J = 5.5 Hz, 2H,

13 (OCH3)2CHCH2), 1.50 (s, 1H, NH). C NMR (151 MHz, Chloroform-d) δ 140.04 , 137.97 ,

128.91 , 128.29 , 127.71 , 125.17 , 103.89 , 53.92 , 53.89 , 50.57 , 21.37 .

2-(4-florobenzylamino)acetaldehyde dimethyl acetal (86k) from 4-flourobenzaldehyde and

Compound 86k was obtained as a colorless liquid in 52.8 % yield (1.127 g). 1H NMR (600 MHz,

Chloroform-d) δ 7.28 (dd, J = 8.5, 5.5 Hz, 2H, Ar), 7.00 (t, J = 8.7 Hz, 2H, Ar), 4.48 (t, J = 5.5

Hz, 1H, CH(OCH3)2), 3.77 (s, 2H, C6H4CH2), 3.37 (s, 6H, CH(OCH3)2), 2.73 (d, J = 5.5 Hz, 2H,

13 (OCH3)2CHCH2), 1.51 (s, 1H, NH). C NMR (151 MHz, Chloroform-d) δ 161.95 (d, J = 244.6

Hz), 135.89 (d, J = 3.1 Hz), 129.69 (d, J = 8.0 Hz), 115.18 (d, J = 21.4 Hz), 103.90 , 53.99 ,

53.14 , 50.46 .

2-(isopropyl)acetaldehyde dimethyl acetal (86l) from acetone and 68

Compound 86l was obtained as a colorless liquid in 86% yield (1.265 g). 1H NMR (600 MHz,

Chloroform-d) δ 4.47 (t, J = 5.6 Hz, 1H, CH(OCH3)2), 3.39 (s, 6H, CH(OCH3)2), 2.79 (hept, J =

6.3 Hz, 1H, CH(CH3)2), 2.73 (d, J = 5.6 Hz, 2H, NHCH2), 1.06 (d, J = 6.3 Hz, 6H,

13 NHCH(CH3)2). C NMR (151 MHz, Chloroform-d) δ 104.05 , 53.86 , 48.76 , 48.57 , 22.82 .

1.4.1.2. Synthesis of 2-(prop-2-enyl-1-amino)acetaldehyde dimethyl acetal 86m96

To a solution of 2-chloroacetaldehyde dimethyl acetal (6.228 g, 5.95 mL, 0.05 mol) in dry acetone, was added sodium iodide (14.98 g, 0.1 mol). The mixture was reflux for 24 h and was then filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The resulted red liquid was transfer to a seal tube. To that tube was added allyl amine (8.56 g, 11.22 mL, 0.15 mol) and the solution was kept at 80 oC for 5 h. The solid formed was filtered off and the filtrate was concentrated under reduced pressure. Water was added and the mixture was extracted with CH2Cl2 (3x50 mL). The organic extracts was combined and dried over MgSO4 anhydrous. The solvent was evaporated and the residue was purified by flash column chromatography (SiO2; 4:1 hexanes/ethyl acetate) to get 3.12 g (43%) of 86m as a yellow oil.

The compound was used without further purification or characterization as being previously

96 1 reported. H NMR (600 MHz, Chloroform-d) δ 5.94 – 5.84 (m, 1H, CH2=CHCH2NH), 5.19

(dq, J = 17.2, 1.6 Hz, 1H, CH2=CHCH2NH), 5.11 (dq, J = 10.2, 1.3 Hz, 1H, CH2=CHCH2NH),

4.48 (t, J = 5.5 Hz, 1H, CH(OCH3)2), 3.39 (s, 6H, CH(OCH3)2), 3.27 (dt, J = 6.0, 1.4 Hz, 2H,

CH2=CHCH2NH), 2.74 (d, J = 5.5 Hz, 2H, (OCH3)2CHCH2), 1.57 (s, 1H, NH).

1.4.1.3. Synthesis of aminoacetaldehyde dimethyl acetals 86n–p

General procudure:

0.6 g of sodiumhydride (NaH) powder was dissolved 20 mL of dry THF in a round bottom flask.

To that mixture was added an aniline derivative (60 mmol) solution in dry THF (10 mL) drop by drop. After stirring for 30 min, Chloroacetaldehyde dimethyl acetal (2.49 g, 2.26 mL, 20 mmol) in dry THF (10 mL) was dropwisely added. The reaction was continued to stirred at room temperature and monitored by TLC. the reaction was then diluted slowly with water and extracted with ether (3 x 50 mL). The organic layer was combined and dried over MgSO4 anhydrous. The solvent was removed under reduced pressure and the residue was purified by column chromatography (SiO2; 4:1 hexanes/ethyl acetate).

2-(4-methoxyphenylamino)acetaldehyde dimethyl acetal (86n) from anisidine

Compound 86n was obtained as a red liquid in 60.0 % yield (2.533 g). 1H NMR (600 MHz,

Chloroform-d) δ 6.70 (dd, J = 105.1, 8.9 Hz, 4H, Ar), 4.55 (t, J = 5.5 Hz, 1H, CH(OCH3)2), 3.73

13 (s, 3H, C6H4OCH3), 3.40 (s, 6H, CH)OCH3)2), 3.21 (d, J = 5.5 Hz, 2H, (OCH3)2CHCH2). C

NMR (151 MHz, Chloroform-d) δ 152.24 , 142.05 , 114.78 , 114.30 , 102.67 , 55.58 , 53.73 ,

46.33 .

2-(4-methylphenylamino)acetaldehyde dimethyl acetal (86o)

Compound 86o was obtained as a red liquid in 53.0 % yield (2.068 g). 1H NMR (600 MHz,

Chloroform-d) δ 7.06 (d, J = 7.3 Hz, 2H, Ar), 6.63 (d, J = 6.7 Hz, 2H, Ar), 4.62 (t, J = 5.5 Hz,

1H, CH(OCH3)2), 3.46 (s, 6H, CH(OCH3)2), 3.30 (d, J = 5.5 Hz, 2H, (OCH3)2CHCH2), 2.32 (s,

13 3H, C6H4CH3). C NMR (151 MHz, Chloroform-d) δ 145.58 , 129.60 , 126.57 , 113.06 , 102.50

, 53.53 , 45.60 , 20.20 .

2-(phenylamino)acetaldehyde dimethyl acetal (86p)

Compound 86p was obtained as a red liquid in 49.0 % yield (1.775 g). 1H NMR (600 MHz,

Chloroform-d) δ 7.23 (dt, J = 15.5, 8.4 Hz, 2H, Ar), 6.73 (ddd, J = 59.1, 14.6, 7.9 Hz, 3H, Ar),

4.60 (dt, J = 14.2, 5.5 Hz, 1H, CH(OCH3)2), 3.96 (s, 1H, NH), 3.45 (d, J = 14.1 Hz, 6H,

13 CH(OCH3)2), 3.30 (dd, J = 15.3, 5.5 Hz, 2H, (OCH3)2CHCH2). C NMR (151 MHz,

Chloroform-d) δ 147.85 , 129.18 , 117.57 , 112.94 , 102.49 , 53.69 , 45.27 .

1.4.2. Synthesis of benzo[f]p-indolequinones 88a–p

The solution of naphthoquinone (15.8 mg, 0.1 mmol), CeCl3·7H2O (1.90 mg, 5 mol%), and an amine 86a–p (1 mmol) in 1 mL of a dry CH3CN was kept in a sonicator. After 24 h the

38 sonication was stopped and to that solution was added 1 mL of the 1M aqueous solution of sulfuric acid and diluted with 1 mL of CH3CN. The reaction was stirred at 70 °C for 24 h. The solvent was evaporated under reduced pressure and the residue was diluted with CH2Cl2 and washed with water. The organic layer was combined and dried over MgSO4 anhydrous. The solvent was removed under reduced pressure and the residue was purified by column chromatography (SiO2; 9:1 hexanes/ethyl acetate).

1-benzyl benzo[f]p-indolequinone

Compound 88a was obtained as a yellow solid in 77.0 % yield (22.0 mg). Mp = 166–169 °C. IR

(neat, cm-1) 1651.91, 1403.52, 1239.59, 1042.91, 928.76, 770.99, 714.44, 693.90. 1H NMR (600

MHz, Chloroform-d) δ 8.20 – 8.16 (m, 1H, Ar), 8.16 – 8.13 (m, 1H, Ar), 7.70 – 7.66 (m, 2H,

Ar), 7.38 – 7.26 (m, 4H, Ar), 7.26 – 7.25 (m, 1H, Ar), 7.00 (d, J = 2.8 Hz, 1H, CH=CHN), 6.80

13 (d, J = 2.8 Hz, 1H, CH=CHN), 5.72 (s, 2H, C6H5CH2N). C NMR (151 MHz, Chloroform-d) δ

180.98 , 176.26 , 136.43 , 134.02 , 133.78 , 133.12 , 133.08 , 130.82 , 130.41 , 129.08 , 128.94 ,

128.16 , 127.49 , 126.62 , 126.51 , 108.28 , 52.39 . HRMS (ESI+): [M–H]+ Calculated: 288.1024;

Found: 288.1038.

1-(4-methoxybenzyl) benzo[f]p-indolequinone

Compound 88b was obtained as a yellow solid in 87.0 % yield (27.6 mg). Mp = 174–176 °C. IR

(neat, cm-1) 3139.06, 3112.95, 2937.16, 2837.50, 1663.02, 1645.49, 1612.02, 1595.59, 1585.79,

1525.91, 1512.81, 1501.11, 1470.54, 1457.89, 1444.64, 1422.52, 1400.52, 1373.52, 1357.28,

1305.82, 1241.63, 1179.85, 1028.46, 922.02, 817.03, 769.24, 717.08, 655.37. 1H NMR (600

MHz, Chloroform-d) δ 8.17 (dt, J = 9.6, 4.7 Hz, 2H, Ar), 7.70 – 7.65 (m, 2H, Ar), 7.24 (d, J =

8.4 Hz, 2H, Ar), 6.98 (d, J = 2.8 Hz, 1H, CH=CHN), 6.88 (d, J = 8.0 Hz, 2H, Ar), 6.77 (d, J =

13 2.8 Hz, 1H, CH=CHN), 5.64 (s, 2H, C6H4CH2N), 3.79 (s, 3H, C6H4OCH3). C NMR (151 MHz,

Chloroform-d) δ 135.65 , 134.05 , 133.91 , 133.39 , 133.30 , 132.23 , 130.89 , 129.24 , 126.84 ,

126.67 , 122.34 , 108.61 , 100.07 , 51.96. HRMS (ESI+): [M–H]+ Calculated: 318.1130; Found:

318.1080.

