Palladium-Catalyzed Asymmetric Allylic Alkylation Reaction of 2-Mono­substituted Indolin-3-ones

Abstract

An efficient and practical method was developed for the synthesis of 2,2-disubstituted indolin-3-ones by palladium-catalyzed asymmetric allylic alkylation. Enantioselective construction of quaternary carbon centers was also realized in this way.

Key words

palladium - allylic substitution - asymmetric catalysis - indolines - quaternary carbon

The 2,2-disubstituted indolin-3-one moiety is an important structural motif in many natural products and compounds of pharmaceutical interest, such as austamide,[1] brevianamide A,[2] (+)-aristotetelone,[3] isatisine A,[4] hinckdentine A,[5] and others[6] (Figure [1]). Therefore, their synthesis has attracted much attention from synthetic chemists. To date several methodologies have been developed,[7] however, the only successful protocol that proceeds through asymmetric catalysis involves addition reactions to the C–N double bond of 2-substituted 3H-indol-3-ones[7m] [n] [o] [p] [q] [r] or their analogues.[7s] Only one report has appeared for the α-alkylation of 2-substituted indolin-3-ones catalyzed by a chiral catalyst, and the reaction proceeds with moderate enantioselectivity.[7t] Palladium-catalyzed asymmetric allylic alkylation (AAA) is one of the most important reactions for the enantioselective construction of C–C and C–hetero atom bonds in organic synthesis.[8] However, a few examples of α-amino ketones being used in the reaction as prenucleophiles via the enolates derived from ketones and carboxylic acid have been successfully demonstrated.[7t] [9] ^, [10d] [e] [f] ^, [i] In the course of our research on palladium-catalyzed AAA during recent years,[10] we have successfully used different types of enolates as nucleophiles.[10d] [e] [f] ^, [i] In this paper, we would like to report our further studies on the use of 2-substituted indolin-3-ones as prenucleophiles to construct chiral quaternary centers by palladium-catalyzed AAA.[10b] [11]

Figure 1 Some natural products containing the indolin-3-one substructure with an α-quaternary carbon center

Initially, the reaction of 1-acetyl-2-benzylindolin-3-one (1a) and allyl methyl carbonate (2a) was carried out in the presence of catalytic amounts of [Pd(C₃H₅)Cl]₂ and (R)-BINAP, using LiHMDS as base in tetrahydrofuran (THF) at –40 °C. The reaction afforded the product 2,2-disubstituted indolin-3-one 3a in 83% yield and 38% ee (Table [1], entry 1). Encouraged by this result, the reaction parameters were investigated (Table [1]).

It was found that good yield was achieved, although enantioselectivity was not high, with ligands L2–L5 (Figure [2] and Table [1], entries 2–5). The ee value decreased significantly when allyl tert-butyl carbonate (2b) was used (Table [1], entry 6 vs 2). A screen of SIOCPhox ligands developed by our group[10] revealed that the ligand (S,S _phos,S)-SIOCPhox L6 afforded better results with respect to both yield and enantioselectivity (entry 7) whereas the other SIOCPhox ligands L7–L14 provided inferior results (entries 8–15).

Figure 2 The structure of ligands L1–L14

On the basis of the above results, the effects of solvents and bases using [Pd(C₃H₅)Cl]₂ and (S,S _phos,S)-L6 as catalyst was investigated. It can be seen that dimethoxyethane (DME) gave better results (Table [1], entry 17) among various solvents screened, including toluene, DME, Et₂O and CH₂Cl₂ (entries 16–19), whereas LiHMDS was found to be the most suitable base (entry 17). Both yield and ee value decreased significantly when NaHMDS, KHMDS, or LDA was used as base (entries 20–22), and NaH and t-BuONa gave only trace amounts of product (not shown). The use of some common additives, such as LiCl, ZnCl₂, and Bn(Et)₃NCl, did not improve the yield and/or ee (entries 23–25).

