Article Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
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Synthesis of Polysubstituted Cyclopentene and Cyclopenta[b]carbazole Analogues from Unsymmetrical 4‑Arylidene-3,6-diarylhex-2-en-5-ynal and Indole Derivatives via an Iodine Mediated Electrocyclization Reaction Vijayalakshmi Bandi,† Veerababurao Kavala,† Ashok Konala,† Che-Hao Hsu,† Bharath Kumar Villuri,† Sabbasani Rajasekhara Reddy,†,‡ LiChun Lin,† Chun-Wei Kuo,† and Ching-Fa Yao*,† †
Department of Chemistry, National Taiwan Normal University, 88, Sec 4, Ting-Chow Road, Taipei 116, Taiwan R.O.C. Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology (VIT), Vellore 632014, India
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‡
S Supporting Information *
ABSTRACT: An efficient method for the synthesis of polysubstituted cyclopentene and cyclopenta[b]carbazole derivatives through the iodine-promoted electrocyclization of substituted indoles and 4-arylidene-3,6-diarylhex-2-en-5-ynal derivatives is reported. Polysubstituted cyclopentene derivatives were produced through 4π electrocyclization reactions with indole, 7methylindole, and 5-bromoindole as coupling partners, whereas cyclopenta[b]carbazole derivatives were produced via 6π electrocyclization in the case of methoxy (−OMe)-substituted indoles. The methods reported herein diastereo- and regioselectively proceed under straightforward and mild conditions.
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INTRODUCTION An electrocyclization strategy is one of the most powerful tools for constructing complex polycyclic carbocycles in a highly regioselective and atom-economic manner.1 The efficient use of dienal and ynal derivatives for preparing a large number of structurally diverse carbocyclic analogues via an electrocyclization approach would be of great interest to the synthetic community.2 Substituted cyclopentene scaffolds are components of a wide variety of natural products and exhibit a variety of pharmacological activities.3 For example α-necrodol, a sex hormone produced by the grape mealybug (Pseudococcus maritimus), is widely distributed in the pests of grapes and pome fruit in the United States.3a The cyclopentanoid monoterpene, chrysomelidial acts as physiologically active and biosynthetically important biomolecule.3b Some representative bioactive natural products that contain a cyclopentene moiety are shown in Figure 1. Several strategies have been reported for the synthesis of polysubstituted cyclopentene derivatives, including Lu’s [3 + 2] cycloaddition reaction of terminal allenoates with electrondeficient olefins, cycloaddition4 reactions of cyclopropane with dienophile,5 and multicomponent reactions (MCR) of βnitrostyrene6 and α,β-unsaturated aldehydes.7 Further, the Nazarov cyclization is also a key strategy for the construction of cyclopentene derivatives.8 An extensive literature survey revealed that 2,4-pentadien-1-al substrates © XXXX American Chemical Society
Figure 1. Bioactive natural products that contain a cyclopentene moiety.
undergo an iso-Nazarov reaction to produce cyclopentenone derivatives under acidic conditions.9 Several reports have recently appeared on this topic in which 2,4-pentadien-1-als were converted into the corresponding cyclopentenyl derivatives by reacting various nucleophiles or dienophiles in the presence of different acidic catalysts.10 Liu and co-workers reported the cyclization of cis-2,4-dien-1-als followed by a double-nucleophile addition of electron-rich alkenes and arenes Received: August 22, 2018
A
DOI: 10.1021/acs.joc.8b02168 J. Org. Chem. XXXX, XXX, XXX−XXX
Article
The Journal of Organic Chemistry Table 1. Optimization Studiesa,b
yieldb (%) entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16c 17c 18c 19
a
reagent
reagent (equiv)
indole
solvent
time
3a
I2 I2 I2 NIS BF3.OEt2 ZnCl2 CuCl2 FeCl3 I2 I2 I2 I2 I2 I2 I2 I2 I2 I2 HI
1 1.1 1.1 1.1 1.1 1 1 1 0.2 0.5 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1
1.1 1.5 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.5 2.5 2.2 2.2 2.2 2.2
EA EA EA EA EA EA EA EA EA EA CHCl3 CH2Cl2 diethyl ether EtOH MeOH EA CH2Cl2 (CH2)2Cl2 EA
2.5 h 40 min 15 min 3 days 10 min 20 h 20 h 20 h 2h 20 min 20 min 20 min 10 h 10 h 10 h 11 h 11 h 11 h 15 min
16 33 55
--20 29 41 51
54 51 51 ---
4a trace 6 12 no reaction decomposed no reaction no reaction 20 9 16 11 7 no reaction no reaction no reaction 19 7 7 ---
All of the reactions were carried out on a 0.25 mmol scale using 15 mL of solvent. bNMR yields. cReaction carried out at 0 °C.
a
Figure 2. ORTEP diagram of 3a and 4a.
