Highly efficient [3 + 2] reaction of 3-vinylindoles with 3-indolylmethanols by Brønsted-acid catalysis

Abstract

This paper describes a highly efficient [3 + 2] reaction between 3-vinylindoles and 3-indolylmethanols. Novel 2,3-bisindolylmethanes were prepared as single diastereoisomers in high yields with the promotion of 1 mol% 2-hydroxy-3,5-dinitrobenzoic acid.

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Bisindolylmethanes (BIMs) are molecules containing two indolyl moieties connected to the same carbon atom.¹ These compounds mainly include 3,3′-BIMs, 2,2′-BIMs and 2,3′-BIMs, and are widely isolated from terrestrial and marine natural sources.² Many of them have extensive biological and pharmaceutical activities.³ So, the synthesis of BIMs attracted extensive attention recently. Due to the high reactivity of the 3-position of indole, the 3,3′-BIMs could be easily prepared and numerous methods were developed for their synthesis.⁴ When the 3-position of indole is occupied, the 2-position can act as a nucleophilic site and afford 2,2′-BIMs.⁵ However, the synthesis of 2,3′-BIMs is much more difficult owing to the high reactivity of 3-position of indole.⁶ In fact, 2,3′-BIMs are of considerable value because they display a broad spectrum of interesting biological and pharmaceutical activities. For example, the natural product Yuehchukene, exhibiting anti-implantation activity, is a typical representation.⁷ So, chemists developed various methods to prepare Yuehchukene analogs and other 2,3′-BIMs. Recently, James McNulty and co-workers described a metal salt catalyzed dimerization of 3-vinylindoles.⁸ Inspired by this, and our previous works about using 3-indolylmethanols as alkylation reagents, we rationally designed a [3 + 2] reaction of 3-vinylindoles⁹ and 3-indolylmethanols¹⁰ to synthesize the 2,3-BIMs (Scheme 1). According to this rout, the 3-indolylmethanols 1 are dehydrated and produce the active vinylogous imino intermediates I in the promotion of an acid catalyst. Then, the 3-vinylindoles 2 will attack intermediate I to form a new active vinylogous imino intermediates II. An intramolecular Fridel–Crafts reaction of II will take place subsequently and the 2,3-bisindole compounds 4 will be formed. Here we reported this efficient and convenient method for the synthesis of 2,3-BIMs in high yields, excellent diastereoselectivities and with broad substrate scopes.

Scheme 1 Our strategy for constructing 2,3′-bisindoles.

The 3-indolylmethanol 1a and trans-3-vinylindole 2a were chose as reactants in the model reaction. As expected, under the promotion of 10 mol% 3,5-dinitrobenzoic acid, the target product 4a was obtained in 80% yield (Table 1, entry 1). The crude ¹H NMR analysis indicated that only one diastereoisomer was formed in this reaction. Encouraged by these good results, several substituted benzoic acids and other acids were screened. We found the acidity of Brønsted-acid was very important for this transformation. For example, the yield of 4a decreased greatly when we used 4-nitrobenzoic acid as catalyst (Table 1, entry 2), and only trace amount of product was obtained in the promotion of 4-methoxybenzoic acid (Table 1, entry 5). The strong Brønsted acids, such as 4-methylbenzenesulfonic acid (PTSA) and trifluoroacetic acid (TFA), also could promote this reaction, but the efficiency was not as well as that of 3,5-dinitrobenzoic acid (Table 1, entries 7, 8 vs. entry 1). In order to further increase the yield, the 2-hydroxy-3,5-dinitrobenzoic acid 3g was introduced in this reaction as a catalyst. Firstly, the 2-hydroxy-3,5-dinitrobenzoic acid 3g has the similar structure with 3,5-dinitrobenzoic acid. Moreover, the 2-hydroxy of 3g can increase the acidity of carboxyl through the formation of an intramolecular hydrogen bond.¹¹ We found the 2-hydroxy-3,5-dinitrobenzoic acid 3g could promote this reaction efficiently in a short reaction time (Table 1, entry 9). Notably, the catalyst loading could be decreased to 1 mol% without any loss of the catalytic efficiency. This was sharply contrasted with the usual organocatalyed reactions in which 5–30 mol% organocatalyst was generally used.¹² A clearer reaction was observed when this reaction was carried out at low temperature (Table 1, entry 10). This reaction stalled when the temperature was further lower (Table 1, entry 14). Based on these results, the optimal reaction condition for the [3 + 2] reaction between 3-indolylmethanol 1a and 3-vinylindole 2a was determined. Generally, this reaction was carried out in DCM at −20 °C by using 1 mol% 2-hydroxy-3,5-dinitrobenzoic acid 3g as the catalyst.

