Organocatalytic enantioselective indole alkylations of α,β-unsaturated ketones

Abstract

The C3-selective enantioselective Michael-type Friedel–Crafts alkylations of indoles with nonchelating α,β-unsaturated alkyl ketones, catalysed by a chiral primary amine derived from natural cinchonine, were investigated. The reactions, in the presence of 30 mol% catalyst, were smoothly conducted at 0 to −20 °C. Moderate to good ee (47–89%) has been achieved.

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Introduction

The Friedel–Crafts reaction and its enantioselective variants have been employed as a powerful carbon–carbon bond forming process.¹ The application of the reaction to the alkylations of indoles triggered special interest because the indole framework has been widely identified in a large amount of natural products and medicinal agents.² Although numerous acid-catalysed Michael-type additions of electron-rich indoles to α,β-unsaturated carbonyl compounds have been reported, the asymmetric process has been less explored.³ Previous examples utilised oxazoline-based metal complexes as the chiral catalysts, and high enantioselectivity has been achieved for the Michael acceptors with bidentate structures.⁴ However, only one example has been presented with nonchelating α,β-unsaturated aryl ketones (up to 89% ee) catalysed by a chiral [Al(salen)Cl] complex, and very low ee (11%) was obtained for simple α,β-unsaturated alkyl ketones.⁵ On the other hand, MacMillan et al. developed a versatile protocol for the asymmetric Michael-type Friedel–Crafts reactions between various aromatic compounds and α,β-unsaturated aldehydes, employing benzyl imidazolidinone salts derived from L-phenylalanine as the LUMO-lowering activation organocatalysts.^6,7 Nevertheless, such a catalytic system was inefficient for the stereoselective addition of indoles to α,β-unsaturated ketones, and poor ee (25%) has been observed.⁸ Therefore, the development of alternative catalysts for the enantioselective Friedel–Crafts reactions between indoles and simple α,β-unsaturated ketones is highly desirable.

During our continuing studies on organocatalysis based on the iminium strategy,⁹ we are interested in the undeveloped asymmetric reaction between indoles and α,β-unsaturated ketones catalysed by chiral aminocatalysts.¹⁰ However, we found that a very sluggish activating rate, or even inert capacity was generally observed for secondary amines which we have successfully applied in the reactions of α,β-unsaturated aldehydes. We realised that the formation of the iminium cation between the α,β-unsaturated ketone and a secondary amine would be relatively unfavoured because of steric hindrance. It could be envisaged that the generation of a ketimine cation from a primary amine salt and the ketone carbonyl should be much more practicable. Thus the LUMO energy of the α,β-unsaturated system could be lowered, and the Michael-type coupling reaction would be facilitated [eqn (1)].¹¹

Results and discussion

Inspired by this initiative, primary amines 1a–1d with various chiral scaffolds (Fig. 1) were screened in the reaction of indole 2a and α,β-unsaturated ketone 3a in the presence of acidic additive. Amino alcohol 1a was inert for the coupling reaction (Table 1, entry 1), and the desired C3-selective Friedel–Crafts alkylation product 4aa was obtained in a racemic form with alanamide 1b¹² (entry 2). Gratifyingly, we found that the diamine compound 1c derived from natural cinchonine¹³ showed promising catalytic activity in the combination with 2 equiv. of CF₃SO₃H, and 4aa was cleanly obtained in 26% isolated yield with 56% ee after 12 h at ambient temperature, while a large amount of starting materials remained unchanged in this period of time (entry 3). A lower ee was attained in the presence of 9-amino-9-deoxyepiquinine 1d¹³ (entry 4). Subsequently, a range of reaction conditions with diamine 1c were further investigated in order to improve the catalytic efficacy. HClO₄ salt gave faster reaction but the ee was much lower (entry 5). p-TsOH salt was less efficient (entry 6) and TFA salt showed almost no catalytic activity (entry 7). Although slow reaction was observed in pure DCM catalysed by 1c–(CF₃SO₃H)₂ (entry 8), it was found that adding 15% i-PrOH (v/v) could accelerate the reaction (entry 9).^6b However, the ee was decreased in the mixture of THF–i-PrOH (entry 10). Excellent yield was obtained in the mixture of DCM–MeOH but the ee was disappointing (entry 11). Finally we conducted the Friedel–Crafts alkylation at lower temperature. The reaction became sluggish with 10 mol% of 1c at −10 °C, 65% ee with 52% yield was obtained after 6 days (entry 12). Nevertheless, up to 75% ee with better yield was achieved catalysed by 30 mol% of 1c at −20 °C (entry 13).¹⁴

