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Synlett 2009(13): 2115-2118  
DOI: 10.1055/s-0029-1217552
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

CaSH Organocatalysis: Enantioselective Friedel-Crafts Alkylation of Indoles with α,β-Unsaturated Aldehydes

Tian Tiana,b, Bao-Jian Peia, Qing-Hua Lia, Hao Hea, Ling-Yan Chena, Xiang Zhoub, Wing-Hong Chana, Albert W. M. Lee*a
a Department of Chemistry, Hong Kong Baptist University, Hong Kong, P. R. of China
Fax: +85234117438; e-Mail: alee@hkbu.edu.hk;
b College of Chemistry and Molecular Sciences, Wuhan University, Hubei, P. R. of China
Further Information

Publication History

Received 1 April 2009
Publication Date:
10 July 2009 (online)

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Abstract

Enantioselective Friedel-Crafts alkylation of indole with α,β-unsaturated aldehyde was catalyzed by camphor sulfonyl hydrazine (CaSH) with good enantioselectivity (81-88%).

Key words

camphor sulfonyl hydrazine (CaSH) - organocatalysis - indole alkylation - α,β-unsaturated aldehydes

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14

Aldehyde 3 (R¹ = Me): ¹H NMR (400 MHz, CDCl3): δ = 9.75 (s, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.31 (m, 1 H), 7.26 (m, 1 H), 7.14 (m, 1 H), 6.84 (s, 1 H), 3.75 (s, 3 H), 3.68 (m, 1 H), 2.87 (m, 1 H), 2.71 (m, 1 H), 1.43 (d, J = 6.8 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 203.1, 137.4, 126.8, 125.4, 121.9, 119.3, 119.0, 109.6, 51.2, 32.9, 26.1, 21.9 ppm.
Alcohol 4 was obtained by NaBH4 reduction. Alcohol 4 (R¹ = Me): ¹H NMR (400 MHz, CDCl3): δ = 7.64 (dd, J = 8.0, 0.8 Hz, 1 H), 7.30 (dd, J = 7.2, 0.8 Hz, 1 H), 7.23 (m, 1 H), 7.10 (m, 1 H), 6.85 (s, 1 H), 3.75 (s, 3 H), 3.66 (m, 1 H), 3.22 (m, 1 H), 2.06 (m, 1 H), 1.96 (m, 1 H), 1.40 (d, J = 6.8 Hz, 3 H) ppm.

15

General Experimental Procedure for CaSH 1 Catalyzed Friedel-Crafts Reaction of Indoles with α,β-Unsaturated Aldehydes
TFA (0.15 mmol) was added to a solution of CaSH 1 (0.15 mmol) in toluene (1 mL). The solution was stirred for 20 min and then cooled to -40 ˚C. The α,β-unsaturated aldehyde (1.5 mmol) was then added. After stirring for another 20 min, the N-substituted indole (0.5 mmol) was added. The reaction was stirred until complete consumption of the indoles as determined by TLC. MeOH (2 mL) was added to the reaction mixture followed by NaBH4 (3.0 mmol). The mixture was warmed to 0 ˚C and stirred for 20 min. The reaction was quenched by H2O and extracted with EtOAc. The organic solution was dried over anhyd Na2SO4. The product 6 was purified by silica gel chromatography (PE-EtOAc, 4:1). The ee was determined by chiral HPLC (Chiracel AD-H) of the alcohol 6 (5% i-PrOH in hexane
as eluent, 1 mL min-¹).