Under the optimized conditions, the substrate scope was then explored; the results are summarized in Table [2]. Generally the reactions proceeded smoothly for all substrates, with yields of 62–99% and ee values of 68–92% being obtained for substrates with benzyl (entry 1), methyl (entry 2), ethyl (entry 9), phenyl (entry 7), o-Br substituted phenyl (entry 8) and benzyl with electron-withdrawing or electron-donating substituent on phenyl group (entries 10–13) at the α-position to the carbonyl. The reaction was also suitable for indolinones with Cl or F at the 6-position (entries 3–6). It should be noted that the reactions of 1g, 1h, 1l, and 1m afforded the corresponding products in lower yields (not shown), however, the yields were improved when the reaction was carried out at 0 or 15 °C. Substrate 1g afforded the product 3g in 86% yield with 92% ee and substrate 1h gave 3h in 92% yield and 87% ee at 15 °C (entries 7 and 8), whereas 1l gave 3l in 93% yield and 84% ee, and 1m provided 3m in 83% yield and 68% ee at 0 °C (entries 12 and 13). Substrate 1n, with a furan-2-ylmethyl substituent, provided 3n in 80% yield and 76% ee (entry 14). It should be pointed out that the product 3h could be used as a key intermediate in the total synthesis of hinckdentine A.[5b] [c]

Table 1 Optimization of Parameters for the Reaction of 1a with 2 ^a

Entry	L*	Base	Solvent	LG (2)	Yield (%)b	ee (%)c
1	L1	LiHMDS	THF	OCO2Me (2a)	83	38
2	L2	LiHMDS	THF	OCO2Me (2a)	89	55
3	L3	LiHMDS	THF	OCO2Me (2a)	95	40
4	L4	LiHMDS	THF	OCO2Me (2a)	68	–48d
5	L5	LiHMDS	THF	OCO2Me (2a)	75	6
6	L2	LiHMDS	THF	OCO2 tBu (2b)	90	21
7	L6	LiHMDS	THF	OCO2Me (2a)	99	61
8	L7	LiHMDS	THF	OCO2Me (2a)	98	42
9	L8	LiHMDS	THF	OCO2Me (2a)	97	–44d
10	L9	LiHMDS	THF	OCO2Me (2a)	90	–21d
11	L10	LiHMDS	THF	OCO2Me (2a)	73	61
12	L11	LiHMDS	THF	OCO2Me (2a)	87	–16d
13	L12	LiHMDS	THF	OCO2Me(2a)	95	9
14	L13	LiHMDS	THF	OCO2Me (2a)	96	–31d
15	L14	LiHMDS	THF	OCO2Me (2a)	91	48
16	L6	LiHMDS	toluene	OCO2Me (2a)	51	42
17	L6	LiHMDS	DME	OCO2Me (2a)	99	76
18	L6	LiHMDS	Et2O	OCO2Me (2a)	99	63
19	L6	LiHMDS	CH2Cl2	OCO2Me (2a)	97	51
20	L6	NaHMDS	DME	OCO2Me (2a)	7	–16d
21	L6	KHMDS	DME	OCO2Me (2a)	10	9
22	L6	LDA	DME	OCO2Me(2a)	6	37
23e	L6	LiHMDS	DME	OCO2Me (2a)	69	72
24f	L6	LiHMDS	DME	OCO2Me (2a)	71	66
25g	L6	LiHMDS	DME	OCO2Me (2a)	76	54

^a Reaction was carried out at –40 °C, molar ratio of 1a/2/[Pd(C₃H₅)Cl]₂/L/base = 100:150:3:6:120.

^b Yields of 3a based on 1a.

^c Determined by chiral HPLC analysis.

^d Reverse sequence of peaks by HPLC.

^e LiCl as additive.

^f BnN(Et)₃Cl as additive.

^g ZnCl₂ as additive.

The absolute configuration of 3a was determined as R by comparing the sign of the optical rotation of the product with that previously reported.[7t]

In summary, we have realized the palladium-catalyzed asymmetric allylic alkylation of 2-substituted indolin-3-ones with allyl methyl carbonate in good yields and with good enantioselectivities. A chiral quaternary carbon center was also constructed during the reaction. These synthetically useful products could find applications in organic synthesis.[5b] [c] Investigations to extend the scope of the reaction and develop further its application in organic synthesis are in progress.

All the experiments were carried out in flame-dried glassware under a dry argon atmosphere. The solvents were purified and dried over appropriate drying agents and distilled under argon prior to use. ¹H, ¹³C, and ¹⁹F NMR spectra were recorded in CDCl₃ using TMS as internal standard with Bruker Avance 300 MHz, 400 MHz, or 600 MHz, spectrometers at r.t. HRMS measurements were carried out with a Finnigan MAT 8430 spectrometer.