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in the presence of a gold catalyst to produce a series of complicated cyclopentenyl frameworks.11 Liu and co-workers recently reported on the reaction of 2,4-dienals and secondary anilines in the presence of acidic catalyst to produce 1aminocyclopentyl cations, which were then trapped by an arene derivative through intramolecular annulation.12a In addition, a 1-aminocyclopentylcation intermediate was reacted with pyrimidine derivatives to produce therapeutically important carbocyclic nucleoside analogues.12b Inspired by these reports, we investigated the reaction of the recently synthesized 4-benzylidene-3,6-diphenylhex-2-en-5-ynal13 with various carbon nucleophiles. Based on the above literature reports, we predicted that the reaction of 4-benzylidene-3,6-diphenylhex-2en-5-ynal and indole in the presence of acidic conditions would produce highly substituted cyclopentene derivatives.
RESULT AND DISCUSSION
To test our hypothesis, we examined the reaction of 4benzylidene-3,6-diphenylhex-2-en-5-ynal (1a) and indole in ethyl acetate (EA) as the solvent at room temperature for 2.5 h, which afforded a mixture of products. The major product was isolated (16%) (Table 1, entry 1) along with a trace amount of another minor product. Spectral data revealed that the major product was the bisindole-substituted cyclopentene derivative 3a, which was further confirmed by single-crystal X-ray analysis (Figure 2). We then investigated the reaction by increasing the amount of indole to 1.5 equiv. We observed an improvement in the yield of the 3a to 33% (Table 1, entry 2). Next, a remarkable improvement in the yield of 3a was observed when 2.2 equiv of indole was used (Table 1, entry 3). Moreover, in both cases, an unknown minor product was observed in 6% and 12% yields. From the spectral and single-crystal X-ray analysis, the structure of the minor product was found to be cyclopenta[b]carbazole14 B
DOI: 10.1021/acs.joc.8b02168 J. Org. Chem. XXXX, XXX, XXX−XXX
Article
The Journal of Organic Chemistry
the other hand, substituted dienynal substrates possessing electron-withdrawing substituents such as 4-Cl and 3-NO2 gave 3d in 42% yield and 3e in 37% yield. Substituted dienynal substrates equipped with 1- and 2-naphthyl groups also afforded the desired cyclopentene derivatives 3f and 3g in yields of 43% and 46%, respectively. The reaction was also examined with a substrate having a dimethoxy group on the dienynal and indole under the optimal reaction conditions, and the desired polysubstituted cyclopentene derivative 3h was produced in 42% yield. We also examined the reactions of 7-methylindole with various substituted dienynals including substrates containing electron-donating as well as electron-withdrawing groups. In these cases, the desired cyclopentene derivatives were produced as major products in moderate yields (3i−m: 40−54%). We then examined the reactions of 5-bromoindole with dienynal substrates. The reactions also provided 57% and 40% yields of the corresponding cyclopentene derivatives 3n and 3o, respectively. Further, the dienynal substrate equipped with methyl (4-Me) substitution on the phenyl group of alkyne gave 52% yield of compound 3u. Notably, the cyclopenta[b]carbazole derivatives were obtained as minor compounds in all of the aforementioned reactions. Nevertheless, we were unsuccessful in isolating the product in pure form, probably because of its instability. Furthermore, we also investigated the reactions of 4-benzylidene-3,6-diphenylhex-2-en-5-ynal 1a with electron-withdrawing indoles such as 5-chloro- and 5-nitroindoles. Unfortunately, the reactions did not proceed, even after 24 h, and starting materials were recovered. The scope of the methodology was extended to the 5methoxyindole and 4-benzylidene-3,6-diphenylhex-2-en-5-ynal 1a. To our surprise, the reaction gave a 54% yield of the corresponding cyclopenta[b]carbazole derivative 4p as the major product. Overwhelmed by this result, we examined the reactions of 5-methoxyindole with a diverse array of substituted dienynals that contain both electron-donating (Me) as well as electron-withdrawing groups (Cl) to produce 50% of 4q and 48% of 4r. We also investigated the reaction of the dienynal 1a with 4-methoxyindole, which afforded 4s in 52% yield. The reason for obtaining the maximum yield of the product in the case of both 4- and 5-methoxy groups might be due to the strong electron-donating property of the methoxy group in parasubstituted methoxyindoles. It is noteworthy that, in the case of