Fig. 1 Structures of the chiral primary amine catalysts.

Table 1 Screening studies of the asymmetric Friedel–Crafts reaction of indole 2a and α,β-unsaturated ketone 3a^a

Entry	Catalyst	Solvent	Additive	Yield^b (%)	Ee^c (%)
a Unless otherwise noted, the reaction was conducted with 2a (0.1 mmol), 3a (0.2 mmol), catalyst 1 (0.01 mmol) and acidic additive (0.02 mmol) in a solvent (1 mL) at room temperature for 12 h. b Isolated yield. c Determined by chiral HPLC analysis. d Adding 0.01 mmol of CF3SO3H. e At −10 °C for 6 d. f At −20 °C with 30 mol% of 1c for 6d.
1^d	1a	THF	CF3SO3H	—	—
2^d	1b	THF	CF3SO3H	30	0
3	1c	THF	CF3SO3H	26	56
4	1d	THF	CF3SO3H	35	35
5	1c	THF	HClO4	60	22
6	1c	THF	p-TsOH	13	58
7	1c	THF	CF3COOH	Trace	—
8	1c	DCM	CF3SO3H	13	51
9	1c	DCM–i-PrOH	CF3SO3H	44	58
10	1c	THF–i-PrOH	CF3SO3H	44	36
11	1c	DCM–MeOH	CF3SO3H	99	26
12^e	1c	DCM–i-PrOH	CF3SO3H	52	65
13^f	1c	DCM–i-PrOH	CF3SO3H	70	75

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With the reaction conditions in hand, we then examined the scope and limitations of enantioselective indole alkylations catalysed by 30 mol% of 1c. The reaction results are summarised in Table 2. Lower reactivity was observed in the reaction of indole 2a with unsaturated ketone 3b with a branched β-substitution while a good ee (82%) was obtained (entry 2). The alkylation reactions with β-aryl unsaturated ketones 3c and 3d were conducted at 0 °C, and moderate ee was observed (entries 3 and 4). A much higher ee was achieved in the reaction of indole 2a and ethyl enone 3e (entry 5). On the other hand, 5-methoxyindole 2b generally gave higher enantioselectivity in the Friedel–Crafts reactions with various α,β-unsaturated ketones. The coupling reactions with alkyl-substituted substrates 3a and 3b were sluggish but good ees were achieved (entries 6–9). In contrast, high reactivity was noted for β-aryl enone 3d with moderate enantioselectivity (entries 10 and 11). Much lower ees were obtained for enones 3f and 3g with electron-donating substitution (entries 12 and 13). High ees were attained for β-aryl enones 3e, 3h and 3i with bulkier alkyl group at 0 °C (entries 14–17), but lower reactivity was observed for enone 3h (entry 16). The ee was moderate in the case of cyclic enone 3j (entry 18). The enantioselectivity also decreased when indole 2c with an electron-withdrawing substitution was applied. In addition, we explored the asymmetric Friedel–Crafts reaction of 2-methylindole 2d. Interestingly, better reactivity was observed in the reaction with β-alkyl enones compared with indole 2a, and good ee was obtained using enone 3b as the acceptor (entries 20 and 21).