Synthesis of 2,2-Substituted Indolin-3-ones 3; General Procedure

2-Substituted indolin-3-one 1 (0.1 mmol) and DME (1.0 mL) were added into a dry Schlenk tube. LiHMDS (1.0 M in THF, 0.12 mL, 0.12 mmol) was added dropwise and the mixture was stirred for 30 min at –40 °C. In a separate flask, [Pd(C₃H₅)Cl]₂ (1.1 mg, 0.003 mmol) and ligand (S,S _phos,S)-SIOCPhox (L6; 4.1 mg, 0.006 mmol) were dissolved in DME (1.0 mL) and the mixture was stirred at r.t. for 30 min, before being added to the above enolate solution at the temperature indicated in Table [2]. Allyl methyl carbonate 2a (0.15 mmol) was then added and the resulting mixture was stirred at the stated temperature. Upon completion (reaction monitored by TLC), the reaction mixture was quenched by sat. aq NH₄Cl (5.0 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layer was dried (Na₂SO₄) and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel; petroleum ether–EtOAc, 10:1) to afford the desired product.

Table 2 Substrate Scope for Palladium-Catalyzed AAA^a

Entry	Substrate	Product	Yield (%)b	ee (%)c
1	1a	3a	99	75
2	1b	3b	62	88
3	1c	3c	80	74
4	1d	3d	70	86
5	1e	3e	76	86
6	1f	3f	66	86
7d	1g	3g	86	92
8d	1h	3h	92	87
9	1i	3i	60	78
10	1j	3j	83	84
11	1k	3k	81	75
12e	1l	3l	93	84
13e	1m	3m	83	68
14	1n	3n	80	76

^a Reaction was carried out at –40 °C, molar ratio of 1/2a/[Pd(C₃H₅)Cl]₂/L6/base = 100:150:3:6:120.

^b Yield of 3 based on 1.

^c Determined by chiral HPLC analysis.

^d Reaction was carried out at 15 °C.

^e Reaction was carried out at 0 °C.

1-Acetyl-2-allyl-2-benzylindolin-3-one (3a)

Yield: 30.2 mg (99%); pale-yellow solid; mp 72–75 °C; [α]_D ²⁴ +10.0 (c 1.0, CHCl₃); HPLC [Chiralpak AD-H; i-PrOH–hexane (5:95); flow rate: 0.7 mL/min; λ = 214 nm]: t_R = 18.8 (minor), 15.4 (major) min; ee = 75%.

IR (KBr): 3028, 2962, 2921, 2851, 1711, 1667, 1604, 1469, 1433, 1371, 1308, 1031, 751, 703 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.60 (d, J = 7.2 Hz, 1 H), 7.39 (t, J = 7.2 Hz, 1 H), 7.12 (d, J = 5.6 Hz, 1 H), 6.99–6.93 (m, 6 H), 5.36–5.25 (m, 1 H), 5.04 (d, J = 16.8 Hz, 1 H), 4.83 (d, J = 9.6 Hz, 1 H), 3.74 (d, J = 12.4 Hz, 1 H), 3.36 (br, 1 H), 3.22 (d, J = 13.2 Hz, 1 H), 2.82 (br, 1 H), 2.44 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 202.0, 168.6, 152.5, 136.7, 135.1, 131.2, 129.4, 127.8, 126.7, 125.3, 124.1, 123.2, 119.4, 114.7, 77.0, 41.6, 40.4, 27.1.

MS (EI): m/z (%) = 305 (39) [M]⁺, 264 (21), 222 (61), 214 (17), 172 (100), 144 (10), 130 (10), 115 (12), 91 (50), 77 (13), 43 (30).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₀NO₂: 306.1489; found: 306.1495.

1-Acetyl-2-allyl-2-methylindolin-3-one (3b)

Yield: 14.2 mg (62%); pale-yellow solid; mp 90–91 °C; [α]_D ²⁷ +52.9 (c 1.00, CHCl₃); HPLC [Chiralpak AD-H; i-PrOH–hexane (2:98); flow rate: 0.7 mL/min; λ = 214 nm]: t_R = 18.7 (minor), 21.1 (major) min; ee = 88%.

