An asymmetric Brønsted acid-catalyzed Friedel–Crafts reaction of indoles with cyclic N-sulfimines

Abstract

A highly enantioselective organocatalytic Friedel–Crafts reaction of indoles with cyclic N-sulfimines using a chiral phosphoric acid as an organocatalyst has been developed. This organocatalytic reaction provides for the first time 3-indolyl sulfamidate derivatives in good yields and with high enantioselectivities (up to 97% ee) with a broad range of functional groups and substitution patterns.

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The indole skeleton is the most universal heterocycle structure in nature and is well established as a privileged scaffold; it is commonly encountered in many biologically active natural products and pharmaceutical compounds. Owing to the great structural diversity of biologically active indoles, indole units are of great importance in medicinal chemistry and are widely used in the pharmaceutical industry for the design of compounds with pharmacological properties.¹ In particular, indoles bearing a nitrogen atom at the α-position are widely present as the structural core of many natural products and pharmaceuticals that exhibit a broad range of biological activities and have been the focus of extensive synthetic efforts for a long time.² Because of their immense significance, numerous methods for the synthesis of chiral 3-indolyl methanamine structural scaffolds with careful stereochemical control have been developed. The asymmetric catalytic Friedel–Crafts reaction is one of the most powerful, straightforward and convenient methods for the preparation of these useful indole structures.³ To promote these transformations, significant progress has been made by employing both a chiral metal and an organocatalyst in the reaction of indoles with imines.⁴ However, to the best of our knowledge, an asymmetric Friedel–Crafts reaction with cyclic N-sulfimines that could enable the development of new strategies for the asymmetric synthesis of chiral indole derivatives has not yet been reported.⁵

Cyclic N-sulfimines have attracted much attention and have been proven to be powerful building blocks in the syntheses of functionalized benzosulfamidate heterocycles.⁶ These sulfamidate compounds exhibit important biological activities such as antibiotic, antiviral, anticancer, anticonvulsant, antiobesity, antiarthritis, and antiosteoporosis activities.⁷ Therefore, several reactions using cyclic N-sulfimines for the synthesis of sulfamidate derivatives have been reported, including allylation, annulation, cycloaddition, and the Mannich reaction.⁸ Herein, we report the first highly enantioselective Friedel–Crafts reaction of indoles with cyclic N-sulfimines catalyzed by a chiral Brønsted phosphoric acid (Scheme 1).^9,10

Scheme 1 Enantioselective Friedel–Crafts reaction of indole with cyclic N-sulfimine.

In our initial investigation, we began our studies on the Friedel–Crafts reaction between N-methylindole (1a) and benzoxathiazine 2,2-dioxide (2a) as the model substrates in the presence of a chiral BINOL-derived phosphoric acid catalyst 3 in toluene at room temperature (Table 1). The reaction proceeded smoothly to afford the desired product 4a in good yield (78%), but with 20% ee when phosphoric acid 3a (10 mol%) was used as the catalyst (Table 1, entry 1). Encouraged by this result, we investigated catalysts with various substitution patterns at the 3,3′-position of the binaphthyl scaffold (Table 1, entries 2–6), and chiral phosphoric acid 3b bearing two phenyl groups at the 3,3′-position of the binaphthyl scaffold proved to be the optimal catalyst, affording product 4a in 89% yield with 73% ee (Table 1, entry 2).

Table 1 Screening of chiral phosphoric acids in enantioselective Friedel–Crafts reaction of N-methylin dole with cyclic N-sulfimine^a

Entry	3, R	Time (h)	Yield^b (%)	ee^c (%)
a The reactions were carried out in toluene (0.2 M) with 1a (0.15 mmol) and 2a (0.1 mmol) in the presence of 10 mol% catalyst at room temperature.b Isolated yield after chromatographic purification.c Determined by chiral-phase HPLC analysis.
1	3a, H	72	78	20
2	3b, Pheny1	18	89	73
3	3c, 4-Bipheny1	60	52	8
4	3d, 1-Naphthy1	48	43	7
5	3e, 2-Naphthy1	60	28	20
6	3f, 4-NO2-C6H4	48	36	3

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We further optimized the reaction conditions by using chiral phosphoric acid 3b as the catalyst. The results are summarized in Table 2. First, we screened a variety of solvents. Unfortunately, inferior results were generally observed (Table 2, entries 2–8). Then, the effect of the reaction temperature was investigated for this Friedel–Crafts reaction. The temperature was found to have a significant effect on the reaction. In general, lowering the temperature resulted in an increase of the enantioselectivity (73 to 91% ee, from room temperature to −40 °C, Table 2, entries 1, 9–11). Lower catalyst loadings were examined, and the use of 5 mol% of phosphoric acid 3b also led to the desired product in high yield and enantioselectivity, but a longer reaction time was required (Table 2, entry 12).