16

Spectroscopic Data of Products 6 (Table 2) Compound 6 (R² = Me): ¹H NMR (400 MHz, CDCl3): δ = 7.74 (dd, J = 7.6, 0.8 Hz, 1 H), 7.33 (m, 4 H), 7.21 (m, 4 H), 6.96 (s, 1 H), 5.29 (s, 2 H), 3.30 (m, 2 H), 3.27 (m, 1 H), 2.08 (m, 1 H), 1.95 (m, 1H), 1.44 (d, J = 7.2 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 138.0, 137.1, 129.0, 127.7, 127.6, 126.9, 124.6, 122.0, 121.1, 119.8, 119.1, 110.0, 61.7, 50.1, 40.6, 27.9, 22.1 ppm. HRMS (MALDI-TOF): m/z calcd for C19H22NO [M + H]+: 280.1696; found: 280.1695.
Compound 6 (R² = Et): ¹H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 7.6, Hz, 1 H), 7.25 (m, 4 H), 7.14 (m, 1 H), 7.06 (m, 3 H) 6.88 (s, 1 H), 5.24 (s, 2 H), 3.56 (m, 2 H), 2.93 (m, 1 H), 1.98 (m, 2 H), 1.74 (m, 2H), 0.83 (t, J = 7.0 Hz, 3 H) ppm.
Compound 6 (R² = Pr): ¹H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 8.0 Hz, 1 H), 7.33-7.24 (m, 4 H), 7.18 (m, 1 H), 7.17-7.06 (m, 3 H) 6.93 (s, 1 H), 5.29 (s, 2 H), 3.62 (m, 2 H), 3.05 (m, 1 H), 2.03 (m, 2 H), 1.18 (m, 2 H), 1.30 (m, 2 H), 0.88 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 138.0, 137.1, 128.9, 127.8, 127.7, 126.7, 125.6, 121.8, 119.9, 119.0, 118.9, 110.0, 61.9, 50.0, 39.0, 38.9, 33.6, 21.0, 14.4 ppm.
Compound 6 (R² = Bu): ¹H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 7.6 Hz, 1 H), 7.30-7.22 (m, 4 H), 7.14 (t, J = 7.6 Hz, 1 H), 7.09-7.03 (m, 3 H), 6.90 (s, 1 H), 5.27 (s, 2 H), 3.59 (m, 2 H), 3.01 (m, 1 H), 2.00 (m, 2 H), 1.78 (m, 2 H), 1.23 (m, 4 H), 0.83 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 138.0, 137.1, 128.9, 127.8, 127.7, 126.7, 125.6, 121.8, 119.9, 119.0, 110.0, 61.9, 50.0, 39.0, 36.3, 33.8, 30.2, 23.0, 14.3 ppm.
Compound 6 (R² = Ph): ¹H NMR (400 MHz, CDCl3): δ = 7.52 (m, 1 H), 7.38-7.07 (m, 12 H), 7.03 (m, 2 H), 5.30 (s, 2 H), 4.44 (t, J = 7.6 Hz, 1 H), 3.68 (m, 2 H), 2.48 (m, 1 H), 2.29 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 145.1, 138.0, 237.2, 129.0, 128.7, 128.1, 127.9, 127.8, 126.9, 126.4, 125.6, 122.1, 120.0, 119.3, 119.1, 109.9, 61.5, 50.2, 39.4, 39.0 ppm.
Compound 6 (R² = 4-ClC6H4): ¹H NMR (400 MHz, CDCl3): δ = 7.41 (d, J = 8.0 Hz, 1 H), 7.33-7.22 (m, 8 H), 7.15 (m, 3 H), 7.01 (m, 2 H), 5.29 (s, 2 H), 4.40 (t, J = 7.6 Hz, 1 H), 3.64 (m, 2 H), 2.43 (m, 1 H), 2.22 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 143.6, 137.8, 137.2, 131.9, 129.4, 129.0, 128.7, 127.8, 127.6, 126.8, 125.5, 122.2, 119.8, 119.4, 118.5, 110.0, 61.2, 50.2, 38.8, 38.7 ppm.
Compound 6 (R² = 4-BrC6H4): ¹H NMR (400 MHz, CDCl3): δ = 7.40 (m, 3 H), 7.37-7.18 (m, 6 H), 7.15-7.07 (m, 3 H), 6.99 (m, 2 H), 5.28 (s, 2 H), 4.38 (t, J = 8.0 Hz, 1 H), 3.62 (m, 2 H), 2.43 (m, 1 H), 2.22 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 144.1, 137.8, 137.2, 131.7, 129.8, 129.0, 127.8, 127.6, 126.8, 125.5, 122.2, 120.0, 119.8, 119.4, 118.4, 110.0, 61.2, 50.2, 38.8, 38.7 ppm.