Table 2 Asymmetric Friedel–Crafts alkylations of indoles 2 with α,β-unsaturated ketone 3^a

Entry	2	R^2	R^3 (3)	T (°C)/t (d)	4	Yield^b (%)	Ee^c (%)
a Reaction conditions: 2 (0.1 mmol), 3 (0.2 mmol), catalyst 1c (0.03 mmol) and CF3SO3H (0.06 mmol) were stirred in DCM–i-PrOH (85 : 15, 1 mL). b Isolated yield. c Determined by chiral HPLC analysis. d The absolute configuration was determined to be (R) by X-ray analysis, and the other products were assigned accordingly.
1	2a	n-Pr	CH3 (3a)	−20/6	4aa	70	75
2	2a	i-Pr	CH3 (3b)	−10/6	4ab	35	82
3	2a	Ph	CH3 (3c)	0/3	4ac	72	65
4	2a	p-Cl-Ph	CH3 (3d)	0/3	4ad	61	64
5	2a	Ph	C2H5 (3e)	0/6	4ae	47	81
6	2b	n-Pr	CH3 (3a)	−10/6	4ba	74	78
7				−20/6		43	84
8	2b	i-Pr	CH3 (3b)	0/4	4bb	42	81
9				−20/6		23	86
10	2b	p-Cl-Ph	CH3 (3d)	0/2	4bd	99	70
11				−20/6		70	72
12	2b	p-MeO-Ph	CH3 (3f)	0/7	4bf	93	47
13	2b	2-Thienyl	CH3 (3g)	0/7	4bg	83	50
14	2b	Ph	C2H5 (3e)	0/3	4be	91	85
15				−20/6		16	89
16	2b	p-Cl-Ph	C2H5 (3h)	0/7	4bh	41	88^d
17	2b	Ph	C3H7 (3i)	0/5	4bi	78	87
18	2b	–C3H6–	(3j)	−20/8	4bj	82	56
19	2c	n-Pr	CH3 (3a)	0/6	4ca	72	59
20	2d	n-Pr	CH3 (3a)	−20/6	4da	99	65
21	2d	i-Pr	CH3 (3b)	−20/6	4db	78	82

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In order to determine the absolute configuration of the Friedel–Crafts products, single crystals suitable for X-ray crystallographic analysis were obtained from compound 4bh bearing a chlorine atom. Over 99% ee could be gained after two recrystallizations of 4bh (88% ee) from a mixture of ethyl acetate and hexane. The absolute configuration of 4bh was determined to be (R) in the benzylic carbon (Fig. 2).‡ Subsequently, we proposed a possible transitional model for the stereocontrol. As illustrated in Fig. 3, the ketimine cation between 1c and α,β-unsaturated ketone 3h might adopt a trans-conformation. Then nucleophilic attack from re-face of the iminium ion would give the desired (R)-product.¹⁵

Fig. 2 X-Ray structure of enantiopure 4bh. Thermal ellipsoids are shown at 30% probability.

Fig. 3 Plausible iminium ion in the asymmetric Friedel–Crafts reaction.

Conclusions

In conclusion, we have demonstrated for the first time that a chiral primary amine derived from natural cinchonine was an efficient organocatalyst for the asymmetric Michael-type Friedel–Crafts alkylations of indoles and α,β-unsaturated alkyl ketones. Moderate to high enantioselectivity (47–89% ee) has been achieved. To our knowledge, this is the best result for this type of reactions in the limited literature reports. Further expansion of the asymmetric Friedel–Crafts reactions, mechanistic studies and application of the readily available and inexpensive primary aminocatalysts in other environmentally benign stereoselective reactions are actively under way in our laboratory.¹⁶

Experimental

General methods

TLC was performed on glass-backed silica plates. Column chromatography was performed using silica gel (200–300 mesh) eluting with ethyl acetate and petroleum ether. NMR was recorded on Bruker 300 or 400 MHz spectrometers. Chemical shifts were reported in ppm down field from tetramethylsilane with the solvent resonance as the internal standard. ESI HRMS was recorded on a Bruker Apex-2. Enantiomeric excess was determined by HPLC analysis on Chiralpak columns. All other reagents were used without purification as commercially available.