Table 2 Optimization of the reaction conditions^a

Entry	Solvent	T (C)	Time (h)	Yield^b (%)	ee^c (%)
a The reactions were carried out in toluene (0.2 M) with 1a (0.15 mmol) and 2a (0.1 mmol) in the presence of 10 mol% catalyst at the indicated temperature.b Isolated yield after chromatographic purification.c Determined by chiral-phase HPLC analysis.d Reaction using 5 mol% catalyst 3b.
1	Toluene	rt	18	89	73
2	CH2Cl	rt	24	88	41
3	ClCH2CH2Cl	rt	24	73	57
4	CHCl3	rt	24	95	55
5	o-Xylene	rt	18	87	71
6	CH3CN	rt	48	81	33
7	THF	rt	48	95	51
8	MeOH	rt	24	98	5
9	Toluene	0	24	93	78
10	Toluene	−20	24	98	88
11	Toluene	−40	24	93	91
12^d	Toluene	−40	72	87	90

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With the optimized reaction conditions in hand (1.5 equiv. of 1, 1 equiv. of 2, 10 mol% of catalyst 3b, in toluene at −40 °C), the substrate scope and generality of the reaction were investigated. First, we tested a variety of indole substrates 1 to examine the generality of the Friedel–Crafts reaction to yield 3-indolyl sulfamidate derivatives (Table 3).¹¹ It appeared that N-protecting groups on the indole (such as Me, Bn, and allyl groups) were tolerated and the desired products were obtained in good yields (76–93%) with excellent enantioselectivities (90–92% ee, Table 3, entries 1–3). Both electron-donating and electron-withdrawing substituents on the indole ring were well tolerated, mostly leading to the desired products with good to excellent enantioselectivities. Electron-donating groups generally led to higher reaction activities and enantioselectivities than electron-withdrawing groups did (4d, 4e vs. 4f; 4g–4h vs. 4i–4l). Moreover, the position of the substituent on the indole ring was found to have a minimal impact on the reaction efficiency as well as the enantioselectivity, although the reaction with 6-chloroindole provided a moderate yield (Table 3, entries 13–15).

Table 3 Variation of the indole substrate^a

Entry	R^1	R^2	Time (h)	Product	Yield^b (%)	ee^c (%)
a Unless otherwise noted, the reactions were carried out in toluene (0.2 M) with 1 (0.15 mmol) and 2a (0.1 mmol) in the presence of 10 mol% catalyst 3b at −40 °C.b Isolated yield after chromatographic purification.c Determined by chiral-phase HPLC analysis.d Reaction at 0 °C.e Reaction at RT.
1	Me	H	24	4a	93	91
2	Bn	H	48	4b	76	90
3	Allyl	H	68	4c	85	92
4	Bn	5-OMe	72	4d	95	94
5	Bn	5-OBn	72	4e	73	97
6^d	Bn	5-Br	48	4f	74	88
7	Me	5-OMe	24	4g	98	89
8	Me	5-OBn	24	4h	99	89
9^d	Me	5-Br	48	4i	87	68
10^d	Me	5-CN	36	4j	45	84
11^d	Me	5-CO2Me	24	4k	85	87
12^e	Me	5-NO2	168	4l	88	78
13	Me	6-Cl	72	4m	48	78
14	Me	6-F	72	4n	88	85
15	Me	7-Me	18	4o	79	88

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Encouraged by the excellent results obtained with various indoles, we then investigated the Friedel–Crafts reaction with respect to the cyclic N-sulfimines. As shown in Table 4, the 3-indolyl sulfamidate products were obtained in good yields with high enantioselectivities regardless of the electronic nature, bulkiness, and position of the substituent on the phenyl ring of the N-sulfimines. The cyclic N-sulfimines with electron-donating groups in the 6-position led to slightly higher enantioselectivities compare to those with electron-withdrawing groups (4p, 4q vs. 4r–4t). In addition, cyclic N-sulfimines bearing functional groups in the 8-position were also tolerated as substrates (Table 4, entries 8, 9 and 10).