1-(4-chlorobenzyl) benzo[f]p-indolequinone

Compound 88c was obtained as a yellow solid in 81.0 % yield (26.0 mg). Mp = 180–183 °C. IR

(neat, cm-1) 2992.12, 1665.68, 1650.64, 1589.89, 1523.80, 1498.35, 1402.73, 1370.85, 1234.97,

928.52, 759.32, 712.64. 1H NMR (600 MHz, Chloroform-d) δ 8.21 – 8.16 (m, 1H, Ar), 8.16 –

8.11 (m, 1H, Ar), 7.71 – 7.66 (m, 2H, Ar), 7.32 (d, J = 8.5 Hz, 2H, Ar), 7.20 (d, J = 8.5 Hz, 2H,

Ar), 7.00 (d, J = 2.8 Hz, 1H, CH=CHN), 6.81 (d, J = 2.7 Hz, 1H, CH=CHN), 5.67 (s, 2H,

13 C6H4CH2N). C NMR (151 MHz, Chloroform-d) δ 180.87 , 176.26 , 134.97 , 134.09 , 133.90 ,

133.75 , 133.23 , 133.14 , 130.73 , 129.21 , 129.12 , 128.79 , 126.68 , 126.51 , 108.45 , 99.92 ,

51.75 . HRMS (ESI+): [M–H]+ Calculated: 322.0634; Found: 322.0584.

1-(3-methoxybenzyl) benzo[f]p-indolequinone

Compound 88d was obtained as a yellow solid in 88.0 % yield (28.0 mg). Mp = 150–152 °C. IR

(neat, cm-1) 2996.03, 1665.77, 1651.31, 1589.78, 1524.11, 1498.48, 1402.90, 1371.25, 1235.58,

1 1182.88, 928.30, 759.75, 713.84, 694.10. H NMR (600 MHz, DMSO-d6) δ 8.07 – 8.04 (m, 2H,

Ar), 7.82 – 7.78 (m, 2H, Ar), 7.61 (d, J = 2.8 Hz, 1H, Ar), 7.27 – 7.23 (m, 1H, Ar), 6.88 – 6.83

(m, 2H, Ar and CH=CHN), 6.82 – 6.79 (m, 1H, Ar), 6.76 (d, J = 2.8 Hz, 1H, CH=CHN), 5.68 (s,

13 2H, C6H4CH2), 3.71 (s, 3H, C6H4OCH3). C NMR (151 MHz, Chloroform-d) δ 180.99 , 176.28 ,

160.02 , 137.98 , 134.04 , 133.79 , 133.13 , 133.07 , 130.85 , 130.43 , 130.00 , 129.08 , 126.63 ,

126.52 , 119.68 , 113.26 , 108.28 , 99.93 , 55.25 , 52.27 . HRMS (ESI+): [M–H]+ Calculated:

318.1130; Found: 318.1085.

1-(4-methylbenzyl) benzo[f]p-indolequinone

Compound 88e was obtained as a yellow solid in 80.0 % yield (24.0 mg). Mp = 187–188 °C. IR

(neat, cm-1) 2988.09, 1665.92, 1650.72, 1589.83, 1523.95, 1498.27, 1402.81, 1370.93, 1235.02,

1182.54, 928.21, 759.46, 713.37, 693.45. 1H NMR (600 MHz, Chloroform-d) δ 8.21 – 8.13 (m,

2H, Ar), 7.68 (td, J = 6.3, 5.8, 3.0 Hz, 2H, Ar), 7.16 (dt, J = 6.9, 3.5 Hz, 4H, Ar), 6.98 (d, J = 2.8

Hz, 1H, CH=CHN), 6.78 (d, J = 2.8 Hz, 1H, CH=CHN), 5.67 (s, 2H, C6H4CH2), 2.33 (s, 3H,

13 C6H4CH3). C NMR (151 MHz, Chloroform-d) δ 180.99 , 176.26 , 159.99 , 137.96 , 134.01 ,

133.76 , 133.12 , 133.08 , 130.86 , 130.40 , 130.00 , 129.05 , 126.62 , 126.52 , 119.67 , 113.28 ,

113.25 , 108.28 , 55.23 , 52.27 . HRMS (ESI+): [M–H]+ Calculated: 302.1181; Found: 302.1153.

1-(2-methylbenzyl) benzo[f]p-indolequinone

Compound 88f was obtained as a yellow solid in 80.0 % yield (24.0 mg). Mp = 140–141 °C. IR

(neat, cm-1) 3113.15, 2914.92, 1665.71, 1649.20, 1590.12, 1524.01, 1498.63, 1403.22, 1371.36,

1235.67, 1182.83, 928.87, 760.22, 714.01, 693.45. 1H NMR (600 MHz, Chloroform-d) δ 8.21 –

8.12 (m, 2H, Ar), 7.71 – 7.64 (m, 2H, Ar), 7.23 (t, J = 7.8 Hz, 1H, Ar), 7.11 (d, J = 7.4 Hz, 1H,

Ar), 7.05 (d, J = 7.7 Hz, 2H, Ar), 6.98 (d, J = 2.8 Hz, 1H, CH=CHN), 6.79 (d, J = 2.8 Hz, 1H,

13 CH=CHN) 5.68 (s, 2H, C6H4CH2), 2.33 (s, 3H, C6H4CH3). C NMR (151 MHz, Chloroform-d)

δ 181.01 , 176.26 , 138.71 , 136.33 , 134.06 , 133.79 , 133.10 , 133.06 , 130.83 , 130.40 , 129.03 ,

128.93 , 128.82 , 128.16 , 126.60 , 126.53 , 124.58 , 108.24 , 52.33 , 21.43 . HRMS (ESI+): [M–

H]+ Calculated: 302.181; Found: 302.1159.

1-(2-hydroxybenzyl) benzo[f]p-indolequinone

Compound 88g was obtained as a yellow solid in 83.0 % yield (25.0 mg). Mp = 140–141 °C. IR

(neat, cm-1) 3194.44, 3143.29, 2837.92, 1641.41, 1592.44, 1498.34, 1459.23, 1422.84, 1386.94,

1 1231.18, 932.65, 716.67. H NMR (600 MHz, DMSO-d6) δ 9.85 (s, 1H, OH), 8.06 – 7.97 (m,

2H, Ar), 7.77 (td, J = 5.2, 2.6 Hz, 2H, Ar), 7.38 (d, J = 2.8 Hz, 1H, CH=CHN), 7.11 – 7.04 (m,

1H, Ar), 6.83 (dd, J = 8.5, 4.0 Hz, 1H, Ar), 6.75 (d, J = 7.5 Hz, 1H, Ar), 6.70 (d, J = 2.8 Hz, 1H,

13 CH=CHN), 6.69 – 6.63 (m, 1H, Ar), 5.61 (s, 2H, C6H4CH2). C NMR (151 MHz, DMSO-d6) δ

180.60 , 175.53 , 155.45 , 134.10 , 134.01 , 133.62 , 133.31 , 130.38 , 129.39 , 128.62 , 128.32 ,

126.70 , 126.58 , 124.04 , 119.66 , 115.53 , 108.01 , 47.81 . HRMS (ESI+): [M–H]+ Calculated:

309.0974; Found: 309.0951.

1-(3-phenylprop-2-ynyl) benzo[f]p-indolequinone

Compound 88h was obtained as a yellow solid in 45.0 % yield (14.0 mg). Mp = °C. IR (neat, cm-

1) 3112.11, 2923.59, 2837.67, 2222.22, 1663.58, 1645.68, 1593.75, 1512.09, 1494.62, 1400.95,

1373.57, 1232.02, 1178.92, 932.87, 715.58. 1H NMR (600 MHz, Chloroform-d) δ 8.19 (td, J =

6.4, 3.3 Hz, 2H, Ar), 7.76 – 7.62 (m, 2H, Ar), 7.47 (d, J = 7.7 Hz, 2H, Ar), 7.41 (d, J = 2.6 Hz,

1H, CH=CHN), 7.37 – 7.30 (m, 3H, Ar), 6.83 (d, J = 2.7 Hz, 1H, CH=CHN), 5.59 (s, 2H,

13 C≡CCH2). C NMR (151 MHz, Chloroform-d) δ 181.05 , 176.45 , 133.33 , 133.23 , 131.96 ,

129.92 , 129.07 , 128.50 , 126.79 , 126.57 , 108.16 , 100.00 , 39.49 . HRMS (ESI+): [M–H]+

Calculated: 312.1024; Found: 312.0985.

1-(1-naphthylmethylene) benzo[f]p-indolequinone

Compound 88i was obtained as a yellow solid in 70.0 % yield (23.6 mg). Mp = 197–200 °C. IR

(neat, cm-1) 3138.88, 2933.58, 1644.94, 1586.59, 1499.87, 1400.47, 1373.18, 1241.27, 1182.88,

930.15, 715.19. 1H NMR (600 MHz, Chloroform-d) δ 8.24 – 8.15 (m, 2H, Ar), 7.98 – 7.89 (m,

2H, Ar), 7.87 (d, J = 8.7 Hz, 1H, Ar), 7.70 (dt, J = 5.7, 2.6 Hz, 2H, Ar), 7.54 (dt, J = 6.7, 2.0 Hz,

2H, Ar), 7.46 – 7.40 (m, 1H, Ar), 7.16 (d, J = 7.7 Hz, 1H, Ar), 6.82 (d, J = 2.7 Hz, 1H,

13 CH=CHN), 6.75 (d, J = 2.7 Hz, 1H, CH=CHN), 6.21 (s, 2H, ArCH2N). C NMR (151 MHz,

Chloroform-d) δ 181.14 , 176.57 , 134.17 , 133.90 , 133.25 , 133.21 , 131.69 , 131.14 , 130.77 ,

130.69 , 129.30 , 129.17 , 129.04 , 127.13 , 126.74 , 126.65 , 126.35 , 126.15 , 125.55 , 122.85 ,

108.31 , 100.00 , 50.51. HRMS (ESI+): [M–H]+ Calculated: 338.1181; Found: 338.1108.

