The Tertiary Amino Effect: An Efficient Method for the Synthesis of α-Carbolines

Abstract

Functionalized annelated α-carbolines have been synthesized from oxindole following a tertiary amino effect reaction strategy.

Key words

α-carboline - oxindole - tertiary amino effect - α-halo ­aldehyde

References and Notes

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21

Synthesis of 2-Chloro-3-formylindole (2) To a mixture of anhyd DMF (10 mL) and anhyd CHCl₃ (10 mL) was added phosphorous oxychloride (10 mL) over 15 min. To this a solution of oxindole 1 (3.2 g, 24 mmol) and pyridine (5 mL), both in anhyd CHCl₃ (25mL), was slowly added. The reaction mixture was kept for 48 h at r.t. and then poured into ice-cold H₂O (100 mL). The solid compound 2 formed was filtered and dried. Yield 2.48 g (80%); mp 167-168 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 7.22-7.38 (m, 2 H), 7.95-7.99 (m, 1 H), 8.15-8.18 (m, 1 H), 9.61 (s, 1 H), 10.10 (s, 1 H).
Synthesis of 1-( tert -Butoxycarbonyl)-2-chloro-3-formylindole (3) Equimolar amounts of 2-chloro-3-formylindole (2; 10 mmol, 1.79 g) and Boc₂O (10 mmol, 2.18 g) were stirred in the presence of catalytic amount of DMAP (0.12 g) and Et₃N (0.10 g) at 0-5 ˚C for 1 h using CH₂Cl₂ (15 mL) as solvent. The solvent was evaporated under reduced pressure, and ­
the solid compound obtained was purified by column chromatography using PE-EtOAc (9:1) as eluent. The product 3 was obtained in 70% yield (1.20 g) as colorless crystals; mp 89-90 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.72 (s, 9 H), 7.26-7.40 (m, 2 H), 8.02-8.06 (m, 1 H), 8.27-8.30 (m, 1 H), 10.29 (s, 1 H).
Synthesis of 1-( tert -Butoxycarbonyl)-2-diethylamino-3-formylindole (5a) Equimolar amounts of 3 (10 mmol 2.79 g), Et₂NH (4a; 10 mmol, 0.72 g), and Et₃N (10 mmol, 1.01g) were treated at r.t. for 4 h using CH₂Cl₂ (10 mL) as solvent. The solvent was evaporated under reduced pressure, and the compound 5a obtained was purified by preparative TLC using PE-EtOAc (8:2) as eluent. The compound was not crystallized and used directly in the next step; yield 1.98 g (71%). ^¹H NMR (300 MHz, CDCl₃): δ = 1.17 (t, 6 H), 1.71 (s, 9 H), 3.43 (q, 4 H), 7.22-7.31 (m, 2 H), 7.82-7.85 (m, 1 H), 8.20-8.23 (m, 1 H), 10.16 (s, 1 H). Similarly compounds 5b-e were synthesized and characterized.
Synthesis of Compound 7a via Knoevenagel Condensation To equimolar amounts of 1-(tert-butoxycarbonyl)-2-diethylamino-3-formylindole (5a; 5 mmol, 1.5 g) and malononitrile (6a; 5 mmol, 0.33 g) in EtOH (10 mL) was added a catalytic amount of piperidine (1 drop), and the resulting solution was stirred for 30 min. The resultant solid was filtered washed with small amount of EtOH and dried. The bright yellow product 7a was obtained in pure form. Yield 1.20 g (80%); mp 122-123 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.18 (t, 6 H), 1.70 (s, 9 H), 3.43 (q, 4 H), 7.26-7.38 (m, 2 H), 7.74 (s, 1 H), 7.82-7.85 (m, 1 H), 7.96-7.98 (m, 1 H).
Synthesis of α-Carboline 8a from 7a under Thermolytic Conditions Compound 7a (2 mmol, 0.73 g) was heated at 80-90 ˚C for 1 h using DMF (5 mL) as solvent (the conversion was monitored by TLC). The reaction mixture was poured into H₂O and the solid filtered off. The compound was purified by column chromatography using PE-EtOAc (6:4) as eluent to obtain 8a as a yellow solid; yield 0.62 g (85%); mp 219-220 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.25-1.35 (m, 6 H), 1.70 (s, 9 H), 3.48-3.58 (m, 3 H), 4.57 (s, 2 H), 7.15-7.26 (m, 2 H), 7.61-7.65 (m, 2 H). ^¹³C NMR (75 MHz, DMSO): δ = 13.46, 14.20, 28.42, 39.77, 40.05, 40.33, 47.31, 61.82, 99.22, 110.46, 119.23, 121.34, 121.95, 122.74, 125.45, 135.24, 148.74, 155.37. IR: ν_max = 2210, 1736, 1631, 1540. MS: m/z = 363 [M⁺]. Anal. Calcd (%) for C₂₁H₂₃N₄O₂: C, 69.42; H, 6.33; N 15.42. Found: C, 69.65; H, 5.98; N, 15.56.