HMPA-Catalyzed One-Pot Multistep Hydrogenation Method for the Synthesis of 1,2,3-Trisubstituted Indolines

Abstract

A convenient and facile method was developed for the synthesis of 1,2,3-trisubstituted indolines. Starting from indole derivatives and ketones/aldehydes, the corresponding indoline products could be obtained with high yield by the hexamethylphosphoramide (HMPA) catalyzed indole Friedel–Crafts reaction, reduction and direct reductive amination process.

The structure of multiple substituted indolines have been found in numerous naturally occurring products, such as ajmaline, strychnine, vinblastine, (+)-aspidospermidine and (–)-physostigmine.[1] [2] [3] [4] [5] [6] In principle, the direct reduction of indoles was one of the straightforward methods to get a series of indolines. In the last decade, the asymmetric hydro­genation of protected indoles has been developed as the straightest and the most powerful approach to obtain such molecules, but the efficient synthesis of simple unprotected indoles remains a great challenge.[7–11] In 2010, Zhou and co-workers reported the first Pd-catalyzed asymmetric hydrogenation method of unprotected indoles for the preparation of a broad range of substituted indolines with good yields.[12] However, in this method, multiple steps were needed to prepare the 2,3-disubstituted indole substrates. To address this limitation, a Brønsted acid/Pd catalyzed consecutive process has been reported to construct the 2,3-disubstituted indolines from 2-substitued indoles and aldehydes.[13] Despite the progress achieved in transition-metal-catalyzed asymmetric hydrogenation of indoles and other heteroaromatic compounds in the past decade,[14] [15] [16] the reduction of indoles catalyzed by small organic molecules is still rarely studied.

An organic Lewis base/HSiCl₃ system has proven to be a powerful combination for the reduction of C=N, C=O and C=C bonds by us and others.[17] [18] [19] [20] [21] [22] [23] [24] [25] In 2011, we developed the first organic Lewis base/HSiCl₃ system for the asymmetric hydrosilylation of 2,3-disubstituted indoles affording high stereoselectivities and good substrate generality (Scheme [1]).[17] We also developed the first organic Lewis base catalyzed tandem approach to get chiral 2,3-disubstituted indolines from indoles and aldehydes.[18] In 2016, we successfully developed the first direct reductive hydrazination of hydrazines with ketones/aldehydes for the preparation of 1,1-disubstituted hydrazines.[19] Enlightened by these results, we envisioned that a highly efficient method could be obtained for the preparation of 1,2,3-trisubstitued indolines if the Lewis base catalyzed Friedel–Crafts reaction, reduction and direct reductive amination process could be realized in one pot. Herein, we wish to report the first organic Lewis base catalyzed tandem approach for the preparation of 1,2,3-trisubstitued indolines.

To implement our design, we tested the reaction of 2-methylindole, acetophenone, and benzaldehyde with HSiCl₃ in the presence of hexamethylphosphoramide (HMPA). However, yield of the desired product 4a was 27% and the side products 5a and 5aa were obtained with 31% and 34% yield, respectively (Table [1], entry 1). A trace of 4a could be obtained when the reaction temperature was decreased to –20 °C and –40 °C, respectively, and the Friedel–Crafts-­Aldol-reduction product 7a was obtained as the major product in both cases (Table [1], entries 2 and 3). Gratifyingly, 4a could be obtained with 73% yield when the reaction was carried out first with stirring at –20 °C for 48 hours and then at 0 °C for 18 hours (Table [1], entry 5). Other Lewis bases such as TEA, DMAP, DMF and DMAc could all be used in the reaction, but HMPA was found to have the best performance (Table [1], entries 6–10). It was found that CH₂Cl₂ was the best solvent among the choices from CHCl₃, CCl₄, DCE, toluene, MeCN, and THF (Table [1], entries 11–16). An 84% yield could be obtained when the amount of HMPA was reduced to 20 mol%. After careful investigation, we identified the best reaction conditions in which the reaction of ketone, indole and aldehyde could be performed using 20 mol% of HMPA and trichlorosilane (6.0 equiv) in CH₂Cl₂ at –20 °C for 48 hours and then at 0 °C for 18 hours.

