A highly enantioselective thiolation of sulfonyl indoles to access 3-sec-sulfur-substituted indoles in water

Abstract

A highly enantioselective approach for the synthesis of 3-alkyl- indole or indoline derivatives with a functional thiol group is presented. The chemistry is based on the asymmetric 1,4-addition of thiol to vinylogous imine intermediates, which are generated in situ from sulfonylindoles. The broad substrate transformation proceeds with high yields (up to 96%) and enantioselectivity (up to 98% ee) in a water-compatible system.

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Indoles and their derivatives are ubiquitously found in natural alkaloids, agrochemicals and pharmaceuticals, therefore, considerable efforts have been made to construct or functionalize indole cores.¹ Among them, fused heterocyclic substances including both sulfur atom and indole moieties are verified to be biologically active examples including antioxidant, antibacterial, anti-insecticidal and anticancer activity.² In this context, methodologies for the synthesis of indole thiolethers have been developed using different sulfenylating agents.³ However, as a significant class of biologically active compounds (Fig. 1),⁴ methods for incorporating sulfur atoms in 3-subsititued indoles have been rarely reported and all of them are racemic.⁵ Yao and coworkers developed tandem 1,4-addition-decarboxylation between thiols and 3-indoleacrylic acids at high temperature (Scheme 1, eqn (1)).^5a Later, Khan and Shariati reported three-component reactions of indoles, aromatic aldehydes and thiols in the presence of a protic or Lewis acid (Scheme 1, eqn (2)).^5b,c In Tian's work, N-benzylic sulfonamides underwent kinetic resolution with benzyl thiol, yielding a racemic thioether (Scheme 1, eqn (3)).^5d Considering the biological importance and synthetic challenges of enantioenriched 3-sec-sulfur-substituted indoles, developing efficient methods for accessing these compounds is in high demand.

Fig. 1 Sulfur-containing 3-sec-substituted indole derivatives with bioactivities.

Scheme 1 Synthesis of 3-sec-surfur-substituted indoles.

In 2006, Petrini and co-workers reported a privileged 3-substituted sulfonylindole structural skeleton, which can generate vinylogous imine electrophiles under basic conditions.⁶ Since the sulfa-Michael addition (SMA) reaction is one of the most powerful strategies for asymmetric new C–S bond formation,⁷ it is supposed that chiral sulfur-containing 3-alkylindoles can be synthesized by the asymmetric 1,4-addition of thiol to vinylogous imines. In fact, some studies on asymmetric additions of different carbon nucleophiles to vinylogous imine intermediates using metal-catalysts, chiral phase-transfer catalysts, and organocatalysts have been well documented.⁸ Despite these important advances, the asymmetric catalytic addition of thiol nucleophiles to vinylogous imines generated in situ from sulfonylindoles, to the best of our knowledge, has not been reported. The major difficulty may be the severe racemic background reaction caused by the strong nucleophilicity of thiols.

Recently, we developed the organic base catalyzed asymmetric catalytic thiol-addition to in situ generated ortho-quinone methides in the presence of water.⁹ In this reaction, the racemic background reaction was subdued in the presence of water. In 2010, Johnston et al. reported that enantioselectivity can be improved by the addition of water in the reaction of nitroalkanes with sulfonylindoles.^8c To further demonstrate the advantage of the water–oil biphasic system, we report herein the first conjugate addition of tritylthiol to in situ generated vinylogous imines catalyzed by a chiral organic base with excellent enantioselectivities (87–98% ee.) using water as the solvent (Scheme 1). Moreover, experimental results indicate that water is crucial for achieving the high reactivity and stereoselectivity.