1-(4-bromobenzyl) benzo[f]p-indolequinone

Compound 88j was obtained as a yellow solid in 77.0 % yield (28.0 mg). Mp = 167–170 °C. IR

(neat, cm-1) 2937.54, 2837.70, 1662.95, 1645.18, 1585.83, 1513.02, 1400.51, 1373.53, 1241.75,

1179.45, 1028.37, 921.71, 769.31, 717.05, 701.79, 655.44. 1H NMR (600 MHz, Chloroform-d) δ

8.20 – 8.11 (m, 2H, Ar), 7.72 – 7.64 (m, 2H, Ar), 7.47 (d, J = 8.5 Hz, 2H, Ar), 7.14 (d, J = 8.6

Hz, 2H, Ar), 7.00 (d, J = 2.8 Hz, 1H, CH=CHN), 6.81 (d, J = 2.8 Hz, 1H, CH=CHN), 5.65 (s,

13 2H, C6H4CH2N). C NMR (151 MHz, Chloroform-d) δ 176.28 , 171.46 , 133.10 , 133.06 ,

130.56 , 129.18 , 128.44 , 126.61 , 126.51 , 114.29 , 108.21 , 99.92 , 55.29 , 51.93. HRMS

(ESI+): [M–H]+ Calculated: 366.0130; Found: 366.0033.

1-(4-florobenzyl) benzo[f]p-indolequinone

Compound 88k was obtained as a yellow solid in 82.0 % yield (25.0 mg). Mp = 195–197 °C. IR

(neat, cm-1) 3106.21, 2838.25, 1650.96, 1591.14, 1510.69, 1500.88, 1402.14, 1370.31, 1240.75,

1 1219.14, 925.52, 762.23, 714.99, 700.23. H NMR (600 MHz, DMSO-d6) δ 8.05 (dt, J = 5.3, 3.4

Hz, 2H, Ar), 7.83 – 7.77 (m, 2H, Ar), 7.63 (d, J = 2.8 Hz, 1H, CH=CHN), 7.36 (dd, J = 8.9, 5.5

Hz, 2H, Ar), 7.18 (t, J = 8.9 Hz, 2H, Ar), 6.76 (d, J = 2.7 Hz, 1H, CH=CHN), 5.69 (s, 2H,

13 C6H4CH2N). C NMR (151 MHz, Chloroform-d) δ 181.06, 176.39, 134.09, 133.89, 133.35,

133.27, 132.41, 130.80, 130.40, 129.48 (d, J = 8.1 Hz), 126.73 (d, J = 23.2 Hz), 124.17, 123.71,

116.03 (d, J = 21.7 Hz), 108.56, 51.91. HRMS (ESI+): [M–H]+ Calculated: 306.0930; Found:

306.0902.

1-(prop-2-enyl) benzo[f]p-indolequinone

Compound 88m was obtained as a yellow solid in 25.0 % yield (6.0 mg). Mp =106–109 °C. IR

(neat, cm-1) 3110.77, 2958.77, 2922.69, 2852.81, 1734.28, 1651.91, 1586.95, 1499.22, 1400.22,

1371.62, 1258.36, 1237.05, 1021.43, 930.28, 791.96, 711.25, 698.75. 1H NMR (600 MHz,

Chloroform-d) δ 8.16 – 8.03 (m, 2H, Ar), 7.65 – 7.58 (m, 2H, Ar), 6.92 (d, J = 2.7 Hz, 1H,

CH=CHN), 6.72 (d, J = 2.7 Hz, 1H, CH=CHN), 6.00 (ddt, J = 16.0, 10.5, 5.6 Hz, 1H,

CH2=CHCH2N), 5.19 (d, J = 10.3 Hz, 1H, HCH=CHCH2N), 5.12 – 5.03 (m, 3H,

13 HCH=CHCH2N). C NMR (151 MHz, Chloroform-d) δ 179.97 , 175.13 , 132.96 , 132.76 ,

132.08 , 132.05 , 131.89 , 129.48 , 127.96 , 125.60 , 125.43 , 117.08 , 107.06 , 50.28 , 28.68.

HRMS (ESI+): [M–H]+ Calculated: 238.0868; Found: 238.0799.

1.4.3. Synthesis of benzo[f]p-indolequinone 80

The solution of naphthoquinone (15.8 mg, 1 mmol), CeCl3·7H2O (19.0 mg, 5 mol%), and amine 68 (158 mg, 1.5 mmol) in dry acetonitrile (3 mL) was stirred at room temperature for 24 h. After 24 h the solvent was evaporated under reduced pressure and the residue was dissolved in

DCE (3mL). To that solution was added triethyl amine (15.2 mg, 0.21 mL, 1.5 mmol), triflouroacetic anhydride (31.5 mg, 0.21 mL, 1.5 mmol) and the reaction was relux for 24 h. The solvent was evaporated under reduced pressure and the residue was dilute with CH2Cl2 and washed with water. The organic layer was combined and dried over MgSO4 anhydrous. The solvent was removed under reduced pressure and the residue was purified by column chromatography (SiO2; 3:1 hexanes/ethyl acetate) to get 69.0 mg (35%) of 80 as a bright yellow solid. The 1H NMR of 80 matches with the precedent report.97 1H NMR (600 MHz, Chloroform- d) δ 9.54 (s, 1H, NH), 8.22 (dd, J = 7.2, 1.9 Hz, 1H, Ar), 8.17 (dd, J = 7.0, 1.9 Hz, 1H, Ar), 7.75

– 7.65 (m, 2H, Ar), 7.15 (t, J = 2.7 Hz, 1H, CH=CHN), 6.85 (t, J = 2.5 Hz, 1H, CH=CHN).

1.4.4. Synthesis of 1-(2-hydroxyethyl) benzo[f]p-indolequinone 90

The solution of naphthoquinone (158 mg, 1 mmol), CeCl3·7H2O (19.0 mg, 5 mol%), and diethanol amine (158 mg, 1.5 mmol) in dry acetonitrile (3 mL) was stirred at room temperature for 24 h. To that solution was added Dess-Martin reagent (1.70 g, 4 mmol), 5 mL of acetonitrile, and kept stirring at room temperature for another 24 h. The reaction was then quenched with saturated solutions of sodium thiosulfate and sodium bicarbonate. The resulted mixture were extracted with with CH2Cl2 (3x50 mL) and washed with water. The organic layer was combined and dried over MgSO4 anhydrous. The solvent was removed under reduced pressure and the

47 residue was purified by column chromatography (SiO2; 3:1 hexanes/ethyl acetate) to get 118 mg

(49%) of 90 as a yellow solid. Mp = 124–127 °C. IR (neat, cm-1) 3251.29, 3107.49, 2922.88,

2852.53, 1651.82, 1592.75, 1500.22, 1401.00, 1372.75,1238.50, 1185.55, 928.26, 770.27,

713.52, 693.06. 1H NMR (600 MHz, Chloroform-d) δ 8.18 – 8.13 (m, 1H, Ar), 8.13 – 8.10 (m,

1H, Ar), 7.69 – 7.66 (m, 2H, Ar), 7.06 (d, J = 2.7 Hz, 1H, CH=CHN), 6.75 (d, J = 2.7 Hz, 1H,

13 CH=CHN), 4.63 (t, J = 6 Hz, 2H, HOCH2CH2N), 4.05 (t, J = 6 Hz, 2H, HOCH2CH2N). C

NMR (151 MHz, Chloroform-d) δ 184.43 , 179.90 , 155.86 , 155.60 , 115.96 , 114.05 . HRMS

(ESI+): [M–H]+ Calculated: 242.0817; Found: 242.0950.

1.4.5. Aldehyde intermediate investigation experiment

The solution of naphthoquinone (15.8 mg, 0.1 mmol), CeCl3·7H2O (1.90 mg, 5 mol%), and amine 86d (1 mmol) in 1 mL of a dry CH3CN was kept in a sonicator. After 24 h the sonication was stopped and to that solution was added 1 mL of the 1M H2O solution of sulfuric acid and diluted with 1 mL of CH3CN. The reaction was stirred under reflux for 5 h. The solvent was evaporated under reduced pressure and the residue was dilute with CD3Cl and washed with

1 H2O. The organic layer was dried over MgSO4 and was checked with H NMR. The spectrum showed an aldehyde characteristic peak at 9.97 ppm

1.4.6. Synthesis of aminoquinone 77a

To a solution of naphthoquinone (15.8 mg, 0.1 mmol), CeCl3·7H2O (1.9 mg, 5 mol%) in

CH3CN (1 mL), was added amine 68 (0.1 mmol). The solution was stirred at room temperature for 24 hours and then was filtered through celite. The resulted solution was concentrated under

48 reduced pressure and compound 77a was obtained as dark orange solid in quantitative yield. The

1H NMR of compound 77a matches with the precedent report.98 1H NMR (600 MHz,

Chloroform-d) δ 8.10 (dd, J = 7.7, 1.3 Hz, 1H, Ar), 8.06 (dd, J = 7.7, 1.3 Hz, 1H, Ar), 7.73 (td, J

= 7.5, 1.3 Hz, 1H, Ar), 7.63 (td, J = 7.5, 1.3 Hz, 1H, Ar), 6.05 (s, 1H, NH), 5.77 (s, 1H,

COCH=CNH), 4.60 (t, J = 5.3 Hz, 1H, CH(OCH3)2), 3.44 (s, 6H, CH(OCH3)2), 3.31 (t, J = 5.7

Hz, 2H, (CH3O)2CHCH2NH).