Table 1 Optimization of reaction conditions^a

Entry	3 (x)	T (°C)	Time (h)	Yield^b (%)
a The reaction was carried out with 1a (0.1 mmol), 2a (0.1 mmol), 3 in solvent (1 mL).b Isolated yield.
1	3a (10)	0	23	80
2	3b (10)	0	138	30
3	3c (10)	0	140	13
4	3d (10)	0	155	22
5	3e (10)	0	156	3
6	3f (10)	0	92	84
7	PTSA (10)	0	22	62
8	TFA (10)	0	17	79
9	3g (10)	0	5	86
10	3g (1)	0	4	87
11	3g (1)	−10	3	93
12	3g (1)	−20	4	95
13	3g (1)	−30	23	95
14	3g (1)	−40	30	81

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With the optimal reaction conditions in hand, we then explored the substrate scopes. Firstly, the substituents on the indole ring of 3-vinylindoles 2 were investigated (Table 2, entries 2–6). When electron-withdrawing groups were introduced on the indole ring of 2, the target products 4b–d were obtained as single diastereoisomers in excellent yields (Table 2, entries 2–4). It was found that the position of substituents has little effect on the diastereoselectivity and yield of this reaction. For example, the 4-chloro-3-styryl-1H-indole reacted with 1a under the optimal reaction conditions and produce the product 4b in a completely diastereo-controlling fashion and with quantitative yield (Table 1, entry 2); similar results were obtained when the position of substituents changed (Table 1, entries 3 and 4). Then, the 5-MeO and 6-Me indole substituted 3-vinylindoles were involved in this reaction. The desired products 4e and 4f were obtained in excellent yields (Table 2, entries 5 and 6). Secondly, the substituents effects on phenyl group of 3-indolylmethanols were studied. When electron-withdrawing groups were introduced into the phenyl ring, the reaction speed became slow (Table 2, entries 7–15). In particular, the nitro substituent decreased the reaction speed greatly (Table 2, entries 12–14). In these cases, the desired products 4l–m could be obtained in high yields when the reaction with a prolongation of reaction time (Table 2, entries 12–14). We found the reaction between (1H-indol-3-yl)(2-methoxyphenyl) methanol 1k and 2a produced the target product 4p in 56% yield, even the reaction time was prolonged to 119 hours (Table 2, entry 16). However, the 3-MeO phenyl substituted 1l produced the corresponding product in excellent yield (Table 2, entry 17). The steric influence of 2-MeO group of 1k is the possible reason that leads to the low yield of 4p. The relative structure of compound 4d was determined X-ray crystal analysis (Fig. 1).¹³ The relative structures of 4a–r were assigned correspondingly.

Table 2 Substrate scopes^a

Entry	1	4	Ar	R	T (°C)	Time (h)	Yield^b (%)
a For entries 1–6: 1 (0.1 mmol), 2 (0.1 mmol), 3g (0.001 mmol) in CH2Cl2 (1 mL); entries 7–17: 1 (0.2 mmol), 2 (0.2 mmol), 3g (0.002 mmol) in CH2Cl2 (1 mL).b Isolated yield.
1	1a	4a	Ph	H	−20	4	95
2	1a	4b	Ph	4-Cl	−20	13	99
3	1a	4c	Ph	5-Br	−20	12	87
4	1a	4d	Ph	6-F	−20	18	86
5	1a	4e	Ph	5-MeO	−20	28	86
6	1a	4f	Ph	6-Me	−20	14	97
7	1b	4g	2-FC6H4	H	0	13	96
8	1c	4h	3-FC6H4	H	0	12	99
9	1d	4i	4-FC6H4	H	0	13	85
10	1e	4j	3,4-2ClC6H3	H	0	23	99
11	1f	4k	2-ClC6H4	H	0	14	92
12	1g	4l	2-NO2C6H4	H	0	89	79
13	1h	4m	3-NO2C6H4	H	0	113	93
14	1i	4n	4-NO2C6H4	H	0	113	98
15	1j	4o	4-CF3C6H4	H	0	22	91
16	1k	4p	2-MeOC6H4	H	0	119	56
17	1l	4q	3-MeOC6H4	H	0	17	99

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Fig. 1 X-ray molecular structure of compound 4d.