At the outset of this work, sulfonylindoles 1a and tritylthiol 2 were chosen as the model substrates. When the reactions were carried out in an organic solvent like those reported in the literature, the reaction was rather slow with only 31% conversion and moderate enantioselectivity of 48% in the presence of cinchonine as the chiral catalyst and Na₂CO₃ as the base (Table 1, entry 1). By using Et₃N as the base in an organic solvent, the homogeneous system was pushed to higher reactivity but low enantioselectivity (Table 1, entry 2). Gratefully, when we chose mixture of H₂O/CH₂Cl₂ (solvent v/v = 1/1) as the solvent, the reaction was dramatically accelerated to complete conversion in 12 hours with a moderate ee value (Table 1, entry 3). Encouraged by these results, we turned our attention to catalyst screening in the presence of water.¹⁰ Natural Cinchona alkaloids gave poor enantioselectivities albeit with nearly full conversions (Table 1, entries 5 and 6). Then we began to investigate Cinchona alkaloid-derived squaramide and thiourea catalysts,¹¹ considering the strong interactions between the substrates and the catalyst due to hydrogen bonding. Quinidine-derived squaramide D gave disappointing results regarding enantioselectivity compared to simple Cinchona alkaloid cinchonine. Nevertheless, the Cinchona alkaloid-derived thiourea catalysts E and F showed better performance. The quinidine-derived thiourea catalyst could offer higher enantioselectivity (88% ee vs. 85% ee) than the cinchonine-derived thiourea catalyst (Table 1, entries 8 and 9).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Cat.	Base	Conv^b (%)	ee^c (%)
a Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol, 2 equiv.), catalyst (10 mol%) and base (0.2 mmol, 2 equiv.) in 1 mL solvent at room temperature for 12 h, the mixture solvent v/v = 1/1. b Determined by ^1H NMR spectroscopy of the crude mixture. c Determined by chiral stationary phase HPLC analysis. d The reaction was performed at 0 °C. e The reaction was performed with 1a (0.2 mmol) and 2 (0.22 mmol 1.1 equiv.) in H2O (4 mL) and CHCl3 (200 μL) for 12 h.
1	DCM	A	Na2CO3	31	48
2	DCM	A	Et3N	66	6
3	H2O/DCM	A	Na2CO3	>95	66
4	H2O/DCM	—	Na2CO3	49	—
5	H2O/DCM	B	Na2CO3	>95	48
6	H2O/DCM	C	Na2CO3	>95	29
7	H2O/DCM	D	Na2CO3	>95	50
8	H2O/DCM	E	Na2CO3	>95	85
9	H2O/DCM	F	Na2CO3	>95	88
10	H2O/DCM	F	K2CO3	>95	88
11	H2O/DCM	F	NaHCO3	>95	87
12	H2O/DCM	F	NaOH	>95	86
13	H2O/DCM	F	KOH	>95	84
14	H2O/DCM	F	Cs2CO3	>95	82
15	H2O/CHCl3	F	Na2CO3	>95	89
16^d	H2O/CHCl3	F	Na2CO3	>95	91
17^d	H2O^e	F	Na2CO3	>95	91

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Further screening of inorganic bases suggested that Na₂CO₃ was the optimal inorganic base in terms of conversions and enantioselectivity. The desired product with a better ee value (89% ee) was obtained when methylene chloride was replaced with chloroform (Table 1, entry 15). Subsequently, the effect of temperature was investigated. When the temperature was lowered to 0 °C, the enantioselectivity could be further improved to 91% ee (Table 1, entry 16). When the amount of substrate 2 was reduced to 1.1 equivalents and with water as the solvent (200 μL CHCl₃ added to dissolve the substrates), the conversion and enantioselectivity were maintained (Table 1, entry 17). Using 1a as the substrate, other different thiol nucleophiles were investigated under standard conditions. However, moderate enantioselectivities were obtained albeit with almost quantitative yields (see ESI,† P6).