Consequently, the substrate scope and limitations for the reaction were investigated. Various ketones and aldehyde were examined as substrates (Scheme [2]). It was found that acetophenones which have electron-donating or electron-withdrawing substitutions at the para or meta position of the phenyl ring were tolerated in the existing reaction conditions (Scheme [2, 4a–i]). Product 4b could be obtained with 88% yield when 4-methoxyacetophenone was used in the reaction. And 77–90% yield could also be achieved when the para position of acetophenones was substituted with electron-withdrawing groups such as NO₂, CF₃, F, Cl and Br. Yields of 79% and 75% were obtained, respectively, when o- and m-chloroacetophenone were used in the reaction. Product 4j could be obtained with 82% yield when 2-naphthyl ketone was used in the reaction. Moreover, other ketones such as n-butanone or cyclopentanone could also be used in the reaction to get the desired products with 66% and 61% yields, respectively.

Table 1 Optimization of Reaction Conditions^a

Entry	Solvent	Lewis base (equiv)	Temp (°C)	Yield (%)b
1c	CH2Cl2	HMPA (3)	0	27
2d	CH2Cl2	HMPA (3)	–20	Trace
3e	CH2Cl2	HMPA (3)	–40	Trace
4f	CH2Cl2	HMPA (3)	–40 to 0	55
5	CH2Cl2	HMPA (3)	–20 to 0	73
6	CH2Cl2	TEA (3)	–20 to 0	19
7	CH2Cl2	DMAP(3)	–20 to 0	44
8	CH2Cl2	DMF(3)	–20 to 0	60
9	CH2Cl2	DMAc (3)	–20 to 0	43
10	CH2Cl2	Imidazole (3)	–20 to 0	<10
11	CHCl3	HMPA (3)	–20 to 0	67
12	CCl4	HMPA (3)	–20 to 0	21
13	DCE	HMPA (3)	–20 to 0	46
14	Toluene	HMPA (3)	–20 to 0	36
15	MeCN	HMPA (3)	–20 to 0	38
16	THF	HMPA (3)	–20 to 0	20
17	CH2Cl2	HMPA (5)	–20 to 0	54
18	CH2Cl2	HMPA (2)	–20 to 0	78
19	CH2Cl2	HMPA (1)	–20 to 0	81
20	CH2Cl2	HMPA (0.5)	–20 to 0	83
21	CH2Cl2	HMPA (0.2)	–20 to 0	84

^a Unless noted otherwise, reactions were performed with ketone (0.20 mmol), indole (0.20 mmol), aldehyde (0.24 mmol) and HSiCl₃ (6.0 equiv) in solvent (1.0 mL) at –20 °C for 48 h then at 0 °C for 18 h.

^b Isolated yield of 4a based on ketone.

^c The reaction temperature was 0 °C for 48 h.

^d The reaction temperature was –20 °C for 48 h.

^e The reaction temperature was –40 °C for 48 h.

^f The reaction temperature was –40 °C for 48 h then 0 °C for 18 h; TEA: ­triethylamine, DMAP: 4-dimethylaminopyridine, HMPA: hexamethylphosphoramide, DMAc: dimethylacetamide.

Benzaldehydes bearing either electron-donating or electron-withdrawing substituents are all good substrates for the reaction. The desired products 4m and 4n were obtained with 80% and 85% yields, respectively, when meta substituted benzaldehydes such as m-tolualdehyde, and m-methoxybenzaldehyde were used in the reaction. Products 4o–q could also be obtained with 79–88% yield when para substituted benzaldehydes were used in the reaction.

Next, we found the hydrosilylation–reductive amination process between indole and ketone could be completed in the existing reaction conditions. A series of N-protected indolines was prepared by this method. Both electron-donating and electron-withdrawing substitutions at the para position of the phenyl ring of acetophenone were tolerated (Scheme [3, 10a–g]). Yields of 83–95% could be obtained when the para position of the phenyl ring of acetophenone was substituted with F, Cl, Br, CF₃, NO₂, Me, and MeO, respectively. However, the ortho substituted acetophenone (Scheme [3, 10j–l]), caused a lower yield of 71–84%. Moreover, other ketones such as n-butanone, cyclopentanone, and benzylacetone could also be used in the reaction to get the desired product with 82–89% yields (Scheme [3, 10k–n]).