IR (KBr): 3072, 1703, 1667, 1641, 1608, 1471, 1432, 1371, 1343, 1310, 1191, 1100, 930, 750 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.32 (br, 1 H), 7.78 (d, J = 7.6 Hz, 1 H), 7.65 (dt, J = 7.8, 1.2 Hz, 1 H), 7.20 (t, J = 7.6 Hz, 1 H), 5.33–5.23 (m, 1 H), 5.02 (d, J = 16.8 Hz, 1 H), 4.86 (d, J = 9.6 Hz, 1 H), 3.10 (br, 1 H), 2.76 (br, 1 H), 2.51 (s, 3 H), 1.60 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 201.8, 168.7, 152.8, 137.4, 131.1, 124.7, 123.9, 119.5, 117.1, 116.1, 72.0, 40.9, 26.7, 22.8.

MS (EI): m/z (%) = 229 (14) [M]⁺, 188 (37), 147 (15), 146 (100), 144 (9), 117 (10), 91 (10), 77 (15).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₆NO₂: 230.1176; found: 230.1182.

1-Acetyl-2-allyl-2-benzyl-6-chloroindolin-3-one (3c)

Yield: 27.1 mg (80%); pale-yellow solid; mp 50–52 °C; [α]_D ²⁴ +43.2 (c 1.04, CHCl₃); HPLC [Chiralpak AD-H; i-PrOH–hexane (5:95); flow rate: 0.7 mL/min; λ = 214 nm]: t_R = 11.7 (minor), 11.0 (major) min; ee = 74%.

IR (KBr): 3083, 2956, 2925, 2854, 1716, 1673, 1603, 1574, 1428, 1370, 1312, 1272, 1083, 992, 702 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.52 (d, J = 7.2 Hz, 1 H), 7.13 (s, 1 H), 7.00–6.92 (m, 6 H), 5.34–5.24 (m, 1 H), 5.05 (d, J = 17.2 Hz, 1 H), 4.87 (d, J = 9.2 Hz, 1 H), 3.72 (br, 1 H), 3.34–3.22 (m, 2 H), 2.81 (br, 1 H), 2.44 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 200.6, 168.5, 153.0, 143.3, 134.9, 130.9, 129.4, 128.1, 127.0, 125.0, 123.9, 119.8, 115.1, 77.8, 41.6, 40.5, 27.1.

MS (EI): m/z (%) = 341 (39) [M]⁺, 339 (95) [M]⁺, 298 (45), 258 (67), 256 (100), 208 (97), 207 (97), 206 (100), 164 (26), 143 (33), 115 (29), 91 (96).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₉ClNO₂: 340.1099; found: 340.1098.

1-Acetyl-2-allyl-6-chloro-2-methylindolin-3-one (3d)

Yield: 18.4 mg (70%); slightly yellow oil; [α]_D ²⁰ +51.3 (c 1.05, CHCl_3­); HPLC [Chiralpak AD-H; i-PrOH–hexane (3:97); flow rate: 0.7 mL/min; λ = 214 nm]: t_R = 12.8 (minor), 13.5 (major) min; ee = 86%.

IR (KBr): 3080, 2979, 2928, 2855, 1717, 1672, 1602, 1574, 1425, 1368, 1341, 1269, 1183, 979, 925, 826 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.05 (br, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.15 (dd, J = 8.0, 1.2 Hz, 1 H), 5.29–5.18 (m, 1 H), 5.00 (d, J = 16.8 Hz, 1 H), 4.86 (d, J = 10.4 Hz, 1 H), 3.00 (br, 1 H), 2.73 (br, 1 H), 2.47 (s, 3 H), 1.56 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 200.1, 168.7, 153.1, 143.8, 130.6, 125.2, 124.6, 121.8, 119.8, 117.8, 71.8, 41.1, 26.1, 22.9.

MS (EI): m/z (%) = 265 (6) [M]⁺, 263 (20) [M]⁺, 224 (11), 222 (38), 182 (34), 180 (100), 117 (11), 110 (14), 75 (20), 43 (55).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₅ClNO₂: 264.0786; found: 264.0780.

1-Acetyl-2-allyl-2-benzyl-6-fluoroindolin-3-one (3e)

Yield: 24.5 mg (76%); pale-solid; mp 81–83 °C; [α]_D ²⁰ +17.2 (c 1.12, CHCl₃); HPLC [Chiralpak AD; i-PrOH–hexane (5:95); flow rate: 0.6 mL/min; λ = 214 nm]: t_R = 15.0 (minor), 13.9 (major) min; ee = 86%.