General procedure for Friedel–Crafts alkylations of indoles with α,β-unsaturated ketones

α,β-Unsaturated ketones 3 (0.2 mmol), indole 2 (0.1 mmol) and catalyst 1c 8.8 mg (0.03 mmol) were stirred in a mixture of DCM and i-PrOH (85 : 15, v/v, 1.0 mL) at the desired temperature. Then CF₃SO₃H 5.3 µL (0.06 mmol) was added. The reaction was maintained at this temperature and monitored by TLC analysis. Then the solution was diluted with Et₂O (10 mL), washed with water, dried, and concentrated. The residue was chromatographed on silica gel to give the desired product 4.

4-(1H-Indol-3-yl)heptan-2-one (4aa). 70% yield. [α]²⁰_D +11.0 (c = 0.22, CH₂Cl₂), 75% ee. The enantiomeric excess was determined by HPLC on Chiralpak AS column (5% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 23.69 min, t_major = 26.28 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.03 (br s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.20–7.07 (m, 2H), 6.95 (d, J = 2.4 Hz, 1H), 3.50–3.44 (m, 1H), 2.89 (dd, J = 15.6, 7.6 Hz, 1H), 2.79 (dd, J = 15.8, 7.2 Hz, 1H), 2.02 (s, 3H), 1.78–1.62 (m, 2H), 1.31–1.21 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 208.9, 136.5, 126.5, 121.9, 121.2, 119.3, 119.2, 119.0, 111.2, 50.2, 38.1, 32.6, 30.4, 20.7, 14.0. ESI HRMS: calcd. for C₁₅H₁₉NO + Na 252.1364, found 252.1356.

4-(1H-Indol-3-yl)-5-methylhexan-2-one (4ab). 35% yield. [α]²⁰_D +5.0 (c = 0.16, CH₂Cl₂), 82% ee. The enantiomeric excess was determined by HPLC on Chiralpak AS column (5% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 25.40 min, t_major = 34.18 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.07 (br s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 3.37–3.31 (m, 1H), 2.93–2.81 (m, 2H), 2.09–2.02 (m, 1H), 1.98 (s, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.4 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 209.3, 136.3, 127.2, 121.9, 121.8, 119.4, 119.1, 117.5, 111.1, 47.0, 39.3, 32.6, 30.1, 20.5, 20.4. ESI HRMS: calcd. for C₁₅H₁₉NO + Na 252.1364, found 252.1351.

4-(1H-Indol-3-yl)-4-phenylbutan-2-one (4ac). 72% yield. [α]²⁰_D −25.3 (c = 0.4, CH₂Cl₂), 65% ee. The enantiomeric excess was determined by HPLC on Chiralpak AS column (30% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 8.15 min, t_major = 7.37 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.02 (br s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.33–6.98 (m, 9H), 4.83 (t, J = 7.6 Hz, 1H), 3.25 (dd, J = 16.2, 7.6 Hz, 1H), 3.16 (dd, J = 16.0, 8.0 Hz, 1H), 2.08 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 207.9, 143.9, 136.5, 128.4, 127.6, 126.3, 122.0, 121.3, 119.3, 118.5, 111.1, 50.2, 38.3, 30.3. ESI HRMS: calcd. for C₁₈H₁₇NO + Na 286.1208, found 286.1191.