A plausible reaction mechanism has been proposed for the one-pot multistep synthesis of 1,2,3-trisubstituted indolines in Scheme [4]. The Friedel–Crafts intermediate I is formed very fast and it is reduced to the indoline II by ­Lewis base catalyzed reduction reaction at –20 °C. When the reaction temperature is increased to 0 °C, the indoline II reacts with ketone to get the 1,2,3-trisubstituted indoline product by Lewis base catalyzed reduction amination process.

In conclusion, we have developed a one-pot three-component tandem protocol for the synthesis of 1-alkyl-2-methyl-3-alkylindolines from inexpensive commercially available 2-methylindoles, aldehydes and ketones.[26] [27] [28] [29] [30] This protocol provides a facile and efficient method for the preparation of N-substituted indolines under mild and metal-free conditions by HMPA-catalyzed reduction process. A series of 1,2,3-trisubstituted indolines could be accomplished by this tandem process, which provided a good alternative method for the preparation of these compounds.

• References and Notes

• 1 Liu D. Zhao G. Xiang L. Eur. J. Org. Chem. 2010; 21: 3975
  Search in Google Scholar
• 2 Kuehne ME. Bornmann WG. Marko I. Qin Y. LeBoulluec KL. Frasier DA. Xu F. Mulamba T. Ensinger CL. Borman LS. Huot AE. Exon C. Bizzarro FT. Cheung JB. Bane SL. Org. Biomol. Chem. 2003; 1: 2120
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• 3 Zhang H. Boonsombat J. Padwa A. Org. Lett. 2007; 9: 279
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• 4 Bui T. Syed S. Barbas III C. F. J. Am. Chem. Soc. 2009; 131: 8758
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• 5 Wang T. Xu Q. Yu P. Liu X. Cook JM. Org. Lett. 2001; 3: 345
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• 6 Iyengar R. Schildknegt K. Morton M. Aube J. J. Org. Chem. 2005; 70: 10645
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• 7 Lu SM. Han XW. Zhou YG. Chin. J. Org. Chem. 2005; 25: 634
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• 8 Glorius F. Org. Biomol. Chem. 2005; 3: 4171
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• 9 Zhou YG. Acc. Chem. Res. 2007; 40: 1357
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• 10 Kuwano R. Heterocycles 2008; 76: 909
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• 11 Kobayashi S. Yasuda M. Hachiya I. Chem. Lett. 1996; 25: 407
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• 12 Wang DS. Chen QA. Li W. Yu CB. Zhou YG. Zhang XM. J. Am. Chem. Soc. 2010; 132: 8909
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• 13 Duan Y. Chen MW. Ye ZS. Wang DS. Chen QA. Zhou YG. Chem. Eur. J. 2011; 17: 7193
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• 14 Wang DS. Tang J. Zhou YG. Chen MW. Yu CB. Duan Y. Jiang G.-F. Chem. Sci. 2011; 2: 803
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• 15 Duan Y. Chen MW. Chen QA. Yu C.-B. Zhou YG. Org. Biomol. Chem. 2012; 10: 1235
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• 16 Duan Y. Li L. Chen MW. Yu CB. Fan HJ. Zhou YG. J. Am. Chem. Soc. 2014; 136: 7688