Subsequently, we investigated a series of sulfonylindoles 1 to establish the generality of this asymmetric methodology. As listed in Table 2, by using a catalytic amount of F, the asymmetric thiol addition with most sulfonylindoles afforded the desired products with excellent yields and ee values under optimized conditions. Notably, in the substrates, R₁ could be different substituents with phenyl, 1-naphthyl or alkyl groups. A substituent at different positions of the aryl moiety (R₁) had a distinct impact on the enantioselectivity (Table 2, entries 2–4). Those substrates with an ortho substituted phenyl ring (R₁) gave better enantioselectivities (entry 3 vs. entries 2 and 4). An electron-donating (Me) or electron-withdrawing (F, Br, CF₃) substituent on the aryl moiety (R₁) fit well to furnish the corresponding products (Table 2, entries 2–11). Fortunately, alkyl-substituted (R₁) sulfonylindoles were also demonstrated to be acceptors amenable to the reaction protocol, giving satisfying enantiomeric excesses (96% ee and 98% ee) with acceptable yields (Table 2, entries 12 and 13). Substrate 1n bearing the 2-thienyl group at the R₁ position can also achieve good enantioselectivity (87% ee) with an almost quantitative yield (Table 2, entry 14). Variations in the electronic nature of the indole core had little effect on the outcome when sulfonylindole substrates tolerated fluorine or methyl as the substituents at the 5-position of the indole ring (Table 2, entries 15 and 16). When the R₃ group was changed from methyl to phenyl, lower reactivity was observed with moderate yield (57% within four days) while the enantioselectivity was maintained (Table 2, entry 17). The absolute configuration of the stereocenter of the Michael addition product 3c was unambiguously assigned to be S by single-crystal X-ray diffraction analysis (see Fig. 2) and those of others were assigned by analogy.

Table 2 Scope for the reaction of tritylthiol with arylsulfonyl indoles^a

Entry	R1/R2/R3	Time (h)	Yield^b (%)	ee^c (%)
a Reaction conditions: 1 (0.2 mmol), tritylthiol (1.1 equiv., 0.22 mmol) and catalyst F (0.02 mmol, 10 mol%) in water 4 mL at 0 °C, 200 μL CHCl3 was added to dissolve the substrates. b Isolated yield based on 1. c Determined by chiral stationary phase HPLC analysis. d Because of the insolubility of substrates, solvent: CHCl3 (2 mL) and H2O (2 mL).
1	Ph/H/Me	12	3a, 95	91
2	4-ClC6H4/H/Me	12	3b, 96	91
3	2-ClC6H4/H/Me	24	3c, 91	96
4^d	3-ClC6H4/H/Me	48	3d, 90	88
5	4-FC6H4/H/Me	36	3e, 92	91
6	4-BrC6H4/H/Me	12	3f, 95	91
7	4-CF3C6H4/H/Me	24	3g, 82	98
8	4-MeC6H4/H/Me	12	3h, 75	91
9	2-MeC6H4/H/Me	12	3i, 90	92
10^d	2-NO2C6H4/H/Me	36	3j, 96	98
11	1-Naphthyl/H/Me	12	3k, 96	88
12	^iBu/H/Me	60	3l, 79	96
13	^nBu/H/Me	60	3m, 75	97
14	2-Thienyl/H/Me	12	3n, 99	87
15^d	Ph/F/Me	48	3o, 96	91
16	Ph/Me/Me	12	3p, 95	89
17^d	Ph/H/Ph	96	3q, 57	91

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Fig. 2 X-ray crystal structure of product 3c.

The synthetic utility of this method was demonstrated by the efficient asymmetric synthesis of 3-sec-substituted indoline thiol, starting from the enantioenriched 3a obtained from a gram-scale reaction using the above procedure with F as the catalyst (Scheme 2). The diastereoselective reduction of the indole ring with NaBH₃CN under the conditions of acetic acid, followed by the removal of the trityl group, readily delivered chiral mercaptan 5 without the loss of enantiopurity.

Scheme 2 Synthetic transformations of 3. ^a The d.r. was determined by crude ¹H NMR.

In conclusion, we have developed the first thiol-addition to vinylogous imines generated in situ from sulfonylindoles in a water-compatible system. Compared with organic solvents, the aqueous medium showed a remarkable increase in the activity and enantioselectivity for this asymmetric reaction. This eco-friendly organocatalytic protocol provides efficient and convenient access to valuable chiral sulfur-containing 3-sec-substituted indoles in moderate to high yields with excellent enantioselectivity.

This work is financially supported by the National Natural Science Foundation of China (21322202, 21532006).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1424495. For ESI and crystallographic data in CIF or other electronic format, see DOI: 10.1039/c5cc07721d

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