1.4.7. 1H and 13C NMR spectra

2-(Benzylamino)acetaldehyde dimethyl acetal (86a)

2-(4-methoxybenzylamino)acetaldehyde dimethyl acetal (86b)

2-(4-chlorobenzylamino)acetaldehyde dimethyl acetal (86c)

2-(3-methoxybenzylamino)acetaldehyde dimethyl acetal (86d)

2-(4-methylbenzylamino)acetaldehyde dimethyl acetal (86e)

2-(2-methylbenzylamino)acetaldehyde dimethyl acetal (86f)

2-(2-hydroxybenzylamino)acetaldehyde dimethyl acetal (86g)

2-(3-phenylprop-2-ynyl-1-amino)acetaldehyde dimethyl acetal (86h)

2-(1-Naphthylmethyleneamino)acetaldehyde dimethyl acetal (86i)

2-(4-bromobenzylamino)acetaldehyde dimethyl acetal (86j)

2-(4-florobenzylamino)acetaldehyde dimethyl acetal (86k)

2-(isopropyl)acetaldehyde dimethyl acetal (86l)

2-(prop-2-enyl-1-amino)acetaldehyde dimethyl acetal (86m)

2-(4-methoxyphenylamino)acetaldehyde dimethyl acetal (86n)

2-(4-methylphenylamino)acetaldehyde dimethyl acetal (86o)

2-(phenylamino)acetaldehyde dimethyl acetal (86p)

1-benzyl benzo[f]p-indolequinone (88a)

1-(4-methoxybenzyl) benzo[f]p-indolequinone (88b)

1-(4-chlorobenzyl) benzo[f]p-indolequinone (88c)

1-(3-methoxybenzyl) benzo[f]p-indolequinone (88d)

1-(4-methylbenzyl) benzo[f]p-indolequinone (88e)

1-(2-methylbenzyl) benzo[f]p-indolequinone (88f)

1-(2-hydroxybenzyl) benzo[f]p-indolequinone (88g)

1-(3-phenylprop-2-ynyl) benzo[f]p-indolequinone (88h)

1-(1-naphthylmethylene) benzo[f]p-indolequinone (88i)

1-(4-bromobenzyl) benzo[f]p-indolequinone (88j)

1-(4-florobenzyl) benzo[f]p-indolequinone (88k)

1-(prop-2-enyl) benzo[f]p-indolequinone (88m)

Benzo[f]p-indolequinone (80)

1-(2-hydroxyethyl) benzo[f]p-indolequinone (90)

aminoquinone 77a

aldehyde intermediate

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CHAPTER 2: SELECTIVE OXIDATIVE N-DEBENZYLATION OF TERTIARY AND SECONDARY AMINES BY DESS-MARTIN PERIODINANE

2.1. Introduction

N-Dealkylation is an important reaction both in medicinal and synthetic chemistry. In medicinal chemistry, it is known to be a part of the metabolism of amine-containing drugs.1 In synthetic chemistry, N-dealkylation, especially N-debenzylation, is a powerful tool for the cleavage of benzyl protecting group.2 Three types of reagents have been found to accomplish this task: enzyme-derived species, metal, and non-metal reagents. However, methods using heavy metals have environmental issues in waste-disposal, or result in low selectivity of debenzylation over dealkylation. Furthermore, reported non-metal reagents are mostly efficient for limited substrates such as secondary amines. Therefore, a new methodology is demanded to effectively address these issues. Our main finding demonstrated that DMP as the non-metal reagent can selectively debenzylate both tertiary and secondary amines, and thus solves the problems of current methods. In this section, a background of N-dealkylation will be discussed including their advantages and disadvantages.

2.1.1. N-dealkylation using Cytochromes P-450 and other enzyme-derived species:

The dealkylation of amines has drawn great interest from chemists and biochemists since the

Cytochromes P-450 (CYPs) were found to ezymatically catalyze this reaction during drug metabolism. Cytochromes P-450 are a superfamily of monooxygenases that play a central role in metabolism and detoxification of xenobiotics.3 Because iron-oxene was proved as the sole oxidant in P450-catalyzed N-dealkylation,4 both P-450 itself and other oxoiron containing complexes have been used to identify this reaction mechanism. Two common mechanisms,

85 including single electron transfer (SET) (Scheme 2.1)5-13 and hydrogen atom transfer (HAT)

(Scheme 2.2),14-20 have been under debate for the past three decades.

Scheme 2. 1. SET mechanism of P450-catalyzed N-dealkylation

Scheme 2. 2. HAT mechanism of P450-catalyzed N-dealkylation

On the other hand, when a copper dioxygen adduct derived from copper dioxygenase was used for the oxidation of dimethylaniline (DMA), both HAT and SET mechanisms were observed (Scheme 2.3).

Scheme 2. 3. Mechanism of DMA oxidation by copper dioxygen adduct

2.1.2. N-Dealkylation using metal complexes:

Besides understanding the biological mechanism, in synthetic chemistry, selective debenzylation of amines in the presence of alkyl substituents is also of great interest. Using

Cytochrome P-450 structure, which contains iron center, as the original model, many iron complexes have been developed for the dealkylation of amines. One of the first attempts was reported by Bruice et al. in 1981 using tetraphenylporphyrin (TPP) to make the TPPFeIII complex as the reagent for DMA demethylation.21 Smith and co-workers then demonstrated N- debenzylation by combining TPPFeIII and other oxidants including iodosylbenzene or t-butyl hydroperoxide.22,23 It was confirmed that when iodosylbenzene was used, iron porphyrin played the oxidant role while in the presence of t-butyl hydroperoxide, the active oxidant was the t- butoxyl radicals.23-25 Low selectivity of debenzyl/demethyl was observed (Eq. 32).22 A similar result was obtained when manganese porphyrin was used instead of iron porphyrin (Eq. 33).22

Additionally, zinc amalgam and molecular oxygen were also proved as the effective co- oxidant with iron porphyrin reagent for demethylation.26,27 Moreover, when molecular oxygen was used, a number of dimers (97 and 98) as well as formamide 96 were detected as the byproducts even when TPPFeCl was replaced with other complexes and salts such as

Fe(salen)OAc, Fe(salen)2O, Fe(TPP)OAc, Fe3O(OAc)6(H2O)3Cl, or FeCl3, and Fe(ClO4)3 (Eq.

34).27

Besides porphyrin and salen, pyridine-derived ligands were also used to prepare iron complexes as the reagents for the oxidative N-dealkylation reaction.28-30 Complex [FeIIN4Py]2+ was reported to succesfully dealkylate aniline derivatives 99. The products were a mixture of N- methyl and N-ethylaniline. A demethylation-favored selectivity was also observed (Eq. 35).28,30

Using the same complex with the aid of Sc3+, a dimerization of DMA took place.30 On the other hand, the debenzylation of N,N,N-dibenzylmethylamine 102 was studied using a septipyridine iron complex, [Fe2(septipy)2](ClO4)4, as the catalyst in the presence of oxone. Interestingly, demethylation occurred selectively (Eq. 36).29

Similarly, copper salts also showed their efficient catalytic activity on the N-dealkylation of tertiary amines. Copper acetate monohydrate [Cu(OAc)2•H2O] in oxygen atmosphere effectively produced dibutylamine 105 from tributylamine 104 in-situ to give (E)--unsaturated amides

106 (Scheme 2.4).31

Scheme 2. 4. In-situ generation of dibutylamine 105 for the synthesis of (E)--unsaturated

amides 106

In the same manner, CuBr2 was used as the catalyst for the in-situ generation of secondary amines for the amination of benzoxazoles. However, a low debenzylation selectivity was

32 observed (Eq. 37). In contrast, when CuCl or CoCl2 was used as the catalyst in the presence of acetic anhydride under oxygen atmosphere, a good selectivity was observed (Eq. 38).33 Cobalt

Schiff base complexes were also reported to be effective in debenzylation of amines.34,35 In these reports, debenzylation only happened with aniline derivatives. Moreover, when tertiary amines were used, no reaction occurred.34

Furthermore, ruthenium porphyrin complexes, such as [Ru(2,6-Cl2tpp)CO], [Ru(F20-tpp)CO],

[Ru(tpp)CO], or [Ru(4-MeO-tpp)CO], also contributed to the class of catalysts that could be used for oxidative N-dealkylation reaction. Catalytic amount of a Ru complex along with t-butyl hydroperoxide in toluene afforded demethylated amines 115 from tertiary amines 114 (Scheme

36 37 2.5). On the contrary, treating secondary amines with RuO4 and tetra-n-propylammonium perruthenate (TPAP)38 followed by hydrolysis were proved to be a good method for both debenzylation and dealkylation. The drawback was that only secondary amines were investigated and no benzyl/alkyl selective cleavage was observed.

Scheme 2. 5. Mechanism of demethylation using ruthenium catalysts

Palladium is another metal that was found to dealkylate tertiary amines. Five mol% of

o Pd(Xantphos)(CH3CN)2(OTf)2 in iso-propanol at 112 C was able to cleave the C–N bond in diamine 116. However, only demethylene product 117 was found (Scheme 2.6).39

Scheme 2. 6. Mechanism of dealkylation using Pd catalyst

In addition, Rh(III) porphyrin was reported to catalyze C–N bond activation of amines. Under nitrogen atmostphere, at 120 oC, Rh(ttp)H was able to dealkylate many tertiary amines with ethyl, propyl, butyl, or pentyl substituents.40 When further funtionalized tetra(p-sulfonatophenyl)porphyrin was used as the ligand, the resulted complex [(TSPP)RhIII] could cleave

90 methyl, ethyl, as well as benzyl group from tertiary amines. However, N-deethylation is more favored than N-debenzylation when the substrates have both ethyl and benzyl group.41

Titanium (III) chloride, on the other hand, does not require complexation with ligands to work.

42-44 Instead, TiCl3 needs the assistance of Li–THF and I2 to complete the oxidizing system.

Debenzylated products were obtained (Eq. 39 and 40). However, only debenzylation of heterocyclic aromatic substrates was reported, and no selectivity was studied.

In contrast, a selective debenzylation of benzyl tertiary amines was well studied by Smith and co-workers using ceric ammonium nitrate (CAN).45-47 Their results indicate that CAN can easily debenzylate N,N-dibenzyl-N-alkyl amines 122 (Eq. 41). However, the reaction only happened for propyl, butyl, and hexyl substituent. When ethyl and methyl group were present in the amines substrates, debenzylation did not take place (Eq. 41). No selectivity was observed when the substituent was 4-methoxybenzyl (Eq. 42). This method was also not effective for N-benzyl cyclic amines (Figure 2.1).45

Figure 2. 1. Compounds inert to N-debenzylation by CAN

2.1.3. N-Dealkylation using non-metal reagents:

Some non-metal reagents have been also elaborated. Until now, there are still a limited number of reports using non-metal reagents for N-debenzylaton. These reports involve the use of iodine compounds such as iodosobenzoicacid (IBX), iodosylbenzene (PhIO), alkylperoxy idodane, and N-iodosuccinimide (NIS), or more commonly, 2,3-dichloro-5,6-dicyano benzoquinone (DDQ). However, only two cases were reported to work for tertiary amines. A brief review is provided below.