4-(4-Chlorophenyl)-4-(1H-indol-3-yl)butan-2-one (4ad). 61% yield. [α]²⁰_D −12.2 (c = 0.36, CH₂Cl₂), 64% ee. The enantiomeric excess was determined by HPLC on Chiralpak AS column (30% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 7.81 min, t_major = 6.82 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.04 (br s, 1H), 7.38–7.32 (m, 2H), 7.25–7.14 (m, 5H), 7.05–6.97 (m, 2H), 4.81 (t, J = 7.6 Hz, 1H), 3.24 (dd, J = 16.2, 7.2 Hz, 1H), 3.13 (dd, J = 16.4, 8.0 Hz, 1H), 2.09 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 207.2, 142.5, 136.6, 132.0, 129.1, 128.6, 126.3, 122.3, 121.3, 119.5, 119.3, 118.4, 111.2 50.0, 37.6, 30.4. ESI HRMS: calcd. for C₁₈H₁₆ClNO + Na 320.0818, found 320.0813.

1-(1H-Indol-3-yl)-1-phenylpentan-3-one (4ae). 47% yield. [α]²⁰_D −18.6 (c = 0.22, CH₂Cl₂), 81% ee. The enantiomeric excess was determined by HPLC on Chiralpak AS column (30% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 6.60 min, t_major = 5.69 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (br s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.33–7.23 (m, 5H), 7.18–7.12 (m, 2H), 7.03–6.98 (m, 2H), 4.85 (t, J = 7.6 Hz, 1H), 3.23 (dd, J = 15.8, 7.6 Hz, 1H), 3.14 (dd, J = 15.8, 8.0 Hz, 1H), 2.43–2.24 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 210.2, 144.0, 136.6, 128.4, 127.7, 126.5, 126.3, 122.1, 121.3, 119.5, 119.4, 119.0, 111.1, 49.1, 38.4, 36.4, 7.5. ESI HRMS: calcd. for C₁₉H₁₉NO + Na 300.1364, found 300.1349.

4-(5-Methoxy-1H-indol-3-yl)heptan-2-one (4ba). 43% yield. [α]²⁰_D +8.6 (c = 0.36, CH₂Cl₂), 84% ee. The enantiomeric excess was determined by HPLC on Chiralpak AD column (10% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 13.21 min, t_major = 11.75 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.94 (br s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 8.4, 2.4 Hz, 1H), 3.88 (s, 3H), 3.48–3.41 (m, 1H), 2.87 (dd, J = 15.8, 7.2 Hz, 1H), 2.78 (dd, J = 16.0, 6.8 Hz, 1H), 2.04 (s, 3H), 1.78–1.62 (m, 2H), 1.36–1.23 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 208.9, 153.7, 131.7, 127.0, 121.9, 118.8, 111.8, 111.7, 101.5, 56.0, 50.1, 38.0, 32.4, 30.5, 20.7, 14.1. ESI HRMS: calcd. for C₁₆H₂₁NO₂ + Na 282.1470, found 282.1454.

4-(5-Methoxy-1H-indol-3-yl)-5-methylhexan-2-one (4bb). 23% yield. [α]²⁰_D −6.0 (c = 0.25, CH₂Cl₂), 86% ee. The enantiomeric excess was determined by HPLC on Chiralpak AD column (10% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 12.08 min, t_major = 13.07 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.06 (br s, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 2.0, 9.0 Hz, 1H), 3.87 (s, 3H), 3.32–3.27 (m, 1H), 2.90–2.81 (m, 2H), 2.08–2.01 (m, 1H), 1.99 (s, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.4 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 209.5, 153.7, 131.5, 127.6, 122.7, 117.2, 111.7, 111.6, 101.6, 55.9, 46.9, 39.2, 32.6, 30.1, 20.5, 20.3. ESI HRMS: calcd. for C₁₆H₂₁NO₂ + Na 282.1470, found 282.1457.

