Construction of Polycyclic Indole Derivatives via Multiple Aryne

Letter Cite This: Org. Lett. 2018, 20, 644−647

pubs.acs.org/OrgLett

Construction of Polycyclic Indole Derivatives via Multiple Aryne Reactions with Azaheptafulvenes Zhen Wang,* Yesu Addepalli, and Yun He* Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P.R. China S Supporting Information *

ABSTRACT: An efficient [8 + 2]/aryl−ene tandem reaction between azaheptafulvenes and arynes has been developed, leading to the formation of cyclohepta[b]indoles in a single step with good yield. In addition, employment of excess arynes provides a [8 + 2]/aryl−ene /[6 + 2] tandem reaction to synthesize polycyclic oxacyclohepta[b]indoles. This is the first time that azaheptafulvenes have been employed in tandem reactions with arynes.

T

As a direct synthetic strategy to construct 7,5-fused heterocyclic compounds, the azaheptafulvenes have been demonstrated to undergo [8 + 2] cycloaddition with electrondeficient π systems, providing cycloheptatriene-fused pyrrole derivatives.10,11 However, the reactions usually suffered isomerization of the cycloheptatriene unit in the initially formed [8 + 2] product (Scheme 2A).12 It is too difficult to obtain such pure heterocyclic products by separating these isomers. Due to the factor that polyene analogues have multiple reactivities, the discovery of highly regioselective cyclization reactions involving

he units of indoles fused with a seven-membered ring (cyclohepta[b]indole) and polycyclic oxacyclohepta[b]indoles are privileged heterocyclic skeletons in a series of pharmaceuticals and bioactive natural products,1 such as actinophyllic acid,2 ajmaline,3 ambiguines,4 and the inhibitor of adipocyte fatty acid binding protein (A-FABP) (Scheme 1).5 The Scheme 1. Selected Synthetic Compounds and Natural Products Featuring the Cyclohepta[b]indole Core

Scheme 2. [8 + 2] Cycloadditions with Heptafulvenes

desire to construct such appealing cyclohepta[b]indole skeletons has inspired the development of several versatile synthetic strategies,6−9 among which cycloaddition reaction in a single step is one of the most efficient methods.7−9 In 2012, Wu and coworkers developed a gallium(III)-catalyzed three-component [4 + 3] cycloaddition using indole as a 2π component.7 In subsequent studies, other metals such as rhodium- and platinum-catalyzed [4 + 3] cycloadditions of vinyl Fischer carbenes were reported.8 Recently, Li and co-workers discovered an indole [5 + 2] cycloaddition reaction with an oxidopyrylium ylide for the synthesis of polycyclic oxacyclohepta[b]indoles through a dearomative process.9 Given the importance of cyclohepta[b]indoles as well as the challenges in highly selective assembly of these polycyclic skeletons, the development of new and milder protocols is still in high demand. © 2018 American Chemical Society

Received: December 5, 2017 Published: January 16, 2018 644

DOI: 10.1021/acs.orglett.7b03789 Org. Lett. 2018, 20, 644−647

Letter

Organic Letters azaheptafulvenes is an important goal.13 On the other hand, the application of 2-(trimethylsilyl)aryl triflates as mild aryne precursor has attracted much attention in aryne chemistry.14,15 To the best of our knowledge, the employment of aryne in cyclization reactions with azaheptafulvenes is unknown, which is somewhat surprising.16 Given the fact that [8 + 2] cycloaddition is a common reaction type involving azaheptafulvenes, we set out to explore the cycloadditions between azaheptafulvenes and arynes. The projected cyclization reactions may lead to the construction of biologically active cyclohepta[b]indoles and polycyclic oxacyclohepta[b]indoles (Scheme 2B). Initially, we examined the efficiency of cycloaddition reaction between azaheptafulvene 1a and aryne generated from the 2(trimethylsilyl)aryl triflate precursor 2a in CH3CN at room temperature. In the presence of 1.25 equiv of aryne precursor 2a, the [8 + 2]/aryl−ene reaction proceeded smoothly to afford cyclohepta[b]indole 3a with up to 38% yield, using CsF or KF/ 18-crown-6 as fluoride sources (Table 1, entries 1 and 2).17 To

