One pot hydroamination/[4 + 3] cycloaddition: synthesis towards the cyclohepta[b]indole core of silicine and ervatamine

Abstract

A new and facile tandem reaction of intramolecular hydroamination and novel [4 + 3] cycloaddition was developed for the synthesis of multitudinal indole-containing 5,7,6-tricyclic skeletons. This method was further extended to the quick synthesis of a series of useful motif of natural products, such as the core of ervatamine and silicine.

---

Seven-membered rings fused with an indole block (cyclohepta[b]indole¹), indole-containing 5,7,6-tricyclic skeletons, are widely featured in diverse bioactive natural products such as silicine,² ervatamine,³ actinophyllic acid⁴ and in numerous pharmaceutical products with diverse activities such as an SIRT1 inhibitor⁵ and anti-tubercular agent⁶ (Fig. 1).

Fig. 1 Selective bioactive natural products with cyclohepta[b]indole.

Previously, we reported a novel [4 + 3] cycloaddition for the construction of 5,6,7-tricyclic skeleton and successfully applied it to the synthesis of Liphagal and Frodonsin B.⁷ As one of the most fundamental tools, [4 + 3] cycloaddition is of great value for synthetic chemists to develop efficient and elegant chemical processes which allow the rapid creation of diverse and complex multicyclic skeletons.^8,9 In addition, tandem reactions have received much attention for their high efficiency, low waste and easy manipulation.¹⁰ In order to further investigate 5,7,6-tricyclic bioactive compounds and get more efficient approach to construct seven-membered rings, we have been focusing on [4 + 3] cycloaddition in recent years (Scheme 1). As we know, formation of the allylic cation is responsible for the efficiency and even the selectivity of [4 + 3] cycloadditions.¹¹ However, in the first generation [4 + 3] cycloadditions, the cationization of aryl alcohols required rigorous reaction conditions and accomplished in low efficiency.

Scheme 1 (a) First generation [4 + 3] cycloadditions, and (b) newly designed novel tandem hydroamination/[4 + 3] cycloaddition.

Furthermore, 3-indole alcohols are mostly prepared from corresponding indoles which, while quite useful, possesses certain limitations on Friedel-Craft acetylation.¹² These limitations stimulates the unremitting pursuit of developing new cycloaddition precursors. Compared with the first generation precursor, precursor 2 greatly improved the carbocation efficiency via aromation of 8 into a more stable state 8a (Scheme 2).

Scheme 2 The formation of allylic cation.

Herein a new [4 + 3] cycloaddition involved in a tandem reaction, which provided a more facile synthetic route towards the core of silicine and ervatamine and other 5,7,6-tricyclic skeletons, was reported. The tandem reaction contains a novel tandem reaction of intramolecular hydroamination^13–15 and a new [4 + 3] cycloaddition catalyzed by two reagents in relay. This study has three priorities than the previous works: (a) it contains a new and more challenging [4 + 3] cycloaddition, which has great academic value; (b) the application of tandem reaction makes the synthesis more facile; (c) this method is more suitable for the construction of natural products and their cores.

Optimization studies of the tandem annulation are summarized in Table 1. Neither Pd(OAc)₂ nor AuCl was effective in promoting the 5-exo-dig hydroamination (entries 1–2, Table 1). However, AgOTf was effective in promoting the desired cyclization (entries 3–6, Table 1). Cation generating reagents such as camphorsulfonic acid (CSA), Ph₂SiCl₂, BiCl₃, TiCl₄, and ZnCl₂ were also examined (entries 3–6, Table 1). Protonic acid (CSA) could lead to an isomerization of 2a, which largely decreased the cycloaddition efficiency (entry 4, Table 1). Other Lewis acids (TiCl₄, BiCl₃) resulted in low yields as a consequence of polymerization of dienes or cations (entries 2–3, Table 1). Fortunately, the ZnCl₂/Et₂O solution provided the highest yield of the isolated product 3a (entry 5, Table 1). Organosilicon reagent Ph₂SiCl₂ generated complex mixtures (entry 6). When the Ts-protecting group of nitrogen was replaced by Boc- or Bn-, no cycloaddition products were observed and the starting material was recovered in a near-quantitative yield (entry 7, Table 1). Compound 2a was isolated in nearly quantitative yield without adding any Lewis acid (entry 8, Table 1). Further transformation of compound 2a under ZnCl₂ condition resulted final product 3a in 89% yield (entry 9, Table 1), which indicated that this tandem annulations involved compound 2a. For the consideration of potential hydrolysis of metal triflates, Brønsted acid catalysis (TfOH) was examined (entry 10, Table 1).