methoxy-substituted indoles (Table 3), polysubstituted cyclopentenes were also produced as minor products, which could not be isolated by column chromatography. Next, an attempt was made to react N-methylindole and 4benzylidene-3,6-diphenylhex-2-en-5-ynal 1a under the optimized reaction conditions. We isolated two products, a polysubstituted cyclopentene derivative 3t in 20% yield and the cyclopenta[b]carbazole derivative 4t in 38% yield, in a 2:3.8 ratio (Scheme 1). We next examined the reaction of 4-benzylidene-3,6diphenylhex-2-en-5-ynal 1a and an electron-rich benzene derivative, such as 1,3,5-trimethoxybenzene, using the optimized reaction conditions. To our suprise, the reaction provided 2,4diphenyl-3-(phenylethynyl)-5-(2,4,6-trimethoxyphenyl)cyclopent-3-enol derivative (5a) in 40% yield (Scheme 2). Moreover, the reactions failed to afford the corresponding cyclopentene derivatives with other mild electron-rich heterocycles such as benzofuran or benzothiophene with 4benzylidene-3,6-diphenylhex-2-en-5-ynal under the optimal reaction conditions. Next, the reactions did not proceed in the case of 4-benzylidene-3,6-diphenylhex-2-en-5-ynal and 1-
derivative 4a. It is important to note that the reaction did not occur when I2 was replaced with N-iodosuccinimide (NIS) (using 1.1 equiv of NIS and 2.2 equiv of indole) (Table 1, entry 4). We next examined the reaction with stoichiometric amounts of different Lewis acids, including as BF3·OEt2, FeCl3, ZnCl2, and CuCl2 (1 equiv). The reaction with BF3·OEt2 resulted in decomposition (Table 1, entry 5). No reaction took place in the case of ZnCl2 and CuCl2 (Table 1, entries 6 and 7). The use of FeCl3, however, gave 4a in 20% yield, along with the unidentified products (Table 1, entry 8). Next, a set of experiments was performed with different amounts (0.2 and 0.5 equiv) of the catalytic iodine which resulted in decreased yields for the reactions (Table 1, entries 9 and 10). No marked improvement in product yield was observed when we used different solvents such as chloroform or dichloromethane (Table 1, entries 11 and 12). However, no product was formed when solvents such as diethyl ether, ethanol, and methanol were used, and the starting materials were recovered (Table 1, entries 13−15). Furthermore, when the reactions were carried out at 0 °C in solvents such as EA, dichloromethane, and dichloroethane, the product yields were nearly the same. However, the reaction time was prolonged (Table 1, entries 16−18). Furthermore, the desired products were not observed when Bronsted acid HI was used in the reaction (Table 1, entry 19). Finally, the optimal reaction conditions for this strategy were determined to be 1 equiv of dienynal 1, 2.2 equiv of indole, and 1.1 equiv of I2 in ethyl acetate solvent (25 mL) at room temperature for 15 min. The structures of the compounds 3a and 4a were established from single-crystal X-ray analysis and are depicted in Figure 2. The relative configuration of the compound 3a was assigned on the basis of a single-crystal X-ray analysis as S*,R*,R* (C33, C9, C10). This assignment was further supported by another representative compound 3o, which showed an identical configuration S*,R*,R* (C10, C9, C36). All of the protons attached to C33, C9, and C10 (3a) and C10, C9, and C36 (3o) were observed to be trans to each other (Figure 3).
Figure 3. Relative configuration based on a single-crystal X-ray analysis of 3o (ORTEP diagram ellipsoid contour 30% probability).
Under the optimized conditions, we tested the feasibility of the reaction between various substituted 4-benzylidene-3,6diphenylhex-2-en-5-ynal substrates and indole. As shown in Table 2, the reaction of 4-benzylidene-3,6-diphenylhex-2-en-5ynal 1a with indole 2a provided the corresponding polysubstituted cyclopentene 3a in 51% isolated yield when the reaction was conducted on a 0.5 mmol scale. We also verified the scope of the method with respect to substituted 4-benzylidene-3,6diarylhex-2-en-5-ynal substrates that contained electron-donating substituents such as 4-Me and 4-OMe groups on the phenyl ring. In these cases, the desired cyclopentene derivatives were produced in yields of 52% of 3b and 55% of 3c, respectively. On C
DOI: 10.1021/acs.joc.8b02168 J. Org. Chem. XXXX, XXX, XXX−XXX
Article
The Journal of Organic Chemistry Table 2. Reaction of Indoles with Various Substituted Dienynal Derivativesa−c
a Reaction conditions: 1a (0.5 mmol), 2a (1.1 mmol), I2 (0.55 mmol), solvent (25 mL). bIsolated yields. cIn all of the above reactions, we observed other unidentified products in about