In the total synthesis of Flutimide 127, DDQ was succesfully used for the PMB deprotection of precursor 125 to give 126 in 30% yield (Scheme 2.7).48

Scheme 2. 7. Synthesis of Flutimide 127 by Sheo B. Singh

Another method using diisopropyl azodicarboxylate (DIAD) 128 was reported to effectively debenzylate a variety of secondary amines.49 The reaction proceeded through two steps to afford ammonium salts and benzaldehyde. The mechanism is illustrated in Scheme 2.8. However, this approach is only limited for secondary amine substrates and no selectivity was reported.

Scheme 2. 8. Mechanism of N-debenzylation using DIAD 128

NIS is efficient for deprotecting N-benzyl amines.50 The control of equivalents of NIS contributed to the resulted products (Scheme 2.9).

Scheme 2. 9. N-Debenzylation using NIS

Alkylperoxy iodane 129 also expressed ability to react with amines (Eq. 43). The subtrates were limited to benzylaniline derivatives, and further hydrolysis of the resulted imines to amine was not included in this report.

Additionally, hypervalent iodine compounds have been already used in the reactions with amines. These reports only investigated secondary and primary amines. IBX successfully dehydrogenate secondary benzylamine 131 to form imine 132. No further hydrolysis was reported in this work (Eq. 44).51 Also, dimethylsulfoxide (DMSO) had to be used as the solvent causing difficulty in the purification process. Similarly, benzylamine 133 can be oxidized to aromatic nitriles using Dess-Martin periodinane (DMP) (Eq. 45).52

However, the tertiary amines have never been reported to attack a hypervalent iodine compound such as IBX or DMP. Furthermore N-debenzylation of cyclic amine was reported unsuccessfully even with strong metal reagents.45 Therefore, we sought to develop a methodology using DMP as the non-metal selective N-debenzylation reagent. Our approach turned out to be effective as it prefers cleaving benzyl group over alkyl groups in tertiary amine as well as secondary amine, which is an important characteristic in synthetic chemistry. The use of common solvents such as chloroform and dichloromethane as well as non-metal reagent also enhance the ease of work-up process.

2.2. Results and discussion:

As mentioned before (Chapter 1, Eq. 26), compound 87a could not be isolated by column chromatography either with silica gel or alumina. Moreover, the 1H NMR spectrum of the crude mixture after column chromatography showed characteristic peaks of benzaldehyde at 10 ppm and 7.5–7.9 ppm. Thus, we believe that an oxidative N-debenzylation happened (Eq. 46).

Furthermore, in the process of proving the aldehyde intermediate in our synthesis of benzo[f]- p-indolequinones (Scheme 1.18, Chapter 1), it was found that when intermediate 135 was further heated to 80 oC in the presence of excess DMP (4 equiv), 20% of 80 was formed along with 91

(Scheme 2.10). This suggested an N-dealkylation occured in the course of oxidation-cyclization.

Scheme 2. 10. Treating intermediate 135 with DMP under heating condition

There were two possible pathways by which the mechanism of dealkylation took place

(Scheme 2.11). Path A involves the aldehyde intermediate 136 followed by dealkylation to give

137. Product 80 was then formed by acid-catalyzed cyclization as proposed in chapter 1 (Scheme

1.17). However, it has been proved that aminoquinones with N–H group cannot cyclize to afford benzo[f]-p-indolequinones with only acid catalyst (Scheme 1.15, chapter 1). We believe that N- dealkylation, instead, started from 91 with 138 as the intermediate (Scheme 2.11, path B). Thus, we hypothesized that the presence of carbonyl or phenyl group further enhanced the acidity of H-

(Figure 2.2), which made it easier to form iminium salt intermediate. Among non-metal oxidizing reagents, DMP was well-known as the mild oxidant that can deprotonate only good- acidity H-. Therefore, DMP was chosen to be oxidant to develop a selective method for N- debenzylation of common tertiary as well as secondary amines. For the ease of 1H NMR monitoring as well as conversion calculation, all optimizing reactions was run using deuterated solvents. The conversions reported were calculated based on amount of benzaldehyde formed.

Scheme 2. 11. Speculated mechanism of forming 80 by DMP

Figure 2. 2. Effect of substituent on acidity of H

The optimization for this method started with the equivalent of DMP used (Eq. 47). While one equivalent of DMP gave good conversion of 139 to benzaldehyde and diisopropylamine (DIPA) after 22 h, increasing the amount of DMP to 2 and 3 equivalents significantly retarded the reaction. 1H NMR spectra of these reactions showed a peak of 4.5 ppm of benzylic proton, indicating that starting material 139 was protonated to ammonium salt; and thus it could not attack DMP. The source of proton may come from acetic acid in DMP. Therefore, the larger amount of DMP was used, the more likely starting material was protonated.

Table 2. 1. Solvent effect on formation of benzaldehyde from 139

Solvents CDCl3 CD3CN DMSO-d6 CH2Cl2 CHCl3

Formation of benzaldehyde from 139 (% 80 80 71 88 78 conversion)

Solvent effect was also investigated (Eq. 48 and Table 2.1). The presence of water in this reaction is necessary for the hydrolysis to form benzaldehyde. Therefore, CDCl3 was compared with CD3CN and DMSO-d6. After 22 h, the reactions in CDCl3 and CD3CN showed better results than the one in DMSO-d6. This can be attributed to the solubility of water in DMSO was much higher than in the others. Oxidation by DMP was reported to be enhanced by addition of

98 some equivalents of water. However, a higher equivalent of water or ethanol tends to decompose

DMP into a monoacetate iodinane product.53 Thus, DMSO might have absorbed moist and suppressed the activity of DMP. Chloroform and dichloromethane (DCM) were also used. After reaction, chloroform and DCM were evaporated, and the crude reaction mixture was then

1 dissolved again in CDCl3 for H NMR spectroscopy to calculate conversion. In both cases, it was proved that the use of deuterated solvents is solely for conversion calculation purpose and has no difference for the method to be applied with non-deuterated solvents.

We applied these optimized conditions to investigate the time needed to complete the reaction.

Using CDCl3 as the solvent with 1 equivalent of water, 1 equivalent of DMP selectively debenzylated 139 (Eq. 49). Full conversion of 139 was observed after 30 h (Table 2.2).

Table 2. 2. Formation of benzaldehyde over the course of reaction

Reaction time (h) 18 22 30

Formation of benzaldehyde from 139 (% conversion) 76 80 100

Since the synthesis of DMP involved IBX and 140 (Figure 2.3), these compounds was also tested as reagents for N-debenzylation of amines (Table 2.3). Monoacetate iodinane 140 does not show any reactivity on N-debenzylation or N-dealkylation (entry 2, 5–9). The optimized conditions worked really well for the debenzylation of 139 (entry 1). However, when other tertiary amines were used (entry 2–6), no debenzylation or dealkylation took place. For

99 triethylamine (TEA) 142 and N-ethyldiisopropylamine 141, no dealkylation was observed proving the high selectivity of this method and suggesting the application of DMP for benzyl deprotection when other alkyl amines are present in the molecule.

Figure 2. 3. Structures of DMP, IBX, and monoacetate iodinane 140

Table 2. 3. Oxidative N-debenzylation of various amines

Conversion to benzaldehyde (%) Entry Amines Products DMP IBX 140 DMP/TEA

1 100

2 –

3 –

4 trace – – 4

5 – – – 13

100

6 – – – 14

7 65 50 – 100

8 84 50 – 100

9 27 40 – 30

10 40 (3:2) 44 (3:2) :

11 33a 35a

a2 equiv of DMP was used.

N-benzyldiethylamine 143 as well as cyclic amines 144 and 145 gave no benzaldehyde under optimized condition or when being treated with IBX. 1H NMR spectra of the crude mixture of these reactions only showed the protonated amines. Benzaldehyde could not be found. This result is in agreement with the high basicity of these amines. Due to their basicity, they favored the acid-base reaction with acetic acid present in DMP more than attacking DMP. To address this problem, the reaction was rerun under optimized conditions with the addition of 2 equivalents of

101

TEA. Since TEA has no reaction with DMP (entry 3), it can capture the proton for amines 143–

145 without interfering the debenzylation. As we expected, this approach successfully gave benzaldehyde. 1H NMR of crude reaction mixture still showed protonated amines. Therefore, the formation of benzaldehyde from those amines (143–145) under this condition were still low.

However, these are the first examples that DMP can react with tertiary amines, and even cyclic amines 144 and 145, which were reported unable to be debenzylated by CAN.45 The addition of

TEA also improved the debenzylation of secondary amines 146–150 (entries 7–11).

Additionally, IBX showed lower reactivity than DMP (entries 7–9). Electronic effect of substituents on benzyl groups also have an impact the formation of benzaldehyde.

Electronwithdrawing group such as chloro (entry 8) influences the N-debenzylation positively due to the more acidity of the benzylic protons. On the other hand, methoxy group decreases the acidity of those protons. As a result, lower conversion of 148 to benzaldehyde was observed

(entry 9).

In the reaction of amine 149, low selectivity between benzyl and 4-methoxybenzyl was achieved. Both benzaldehyde and p-anisaldehyde were afforded in 3:2 ratio. In the case of dibenzylamine 150, the primary benzylamine formed along with benzaldehyde can further react with DMP to give nitrile compound and competing with N-debenzylation.52 Therefore, 2 equivalents of DMP was used and 33% conversion of 150 to benzaldehyde was achieved.

We proposed a mechanism involving deprotonation of benzylic proton by DMP to form iminium intermediate 151 followed by hydrolysis (Scheme 2.12).

102

Scheme 2. 12. Plausible mechanism of N-debenzylation by DMP 2.3. Conclusion:

We have successfully developed a selective N-debenzylation method using DMP.

Additionally, the first time, the reactions of tertiary amines, especially cyclic amines, with DMP were demonstrated. Although the conversions of cyclic amines to benzaldehyde were still low.

We believe the reaction can be further improved by adjusting the amount of TEA additive to capture all acetic acid.