4-(4-Chlorophenyl)-4-(5-methoxy-1H-indol-3-yl)butan-2-one (4bd). 70% yield. [α]²⁰_D +20.6 (c = 0.66, CH₂Cl₂), 72% ee. The enantiomeric excess was determined by HPLC on Chiralpak AD column (10% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 32.58 min, t_major = 20.86 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.02 (br s, 1H), 7.22–7.17 (m, 5H), 6.92 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 8.6, 2.4 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 4.75 (t, J = 7.6 Hz, 3H), 3.74 (s, 3H), 3.21 (dd, J = 16.2, 7.2 Hz, 1H), 3.11 (dd, J = 16.0, 8.0 Hz, 1H), 2.08 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 207.3, 153.8, 142.5, 132.0, 131.7, 129.1, 128.5, 126.7, 122.0, 118.0, 112.2, 111.9, 101.3, 55.8, 49.9, 37.5, 30.4. ESI HRMS: calcd. for C₁₉H₁₈ClNO₂ + Na 350.0924, found 350.0914.

4-(5-Methoxy-1H-indol-3-yl)-4-(4-methoxyphenyl)butan-2-one (4bf). 93% yield. [α]²⁰_D +8.3 (c = 0.6, CH₂Cl₂), 47% ee. The enantiomeric excess was determined by HPLC on Chiralpak AD column (15% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 27.20 min, t_major = 20.76 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.99 (br s, 1H), 7.23–7.16 (m, 4H), 6.92 (d, J = 2.4 Hz, 1H), 6.83–6.78 (m, 3H), 4.72 (t, J = 7.6 Hz, 3H), 3.74 (s, 6H), 3.19 (dd, J = 15.8, 7.2 Hz, 1H), 3.11 (dd, J = 16.0, 8.0 Hz, 1H), 2.07 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 207.9, 157.9, 153.7, 136.0, 131.7, 128.6, 126.9, 121.9, 118.8, 113.8, 112.0, 111.8, 101.5, 55.8, 55.2, 50.4, 37.5, 30.4. ESI HRMS: calcd. for C₂₀H₂₁NO₃ + Na 346.1419, found 346.1428.

4-(5-Methoxy-1H-indol-3-yl)-4-(thiophen-2-yl)butan-2-one (4bg). 83% yield. [α]²⁰_D +6.2 (c = 0.5, CH₂Cl₂), 50% ee. The enantiomeric excess was determined by HPLC on Chiralpak AD column (15% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 19.68 min, t_major = 17.30 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.99 (br s, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.10 (t, J = 3.6 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.88 (d, J = 3.6 Hz, 2H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 5.07 (t, J = 7.6 Hz, 1H), 3.78 (s, 3H), 3.25 (d, J = 7.6 Hz, 2H), 2.09 (S, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 207.1, 153.9, 148.4, 131.6, 126.5, 124.1, 123.5, 122.2, 118.3, 112.2, 111.9, 101.3, 55.8, 50.8, 33.4, 30.5. ESI HRMS: calcd. for C₁₇H₁₇NO₂S + Na 322.0878, found :322.0866.

1-(5-Methoxy-1H-indol-3-yl)-1-phenylpentan-3-one (4be). 91% yield. [α]²⁰_D +0.6 (c = 0.5, CH₂Cl₂), 85% ee. The enantiomeric excess was determined by HPLC on Chiralpak AD column (10% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 37.15 min, t_major = 20.68 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.98 (br s, 1H), 7.31–7.14 (m, 6H), 6.93 (d, J = 2.4 Hz, 1H), 6.82–6.78 (m, 2H), 4.79 (t, J = 7.6 Hz, 1H), 3.73 (s, 3H), 3.21 (dd, J = 15.8, 7.6 Hz, 1H), 3.12 (dd, J = 16.0, 8.0 Hz, 1H), 2.41–2.25 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 210.3, 153.7, 144.0, 131.7, 128.4, 127.7, 126.9, 126.3, 122.0, 118.6, 112.1, 111.8, 101.4, 55.8, 49.0, 38.3, 36.5, 7.5. ESI HRMS: calcd. for C₂₀H₂₁NO₂ + Na 330.1470, found 330.1461.