Table 1 Optimization studies

Entry^a	Conditions	Yields^b
a RT, CH2Cl2 5 mol% catalyst, 18 h, then 5 eq. diene 4c 1.1 eq. acid, 2 h, unless noted otherwise.b Yield of isolated product.c No formation of compound 2a.d Cooled to −78 °C.e Complex mixtures.f Polymerization of dienes, products difficult to purify on column chromatography.g Ts protecting group of nitrogen was replaced by Boc- or Bn-.h Lewis acid was not added, and intermediate 2a was isolated in nearly quantitative yield.i Intermediate 2a was added as the starting material of cycloaddition.
1^c	5 mol% Pd(OAc)2, 1.1 eq CSA	No reaction
2^d	5 mol% AuCl, 1.1 eq. TiCl4	0^e
3	5 mol% AgOTf, 1.1 eq. BiCl3	10^f
4	5 mol% AgOTf, 1.1 eq. CSA	35
5	5 mol% AgOTf, 1.1 eq. ZnCl2	88
6	5 mol% AgOTf, 1.1 eq. Ph2SiCl2	0^e
7	5 mol% AgOTf, 1.1 eq. ZnCl2	0^g
8^h	5 mol% AgOTf	0
9^i	1.1 eq ZnCl2	89
10^c	5 mol% TfOH, 1.1 eq. ZnCl2	0

---

In order to explore the scope of the tandem hydroamination/[4 + 3] cycloaddition sequence, a variety of combinations of dienes 4 and alcohols 1 were examined as shown in Table 2. It was found that various dienes 4 underwent the desired reactions with alcohols 1 to afford cyclohepta[b]indole skeletons 3a–o. Generally, the electron-rich dienes showed better reactivity. Various substituents at the indole 2α-position were also examined. The experiments showed that the efficiency of cycloaddition depended on the properties of 2α-substituent. Alkyl substituent such as cyclopropyl-, cyclohexyl-, and t-Bu-appeared to have less influence on the reaction (3c, 3k, 3f, 3h, 3m). Particularly, cyclopropyl group underwent a rearrangement of carbocation under Lewis acid conditions and resulted in a cyclobutene skeleton (3c, 3k, byproduct see ESI, S7†). Aryl substituent such as phenyl- and 3-thienyl- resulted in lower yields (3g, 3i, 3n), as a consequence of complication of the reaction system. Notably, compounds with methoxymethyl group participated in cycloaddition with excellent yields (3a–b, 3d–e, 3j, 3l, 3o, yield of 3b up to 97%). The presence of F-substituent in 1 hindered the hydroamination procedure and resulted in lower yields (3d–h, 3l–m, 3o).

Table 2 Scope of tandem annulation of various alcohols 1 and dienes 4

---

In order to test whether this method could be extend to the synthesis of bioactive natural products, tandem annulation of 1a and silyl enol ethers (4a, 4b) were examined preferentially (Scheme 3) under the optimized condition (entry 5, Table 1). To our surprise, the reaction thin layer chromatography of 1a and 4a turned out to be quite complex. The desired product 5a was generated in low yield (11%). After careful examination of the reaction system, a deprotec-tion/dehydration product 5c was yielded in 53% yield. These facts indicated that the rate of [4 + 3] cycloaddition is faster than the deprotection procedure under the condition of ZnCl₂. To further confirm this assumption, the silyl enol ether 4a was replaced by a more unstable one 4b. To our delight, cycloaddition resulted in 5b (less than 3%) and 5c (69%). Thus we constructed the core skeleton of ervatamine and silicine using the novel tandem annulations.

Scheme 3 One pot synthesis towards the core of ervatamine and silicine.

Using unsymmetrically substituted dienes (4a, 4b, and 4c), all of the [4 + 3] cycloaddition reactions show excellent regioselectivities (5a, 5b, 3a, 3d, and 3f), and no regioisomers were observed (Scheme 3, Table 2). The 2D-COSY NMR spectra of 5a and 3a were evident to confirm this regiochemistry (see ESI†). For the products derived from cyclo-dienes, diastereoselectivities were observed in the range from greater than 20 : 1 to 2 : 1. Electron-rich substituents in 1 provided products with the highest selectivities (3j, 3l, 3n), while electron-poorer and smaller steric substituents exhibited lower selectivity (3k, 3m, 3o). The strong NOE signals between H_a and H_b in the major isomer of 3j, 3k, and 3l were in accordance with the predominant formation of the endo-cycloadduct. The stereo-structure of bridged product 3o was characterized by X-ray crystallography as shown in Fig. 2. This data shows that the 2α-methoxymethyl group is in the cis position of the carbon bridge.

Fig. 2 The X-ray structure of 3o.