It is well known that the BINOL-derived phosphoric acids have excellent catalytic and chiral induction abilities in organocatalysis.^14,15 So, the phosphoric acid 3h was introduced to this reaction as a chiral Brønsted acid catalyst. We wanted to realize this [3 + 2] transformation in an asymmetric version. Disappointedly, the enantioselectivity of 4a was very poor (Table 3, entries 1–3). We thought the poor chiral induction maybe caused by the remote chiral-control, i.e. the reaction sites were far away from the chiral centre of catalysts (TS I).

Table 3 Asymmetric investigation^a

Entry	Time (h)	T (°C)	Yield^b (%)	ee^c (%)
a The reaction was carried out with 1a (0.1 mmol), 2a (0.12 mmol), 3h (10 mol%) in CH2Cl2 (1 mL).b Isolated yield.c HPLC conditions: chiral Lux Cellulose-1 column, ^nhexane : 2-propanol = 90 : 10, 1 mL min^−1, 30 °C, tminor = 31.836, tmajor = 35.743.d The reaction was carried out with 1a (0.12 mmol), 2a (0.1 mmol).
1	2	25	84	8
2	5	−10	75	10
3^d	5	−30	60	5

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In conclusion, we disclosed a highly efficient [3 + 2] reaction between 3-indolylmethanols and 3-vinylindoles. Under the promotion of 1 mol% 2-hydroxy-3,5-dinitrobenzoic acid 3g, the 2,3-BIMs 4a–q were prepared in high yields as single diastereoisomers.

We are grateful for financial support from NSFC (21272002), the Fundamental Research Funds for the Central Universities (XDJK2013B028) and the Program for New Century Excellent Talents in Universities (NCET-12-0929).