Table 4 Variation of the cyclic N-sulfimine substrate^a

Entry	R	Time (h)	Product	Yield^b (%)	ee^c (%)
a The reactions were carried out in toluene (0.2 M) with 1a (0.15 mmol) and 2 (0.1 mmol) in the presence of 10 mol% catalyst 3b at −40 °C.b Isolated yield after chromatographic purification.c Determined by chiral-phase HPLC analysis.
1	6-Me	72	4p	95	91
2	6-OMe	72	4q	99	93
3	6-F	72	4r	96	84
4	6-Cl	72	4s	99	84
5	6-Br	72	4t	92	83
6	7-Me	72	4u	93	89
7	7-OMe	72	4v	45	80
8	6,8-Cl	72	4w	91	81
9	6,8-Br	72	4x	94	84
10	8-OMe	72	4y	96	85

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The absolute configuration was unambiguously determined by X-ray crystallographic analysis of 3-indolyl sulfamidate compound 4n and found to be S (Fig. 1a).¹² The absolute configurations of the other products were assigned by analogy. On the basis of our experimental results and the transition state model of BINOL-phosphoric acids,¹³ we have proposed a simplistic plausible transition state to account for the observed stereoselectivity of the reaction (Fig. 1b). The cyclic N-sulfimine is activated by the phosphoric acid proton and then N-methylindole attacks the N-sulfimine from the Si-face preferentially, leading to an S-configuration adduct. Finally, an asymmetric catalytic Friedel–Crafts reaction of cyclic N-sulfimine with other nucleophiles have been developing. For example, the 2-pyrrolyl sulfamidate compound 6 was obtained in moderate yield and enantioselectivity (57% yield and 74% ee) when the catalytic Friedel–Crafts reaction between N-benzylpyrrole (5) and benzoxathiazine 2,2-dioxide (2a) in the presence of catalyst 3d in toluene at −20 °C (Scheme 2).

Fig. 1 X-ray structure of 4n (a) with thermal ellipsoids at the 50% probability level and the proposed transition state model (b).

Scheme 2 Enantioselective Friedel–Crafts reaction of N-benzylpyrrole 5 with cyclic N-sulfimine 2a.

Conclusions

In summary, we have developed a highly enantioselective Friedel–Crafts reaction of indoles with cyclic N-sulfimines catalyzed by a chiral phosphoric acid. This method represents the first aza-Friedel–Crafts reaction with cyclic N-sulfimines as electrophiles and provides the corresponding optically active 3-indolyl sulfamidate derivatives in good yields and with high enantioselectivities (up to 97% ee) with a broad range of functional groups and substitution patterns. Current work is focused on expanding the substrate scope of this asymmetric catalytic reaction. Studies on the biological activity of these 3-indolyl sulfamidate derivatives against diabetic peripheral neuropathy, in particular, are currently underway, and the results will be presented in due course.

Acknowledgements

This research was supported by the Nanomaterial Technology Development Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2012M3A7B4049645) and the Basic Science Research Program through NRF funded by the Ministry of Education (NRF-2013R1A1A2009850).