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• 17 Xiao YC. Wang C. Yao Y. Sun J. Chen YC. Angew. Chem. 2011; 123: 10849
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• 18 Chen L. Wang C. Zhou L. Sun J. Adv. Synth. Catal. 2014; 356: 2224
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• 19 Wang T. Di X. Wang C. Zhou L. Sun J. Org. Lett. 2016; 18: 1900
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• 20 Malkov AV. Vrankova K. Stoncius S. Kocovsky P. J. Org. Chem. 2009; 74: 5839
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• 21 Guizzetti S. Benaglia M. Eur. J. Org. Chem. 2010; 10: 5529
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• 22 Jones S. Warner CJ. A. Org. Biomol. Chem. 2012; 10: 2189
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• 23 Orlandi M. Tosi F. Bonsignore M. Benaglia M. Org. Lett. 2015; 17: 3941
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• 24 Guizzetti S. Benaglia M. Eur. J.Org. Chem. 2010; 29: 5529
  Search in Google Scholar
• 25 Jones S. Warner CJ. A. Org. Biomol. Chem. 2012; 10: 2189
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• 26 General Procedure for the Synthesis of 1-Alkykl-2-methyl-3-alkylindolines 4: A solution of aromatic aldehyde 2 (0.24 mmol, 1.2 equiv) in CH₂Cl₂ (0.2 mL) was added dropwise to a solution of indole 1 (0.2 mmol), ketone 3 (0.2 mmol) and HMPA (0.04 mmol, 0.2 equiv) in CH₂Cl₂ (0.6 mL) in a fully dried reaction tube at –20 °C, and then trichlorosilane in CH₂Cl₂ (0.2 mL, 6 mol/L) was added dropwise to the solution. The solution was stirred at –20 °C for 48 h, then at 0 °C for 18 h. The reaction was then quenched with sat. aq solution of NaHCO₃ (2 mL) and basified with NaHCO₃ powder. Then the mixture was extracted with EtOAc (10 mL) three times. The combined extracts were washed with brine and dried over anhyd Na₂SO₄. The combined solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc) to afford pure indoline 4.
• 27 Analytical data of compound 4a: light yellow oil; yield: 84%; purification by flash chromatography (PE/EA = 125:1). ¹H NMR (400 MHz, CDCl₃; 2:1 diastereomers): δ = 7.40–7.47 (m, 2 H, ArH, for two diastereomers), 7.11–7.37 (m, 8.4 H, ArH, for two diastereomers), 6.93–7.02 (m, 0.4 H, ArH, minor), 6.79 (t, J = 6.9 Hz, 0.6 H, ArH, major), 6.41–6.54 (m, 2 H, ArH, for two dia­stereomers), 5.97 (d, J = 7.0 Hz, 0.6 H, ArH, major), 4.79 (q, J = 6.9 Hz, 0.3 H, CH, minor), 4.53 (q, J = 6.9 Hz, 0.6 H, CH, major), 3.84–4.02 (m, 1 H, CH, for two diastereomers), 3.42–3.59 (m, 1 H, CH, for two diastereomers), 2.78–3.06 (m, 2 H, CH₂, for two diastereomers), 1.62 (d, J = 6.9 Hz, 1 H, CH₃, minor), 1.51 (d, J = 6.9 Hz, 2 H, CH₃, major), 1.26 (d, J = 6.6 Hz, 2 H, CH₃, major), 0.95 (d, J = 6.6 Hz, 1 H, CH₃, minor). ¹³C NMR (101 MHz, CDCl₃): δ = 149.49, 143.79, 140.55, 133.11, 129.36, 128.54, 128.30, 127.02, 126.94, 126.67, 126.02, 124.21, 116.80, 109.64, 60.93, 53.18, 45.84, 34.66, 15.78, 13.56 (major), 150.67, 143.97, 140.62, 132.33, 129.35, 128.26, 128.20, 127.53, 126.71, 125.98, 124.58, 116.44, 107.27, 60.65, 53.39, 46.03, 34.60, 15.83, 15.69 (minor).