Notes and references

1. M. Shiri, M. A. Zolfigol, H. G. Kruger and Z. Tanbakouchian, Chem. Rev., 2010, 110, 2250.
2. Selected examples: (a) E. Fahy, B. C. M. Potts, D. J. Faulkner and K. Smith, J. Nat. Prod., 1991, 54, 564; (b) T. S. Kam, Alkaloids, Chemical and Biological Perspectives, Pergamon, Amsterdam, 1999; (c) G. Bifulco, I. Bruno, L. Minale, R. Riccio, A. Calignano and C. Debitus, J. Nat. Prod., 1994, 57, 1294; (d) G. Bifulco, I. Bruno, R. Riccio, J. Lavayre and G. Bourdy, J. Nat. Prod., 1995, 58, 1254.
3. See ref. 1 and the references cited in.
4. Selected examples for the synthesis of 3,3′-BIMs: (a) T. V. Moskovkina, A. I. Kalinovskii, E. A. Martyyas and M. M. Anisimov, Chem. Heterocycl. Compd., 2013, 49, 452; (b) G. S. S. Kumar, A. A. M. Prabu, S. J. Jenniefer, N. Bhuvanesh, P. T. Muthiah and S. Kumaresan, J. Mol. Struct., 2013, 1047, 109; (c) S. Gujarathi, H. P. Hendrichson and G. Zheng, Tetrahedron Lett., 2013, 54, 3550; (d) S. B. Bharate, J. B. Bharate, S. I. Khan, B. L. Tekwani, M. R. Jacob, R. Mudududdla, R. R. Yadav, B. Singh, P. R. Shama, S. Maity, B. Singh, I. A. Khan and R. A. Vishwakarma, Eur. J. Med. Chem., 2013, 63, 435; (e) K. Prinsen, M. M. Cona, J. Cleynhens, H. Vanbilloen, J. Li, N. Dyubankova, E. Lescrinier, G. Bormans, Y. Ni and A. Verbruggen, Bioorg. Med. Chem. Lett., 2013, 23, 3216; (f) H. Veisi, M. Ataee, L. Fatolahi and S. Lotfi, Lett. Org. Chem., 2013, 10, 111.
5. Selected examples: (a) R. K. Sharma, Y. Monga and A. Puri, Catal. Commun., 2013, 35, 110; (b) T. Nobuta, A. Fujiya, N. Tada, T. Miura and A. Itoh, Synlett, 2012, 23, 2975; (c) P. Dydio, D. Lichosyt, T. Zieliński and J. Jurczak, Chem. – Eur. J., 2012, 18, 13686; (d) P. J. Das and J. Das, Tetrahedron Lett., 2012, 53, 4718.
6. Selected examples: (a) T. Yokosaka, H. Nakayama, T. Nemoto and Y. Mamada, Org. Lett., 2013, 15, 2978; (b) D. Fokas, M. Kaselj, Y. Isome and Z. Wang, ACS Comb. Sci., 2013, 15, 49; (c) D. Shu, G. N. Winston-McPherson, W. Song and W. Tang, Org. Lett., 2013, 15, 4162; (d) T. P. Pathak, J. G. Osiak, R. M. Vaden, B. E. Welm and M. S. Sigman, Tetrahedron, 2012, 68, 5203.
7. Selected examples for the synthesis of Yuehchukene: (a) K.-F. Cheng, Y.-C. Kong and T.-Y. Chan, J. Chem. Soc., Chem. Commun., 1985, 2, 48; (b) J.-H. Sheu, Y.-K. Chen, H.-F. Chung, S.-F. Lin and P.-J. Sung, J. Chem. Soc., Perkin Trans. 1, 1998, 12, 1959; for Yuehchukene anologies: (c) K.-F. Cheng, T.-T. Chan, T.-F. Lai and Y.-C. Kong, J. Chem. Soc., Perkin Trans. 1, 1988, 12, 3317; (d) K.-F. Cheng, G.-A. Cao, Y.-W. Yu and Y.-C. Kong, Synth. Commun., 1994, 24, 65.
8. J. McNulty and D. McLeod, Synlett, 2011, 5, 717.
9. (a) C. Gioia, A. Hauville, L. Bernardi, F. Fini and A. Ricci, Angew. Chem., Int. Ed., 2008, 47, 9236; (b) B. Tan, G. Hernandez-Torres and C. F. Barbas, III, J. Am. Chem. Soc., 2011, 133, 12354; (c) M. Terada, K. Moriya, K. Kanomata and K. Sorimachi, Angew. Chem., Int. Ed., 2011, 50, 12586; (d) G. Bergonzini, L. Gramigna, A. Mazzanti, M. Fochi, L. Bernardi and A. Ricci, Chem. Commun., 2010, 46, 327; (e) T. P. Pathak, J. G. Osiak, R. M. Vaden, B. E. Welm and M. S. Sigman, Tetrahedron, 2012, 26, 5203.
10. (a) Q.-X. Guo, Y.-G. Peng, J.-W. Zhang, L. Song, Z. Feng and L.-Z. Gong, Org. Lett., 2009, 11, 4620; (b) L. Song, Q.-X. Guo, X.-C. Li, J. Tian and Y.-G. Peng, Angew. Chem., Int. Ed., 2012, 51, 1899; (c) B. Xu, Z.-L. Guo, W.-Y. Jin, Z.-P. Wang, Y.-G. Peng and Q.-X. Guo, Angew. Chem., Int. Ed., 2012, 51, 1059; (d) J.-Z. Huang, S.-W. Luo and L.-Z. Gong, Acta Chim. Sin., 2013, 71, 879; (e) J. Song, C. Guo, A. Adele, H. Yin and L.-Z. Gong, Chem. – Eur. J., 2013, 19, 3319; (f) C. Guo, J. Song, J.-Z. Huang, P.-H. Chen, S.-W. Luo and L.-Z. Gong, Angew. Chem., Int. Ed., 2012, 51, 1046.
11. According to the SciFinder results, pK_a3g = 1.57, pK_a3a = 2.77.
12. Selected examples: (a) H. Zhang, X. Wen, L. Gan and Y. Peng, Org. Lett., 2012, 14, 2126; (b) Q.-X. Guo, H. Liu, C. Guo, S.-W. Luo, Y. Gu and L.-Z. Gong, J. Am. Chem. Soc., 2007, 129, 3790.
13. ESI.†.
14. (a) T. Akiyama, Chem. Rev., 2007, 107, 5744; (b) A. G. Doyle and E. N. Jacobsen, Chem. Rev., 2007, 107, 5713; (c) M. Terada, Chem. Commun., 2008, 4097; (d) T. Akiyama, J. Itoh and K. Fuchibe, Adv. Synth. Catal., 2006, 348, 999.
15. For leading literature references, see: (a) D. Uraguchi and M. Terada, J. Am. Chem. Soc., 2004, 126, 5356; (b) T. Akiyama, J. Itoh, K. Yokota and K. Fuchibe, Angew. Chem., Int. Ed., 2004, 43, 1566.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, structural proofs, CIF file of compound 4d. CCDC 968308. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra47056c

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