1-(4-Chlorophenyl)-1-(5-methoxy-1H-indol-3-yl)pentan-3-one (4bh). 41% yield. [α]²⁰_D +13.3 (c = 0.24, CH₂Cl₂), 88% ee. The enantiomeric excess was determined by HPLC on Chiralpak AD column (10% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 32.79 min, t_major = 19.02 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.94 (br s, 1H), 7.25–7.20 (m, 5H), 6.95 (d, J = 2.0 Hz, 1H), 6.82 (dd, J = 13.4, 2.4 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 4.78 (t, J = 7.2 Hz, 3H), 3.75 (s, 3H), 3.20 (dd, J = 16.0, 6.8 Hz, 1H), 3.10 (dd, J = 16.0, 8.0 Hz, 1H), 2.43–2.27 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 209.8, 153.9, 142.6, 132.0, 131.7, 129.1, 128.5, 126.7, 122.0, 118.3, 112.2, 111.8, 101.4, 55.8, 48.7, 37.6, 36.6, 7.5. ESI HRMS: calcd. for C₂₀H₂₀ClNO₂ + Na 364.1080, found 364.1080.

1-(5-Methoxy-1H-indol-3-yl)-1-phenylhexan-3-one (4bi). 78% yield. [α]²⁰_D +1.3 (c = 0.38, CH₂Cl₂), 87% ee. The enantiomeric excess was determined by HPLC on Chiralpak AD column (10% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 31.07 min, t_major = 17.98 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.99 (br s, 1H), 7.32–7.24 (m, 4H), 7.20–7.14 (m, 2H), 6.93 (d, J = 2.4 Hz, 1H), 6.83 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.4 Hz, 1H), 4.81 (t, J = 7.6 Hz, 1H), 3.74 (s, 3H), 3.20 (dd, J = 16.0, 7.2 Hz, 1H), 3.13 (dd, J = 16.0, 8.0 Hz, 1H), 2.38–2.23 (m, 2H), 1.55–1.46 (m, 2H), 0.80 (t, J = 7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 209.8, 153.7, 144.0, 131.7, 128.4, 127.7, 126.9, 126.3, 122.0, 118.7, 112.1, 111.7, 101.4, 55.8, 49.3, 45.3, 38.2, 16.9, 13.6. ESI HRMS: calcd. for C₂₁H₂₃NO₂ + Na 344.1626, found 344.1636.

3-(5-Methoxy-1H-indol-3-yl)cyclohexanone (4bj). 82% yield. [α]²⁰_D −1.8 (c = 0.4, CH₂Cl₂), 56% ee. The enantiomeric excess was determined by HPLC on Chiralpak AD column (10% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 27.97 min, t_major = 34.58 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.06 (br s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.6, 2.4 Hz, 1H), 3.83 (s, 3H), 3.43–3.36 (m, 1H), 2.82–2.77 (m, 1H), 2.62–2.56 (m, 1H), 2.50–2.36 (m, 2H), 2.28–2.22 (m, 1H), 2.10–2.02 (m, 1H), 1.99–1.77 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ = 211.9, 153.8, 131.6, 126.5, 121.1, 119.3, 112.2, 112.0, 100.9, 56.0, 48.0, 41.5, 35.8, 31.5, 24.9. ESI HRMS: calcd. for C₁₅H₁₇NO₂ + Na 266.1157, found 266.1148.

4-(5-Bromo-1H-indol-3-yl)heptan-2-one (4ca). 72% yield. [α]²⁰_D +4.8 (c = 0.4, CH₂Cl₂), 59% ee. The enantiomeric excess was determined by HPLC on Chiralpak AD column (3% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 26.01 min, t_major = 24.29 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.21 (br s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.26–7.18 (m, 2H), 6.94 (d, J = 2.4 Hz, 1H), 3.43–3.38 (m, 1H), 2.88–2.75 (m, 2H), 2.03 (s, 3H), 1.76–1.61 (m, 2H), 1.27–1.18 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 208.7, 135.1, 128.2, 124.7, 122.5, 121.7, 118.6, 112.7, 112.4, 49.9, 37.9, 32.4, 30.4, 20.7, 14.0. ESI HRMS: calcd. for C₁₅H₁₈BrNO + Na 330.0469, found 330.0461.