Moreover, future work will focus on obtaining the isolated yields of benzaldehyde from these reactions; and extend the method to the synthesis of , , and -ketoamines 153 from cyclic amines 152 (Eq. 50). Furthermore, due to the high selectivity, it can be applied to the synthesis of new Wakayin analog 154 (Scheme 2.13).

103

Scheme 2. 13. Synthesis of new analog of Wakayin derivative

2.4. Experimental procedure and spectral data

All reactions were carried out using oven-dried glassware. Diethyl ether were dried and degassed using a Pure Process Technology solvent purification system prior to being used. 200 proof Ethanol was purchased from EMD. All other solvents, if not stated as dry, were purchased and used without further purification. Thin Layer Chromatography (TLC) was performed on

EMD silicagel 60 F254; chromatogram was visualized with UV light (254 and 360 nm). Flash column chromatography was performed on Sorbtech silica gel 60 (ASTM 230–400 mesh). 1H and 13C NMR was recorded at 600 MHz (Jeol 600 MHz NMR spectrometer). High resolution mass spectra (HRMS) were obtained on an ESI-TOF-MS. Infra-red (IR) spectroscopy was performed on a Perkin-Elmer Spectrum 100.

Commercial chemicals including amines 141, 142, and 150 were purchased from Sigma-

Aldrich, Alfa Aesar, Acros Organics and were used without further purification.

2.4.1. Synthesis of Dess-Martin Periodinane (DMP)53-56

Step 1: Synthesis of IBX

Oxone (0.29 mol, 181 g) was dissolved in 650 mL of water. To that solution, iodobenzoic acid

(0.2 mol, 50 g) was added at once. The mixture was warmed to 70 oC over 20 min and stirred for

24 h. The suspension was then cooled to 5 oC and left at this temperature for 1.5 h with slow stirring. The mixture was filtered and washed with water (6 x 100 mL) then acetone (2 x 100

104 mL). The white crystalline was left to dry at room temperature for 16 h to yield IBX in 80% (45 g). 1H NMR of the product matched with the previously reported data.59 1H NMR (600 MHz,

DMSO-d6) δ 8.14 (dd, J = 8.0, 0.7 Hz, 1H, Ar), 8.03 (dd, J = 7.5, 1.3 Hz, 1H, Ar), 8.00 (td, J =

8.3, 7.8, 1.4 Hz, 1H, Ar), 7.88 – 7.81 (m, 1H, Ar).

Step 2: Synthesis of DMP*

IBX (18 mmol, 5.0 g) and TsOH•H2O (5 mol%, 25 mg) was added to a schlenk flask equipped with a sintered glass filter male-to-male adapter. To that mixture was added 20 mL of acetic

o anhydride. The reaction was stirred at 80 C under dry N2 atmostphere for 24 h until completely dissolution was reached. The resulted yellow solution was cooled in an ice bath and filtered off under N2 atmostphere, washed with dry ether (5 x 5 mL), dried under vacuum and was reflushed

1 with N2 after every use. The white crystalline products yield 82% (6.3 g). H NMR matched with previously reported data.55,56 1H NMR (600 MHz, Chloroform-d) δ 8.32 (dd, J = 7.6, 1.5 Hz, 1H,

Ar), 8.29 (dd, J = 8.4, 0.8 Hz, 1H, Ar), 8.10 – 8.06 (m, 1H, Ar), 7.91 (td, J = 7.4, 0.9 Hz, 1H,

Ar), 2.34 (s, 3H, OCOCH3), 2.01 (s, 6H, (OCOCH3)2).

*Note: The synthesis of DMP reagent has been reported by many reseachers beside Dess and Martin.53-58 In our case, utilizing methods reported by either Dess-Martin,55,56 Meyer et al.53 or Ireland et al.54 did not always give clean

DMP. The product was contaminated with a large amount of monoacetate iodinane 140 However, when a combination of Meyer's and Ireland's method was used, DMP was obtained purely.

2.4.2. Synthesis of amines 139 and 143–145

General procedure:

A secondary amine (30 mmol) was dissolved in 50 mL of DCM. To that solution was slowly added benzylbromide (27 mmol, 4.6 g). After stirring for 2 h. DCM was evaporated under vacuum. The resulted white solid was wash with 50% NaOH aq. and extracted with diethyl ether.

105

The combined organic layer was dried with MgSO4 anhydrous and solvent was removed under reduced pressure to yield N-benzyl tertiary amines as the product.

Amine 139 from diisopropylamine

Amine 139 was obtained in 87% yield (4.5 g) as a clear oily compound. 1H NMR matched with previously reported data.60 1H NMR (600 MHz, Chloroform-d) δ 7.45 – 7.20 (m, 5H, Ar),

3.68 (s, 2H, C6H5CH2), 3.05 (dq, J = 13.2, 6.6 Hz, 2H, CH(CH3)2), 1.06 (t, J = 7.1 Hz, 12H,

CH(CH3)2).

Amine 143 from diethylamine

Amine 143 was obtained in 81% yield (4.2 g) as a light yellow oily compound. 1H NMR matched with previously reported data.61 1H NMR (600 MHz, Chloroform-d) δ 7.40 – 7.20 (m,

5H, Ar), 3.58 (s, 2H, C6H5CH2), 2.54 (q, J = 7.1 Hz, 4H, NCH2CH3), 1.06 (t, J = 7.1 Hz, 6H,

NCH2CH3).

Amine 144 from pyrrolidine

106

Amine 144 was obtained in 46% yield (1.0 g) as a yellow oily compound. 1H NMR matched with previously reported data.61 1H NMR (600 MHz, Chloroform-d) δ 7.32 – 7.13 (m, 5H, Ar),

3.55 (s, 2H, C6H5CH2), 2.49 – 2.39 (m, 4H, N(CH2)4), 1.72 (dq, J = 6.4, 3.2 Hz, 4H, N(CH2)4).

Amine 145 from piperidine

Amine 145 was obtained in 60% yield (2.8 g) as a yellow oily compound. 1H NMR matched with previously reported data.61 1H NMR (600 MHz, Chloroform-d) δ 7.35 – 7.10 (m, 5H, Ar),

3.42 (s, 2H, C6H5CH2), 2.32 (s, 4H, N(CH2)4CH2), 1.58 – 1.47 (m, 4H, N(CH2)4CH2), 1.43 –

1.31 (m, 2H, N(CH2)4CH2).

2.4.3. Synthesis of amines 146–149:

General procedure:

A solution of an amine (10 mmol), and an aldehyde (10 mmol) in dry ethanol was placed in a round bottom flask and stirred for 12 h. To that solution, sodium borohydride powder (0.567 g,

15 mmol) was added at 0 oC slowly over 5 minutes. the solution was then warmed to room temperature. After stirring for 4 h, the reaction was quenched with 3 drops of water and the mixture was filtered through a pad of celite. The solvent was evaporated under reduced pressure, the residue was extracted with 100 mL of ethyl ether and washed with 100 mL of water. The organic layer was dried over MgSO4 anhydrous. Ethyl ether was then evaporated and the resulted viscous liquid was purified by flash column chromatography (SiO2; 4:1 then 3:1 and finally 1:1 hexanes/ethyl acetate).

Amines 146 from cyclohexyl amine and benzaldehyde

107

Amine 146 was obtained in 90% yield (1.7 g) as a colorless oily compound. 1H NMR match with previously reported data.62 1H NMR (600 MHz, Chloroform-d) δ 7.30 – 7.10 (m, 5H, Ar),

3.80 (s, 2H, C6H5CH2), 2.47 (tt, J = 10.4, 3.7 Hz, 1H, CH2NHCH), 1.95 – 1.86 (m, 2H,

(CH2)5CHNH), 1.72 (dt, J = 12.2, 3.1 Hz, 2H, (CH2)5CHNH), 1.64 – 1.57 (m, 1H,

(CH2)5CHNH), 1.34 – 1.01 (m, 6H, (CH2)5CHNH).

Amine 147 from cyclohexylamine and 4-chlorobenzaldehyde

Amine 147 was obtained in 87% yield (1.9 g) as a colorless oily compound. 1H NMR (600

MHz, Chloroform-d) δ 7.25 (d, J = 8.4 Hz, 5H, Ar), 3.75 (s, 2H, C6H4CH2), 2.43 (ddd, J = 14.1,

10.4, 3.7 Hz, 1H, CH2NHCH(CH2)5), 1.94 – 1.51 (m, 5H, CH2NHCH(CH2)5), 1.28 – 0.99 (m,

13 5H, CH2NHCH(CH2)5). C NMR (151 MHz, Chloroform-d) δ 139.61 , 132.52 , 129.52 , 128.57

, 56.25 , 50.38 , 33.66 , 26.27 , 25.10 .

Amine 148 from cyclohexylamine and p-anisaldehyde

108

Amine 148 was obtained in 72% yield (1.6 g) as a colorless oily compound. 1H NMR match with previously reported data.63 1H NMR (600 MHz, Chloroform-d) δ 7.22 (d, J = 8.5 Hz, 3H,

Ar), 6.85 (d, J = 8.4 Hz, 2H, Ar), 3.78 (s, 3H, C6H4OCH3), 3.73 (s, 2H, C6H4CH2), 2.52 – 2.40

(m, 1H, CH2NHCH(CH2)5), 1.90 (d, J = 12.3 Hz, 2H, CH2NHCH(CH2)5), 1.72 (dt, J = 12.3, 3.4

Hz, 2H, CH2NHCH(CH2)5), 1.61 (dt, J = 12.5, 3.3 Hz, 1H, CH2NHCH(CH2)5), 1.31 – 1.04 (m,

6H, CH2NHCH(CH2)5).

Amine 149 from benzyl amine and anisaldehyde

Amine 149 was obtained in 98% yield (2.2 g) as a colorless oily compound. 1H NMR matched with previously reported data.63 1H NMR (600 MHz, Chloroform-d) δ 7.37 (d, J = 13.4 Hz, 4H,

Ar), 7.30 (d, J = 8.7 Hz, 3H, Ar), 6.92 (d, J = 8.7 Hz, 2H, Ar), 3.83 (s, 2H, MeOC6H4CH2), 3.83

(s, 3H, C6H4OCH3), 3.78 (s, 2H, C6H5CH2).