IR (KBr): 3084, 3032, 2931, 1716, 1677, 1619, 1589, 1488, 1436, 1372, 1275, 1184, 924, 703 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.62 (t, J = 4.8 Hz, 1 H), 7.03–7.00 (m, 3 H), 6.94–6.92 (m, 2 H), 6.81 (br, 1 H), 6.72 (dt, J = 8.1, 2.0 Hz, 1 H), 5.37–5.26 (m, 1 H), 5.07 (d, J = 17.2 Hz, 1 H), 4.89 (d, J = 8.8 Hz, 1 H), 3.73 (br, 1 H), 3.36–3.23 (m, 2 H), 2.83 (br, 1 H), 2.44 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 200.2, 168.5, 168.2 (d, J _C–F = 255.0 Hz), 153.9, 134.9, 131.0, 129.4, 128.0, 126.9, 126.3, 121.9, 119.7, 111.4 (d, J _C–F = 22.6 Hz), 102.6 (d, J _C–F = 27.1 Hz), 77.9, 41.6, 40.4, 27.0.

¹⁹F NMR (376 MHz, CDCl₃): δ = –97.44.

MS (EI): m/z (%) = 323 (55) [M]⁺, 282 (20), 240 (95), 232 (30), 191 (28), 190 (100), 162 (19), 148 (17), 91 (62).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₉FNO₂: 324.1394; found: 324.1381.

1-Acetyl-2-allyl-6-fluoro-2-methylindolin-3-one (3f)

Yield: 16.3 mg (66%); slightly yellow oil; [α]_D ^20.7 +63.0 (c 1.00, CHCl₃); HPLC [Chiralpak AD-H; i-PrOH–hexane (3:97); flow rate: 0.7 mL/min; λ = 214 nm]: t_R = 13.6 (minor), 14.7 (major) min; ee = 86%.

IR (KBr): 3082, 2980, 2931, 2856, 1717, 1673, 1618, 1589, 1437, 1370, 1345, 1267, 1192, 987, 924, 843 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.86 (br, 1 H), 7.73 (dd, J = 8.0, 6.4 Hz, 1 H), 6.87 (t, J = 8.4 Hz, 1 H), 5.29–5.18 (m, 1 H), 4.99 (d, J = 16.8 Hz, 1 H), 4.85 (d, J = 10.0 Hz, 1 H), 2.99 (br, 1 H), 2.74 (br, 1 H), 2.45 (s, 3 H), 1.56 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 199.6, 170.3, 168.6, 166.9, 154.0, 130.5, 126.3, 119.6, 112.0 (d, J _C–F = 23.9 Hz), 105.1, 72.1, 41.0, 25.9, 22.8.

¹⁹F NMR (376 MHz, CDCl₃): δ = –97.04.

MS (EI): m/z (%) = 247 (41) [M]⁺, 206 (89), 165 (44), 164 (100), 162 (21), 135 (24), 109 (22), 95 (25), 94 (36).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₅FNO₂: 248.1081; found: 248.1072.

1-Acetyl-2-allyl-2-phenylindolin-3-one (3g)

Yield: 25.0 mg (86%); pale solid; mp 121–123 °C; [α]_D ^25.5 +338.9 (c 0.70, CHCl₃); HPLC [Chiralpak AD; i-PrOH–hexane (5:95); flow rate: 0.6 mL/min; λ = 214 nm]: t_R = 23.2 (minor), 22.0 (major) min; ee = 92%.

IR (KBr): 3067, 2919, 2852, 1721, 1670, 1606, 1460, 1370, 1337, 1292, 1149, 914, 756, 701 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.81 (d, J = 8.0 Hz, 1 H), 7.76–7.72 (m, 2 H), 7.38–7.32 (m, 3 H), 7.28–7.24 (m, 3 H), 5.46–5.36 (m, 1 H), 5.19 (d, J = 16.8 Hz, 1 H), 5.02 (d, J = 10.0 Hz, 1 H), 3.66 (dd, J = 13.2, 4.8 Hz, 1 H), 3.15 (dd, J = 13.2, 8.0 Hz, 1 H), 2.00 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 197.7, 170.1, 154.6, 137.8, 137.6, 129.6, 129.5, 128.5, 125.1, 124.8, 124.7, 122.3, 120.6, 118.9, 74.7, 40.2, 25.1.