4-(2-Methyl-1H-indol-3-yl)heptan-2-one (4da). 99% yield. [α]²⁰_D +18.2 (c = 0.34, CH₂Cl₂), 65% ee. The enantiomeric excess was determined by HPLC on Chiralpak AD column (5% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 13.90 min, t_major = 10.83 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.76 (br s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.10–7.02 (m, 2H), 3.42–3.34 (m, 1H), 3.04 (dd, J = 13.4, 8.0 Hz, 1H), 2.81 (dd, J = 16.0, 6.0 Hz, 1H), 2.37 (s, 3H), 1.94 (s, 3H), 1.91–1.82 (m, 1H), 1.69–1.61 (m, 1H), 1.26–1.10 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 209.0, 135.6, 131.4, 127.1, 120.6, 118.9, 118.8, 113.3, 110.4, 49.3, 37.3, 32.4, 30.7, 21.0, 14.0, 12.0. ESI HRMS: calcd. for C₁₆H₂₁NO + Na 266.1521, found 266.1506.

5-Methyl-4-(2-methyl-1H-indol-3-yl)hexan-2-one (4db). 78% yield. [α]²⁰_D +35.9 (c = 0.44, CH₂Cl₂), 82% ee. The enantiomeric excess was determined by HPLC on Chiralpak AD column (10% 2-propanol–hexane, 1 mL min⁻¹), UV 254 nm, t_minor = 7.42 min, t_major = 6.32 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.73 (br s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.10–7.01 (m, 2H), 3.14–3.01 (m, 2H), 2.88 (dd, J = 14.4, 3.6 Hz, 1H), 2.36 (s, 3H), 2.20–2.10 (m, 1H), 1.86 (s, 3H), 1.04 (d, J = 6.8 Hz, 3H), 0.72 (d, J = 6.4 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ = 209.5, 135.5, 131.9, 127.3, 120.5, 119.2, 118.8, 113.1, 110.4, 46.7, 40.0, 32.4, 30.7, 21.5, 21.4, 12.1. ESI HRMS: calcd. for C₁₆H₂₁NO + Na 266.1521, found 266.1528.

Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (20502018), Ministry of Education of China (NCET-05-0781) and Fok Ying Tung Education Foundation (101037).

References

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Footnotes

† Electronic supplementary information (ESI) available: NMR and HPLC spectra of the products. See DOI: 10.1039/b616504d

‡ Crystal data for enantiopure 4bh C₂₀H₂₀ClNO₂ (341.82), orthorhombic, space group P2₁2₁2₁, a = 5.1480(1), b = 15.8080(3), c = 21.3073(5) Å, U = 1733.98(6) ų, Z = 4, specimen 0.55 × 0.19 × 0.16 mm³, T = 153(2) K, Mac Science M18XHF22-SRA diffractometer, absorption coefficient 0.232 mm⁻¹, reflections collected/unique 17187/3985 [R(int) = 0.0185], refinement by full-matrix least-squares on F², data/restraints/parameters 3985/0/224, goodness-of-fit on F² = 1.008, final R indices [I > 2σ(I)] R1 = 0.0296, wR2 = 0.0778, R indices (all data) R1 = 0.0302, wR2 = 0.0782, absolute structure parameter 0.02(5), extinction coefficient 0.0117(15), largest diff. peak and hole 0.375 and −0.442 e Å⁻³. CCDC reference number 624251. For crystallographic data in CIF or other electronic format see DOI: 10.1039/b616504d

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