Notes and references

1. For recent reviews, see: (a) R. Dalpozzo, Chem. Soc. Rev., 2015, 44, 742; (b) G. Bartoli, G. Bencivenni and R. Dalpozzo, Chem. Soc. Rev., 2010, 39, 4449; (c) M. Bandini and A. Eichholzer, Angew. Chem., Int. Ed., 2009, 48, 9608; (d) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106, 2875; (e) S. Cacchi and G. C. Fabrizi, Chem. Rev., 2005, 105, 2873.
2. (a) P. M. Dewick, Medicinal Natural Products: A Biosynthetic Approach, Wiley-VCH, Chichester, 2009; (b) D. J. Faulkner, Nat. Prod. Rep., 2002, 19, 1–48; (c) D. H. R. Barton, K. Nakanishi, O. Meth-Cohn and J. W. Kelly, Comprehensive Natural Products Chemistry, Pergamon, Oxford, 1999.
3. For recent reviews for catalytic asymmetric Friedel–Crafts reaction, see: (a) I. P. Beletskaya and A. D. Averin, Curr. Organocatal., 2016, 3, 60; (b) J. Vesely and R. Rios, Chem. Soc. Rev., 2014, 43, 611; (c) S. Kobayashi, Y. Mori, J. S. Fossey and M. M. Salter, Chem. Rev., 2011, 111, 2626; (d) M. Zeng and S.-L. You, Synlett, 2010, 1289; (e) V. Terrasson, R. M. de Figueiredo and J. M. Campagne, Eur. J. Org. Chem., 2010, 2635.
4. For the selected recent examples of asymmetric Friedel–Crafts reaction of indoles with imines, see: (a) T. Arai and J. Kakino, Angew. Chem., Int. Ed., 2016, 55, 15263; (b) L. Osorio-Planes, C. Rodrŕguez-Escrich and M. A. Pericàs, Chem.–Eur. J., 2014, 20, 2367; (c) T. Kano, R. Takechi, R. Kobayashi and K. Maruoka, Org. Biomol. Chem., 2014, 12, 724; (d) K.-F. Zhang, J. Nie, R. Guo, Y. Zheng and J.-A. Ma, Adv. Synth. Catal., 2013, 355, 3497; (e) K. Wu, Y.-J. Jiang, Y.-S. Fan, D. Sha and S. Zhang, Chem.–Eur. J., 2013, 19, 474; (f) J. Feng, W. Yan, D. Wang, P. Li, Q. Sun and R. Wang, Chem. Commun., 2012, 48, 8003; (g) Y. Qian, C. Jing, C. Zhai and W.-H. Hu, Adv. Synth. Catal., 2012, 354, 301; (h) L.-Y. Chen, H. He, W.-H. Chan and A. W. M. Lee, J. Org. Chem., 2011, 76, 7141; (i) C.-H. Xing, Y.-X. Liao, J. Ng and Q.-S. Hu, J. Org. Chem., 2011, 76, 4125; (j) R. Husmann, E. Sugiono, S. Mersmann, G. Raabe, M. Rueping and C. Bolm, Org. Lett., 2011, 13, 1044; (k) M. Rueping, S. Raja and A. Núñez, Adv. Synth. Catal., 2011, 353, 563; (l) F. Xu, D. Huang, C. Han, W. Shen, X. Lin and Y. Wang, J. Org. Chem., 2010, 75, 8677; (m) Y. Qian, G. Ma, A. Lv, H.-L. Zhu, J. Zhao and V. H. Rawal, Chem. Commun., 2010, 46, 3004; (n) G.-W. Zhang, L. Wang, J. Nie and J.-A. Ma, Adv. Synth. Catal., 2008, 350, 1457.
5. For the asymmetric Cu-catalyzed Friedel–Crafts reaction of indoles with cyclic N-sulfonyl ketimino esters, see: L. Wu, R.-R. Liu, G. Zhang, D.-J. Wang, H. Wu, J. Gao and Y.-X. Jia, Adv. Synth. Catal., 2015, 357, 709.
6. A. Kamal and P. B. Sattur, Synthesis, 1981, 272.
7. (a) S. J. Williams, Expert Opin. Ther. Pat., 2013, 23, 79; (b) L. W. L. Woo, A. Purohit and B. V. L. Potter, Mol. Cell. Endocrinol., 2011, 340, 175; (c) J.-Y. Winum, A. Scozzafava, J.-L. Montero and C. T. Supuran, Expert Opin. Ther. Pat., 2006, 16, 27; (d) J.-Y. Winum, A. Scozzafava, J.-L. Montero and C. T. Supuran, Med. Res. Rev., 2005, 25, 186.