• 28 Analytical data of compound 4b: light yellow oil; yield: 88%; purification by flash chromatography (PE/EA = 100:1). ¹H NMR (400 MHz, CDCl₃; 2:1 diastereomers): δ = 7.12–7.37 (m, 7 H, ArH, for two diastereomers), 6.94–7.02 (m, 0.4 H, ArH, minor), 6.74–6.91 (m, 2.5 H, ArH, for two diastereomers), 6.41–6.50 (m, 2 H, ArH, for two diastereomers), 6.01 (d, J = 8.0 Hz, 0.6 H, ArH, major), 4.76 (q, J = 6.8 Hz, 0.3 H, CH, minor), 4.50 (q, J = 6.8 Hz, 0.6 H, CH, major), 3.89 (m, 1 H, CH, for two diastereomers), 3.79 (s, 3 H, CH₃, for two diastereomers), 3.42–3.58 (m, 1 H, CH, for two diastereomers), 2.77–3.05 (m, 2 H, CH₂, for two diastereomers), 1.59 (d, J = 6.9 Hz, 1 H, CH₃, minor), 1.49 (d, J = 6.9 Hz, 2 H, CH₃, major), 1.25 (d, J = 6.8 Hz, 2 H, CH₃, major), 0.94 (d, J = 6.8 Hz, 1 H, CH₃, minor). ¹³C NMR (101 MHz, CDCl₃): δ = 158.36, 149.59, 140.58, 135.74, 133.09, 129.37, 128.29, 127.74, 126.97, 126.00, 124.21, 116.72, 113.85, 109.57, 60.81, 55.31, 52.57, 45.83, 34.67, 15.80, 13.69 (major), 150.68, 140.65, 135.90, 132.38, 129.35, 128.26, 128.11, 127.52, 125.97, 124.56, 116.38, 113.50, 107.31, 60.54, 52.85, 46.04, 34.57, 15.94, 15.69 (minor).
• 29 Analytical data of compound 4c: yellow oil; yield: 88%; purification by flash chromatography (PE/EA = 80:1). ¹H NMR (400 MHz, CDCl₃; 2:1 diastereomers): δ = 8.17 (t, J = 8.5 Hz, 2 H, ArH, for two diastereomers), 7.61 (d, J = 8.8 Hz, 2 H, ArH, for two diastereomers), 7.08–7.35 (m, 5 H, ArH, for two diastereomers), 7.00 (t, J = 7.0 Hz, 0.3 H, ArH, minor), 6.78 (t, J = 7.0 Hz, 0.6 H, ArH, major), 6.46–6.61 (m, 2 H, ArH, for two diastereomers), 6.38 (d, J = 7.0 Hz, 0.3H, ArH, minor), 5.80 (d, J = 7.0 Hz, 0.6 H, ArH, major), 4.83 (q, J = 7.0 Hz, 0.3 H, CH, minor), 4.54 (q, J = 7.0 Hz, 0.6 H, CH, major), 3.79–4.21 (m, 1 H, CH, for two diastereomers), 3.40–3.66 (m, 1 H, CH, for two diastereomers), 2.66–3.12 (m, 2 H, CH₂, for two diastereomers), 1.66 (d, J = 6.9 Hz, 1 H, CH₃, minor), 1.54 (d, J = 6.9 Hz, 2 H, CH₃, major), 1.28 (d, J = 6.9 Hz, 2 H, CH₃, major), 0.97 (d, J = 6.9 Hz, 1 H, CH₃, minor). ¹³C NMR (101 MHz, CDCl₃): δ = 151.92, 148.67, 146.99, 140.18, 133.30, 129.33, 128.35, 127.79, 127.46, 126.12, 124.48, 123.89, 117.67, 109.67, 61.20, 53.16, 45.85, 34.61, 15.77, 13.21 (major), 152.15, 150.11, 140.22, 132.32, 129.34, 128.29, 127.61, 126.93, 126.09, 124.91, 123.48, 117.26, 107.15, 60.81, 46.00, 34.68, 15.92, 15.42 (minor).
• 30 Analytical data of compound 10c: light yellow oil; yield: 89%; purification by flash chromatography (PE/EA = 100:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.23–7.41 (m, 4 H), 7.05 (d, J = 7.3 Hz, 2 H), 6.60 (t, J = 7.3 Hz, 1 H), 6.29 (d, J = 6.9 Hz, 1 H), 4.64 (q, J = 6.9 Hz, 1 H), 3.19–3.49 (m, 2 H), 3.93 (t, J = 8.3 Hz, 2 H), 1.49 (d, J = 6.9 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 151.22, 141.61, 132.64, 130.21, 128.60, 128.47, 127.22, 124.52, 117.35, 107.37, 54.24, 48.14, 28.28, 16.73.