MS (EI): m/z (%) = 291 (64) [M]⁺, 250 (96), 220 (21), 209 (91), 208 (100), 180 (31), 152 (27), 77 (42).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₈NO₂: 292.1332; found: 292.1334.

1-Acetyl-2-allyl-2-(2-bromophenyl)indolin-3-one (3h)

Yield: 33.9 mg (92%); pale-yellow solid; mp 120–122 °C; [α]_D ^25.5 +157.4 (c 1.09, CHCl₃); HPLC [Chiralpak AD-H; i-PrOH–hexane (20:80); flow rate: 0.7 mL/min; λ = 214 nm]: t_R = 14.9 (minor), 19.8 (major) min; ee = 87%.

IR (KBr): 3077, 2923, 2850, 1718, 1668, 1607, 1588, 1460, 1369, 1339, 1291, 1197, 1004, 911, 750 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.62 (br, 1 H), 7.76 (m, 3 H), 7.50 (d, J = 7.5 Hz, 1 H), 7.41 (t, J = 7.5 Hz, 1 H), 7.23–7.15 (m, 2 H), 5.41–5.25 (m, 1 H), 5.08 (d, J = 15.9 Hz, 1 H), 4.88 (d, J = 10.2 Hz, 1 H), 3.37 (br, 1 H), 3.23 (br, 1 H), 1.95 (br, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 198.3, 168.5, 154.3, 137.2, 135.2, 130.5, 130.0, 129.6, 127.8, 125.7, 124.2, 123.3, 121.6, 120.8, 119.0, 74.4, 41.8, 25.1.

MS (EI): m/z (%) = 371 (5) [M]⁺, 369 (6) [M]⁺, 330 (17), 328 (23), 290 (53), 288 (93), 286 (95), 207 (100), 178 (18), 151 (18), 102 (18), 76 (36).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₇BrNO₂: 370.0437; found: 370.0437.

1-Acetyl-2-allyl-2-ethylindolin-3-one (3i)

Yield: 14.6 mg (60%); slightly yellow oil; [α]_D ^24.5 +6.3 (c 1.00, CHCl₃); HPLC [Chiralpak AD; i-PrOH–hexane (5:95); flow rate: 0.6 mL/min; λ = 214 nm]: t_R = 13.6 (minor), 14.1 (major) min; ee = 78%.

IR (KBr): 3079, 2971, 2934, 2878, 1714, 1667, 1609, 1460, 1370, 1295, 920, 754 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.67 (br, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.65 (td, J = 8.0, 1.2 Hz, 1 H), 7.19 (t, J = 7.6 Hz, 1 H), 5.33–5.23 (m, 1 H), 5.01 (d, J = 16.8 Hz, 1 H), 4.85 (d, J = 10.0 Hz, 1 H), 3.14 (br, 1 H), 2.72–2.52 (m, 5 H), 2.04 (br, 1 H), 0.56 (t, J = 7.6 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 202.2, 168.3, 152.9, 137.2, 131.2, 125.1, 124.1, 123.6, 119.3, 115.2, 74.4, 40.6, 29.6, 26.9, 7.8.

MS (EI): m/z (%) = 243 (20) [M]⁺, 202 (50), 161 (18), 160 (100), 132 (26), 130 (19), 117 (15), 77 (18).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₈NO₂: 244.1332; found: 244.1333.

1-Acetyl-2-allyl-2-(2-bromobenzyl)indolin-3-one (3j)

Yield: 31.8 mg (83%); pale-yellow solid; mp 55–57 °C; [α]_D ^24.5 –20.2 (c 1.00, CHCl₃); HPLC [Chiralpak AD-H; i-PrOH–hexane (5:95); flow rate: 0.7 mL/min; λ = 214 nm]: t_R = 22.0 (minor), 17.3 (major) min; ee = 84%.