Mechanism of AgOTf catalyzed hydroamination has been well explored.¹⁶ Moreover, cycloaddition of furfuryl, benzofuran, indole, and thiofuran cations were also studied experimentally or computationally.¹⁷ Winne's work on furfuryl cation concluded that both the theoretical and experimental results preferred a two-step cationic cyclization.^9a Wu's report supported a stepwise cyclization process by DFT calculations.^9b Our previous synthesis of frondosin B via [4 + 3] cycloaddition of benzofuran cation also obtained stepwise cationic product, which was evident for a two-step process.^7a The above information provided a clue on the plausible mechanism of the described hydroamination/[4 + 3] cycloaddition, as illustrated in Scheme 4. Coordination of the silver catalyst with the alkyne moiety of 1 provided the silver(I) coordinated intermediate 5. The activated species 5 underwent the intramolecular amination process through anti-addition of the sulfonamide block to the activated alkyne bond, which afforded the vinyl silver complex 6. An intermolecular or intramolecular protodemetalation of this hypothetic organosilver complex 6 would then generate 2. Cation intermediate 8 was achieved under Lewis acid conditions, and further aromatized into a more stable state 8a (Scheme 2). Cycloaddition between 8a and dienes 4 via endo-cycloaddition transition state 9 resulted in a 6,5,7-skeleton 10 carrying a positive charge on position 2. Based on these experimental data, we hypothesized that diastereoselectivities were generated due to endo-cycloaddition process. For the unsymmetrically substituted dienes, the excellent regioselectivities might obtain from electronic difference between R³ (Me) and H during the stepwise-like electron transfer process. Cyclohepta[b]indole skeleton 3 was achieved via intramolecular proton translocation.

Scheme 4 Proposed mechanisms for the newly designed novel tandem hydroamination/[4 + 3] cycloaddition.

In conclusion, a novel tandem reaction containing hydroamination/[4 + 3] cycloaddition was explored for the synthesis of multitudinal indole-containing 5,7,6-tricyclic skeletons. Both seven-membered rings and indole were constructed very expeditiously in this tandem process from various simple building blocks. Significantly, for the consideration of functionally and stereochemically defined complexity in natural products, this tandem reaction provided a more convenient, economical, and mild method, using which the core skeleton of ervatamine and silicine were synthesized smoothly. The mechanisms of the regio- and stereo-selectivity were also discussed in detail based on experimental results. Deeper investigation on this transformation will be devoted into the application in the synthesis of bioactive compounds.

Acknowledgements

The authors acknowledge financial support from the National Natural Science Foundation of China (21272099, 21372107), and Fundamental Research Funds for the Central Universities (lzujbky-2014-241).