• References and Notes

• 1 Liu D. Zhao G. Xiang L. Eur. J. Org. Chem. 2010; 21: 3975
  Search in Google Scholar
• 2 Kuehne ME. Bornmann WG. Marko I. Qin Y. LeBoulluec KL. Frasier DA. Xu F. Mulamba T. Ensinger CL. Borman LS. Huot AE. Exon C. Bizzarro FT. Cheung JB. Bane SL. Org. Biomol. Chem. 2003; 1: 2120
  CrossrefPubMedSearch in Google Scholar
• 3 Zhang H. Boonsombat J. Padwa A. Org. Lett. 2007; 9: 279
  CrossrefPubMedSearch in Google Scholar
• 4 Bui T. Syed S. Barbas III C. F. J. Am. Chem. Soc. 2009; 131: 8758
  CrossrefSearch in Google Scholar
• 5 Wang T. Xu Q. Yu P. Liu X. Cook JM. Org. Lett. 2001; 3: 345
  CrossrefPubMedSearch in Google Scholar
• 6 Iyengar R. Schildknegt K. Morton M. Aube J. J. Org. Chem. 2005; 70: 10645
  CrossrefPubMedSearch in Google Scholar
• 7 Lu SM. Han XW. Zhou YG. Chin. J. Org. Chem. 2005; 25: 634
  Search in Google Scholar
• 8 Glorius F. Org. Biomol. Chem. 2005; 3: 4171
  CrossrefPubMedSearch in Google Scholar
• 9 Zhou YG. Acc. Chem. Res. 2007; 40: 1357
  CrossrefSearch in Google Scholar
• 10 Kuwano R. Heterocycles 2008; 76: 909
  CrossrefSearch in Google Scholar
• 11 Kobayashi S. Yasuda M. Hachiya I. Chem. Lett. 1996; 25: 407
  CrossrefSearch in Google Scholar
• 12 Wang DS. Chen QA. Li W. Yu CB. Zhou YG. Zhang XM. J. Am. Chem. Soc. 2010; 132: 8909
  CrossrefPubMedSearch in Google Scholar
• 13 Duan Y. Chen MW. Ye ZS. Wang DS. Chen QA. Zhou YG. Chem. Eur. J. 2011; 17: 7193
  CrossrefPubMedSearch in Google Scholar
• 14 Wang DS. Tang J. Zhou YG. Chen MW. Yu CB. Duan Y. Jiang G.-F. Chem. Sci. 2011; 2: 803
  CrossrefSearch in Google Scholar
• 15 Duan Y. Chen MW. Chen QA. Yu C.-B. Zhou YG. Org. Biomol. Chem. 2012; 10: 1235
  CrossrefPubMedSearch in Google Scholar
• 16 Duan Y. Li L. Chen MW. Yu CB. Fan HJ. Zhou YG. J. Am. Chem. Soc. 2014; 136: 7688
  CrossrefSearch in Google Scholar
• 17 Xiao YC. Wang C. Yao Y. Sun J. Chen YC. Angew. Chem. 2011; 123: 10849
  CrossrefSearch in Google Scholar
• 18 Chen L. Wang C. Zhou L. Sun J. Adv. Synth. Catal. 2014; 356: 2224
  CrossrefSearch in Google Scholar
• 19 Wang T. Di X. Wang C. Zhou L. Sun J. Org. Lett. 2016; 18: 1900
  CrossrefPubMedSearch in Google Scholar
• 20 Malkov AV. Vrankova K. Stoncius S. Kocovsky P. J. Org. Chem. 2009; 74: 5839
  CrossrefPubMedSearch in Google Scholar
• 21 Guizzetti S. Benaglia M. Eur. J. Org. Chem. 2010; 10: 5529
  Search in Google Scholar
• 22 Jones S. Warner CJ. A. Org. Biomol. Chem. 2012; 10: 2189
  CrossrefSearch in Google Scholar
• 23 Orlandi M. Tosi F. Bonsignore M. Benaglia M. Org. Lett. 2015; 17: 3941
  CrossrefSearch in Google Scholar