IR (KBr): 3077, 2929, 1715, 1668, 1608, 1470, 1435, 1369, 1298, 1024, 926, 751 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.50 (br, 1 H), 7.61 (d, J = 7.5 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 1 H), 7.30 (d, J = 8.1 Hz, 1 H), 7.06–6.96 (m, 3 H), 6.86 (t, J = 8.1 Hz, 1 H), 5.37–5.24 (m, 1 H), 5.08 (d, J = 16.2 Hz, 1 H), 4.89 (d, J = 9.9 Hz, 1 H), 3.85 (br, 1 H), 3.52 (br, 1 H), 3.43 (d, J = 14.1 Hz, 1 H), 2.91 (br, 1 H), 2.50 (s, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 200.6, 168.5, 152.2, 136.6, 135.0, 132.8, 132.1, 131.2, 128.3, 126.7, 125.2, 125.0, 124.3, 123.3, 119.6, 115.0, 76.3, 40.7, 39.9, 27.0.

MS (EI): m/z (%) = 385 (36) [M]⁺, 383 (37) [M]⁺, 344 (24), 342 (27), 302 (69), 300 (72), 220 (52), 214 (98), 173 (84), 172 (100), 144 (33), 130 (28), 115 (25), 90 (25).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₉BrNO₂: 384.0594; found: 384.0593.

1-Acetyl-2-allyl-2-(4-isopropylbenzyl)indolin-3-one (3k)

Yield: 28.1 mg (81%); slightly yellow oil; [α]_D ^24.6 +6.4 (c 0.92, CHCl₃­); HPLC [Chiralpak AD-H; i-PrOH–hexane (5:95); flow rate: 0.7 mL/min; λ = 214 nm]: t_R = 15.4 (minor), 12.5 (major) min; ee = 75%.

IR (KBr): 3080, 2960, 2927, 2871, 1716, 1670, 1609, 1470, 1372, 1311, 1290, 924, 795 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 7.6 Hz, 1 H), 7.41 (t, J = 8.0 Hz, 1 H), 7.13 (d, J = 6.4 Hz, 1 H), 7.00 (t, J = 7.6 Hz, 1 H), 6.86–6.81 (m, 4 H), 5.38–5.27 (m, 1 H), 5.06 (d, J = 17.2 Hz, 1 H), 4.86 (d, J = 10.0 Hz, 1 H), 3.72 (d, J = 12.4 Hz, 1 H), 3.40–3.33 (m, 1 H), 3.20 (d, J = 13.2 Hz, 1 H), 2.85–2.80 (m, 1 H), 2.69–2.61 (m, 1 H), 2.46 (s, 3 H), 1.05 (d, J = 2.4 Hz, 3 H), 1.03 (d, J = 2.4 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 202.2, 168.7, 152.6, 147.3, 136.6, 132.4, 131.4, 129.4, 125.8, 125.5, 124.3, 123.1, 119.4, 114.9, 74.3, 41.3, 40.3, 33.6, 27.2, 23.9.

MS (EI): m/z (%) = 347 (15) [M]⁺, 264 (21), 214 (12), 172 (100), 133 (38), 117 (18), 105 (11), 91 (11).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₆NO₂: 348.1958; found: 348.1959.

2-[(1-Acetyl-2-allyl-3-oxoindolin-2-yl)methyl]benzonitrile (3l)

Yield: 30.7 mg (93%); pale-solid; mp 83–85 °C; [α]_D ^24.7 –14.3 (c 1.35, CHCl₃); HPLC [Chiralpak AD-H; i-PrOH–hexane (8:92); flow rate: 1.0 mL/min; λ = 214 nm]: t_R = 22.9 (minor), 20.6 (major) min; ee = 84%.

IR (KBr): 3080, 3025, 2937, 2854, 2225, 1707, 1674, 1608, 1470, 1368, 1272, 933, 910, 753 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.59 (d, J = 8.0 Hz, 1 H), 7.53 (t, J = 8.0 Hz, 1 H), 7.41 (d, J = 7.2 Hz, 1 H), 7.35 (br, 1 H), 7.28 (t, J = 7.6 Hz, 1 H), 7.14 (t, J = 7.2 Hz, 2 H), 7.05 (t, J = 7.2 Hz, 1 H), 5.36–5.26 (m, 1 H), 5.10 (d, J = 17.2 Hz, 1 H), 4.91 (d, J = 9.6 Hz, 1 H), 3.98 (d, J = 10.8 Hz, 1 H), 3.52–3.43 (m, 2 H), 2.90 (br, 1 H), 2.56 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 200.4, 168.8, 152.5, 138.9, 137.1, 133.1, 132.1, 131.4, 130.9, 127.5, 124.8, 124.5, 123.5, 120.1, 118.1, 115.2, 113.5, 76.1, 40.0, 39.7, 27.1.