With the optimized reaction conditions established (Table 1, entry 7), the substrate scope of the [8 + 2]/aryl−ene tandem reaction with various azaheptafulvenes and arynes was examined (Scheme 3). The study showed that the electronic nature of Scheme 3. Substrate Scope of [8 + 2]/Aryl−Ene Reactions with Azaheptafulvenes 1a

Table 1. Optimization Studies for the Tandem Reactions of Azaheptafulvene (1a) with Aryne (2a)a

a

entry

2a (x equiv)

1 2

1.25 1.25

3

2.5

4 5 6 7

2.5 2.5 2.5 2.5

8

3.0

c

9

5.0

10c,d

5.0

F source (y equiv) CsF (2.5) KF/18-C-6 (2.5) KF/18-C-6 (5.0) TBAT (5.0) TBAF (5.0) CsF (5.0) KF/18-C-6 (5.0) KF/18-C-6 (6.0) KF/18-C-6 (10) KF/18-C-6 (10)

solvent CH3CN CH3CN THF

time (h)

yield 3a (4a) (%)b

12 6

24 (trace) 38 (trace)

6

65 (10)

THF THF CH3CN CH3CN

6 6 12 6

38 (10) 45 (14) 62 (4) 88 (6)

CH3CN

6

56 (38)

CH3CN

2

22 (56)

CH3CN/ toluene

2

9 (76)

Reactions were carried out on a 0.2 mmol scale; isolated yield of the product 3; data in parentheses refer to the isolated yield of byproducts 4. Ar = 4-Cl-C6H4.

substituents on the aromatic ring at the N position had slight influence on the reactivity. The corresponding cyclohepta[b]indoles 3a−f were generated in 72−88% yield, and oxacyclohepta[b]indoles were obtained in 5−11% yield. The reactions proceeded well with disubstituted symmetrical aryne precursors. It is worth pointing out that the reactivity could not be affected obviously by electronic nature and position of the substituents. 4,5-Disubstituted symmetrical aryne precursors such as dimethyl, dimethoxy, difluoro, and indane derivatives were suitable substrates for the reaction and afforded products 3g−i,k in 70−82% yield. Electronically rich 4,5-benzodioxolebenzyne also reacted smoothly to give cyclohepta[b]indole 3j in 74% yield. Sterically hindered 3,6-dimethylbenzyne also furnished cyclic product 3l efficiently with 75% yield. Unsymmetrical 3,5-dimethoxylbenzyne and azaheptafulvene 1a only underwent [8 + 2]/aryl−ene reaction, providing cyclohepta[b]indole 3m in 81% yield with excellent regioselectivity. With these results in hand, the substrate scope of the [8 + 2]/ aryl−ene/[6 + 2] tandem reaction was examined (Scheme 4). The electronic nature of substituents on the aromatic ring of Ar group at N position had slight influence on the reactivity. In addition, the reactions proceeded well for disubstituted symmetrical aryne precursors. 4,5-Disubstituted symmetrical aryne precursors such as dimethyl, dimethoxy, benzodioxole, and indane derivatives reacted smoothly to afford products 4g−j in 68−72% yields. 4,5-Difluorobenzyne and 3,6-dimethylbenzyne furnished the products 4k and 4l in moderate yields, albeit with 28−30% isolated yield of the [8 + 2]/aryl−ene products. Meanwhile, the [8 + 2]/aryl−ene products could further react with substituted arynes to give polycyclic oxacyclohepta[b]indoles 4aa−af in 52−74% yields.18 Interestingly, polycyclic products exhibited fluorescence emission.18