2.4.4. N-debenzylation reaction:

General procedure:

DMP was dissolved in CDCl3. A solution of amine (0.1 mmol) in 1 mL of CDCl3 was added slowly. The resulted mixture was stirred at room temperature for 30 h and 1H NMR was performed to calculate conversion of amines based on benzaldehyde formed.

The conversions were calculated by comparing the integral ratio between aldehyde proton signal and benzylic proton signal.

Call x: integration value of aldehyde proton signal

109

and y: integration value of benzylic proton signal.

2푥 then conversion (%) = × 100 푦+2푥

Reactions running in non-deuterated solvents (CH2Cl2 and CHCl3):

DMP was dissolved in DCM or chloroform. To that solution was added slowly a 1M solution of amine (0.1 mmol in 1 mL). The reaction mixture was stirred at room temperature for 22 h and solvents were then evaporated under vacuum. The resulted viscous product was redissolved in

1 CDCl3 for H NMR spectroscopy and conversion calculation.

2.4.5. NMR spectra:

NMR spectra of IBX and DMP

IBX

110

DMP

111

NMR spectra of amines 139, 143–149

Amine 139

112

Amine 143

113

Amine 144

114

Amine 145

115

Amine 146

116

Amine 147

117

Amine 148

118

Amine 149

119

NMR spectra of N-debenzylation reaction

N-debenzylation of amine 139

120

N-debenzylation of amine 141

121

N-debenzylation of amine 142

122

N-debenzylation of amine 143

123

N-debenzylation of amine 144

124

N-debenzylation of amine 145

125

N-debenzylation of amine 146

126

N-debenzylation of amine 147

127

N-debenzylation of amine 148

128

N-debenzylation of amine 149

129

N-debenzylation of amine 150

130

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131

(33) Murata, S.; Suzuki, K.; Tamatani, A.; Miura, M.; Nomura, M. J. Chem. Soc. Perkin Trans. 1 1992, 1387. (34) Nishinaga, A.; Yamazaki, S.; Matsuura, T. Tetrahedron Lett. 1988, 29, 4115. (35) Maruyama, K.; Kusukawa, T.; Higuchi, Y.; Nishinaga, A. Chem. Lett. 1991, 20, 1093. (36) Wang, M.-Z.; Zhou, C.-Y.; Wong, M.-K.; Che, C.-M. Chem. Eur. J. 2010, 16, 5723. (37) Gao, X.; Jones, R. A. J. Am. Chem. Soc. 1987, 109, 1275. (38) Goti, A.; Romani, M. Tetrahedron Lett. 1994, 35, 6567. (39) Xie, Y.; Hu, J.; Wang, Y.; Xia, C.; Huang, H. J. Am. Chem. Soc. 2012, 134, 20613. (40) Au, C. C.; Lai, T. H.; Chan, K. S. J. Organomet. Chem. 2010, 695, 1370. (41) Ling, Z.; Yun, L.; Liu, L.; Wu, B.; Fu, X. Chem. Commun. 2013, 49, 4214. (42) Suzuki, H.; Tsukuda, A.; Kondo, M.; Aizawa, M.; Senoo, Y.; Nakajima, M.; Watanabe, T.; Yokoyama, Y.; Murakami, Y. Tetrahedron Lett. 1995, 36, 1671. (43) Talukdar, S., Ph.D. Thesis, University of Mumbai, 1997. (44) Talukdar, S.; Nayak, S. K.; Banerji, A. J. Org. Chem. 1998, 63, 4925. (45) Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.; Smith, A. D. J. Chem. Soc. Perkin Trans. 1 2000, 3765. (46) Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.; Smith, A. D. Chem. Commun. 2000, 337. (47) Bull, S. D.; Davies, S. G.; Kelly, P. M.; Gianotti, M.; Smith, A. D. J. Chem. Soc. Perkin Trans. 1 2001, 3106. (48) Singh, S. B. Tetrahedron Lett. 1995, 36, 2009. (49) Kroutil, J.; Trnka, T.; Černý, M. Synthesis 2004, 446. (50) Grayson, E. J.; Davis, B. G. Org. Lett. 2005, 7, 2361. (51) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew. Chem. Int. Ed. 2003, 42, 4077. (52) Nicolaou, K. C.; Mathison, C. J. N. Angew. Chem. Int. Ed. 2005, 44, 5992. (53) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549. (54) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. (55) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (56) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (57) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001. (58) Bailey, S. W.; Chandrasekaran, R. Y.; Ayling, J. E. J. Org. Chem. 1992, 57, 4470. (59) Fallis, A. G.; Tessier, P. E. In Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons, Ltd: 2001. (60) Zhou, S.; Junge, K.; Addis, D.; Das, S.; Beller, M. Angew. Chem. Int. Ed. 2009, 48, 9507. (61) Le Gall, E.; Decompte, A.; Martens, T.; Troupel, M. Synthesis 2010, 2010, 249. (62) Hamid, M. H. S. A.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.; Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem. Soc. 2009, 131, 1766. (63) Lee, O.-Y.; Law, K.-L.; Yang, D. Org. Lett. 2009, 11, 3302.

132

CHAPTER 3: SYNTHESIS OF PYRIDAZINEDIONES, QUINONE

DIMERS, AND POLYQUINONES

3.1. Synthesis of pyridazinediones from alkynes and diformyl hydrazine:

Pyridazinediones are generally known to possess herbicidal, insecticidal, and anticonvulsant properties.1,2 Additionally, they serve as important precursors to anticancer compounds used for the treatment of SK-Hep-1 and HL-60 cells.3,4 The cytotoxicity of pyridazinediones is strongly related to different substituents included in the structure of these compounds.1 They are most commonly synthesized by the reaction of hydrazine and maleic anhydride (Eq. 51).1,5 This pathway, however, results in pyridazinediones with a limited number of substituents. It, therefore, inhibits the possibility of exploring multiple biological activities.

Our plan is to develop a new synthetic methodology for pyridazinediones. The reaction involves the formation of amide radicals from diformylhydrazine 155, followed by the addition to a diverse set of alkynes 156 to obtain pyridazinediones 157 (Scheme 3.1).

Additionally, we hypothesize that by introducing different functional groups, we can obtain resourceful data of biological activity for medicinal research. Alkynes are generally abundant and inexpensive materials, therefore favore their use in the experiment. This methodology consists of a one-pot synthesis with a greater possibility of different substituent arragements from affordable starting materials. Furthermore, the biological activity of different

133 pyridazinediones would be tested and analyzed. Ultimately, the relation between the cytotoxicity and different types of (R) groups would be investigated.

Scheme 3. 1. Planned synthesis of pyridazinediones 156

The key compound in this methodology is diformylhydrazine 155. This compound can be easily synthesized by amide formation between 2 equivalents of formic acid and anhydrous hydrazine (Eq. 52). Diformylhydrazine was obtained quantitatively as a white solid.

Since diformylhydrazine 155 only dissolved in water and slightly soluble in DMSO, the experiment was designed using acetone/water as the solvent system. Furthermore, acetone was reported to abstract hydrogen in its triplet state.6,7 Therefore, solution of diformylhydrazine 155 and diphenylacetylene 156a in acetone/water was put under sunlight and monitored by thin layer chromatography (TLC) (Eq. 53). After 7 days, no reaction was observed.

We believe that either acetone in its triplet state cannot abstract hydrogen from amide 155 or

134 sunlight cannot excite acetone to its triplet state. Thus, acetone was replaced with other ketones that were known to be more susceptible to photo-excitement such as 1,4-benzoquinone, 1,4- naphthoquinone, and benzophenone. Moreover, a mercury-lamp light source (254 nm) was used instead of sunlight (Eq. 54 and Table 3.1). However, all of these conditions did not give product

157a. Interestingly, with the addition of additives, a yellow oily layer was formed on top of the acetone/water reaction medium. After solvent was evaporated under reduced pressure, the yellow compound obtained was confirmed to be diphenylacetylene 156a. When solvent system was changed to acetonitrile/water, diphenylacetylene was still fully recovered.

Table 3. 1. Reaction conditions for Eq. 53

Additives Light source

Benzophenone Sunlight, 7 d

1,4-Benzoquinone Sunlight, 7 d

1,4-Naphthoquinone Sunlight, 7 d

— Mercury lamp, 10 h

Benzophenone Mercury lamp, 10 h

1,4-Benzoquinone Mercury lamp, 10 h

135

Beside photochemistry approach, hydrogen abstraction from amides was also known to happen with hydroxyl radicals. Therefore, a revised planned synthesis of pyridazinediones 157 was designed involving the use of metal reagents to generate hydroxyl radical from hydrogen peroxide in-situ as the hydrogen abstraction species (Scheme 3.2). The generation of hydroxyl radicals, thus, plays the key role in this revised planned synthesis.

Scheme 3. 2. Revised planned synthesis of pyridazinediones 156

Titanium (III) and iron (II) have been reported to successfully catalyze the formation of hydroxyl radicals from hydrogen peroxide followed by hydrogen abstraction from formamide.8-10

We, therefore, investigated the use of these metals with or without zinc as a reducing agent

([Re]) (Scheme 3.2 and Table 3.2). However, the formation of pyridazinediones 157 was not observed under all of these conditions.

Table 3. 2. Reaction conditions for revised synthesis of pyridazinediones using metal reagents

Reagents [Re] R1 R2

FeCl2 (cat.)/H2O2/HCl Zn Ph Ph

FeCl2 (cat.)/H2O2/HCl Zn Ph H

136

FeCl2 (cat.)/H2O2/HCl Zn But H

TiCl3 (2 equiv)/H2O2/HCl – Ph H

TiCl3 (2 equiv)/H2O2/HCl – Ph Ph

TiCl3 (2 equiv)/H2O2/HCl – But H

TiCl3 (cat.)/H2O2/HCl Zn But H

3+ 2+ We believe that in the presence of Ti or Fe in H2O2 and HCl solution, hydroxyl radicals were formed and abstracted one hydrogen from amide as reported.8-10 Therefore, the problem should lay on the abstraction of the second hydrogen from diformylhydrazine 155. A simple calculation was performed and showed an agreement with our speculation (Scheme 3.3). The second hydrogen abstraction by hydroxyl would happen on N–H forming intermediate 158 and quickly convert into 159. This isocyanide compound cannot further cyclize with alkynes to give pyridazinediones 157.