MS (EI): m/z (%) = 330 (13) [M]⁺, 288 (6), 248 (18), 247 (100), 214 (20), 172 (67), 144 (7), 130 (7), 116 (19), 89 (16).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₉N₂O₂: 331.1441; found: 331.1445.

1-Acetyl-2-allyl-2-(3-methylbenzyl)indolin-3-one (3m)

Yield: 26.5 mg (83%); pale-solid; mp 62–64 °C; [α]_D ^24.6 +8.2 (c 1.10, CHCl₃); HPLC [Chiralpak AD-H; i-PrOH–hexane (5:95); flow rate: 0.7 mL/min; λ = 214 nm]: t_R = 15.5 (minor), 12.9 (major) min; ee = 68%.

IR (KBr): 3079, 3024, 2961, 2924, 1715, 1670, 1609, 1471, 1436, 1372, 1300, 804, 781, 702 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.63 (d, J = 7.2 Hz, 1 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 1 H), 7.02 (t, J = 7.2 Hz, 1 H), 6.87 (t, J = 7.2 Hz, 1 H), 6.78–6.73 (m, 3 H), 5.37–5.27 (m, 1 H), 5.06 (d, J = 17.2 Hz, 1 H), 4.85 (d, J = 9.6 Hz, 1 H), 3.71 (d, J = 12.8 Hz, 1 H), 3.38 (dd, J = 12.0, 8.0 Hz, 1 H), 3.20 (d, J = 13.2 Hz, 1 H), 3.82 (dd, J = 11.6, 8.0 Hz, 1 H), 2.45 (s, 3 H), 2.09 (s, 3 H).

¹³C NMR (150 MHz, acetone-d ₆): δ = 201.9, 169.5, 153.6, 138.0, 137.7, 136.1, 132.4, 130.9, 128.5, 128.1, 127.3, 126.1, 124.2, 123.9, 119.4, 116.2, 77.2, 42.0, 41.2, 27.3, 21.2.

MS (EI): m/z (%) = 319 (35) [M]⁺, 278 (13), 236 (68), 214 (15), 172 (100), 115 (12), 105 (34), 77 (22).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₂NO₂: 320.1645; found: 320.1637.

1-Acetyl-2-allyl-2-(furan-2-ylmethyl)indolin-3-one (3n)

Yield: 23.6 mg (80%); slightly yellow oil; [α]_D ^24.6 +10.1 (c 1.00, CHCl₃); HPLC [Chiralpak AD-H; i-PrOH–hexane (5:95); flow rate: 0.7 mL/min; λ = 214 nm]: t_R = 25.0 (minor), 20.5 (major) min; ee = 76%.

IR (KBr): 3080, 2982, 2853, 1716, 1668, 1607, 1504, 1435, 1371, 1292, 973, 922, 750 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.70 (d, J = 7.6 Hz, 1 H), 7.52 (t, J = 8.0 Hz, 1 H), 7.27 (br, 1 H), 7.09 (t, J = 7.2 Hz, 1 H), 6.95 (s, 1 H), 5.98 (s, 1 H), 5.85 (s, 1 H), 5.36–5.26 (m, 1 H), 5.05 (d, J = 17.2 Hz, 1 H), 4.86 (d, J = 10.0 Hz, 1 H), 3.85 (d, J = 9.2 Hz, 1 H), 3.28 (br, 2 H), 2.77 (br, 1 H), 2.48 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 201.4, 168.6, 150.2, 141.6, 136.8, 131.0, 124.9, 124.5, 123.3, 119.6, 114.9, 110.0, 107.9, 75.4, 40.1, 34.3, 27.0.

MS (EI): m/z (%) = 295 (20) [M]⁺, 253 (21), 214 (71), 173 (32), 172 (100), 154 (17), 144 (30), 130 (29), 81 (52).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₈NO₃: 296.1281; found: 296.1275.

Acknowledgment

This research was financially supported by the Major Basic Re­search Development Program (Grant No. G 2010CB833300), National Natural Science Foundation of China (21121062, 21032007, 21302205), Chinese Academy of Sciences, Technology Commission of Shanghai Municipality, and the Croucher Foundation of Hong Kong. We thank Dr. Bai-Lin Lei for inspiring discussions.

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