Notes and references

1. For a recent elegant work by Tang's group, see: (a) D. Shu, W. Song, X. Li and W. Tang, Angew. Chem., Int. Ed., 2013, 52, 3237 ; for other selected work on cyclohepta[b]indoles, see: ; (b) K. Sun, S. Liu, P. M. Bec and T. G. Driver, Angew. Chem., Int. Ed., 2011, 50, 1702; (c) B. Alcaide, P. Almendros, M. T. Quirós, R. López, M. I. Menéndez and A. Sochacka-Ćwikła, J. Am. Chem. Soc., 2013, 135, 898; (d) M.-L. Bennasar, T. Roca and D. Garcıa-Dıaz, J. Org. Chem., 2007, 72, 4562; (e) P. J. Gritsch, E. Stempel and T. Gaich, Org. Lett., 2013, 15, 5472.
2. (a) R. Sato, T. Sawabe, H. Kishimura, K. Hayashi and H. Saeki, J. Agric. Food Chem., 2000, 48, 17; (b) M. Amat, N. Llor, B. Checa, E. Molins and J. Bosch, J. Org. Chem., 2010, 75, 178; (c) M. Amat, B. Checa, N. Llor, E. Molins and J. Bosch, Chem. Commun., 2009, 2935.
3. (a) A. Shafiee, A. Ahond, A. M. Bui, Y. Langlois, C. Riche and P. Potier, Tetrahedron Lett., 1976, 17, 921; (b) D. S. Grierson, J. Bettiol, I. Buck and H. Husson, J. Org. Chem., 1992, 57, 6414; (c) M.-L. Bennasar, B. Vidal and J. Bosch, J. Org. Chem., 1997, 62, 3597.
4. (a) A. R. Carroll, E. Hyde, J. Smith, R. J. Quinn, G. Guymer and P. I. Forster, J. Org. Chem., 2005, 70, 1096; (b) B. A. Granger, I. T. Jewett, J. D. Butler, B. Hua, C. E. Knezevic, E. I. Parkinson, P. J. Hergenrother and S. F. Martin, J. Am. Chem. Soc., 2013, 135, 12984; (c) C. L. Martin, L. E. Overman and J. M. Rohde, J. Am. Chem. Soc., 2008, 130, 7568; (d) C. L. Martin, L. E. Overman and J. M. Rohde, J. Am. Chem. Soc., 2010, 132, 4894; (e) B. A. Granger, I. T. Jewett, J. D. Butler and S. F. Martin, Tetrahedron, 2014, 70, 4094.
5. A. D. Napper, J. Hixon, T. McDonagh, K. Keavey, J. F. Pons, J. Barker, W. T. Yau, P. Amouzegh, A. Flegg, E. Hamelin, R. J. Thomas, M. Kates, S. Jones, M. A. Navia, J. Saunders, P. S. DiStefano and R. Curtis, J. Med. Chem., 2005, 48, 8045.
6. E. Yamuna, R. A. Kumar, M. Zeller and K. J. R. Prasad, Eur. J. Med. Chem., 2012, 47, 228.
7. (a) J. Zhang, L. Li, Y. Wang, W. Wang, J. Xue and Y. Li, Org. Lett., 2012, 14, 4528; (b) W. Gong, Y. Liu, J. Zhang, Y. Jiao, J. Xue and Y. Li, Chem.–Asian J., 2013, 8, 546.
8. For selected studies, see: (a) H. M. L. Davies and X. Dai, J. Am. Chem. Soc., 2004, 126, 2692; (b) I. V. Hartung and H. M. R. Hoffmann, Angew. Chem., Int. Ed., 2004, 43, 1934; (c) W. K. Chung, S. K. Lam, B. Lo, L. L. Liu, W.-T. Wong and P. Chiu, J. Am. Chem. Soc., 2009, 131, 4556; (d) M. Harmata, Chem. Commun., 2010, 46, 8886; (e) F. Yu, G. Li, P. Gao, H. Gong, Y. Liu, Y. Wu, B. Cheng and H. Zhai, Org. Lett., 2010, 12, 5135; (f) M. G. Nilson and R. L. Funk, J. Am. Chem. Soc., 2011, 133, 12451.
9. (a) J. M. Winne, S. Catak, M. Waroquier and V. van Speybroeck, Angew. Chem., Int. Ed., 2011, 50, 11990; (b) X. Han, H. Li, R. P. Hughes and J. Wu, Angew. Chem., Int. Ed., 2012, 51, 10390.
10. For selected studies, see: (a) A. E. Allen and D. W. C. MacMillan, Chem. Sci., 2012, 3, 633; (b) K. C. Nicolaou, T. Montagnon and S. A. Snyder, Chem. Commun., 2003, 39, 551; (c) M. J. Climent, A. Corma and S. Iborra, Chem. Rev., 2011, 111, 1072; (d) S. Rajkumar, K. Shankland, G. D. Brown and A. J. A. Cobb, Chem. Sci., 2012, 3, 584.
11. (a) J. D. White and Y. Fukuyama, J. Am. Chem. Soc., 1979, 101, 226; (b) M. Harmata and S. Wacharasindhu, Org. Lett., 2005, 7, 2563; (c) P. A. Wender and L. Zhang, Org. Lett., 2000, 2, 2323; (d) J. C. Lee and J. K. Cha, J. Am. Chem. Soc., 2001, 123, 3243.
12. (a) L. Yu, P. Li and L. Wang, Chem. Commun., 2013, 49, 2368; (b) S. Liu and L. S. Liebeskind, J. Am. Chem. Soc., 2008, 130, 6918; (c) G. W. Gribble, H. L. Fraser and J. C. Badenock, Chem. Commun., 2001, 37, 805.
13. For selected studies on gold-catalyzed amination see: (a) D. Ye, J. Wang, X. Zhang, Y. Zhou, X. Ding, E. Feng, H. Sun, G. Liu, H. Jiang and H. Liu, Green Chem., 2009, 11, 1201; (b) P. Kothandaraman, S. J. Foo and P. W. H. Chan, J. Org. Chem., 2009, 74, 5947.
14. For selected studies on silver-catalyzed amination see: (a) P. Kothandaraman, W. Rao, S. J. Foo and P. W. H. Chan, Angew. Chem., Int. Ed., 2010, 49, 4619; (b) M. Harmata, in Silver in Organic Chemistry, ed. P. A. Wender, Wiley, Hoboken, NJ, 2011.
15. For other transition metal catalyzed examples: (a) B. P. Berciano, S. Lebrequier, F. Besselivre and S. Piguel, Org. Lett., 2010, 12, 4038; (b) A. S. Dudnik and V. Gevorgyan, Angew. Chem., Int. Ed., 2010, 49, 2096.
16. D. Susanti, F. Koh, J. A. Kusuma, P. Kothandaraman and P. W. H. Chan, J. Org. Chem., 2012, 77, 7166.
17. (a) E. H. Krenske, K. N. Houk, A. G. Lohse, J. E. Antoline and R. P. Hsung, Chem. Sci., 2010, 1, 387; (b) E. H. Krenske, K. N. Houk and M. Harmata, Org. Lett., 2010, 12, 444.

---

Footnote

† Electronic supplementary information (ESI) available. CCDC 1001592. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra13249a

---