8. (a) L. De Munck, A. Monleón, C. Vila and J. R. Pedro, Adv. Synth. Catal., 2017, 359, 1582; (b) M. Quan, L. Tang, J. Shen, G. Yang and W. Zhang, Chem. Commun., 2017, 53, 609; (c) H. B. Hepburn, G. Magagnano and P. Melchiorre, Synthesis, 2017, 49, 76; (d) L. De Munck, C. Vila, M. C. Muñoz and J. R. Pedro, Chem.–Eur. J., 2016, 22, 17590; (e) J. Wang, F. Li, Q. Shen, W. Pei, W.-X. Zhao and L. Liu, Synthesis, 2016, 48, 441; (f) B.-N. Lai, J.-F. Qiu, H.-X. Zhang, J. Nie and J.-A. Ma, Org. Lett., 2016, 18, 520; (g) M. Montesinos-Magraner, R. Cantón, C. Vila, G. Blay, I. Fernández, M. C. Muñoz and J. R. Pedro, RSC Adv., 2015, 5, 60101; (h) N. Gigant, E. Drège, P. Retailleau and D. Joseph, Chem.–Eur. J., 2015, 21, 15544; (i) L. D. Munck, A. Monleón, C. Vila, M. C. Muñoz and J. R. Pedro, Org. Biomol. Chem., 2015, 5, 60101; (j) T. Jiang, Z. Wang and M.-H. Xu, Org. Lett., 2015, 17, 528; (k) C. Jiang, Y. Lu and T. Hayashi, Angew. Chem., Int. Ed., 2014, 53, 9936; (l) H.-X. Zhang, J. Nie, H. Cai and J.-A. Ma, Org. Lett., 2014, 16, 2542; (m) K. Parthasarathy, A. R. Azcargorta, Y. Cheng and C. Bolm, Org. Lett., 2014, 16, 2538; (n) H. Yu, L. Zhang, Z. Yang, Z. Li, Y. Zhao, Y. Xiao and H. Guo, J. Org. Chem., 2013, 78, 8427; (o) Y. Liu, T.-R. Kang, Q.-Z. Liu, L.-M. Chen, Y.-C. Wang, J. Liu, Y.-M. Xie, J.-L. Yang and L. He, Org. Lett., 2013, 15, 6090; (p) Y.-Q. Wang, Y. Zhang, H. Dong, J. Zhang and J. Zhao, Eur. J. Org. Chem., 2013, 3764.
9. For selected reviews on organocatalysis, see: (a) H. Pellissier, Recent Developments in Asymmetric Organocatalysis, RSC, Cambridge, 2010; (b) S. Bertelsen and K. A. Jørgensen, Chem. Soc. Rev., 2009, 38, 2178; (c) A. Dondoni and A. Massi, Angew. Chem., Int. Ed., 2008, 47, 4638; (d) S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem. Rev., 2007, 107, 5471; (e) P. I. Dalko, Enantioselective Organocatalysis, Wiley-VCH, Weinheim, 2007; (f) A. Erkkilä, I. Majander and P. M. Pihko, Chem. Rev., 2007, 107, 5416; (g) A. Berkessel and H. Gröger, Asymmetric Organocatalysis, Wiley-VCH, Weinheim, 2005.
10. For selected reviews on chiral BINOL-derived phosphoric acids, see: (a) H. Wu, Y.-P. He and F. Shi, Synthesis, 2015, 47, 1990; (b) D. Parmar, E. Sugiono, S. Raja and M. Rueping, Chem. Rev., 2014, 114, 9047; (c) M. Rueping, A. Kuenkel and I. Atodiresei, Chem. Soc. Rev., 2011, 40, 4539; (d) A. Zamfir, S. Schenker, M. Freund and S. B. Tsogoeva, Org. Biomol. Chem., 2010, 8, 5262.
11. The reaction of unprotected indole with benzoxathiazine 2,2-dioxide 2a under the optimized reaction conditions provided no desired 3-indolyl sulfamidate product, and no reaction was observed in the case of Boc- and Ts-protected indoles.
12. CCDC 1540070 contains the supplementary crystallographic data for 4n.†.
13. (a) M. Rueping, B. J. Nachtsheim, W. Ieawsuwan and I. Atodiresei, Angew. Chem., Int. Ed., 2011, 50, 6706; (b) L. Simón and J. M. Goodman, J. Org. Chem., 2010, 75, 589; (c) I. D. Gridnev, M. Kouchi, K. Sorimachi and M. Terada, Tetrahedron Lett., 2007, 48, 497.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1540070. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7ra06244c

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