• 24 Guizzetti S. Benaglia M. Eur. J.Org. Chem. 2010; 29: 5529
  Search in Google Scholar
• 25 Jones S. Warner CJ. A. Org. Biomol. Chem. 2012; 10: 2189
  CrossrefSearch in Google Scholar
• 26 General Procedure for the Synthesis of 1-Alkykl-2-methyl-3-alkylindolines 4: A solution of aromatic aldehyde 2 (0.24 mmol, 1.2 equiv) in CH₂Cl₂ (0.2 mL) was added dropwise to a solution of indole 1 (0.2 mmol), ketone 3 (0.2 mmol) and HMPA (0.04 mmol, 0.2 equiv) in CH₂Cl₂ (0.6 mL) in a fully dried reaction tube at –20 °C, and then trichlorosilane in CH₂Cl₂ (0.2 mL, 6 mol/L) was added dropwise to the solution. The solution was stirred at –20 °C for 48 h, then at 0 °C for 18 h. The reaction was then quenched with sat. aq solution of NaHCO₃ (2 mL) and basified with NaHCO₃ powder. Then the mixture was extracted with EtOAc (10 mL) three times. The combined extracts were washed with brine and dried over anhyd Na₂SO₄. The combined solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc) to afford pure indoline 4.
• 27 Analytical data of compound 4a: light yellow oil; yield: 84%; purification by flash chromatography (PE/EA = 125:1). ¹H NMR (400 MHz, CDCl₃; 2:1 diastereomers): δ = 7.40–7.47 (m, 2 H, ArH, for two diastereomers), 7.11–7.37 (m, 8.4 H, ArH, for two diastereomers), 6.93–7.02 (m, 0.4 H, ArH, minor), 6.79 (t, J = 6.9 Hz, 0.6 H, ArH, major), 6.41–6.54 (m, 2 H, ArH, for two dia­stereomers), 5.97 (d, J = 7.0 Hz, 0.6 H, ArH, major), 4.79 (q, J = 6.9 Hz, 0.3 H, CH, minor), 4.53 (q, J = 6.9 Hz, 0.6 H, CH, major), 3.84–4.02 (m, 1 H, CH, for two diastereomers), 3.42–3.59 (m, 1 H, CH, for two diastereomers), 2.78–3.06 (m, 2 H, CH₂, for two diastereomers), 1.62 (d, J = 6.9 Hz, 1 H, CH₃, minor), 1.51 (d, J = 6.9 Hz, 2 H, CH₃, major), 1.26 (d, J = 6.6 Hz, 2 H, CH₃, major), 0.95 (d, J = 6.6 Hz, 1 H, CH₃, minor). ¹³C NMR (101 MHz, CDCl₃): δ = 149.49, 143.79, 140.55, 133.11, 129.36, 128.54, 128.30, 127.02, 126.94, 126.67, 126.02, 124.21, 116.80, 109.64, 60.93, 53.18, 45.84, 34.66, 15.78, 13.56 (major), 150.67, 143.97, 140.62, 132.33, 129.35, 128.26, 128.20, 127.53, 126.71, 125.98, 124.58, 116.44, 107.27, 60.65, 53.39, 46.03, 34.60, 15.83, 15.69 (minor).
• 28 Analytical data of compound 4b: light yellow oil; yield: 88%; purification by flash chromatography (PE/EA = 100:1). ¹H NMR (400 MHz, CDCl₃; 2:1 diastereomers): δ = 7.12–7.37 (m, 7 H, ArH, for two diastereomers), 6.94–7.02 (m, 0.4 H, ArH, minor), 6.74–6.91 (m, 2.5 H, ArH, for two diastereomers), 6.41–6.50 (m, 2 H, ArH, for two diastereomers), 6.01 (d, J = 8.0 Hz, 0.6 H, ArH, major), 