Reactions were carried out with 1a (0.2 mmol), 2a, fluoride source, and solvent (3.0 mL). bYield of isolated 3a, and data in parentheses was related to the yield of 4a. c1.2 equiv of Cs2CO3 was added. dThe mixed solvent of CH3CN/toluene (1:1 v/v) was used. a

further improve the yield of product 3a, the reactions were then carried out with 2.5 equiv of aryne precursor 2a (entries 3−7). A screen of fluoride sources indicated that a higher yield of 88% was obtained when KF was used in the presence of 18-crown-6 (entry 7). Interestingly, the polycyclic oxacyclohepta[b]indole 4a also could be isolated in 4−14% yield as a minor product. We next explored the effect of additives and solvents. The use of Cs2CO3 as a coadditive with KF/18-crown-6 and CH3CN/toluene (1:1 v/v) as a mixed solvent exhibited a positive effect on the yield of 4a with up to 76% (entry 10), and the reaction time was shortened to 2 h (entries 8−10). Furthermore, the structures of 3c and 4c were confirmed on the basis of X-ray crystal structural analysis. 645

DOI: 10.1021/acs.orglett.7b03789 Org. Lett. 2018, 20, 644−647

Letter

Organic Letters Scheme 4. Substrate Scope of [8 + 2]/Aryl−Ene/[6 + 2] Tandem Reactionsa

Scheme 5. Substrate Scope of [8 + 2]/Aryl−Ene Reactions with Heteroazulenes 5a

a

Reactions were carried out on a 0.2 mmol scale; combined yields of isolated products 6 and 7; ratio of 6/7 was determined by 1H NMR analysis of the crude mixture. Ar1 = 4-Cl-C6H4.

a

Reactions were carried out on a 0.2 mmol scale; isolated yield of products 4; data in parentheses refer to the isolated yield of byproducts 3. Ar1 = 4-Cl-C6H4.

Scheme 6. Cycloaddition Reaction between 2m and 5a Then, the reaction between heteroazulenes 5 and arynes was investigated. Pleasingly, the scope of this [8 + 2]/aryl-ene reaction was found to be general with various substituted arynes and different heteroazulenes. The reaction underwent an efficient [8 + 2]/aryl−ene reaction to access tricyclic fused indole derivatives with 51−84% yields (Scheme 5). Although a 1:1 ratio of indoles 6 to indolines 7 was observed, the regioisomers could be separated and purified by flash column chromatography on silica gel. The regioselectivity was obviously affected by electronic nature and position of substituents on the arynes. 4, 5-Dimethyl aryne precursor and indane derivative furnished the desired products with 1:1 regioselectivity, while 2:1 regioselectivity was obtained with 4,5-benzodioxolebenzyne. In addition, electronically rich substrate 4,5-dimethoxylbenzyne led to excellent regioselectivity, affording the tricyclic fused indoline 7h as an only product with 52% yield. Interestingly, sterically hindered substrate 3,6-dimethylbenzyne resulted in the switch of regioselectivity to yield the desired product 6i. Furthermore, another unexpected tandem [8 + 2]/aryl-ene/ ring opening tandem reaction was discovered with unsymmetrical aryne precursor 2m. As shown in Scheme 6, cyclic fused indolines 8a and 9a were obtained in the reaction. Finally, the structures of compounds 6a, 7a, 8a, and 9a were unequivocally confirmed by single-crystal X-ray analysis. To evaluate the synthetic potential of the present approach, a gram-scale synthesis of 3a was performed, and the cyclic products 3a and 4a were efficiently transformed into functionalized compounds 15 and 16 through hydrogenation processes.18 Moreover, the synthetic applicability of 6a and 7a has been demonstrated by the synthesis of N−H indole 12 and indoline 14, which are present in a number of biologically active compounds.18 Treatment of compound 10 with potassium hydroxide/18-crown-6 under air condition underwent an efficient Winterfeldt oxidation process to provide quinolone 11