Scheme 3. 3. Calculated pathway of hydrogen abstraction from diformylhydrazine 155 by

hydroxyl radicals

As a result, our future plan will be derivatization of diformyl hydrazine 155 by using

137 substituted hydrazine as the starting materials (Scheme 3.4) to avoid hydrogen abstraction from

N–H. Furthermore, with hydrophobic substituents, the new starting material 160 may exhibit better solubility in organic solvents, which will enhance the contact with alkynes for addition reaction.

Scheme 3. 4. Future synthesis of pyridazinediones

3.2. Synthesis of naphthoquinone dimers:

Sunlight provides an endless supply of renewable energy that can drive numerous chemical reactions. Our lab has also utilized this energy source for our acylation reaction.11,12 Moreover, we planned to further extend the use of sunlight to the photo-dimerization of 1,4- naphthoquinone. Photo-dimerization of 1,4-naphthoquinone provides a fundamental understanding of organic chemistry, especially the mechanism of [2+2] photochemical cycloaddition. This type of reaction has been investigated since the 1960's and was found to achieve high yield when irradiating with high-pressure mercury lamps or when being assisted by heavy metal complexes.13 UV lamps and heavy metal complexes come with a socioeconomic cost and can result in environmental harm. Self-assemble coordination cages directed highly stereoselective photodimerization of 1,4-naphthoquinone giving a syn conformation (Figure 3.1) using a 400 W high-pressure mercury lamp.14 Utilizing sunlight, on the other hand, offers sustainable green chemistry at a lower cost by synthesizing chemicals with energy that is readily

138 available. However, solar driven dimerization of 1,4-naphthoquinone in benzene resulted in low yield without any syn or anti stereoselectivity.15 Therefore, we sought to use sunlight and solvent effect to investigate the stereoselectivity as well as increase the product yield of this reaction.

Figure 3. 1. Syn and anti conformation of 1,4-naphthoquinone dimer

During our attempt for the synthesis of pyridazinediones 157 (section 3.1), when naphthoquinone was used as the additive in acetonitrile/water solvent, although pyridazinediones were not formed, an insoluble white solid precipitated at the bottom of the reaction mixture after

1 day of irradiating under sunlight. The compound was filtrated and confirmed by 1H and 13C

NMR to be anti-1,4-naphthoquinone dimer 161 in 80% yield (Eq. 55). The experiment was then repeated with only 1,4-naphthoquinone in acetonitrile without water and the same result was obtained. The selectivity was well-achieved in acetonitrile under sunlight.

We, therefore, further investigated this stereoselective reaction by extending to substituted 1,4-

139 naphthoquinone 165 as starting material. A general planned synthesis is illustrated in Scheme

3.5.

Scheme 3. 5. Planned synthesis of substituted 1,4-naphthoquinone dimers

Compounds 163 was obtained using our reported photo-Friedel–Craft acylation reaction11 and was then treated with Zn/AcOH/HCl to afford 164. This modified Clemmensen reduction16 gave

164a from 163a in 34% yield (Eq. 56). Our future work will be the continuation of the planned synthesis (Scheme 3.5).

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3.3. Synthesis of polyquinones:

Polyacenes, despite their instable nature, have been widely invetsigated since they possesses a unique properties as organic semiconductors. Especially, polyquinones have been reported to be a potential cathode for rechargeable lithium battery.17 However, the synthesis of these polyquinones is limited and requires special techniques or many reaction. Thus, we want to develop our photoacylation reaction into a new methodology that contains only two reactions in a repeating manner to afford long chain of quinone moieties (Scheme 3.6).

Scheme 3. 6. Planned synthesis of polyquinones using photoacylation

Compound 166 plays an important role in the planned synthesis. However, the availability of this compound is really limited. Our first task of this project was to synthesize compound 166.

Maleic anhydride 167 was successfully converted into diethyl maleate 168 in 91% yield using simple esterification with ethanol in toluene (Scheme 3.7). However, the following step of reduction using DIBAL-H could not afford 166 (Scheme 3.7).

Scheme 3. 7. Synthesis of 165 from maleic anhydride 166

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Another approach was then taken, in which acidification of compound 169 by 0.35N H2SO4 aq. saturated with was reported to give 166 (Eq. 57).18 1H NMR of the crude reaction mixture show the formation of both cis and trans products (cis/trans =3/1), which was unable to be isolated by column chromatography. As a result, the synthesis of 166 was changed to oxidation method.

Oxidation of but-2-ene-1,4-diol 171 was carried out using 3 equivalent of pyridinum dichromate (PDC) in dry DCM (Eq. 58). However, the reaction gave low product yield (1H NMR yield) as well as resulted in a mixture with pyridinium salt, which could not be purified.

Replacing PDC/DCM with MnO2/CHCl3 also could not afford 166. The use of selenium oxide

(SeO2) for the allylic methyl oxidation of crotonaldehyde 172 also turned out not effective (Eq.

59). The same result was obtained when compound 173 was attempted to be oxidized by SeO2 in dry DCM, ethanol, or 10% AcOH aq (Eq. 60). When dioxane was used as the solvent, the products could be isolated by filtering of selenium species and evaporating solvent. However, product 166 quickly polymerize at room temperature and could not be used further.

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Consequently, the planned synthesis was redesigned as illustrated in Scheme 3.8. A monoprotected of but-2ene-1,4-diol 171 would be used as starting material and undergo oxidation to give 175. Photoacylation of 1,4-naphthoquinone and 175 would start the replication cycle to yield polyquinones. The presence of protecting group would decrease the possibility of polymerization of 175.

Scheme 3. 8. Revised planned synthesis of polyquinones

The preparation of benzyl protected compound (175a) is summarized in Scheme 3.9.

Compound 175a was obtained in 72% yield after Swern oxidation and did not undergo polymerization; and thus was further used in the photoacylation with 1,4-naphthoquinone followed by deprotection of benzyl group. However, the deprotection did not take place with

CAN or HCl. We believe that the reductive debenzylation with H2/Pd/C would happen but at the

143 same time hydrogenation would occur. Therefore, a more labile protecting group such as tert- butyldimethylsilyl was used in place of benzyl (Scheme 3.10).

Scheme 3. 9. Preparation of 175a

Scheme 3. 10. Preparation of 175b

Interestingly, Swern oxidation did not give the desired product 175b but instead afforded the trans isomer 175c in 58% yield. Treating 174b with DMP/DCM, on the other hand, furnished

175b in 82% yield. Photoacylation of 175b and 1,4-naphthoquinone was carried out (Scheme

3.11). The intermediate 176 could not be isolated and therefore was further treated with

1 TBAF/THF followed by reoxidation with CAN/CH3CN/H2O (Scheme 3.11). Crude H NMR showed the formation of product 177. Future work will focus on the isolation of 178 and continue the repeating cycle starting again with oxidation and photoacylation under sunlight.

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Scheme 3. 11. Preparation of compound 177 and future plan

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References

(1) Sivakumar, R.; Anbalagan, N.; Gunasekaran, V.; Leonard, J. T. Biol. Pharm. Bull. 2003, 26, 1407. (2) Sun, R.; Zhang, Y.; Bi, F.; Wang, Q. J. Agric. Food Chem. 2009, 57, 6356. (3) Lee, M.-S.; Kim, E.-S.; Moon, A.; Park, M.-S. Bull. Korean Chem. Soc. 2009, 30, 83. (4) Mayer, C. D.; Bracher, F. Eur. J. Med. Chem. 2011, 46, 3227. (5) Feuer, H.; White, E. H.; Wyman, J. E. J. Am. Chem. Soc. 1958, 80, 3790. (6) Porter, G.; Dogra, S. K.; Loutfy, R. O.; Sugamori, S. E.; Yip, R. W. J. Chem. Soc., Faraday Trans. 1 1973, 69, 1462. (7) Tachikawa, H.; Kawabata, H. Theor. Chem. Acc. 2011, 128, 207. (8) Cannella, R.; Clerici, A.; Panzeri, W.; Pastori, N.; Punta, C.; Porta, O. J. Am. Chem. Soc. 2006, 128, 5358. (9) Drug, E.; Gozin, M. J. Am. Chem. Soc. 2007, 129, 13784. (10) Pastori, N.; Greco, C.; Clerici, A.; Punta, C.; Porta, O. Org. Lett. 2010, 12, 3898. (11) De Leon, F.; Kalagara, S.; Navarro, A. A.; Mito, S. Tetrahedron Lett. 2013, 54, 3147. (12) Pedroza, D. A.; De Leon, F.; Varela-Ramirez, A.; Lema, C.; Aguilera, R. J.; Mito, S. Bioorg. Med. Chem. 2014, 22, 842. (13) Werbin, H.; Strom, E. T. J. Am. Chem. Soc. 1968, 90, 7296. (14) Yoshizawa, M. Angew. Chem. Int. Ed. 2002, 41, 1347. (15) Schonberg, A.; Mustafa, A.; Barakat, M. Z.; Latif, N.; Moubasher, R.; Mustafa, A. J. Chem. Soc. 1948, 2126. (16) Kappe, T.; Aigner, R.; Roschger, P.; Schnell, B.; Stadibauer, W. Tetrahedron 1995, 51, 12923. (17) Zou, Q.; Wang, W.; Wang, A.; Yu, Z.; Yuan, K. Mater. Lett. 2014, 117, 290. (18) Hufford, D. L.; Tarbell, D. S.; Koszalka, T. R. J. Am. Chem. Soc. 1952, 74, 3014.

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CURRICULUM VITA

Quang H. Luu was born in Ben Tre, a small province in Vietnam. In summer 2012, he earned his Bachelor of Engineering degree from the Honor program at the Ho Chi Minh University of

Technology (HCMUT), where he conducted his undergraduate research under the supervision of

Professor Nam Phan. During his college time, he received the Vietnam National University award for excellent academic performance to cover his 5-year tuition and the HCMUT stipend for students from Talented Engineers program. In Spring 2013, he entered the Graduate School of the University of Texas at El Paso. He has been working in Organic synthesis under the guidance of Dr. Shizue Mito since then and got the award for outstanding teaching by a graduate student in 2015.

Permanent Address: 8604 SW 45th Terrace

Oklahoma City, OK 73179

[email protected]

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