4.76 (q, J = 6.8 Hz, 0.3 H, CH, minor), 4.50 (q, J = 6.8 Hz, 0.6 H, CH, major), 3.89 (m, 1 H, CH, for two diastereomers), 3.79 (s, 3 H, CH₃, for two diastereomers), 3.42–3.58 (m, 1 H, CH, for two diastereomers), 2.77–3.05 (m, 2 H, CH₂, for two diastereomers), 1.59 (d, J = 6.9 Hz, 1 H, CH₃, minor), 1.49 (d, J = 6.9 Hz, 2 H, CH₃, major), 1.25 (d, J = 6.8 Hz, 2 H, CH₃, major), 0.94 (d, J = 6.8 Hz, 1 H, CH₃, minor). ¹³C NMR (101 MHz, CDCl₃): δ = 158.36, 149.59, 140.58, 135.74, 133.09, 129.37, 128.29, 127.74, 126.97, 126.00, 124.21, 116.72, 113.85, 109.57, 60.81, 55.31, 52.57, 45.83, 34.67, 15.80, 13.69 (major), 150.68, 140.65, 135.90, 132.38, 129.35, 128.26, 128.11, 127.52, 125.97, 124.56, 116.38, 113.50, 107.31, 60.54, 52.85, 46.04, 34.57, 15.94, 15.69 (minor).
• 29 Analytical data of compound 4c: yellow oil; yield: 88%; purification by flash chromatography (PE/EA = 80:1). ¹H NMR (400 MHz, CDCl₃; 2:1 diastereomers): δ = 8.17 (t, J = 8.5 Hz, 2 H, ArH, for two diastereomers), 7.61 (d, J = 8.8 Hz, 2 H, ArH, for two diastereomers), 7.08–7.35 (m, 5 H, ArH, for two diastereomers), 7.00 (t, J = 7.0 Hz, 0.3 H, ArH, minor), 6.78 (t, J = 7.0 Hz, 0.6 H, ArH, major), 6.46–6.61 (m, 2 H, ArH, for two diastereomers), 6.38 (d, J = 7.0 Hz, 0.3H, ArH, minor), 5.80 (d, J = 7.0 Hz, 0.6 H, ArH, major), 4.83 (q, J = 7.0 Hz, 0.3 H, CH, minor), 4.54 (q, J = 7.0 Hz, 0.6 H, CH, major), 3.79–4.21 (m, 1 H, CH, for two diastereomers), 3.40–3.66 (m, 1 H, CH, for two diastereomers), 2.66–3.12 (m, 2 H, CH₂, for two diastereomers), 1.66 (d, J = 6.9 Hz, 1 H, CH₃, minor), 1.54 (d, J = 6.9 Hz, 2 H, CH₃, major), 1.28 (d, J = 6.9 Hz, 2 H, CH₃, major), 0.97 (d, J = 6.9 Hz, 1 H, CH₃, minor). ¹³C NMR (101 MHz, CDCl₃): δ = 151.92, 148.67, 146.99, 140.18, 133.30, 129.33, 128.35, 127.79, 127.46, 126.12, 124.48, 123.89, 117.67, 109.67, 61.20, 53.16, 45.85, 34.61, 15.77, 13.21 (major), 152.15, 150.11, 140.22, 132.32, 129.34, 128.29, 127.61, 126.93, 126.09, 124.91, 123.48, 117.26, 107.15, 60.81, 46.00, 34.68, 15.92, 15.42 (minor).
• 30 Analytical data of compound 10c: light yellow oil; yield: 89%; purification by flash chromatography (PE/EA = 100:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.23–7.41 (m, 4 H), 7.05 (d, J = 7.3 Hz, 2 H), 6.60 (t, J = 7.3 Hz, 1 H), 6.29 (d, J = 6.9 Hz, 1 H), 4.64 (q, J = 6.9 Hz, 1 H), 3.19–3.49 (m, 2 H), 3.93 (t, J = 8.3 Hz, 2 H), 1.49 (d, J = 6.9 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 151.22, 141.61, 132.64, 130.21, 128.60, 128.47, 127.22, 124.52, 117.35, 107.37, 54.24, 48.14, 28.28, 16.73.

• Supplementary Material