bearing a quaternary stereocenter.19 Interestingly, the free cyclohepta[b]indole 12 was formed under similar conditions in an N2 atmosphere. Furthermore, stepwise hydrogenation of 7a followed by the hydrolysis in the presence of KOH/18-crown-6 furnished NH free indoline 14 in good yield. In summary, we have successfully developed a mild, general, and efficient [8 + 2]/aryl−ene tandem reaction between azaheptafulvenes and arynes for synthesis of biologically interesting cyclohepta[b]indoles. We have also applied the tandem [6 + 2] cycloaddition to arynes to further derivatize cyclohepta[b]indoles into polycyclic oxacyclohepta[b]indoles. Notably, employment of heteroazulenes provides a unique opportunity for the synthesis of nitrogen-containing tricyclicfused ring system. The tandem reaction reported herein represents a new synthetic approach to access cyclohepta[b]indoles and polycyclic oxacyclohepta[b]indoles. We are currently evaluating the biological profiles of the novel structural motifs synthesized in this report, and our findings will be reported in due course. 646

DOI: 10.1021/acs.orglett.7b03789 Org. Lett. 2018, 20, 644−647

Letter

Organic Letters

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(7) Han, X.; Li, H.; Hughes, R. P.; Wu, J. Angew. Chem., Int. Ed. 2012, 51, 10390. (8) (a) Shu, D.; Song, W.; Li, X.; Tang, W. Angew. Chem., Int. Ed. 2013, 52, 3237. (b) Kusama, H.; Sogo, H.; Saito, K.; Suga, T.; Iwasawa, N. Synlett 2013, 24, 1364. (9) Mei, G.; Yuan, H.; Gu, Y.; Chen, W.; Chung, L. W.; Li, C.-C. Angew. Chem., Int. Ed. 2014, 53, 11051. (10) For reviews, see: (a) Nair, V.; Abhilash, K. G. Top. Heterocycl. Chem. 2008, 13, 173. (b) Nair, V.; Abhilash, K. G. Synlett 2008, 301. (11) For examples see: (a) Yamamoto, K.; Kajigaeshi, S.; Kanemasa, S. Chem. Lett. 1977, 6, 85. (b) Yamamoto, K.; Kajigaeshi, S.; Kanemasa, S. Chem. Lett. 1977, 6, 91. (c) Truce, W. E.; Shepherd. J. Am. Chem. Soc. 1977, 99, 6453. (d) Nair, V.; Abhilash, K. G. Tetrahedron Lett. 2006, 47, 8707. (e) Lage, M. L.; Fernández; Sierra, M. A.; Torres, M. R. Org. Lett. 2011, 13, 2892. (12) (a) Sanechika, K.; Kajigaeshi, S.; Kanemasa, S. Chem. Lett. 1977, 6, 861. (b) Ishizu, T.; Harano, K.; Yasuda, M.; Kanematsu, K. J. Org. Chem. 1981, 46, 3630. (c) Hayakawa, K.; Nishiyama; Kanematsu, K. J. Org. Chem. 1985, 50, 512. (d) Barluenga, J.; García-Rodríguez, J.; Martínez, S.; Suárez-Sobrino, Á . L.; Tomás, M. Chem. - Asian J. 2008, 3, 767. (e) Barluenga, J.; García-Rodríguez, J.; Suárez-Sobrino, Á . L.; Tomás, M. Chem. - Eur. J. 2009, 15, 8800. (13) For a successful example of asymmetric [8 + 2] with azaheptafulvenes, see: Xie, M. S.; Liu, X. H.; Wu, X. X.; Cai, Y. F.; Lin, L. L.; Feng, X. M. Angew. Chem., Int. Ed. 2013, 52, 5604. (14) For the generation of arynes from 2-(trimethylsilyl)aryltriflates, see: (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 12, 1211. For a modified procedure, see: (b) Peña, D.; Cobas, A.; Pérez, D.; Guitián, E. Synthesis 2002, 1454. (15) For reviews of aryne chemistry, see: (a) Bhojgude, S. S.; Bhunia, A.; Biju, A. T. Acc. Chem. Res. 2016, 49, 1658. (b) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550. (c) Chen, Y.; Larock, R. C. In Modern Arylation Methods; Ackermann, L., Ed.; Wiley-VCH: Weinheim, Germany, 2009; p 401;. (d) Kessar, S. V. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 4, p 483. For selected examples of reactions with arynes, see: (e) Banne, S.; Reddy, D. P.; Li, W.; Wang, C.; Guo, J.; He, Y. Org. Lett. 2017, 19, 4996. (f) Roy, T.; Thangaraj, M.; Gonnade, R. G.; Biju, A. T. Chem. Commun. 2016, 52, 9044. (g) Reddy, R. S.; Lagishetti, C.; Chen, S.; Kiran, I. N. C.; He, Y. Org. Lett. 2016, 18, 4546. (h) Guo, J.; Kiran, I. N. C.; Reddy, R. S.; Gao, J.; Tang, M.; Liu, Y.; He, Y. Org. Lett. 2016, 18, 2499. (i) Bhunia, A.; Roy, T.; Pachfule, P.; Rajamohanan, P. R.; Biju, A. T. Angew. Chem., Int. Ed. 2013, 52, 10040. (j) Bhojgude, S. S.; Kaicharla, T.; Bhunia, A.; Biju, A. T. Org. Lett. 2012, 14, 4098. (k) Allan, K. M.; Gilmore, C. D.; Stoltz, B. M. Angew. Chem., Int. Ed. 2011, 50, 4488. (l) Yoshioka, E.; Kohtani, S.; Miyabe, H. Angew. Chem., Int. Ed. 2011, 50, 6638. (m) Bronner, S. M.; Bahnck, K. B.; Garg, N. K. Org. Lett. 2009, 11, 1007. (n) Sha, F.; Huang, X. Angew. Chem., Int. Ed. 2009, 48, 3458. (o) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558. (p) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340. (q) Yoshikawa, E.; Yamamoto, Y. Angew. Chem., Int. Ed. 2000, 39, 173 and references cited therein. (16) For related reactions of aryne with 8-cyanoheptafulvene, tropothione, and tropone, see: (a) Oda, M.; Kitahara, Y. Bull. Chem. Soc. Jpn. 1970, 43, 1920. (b) Yamabe, S.; Minato, T.; Ishiwata, A.; Irinamihira, O.; Machiguchi, T. J. Org. Chem. 2007, 72, 2832. (c) Yamabe, S.; Minato, T.; Watanabe, T.; Machiguchi, T. Theor. Chem. Acc. 2011, 130, 981. (d) Thangaraj, M.; Bhojgude, S. S.; Bisht, R. H.; Gonnade, R. G.; Biju, A. T. J. Org. Chem. 2014, 79, 4757. (17) The [8 + 2] product could not be detected. (18) See the Supporting Information for details. (19) Mentel, M.; Breinbauer, R. Curr. Org. Chem. 2007, 11, 159.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03789. Synthesis procedure, analytical details, and NMR spectra of all of the compounds (PDF) Accession Codes

CCDC 1580114, 1580116−1580117, 1580124, and 1580126− 1580127 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected] ORCID

Zhen Wang: 0000-0002-1165-2552 Yun He: 0000-0002-5322-7300 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the financial support from the National Science Foundation of China (Nos. 21572027, 21602023, and 21372267) and Chongqing Research and Frontier Technology (cstc2016jcyjA0403). We thank Dr. Daibing Luo (Sichuan University) for the X-ray crystallographic analysis.

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DOI: 10.1021/acs.orglett.7b03789 Org. Lett. 2018, 20, 644−647