Synlett 2011(11): 1547-1550  
DOI: 10.1055/s-0030-1260787
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Efficient One-Pot, Three-Component Reaction: Synthesis of Complex-Annelated α-Carbolines via an Intramolecular [3+2]-Dipolar Cycloaddition Reaction

Swarup Majumder, Pulak J. Bhuyan*
Medicinal Chemistry Division, North East Institute of Science & Technology (CSIR), Jorhat 785006, Assam, India
Fax: +91(376)2370011; e-Mail: pulak_jyoti@yahoo.com;
Further Information

Publication History

Received 17 March 2011
Publication Date:
15 June 2011 (online)

Abstract

Novel annelated α-carbolines have been synthesized from oxindole using three components in a one-pot procedure involving an intramolecular [3+2]-dipolar cycloaddition reaction of azides to nitriles.

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19

General Procedure for Three-Component Reaction To a mixture of 1-Boc-2-chloro-3-formylindole (3a, 279 mg, 1 mmol), ethyl cyanoacetate (4a, 170 mg, 1.5 mmol), and NaN3 (5, 80 mg, 1.24 mmol) in DMF (5 mL) were added 2 drops of H2O. A catalytic amount (1-2 drops) of Et3N was then added, and the reaction mixture allowed to stir for 3 h at 50-60 ˚C. After completion of the reaction, the mixture was cooled to r.t. and poured into H2O with continuous stirring. A yellow-brownish solid product was formed after keeping the mixture inside the freezer overnight. Product 6a was purified by preparative TLC using EtOAc-hexane (3:7).
Compound 6a
Yield 270 mg (71%); mp 221-223 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.25 (t, J = 7.07 Hz, 3 H), 1.72 (s, 9 H), 4.17-4.23 (m, 2 H), 7.20-7.86 (m, 3 H), 8.18 (s, 1 H), 8.57-8.63 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 14.23, 28.08, 62.20, 86.81, 105.09, 113.52, 115.22, 115.66, 121.09, 124.08, 124.40, 125.77, 130.83, 135.66, 146.37, 147.89, 162.57. MS (EI): m/z = 382.4 [M + H]+. Anal. Calcd (%) for C19H19N5O4: C, 59.84; H, 4.98; N, 18.37. Found: C, 59.65; H, 4.93; N, 18.42. IR (CHCl3): νmax = 2983.00, 2856.50, 1751.90, 1728.10 cm. Similar compounds 6b-i were synthesized and characterized.

20

Synthesis of Compound 3a
Equimolar amounts of 2-chloro-3-formyl indole (2, 10 mmol, 1.79 g) and Boc-anhydride (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 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 white crystalline compound; 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 Compound 3b
2-Chloro-3-formyl-indole (2, 1.78 g, 10 mmol) was taken in a round-bottom flask in DMF (10 mL) on magnetic stirrer. NaH (0.48 g, 20 mmol) was added into the mixture. When the temperature reached 0 ˚C, MeI (1.42 g, 10 mmol) was added gradually, and the reaction mixture allowed to stir for 1.5 h. An off-white solid formed which was almost pure product. Yield 1.59 g (82%); mp 79-80 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 3.80 (s, 3 H), 7.20-8.30 (m, 4 H), 10.12 (s, 1 H).
Synthesis of Compound 3c
2-Chloro-3-formyl-indole (2, 1.78 g, 10 mmol) was refluxed with allyl bromide(10 mmol) in the presence of K2CO3 (10 mmol) using acetone (10 mL) as solvent for 10 h to afford 3c, 1.69 g (76%) as a colorless solid, mp 148-149 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 4.80 (d, J = 11.4 Hz, 2 H), 5.10-5.27 (d, J = 10.2 Hz, 2 H), 5.95-6.07 (m, 1 H), 7.20-8.26 (m, 4 H), 10.16 (s, 1 H).

21

Synthesis of Compound [A] 1-Boc-2-chloro-3-formylindole (3a, 558 mg, 2 mmol) was treated with ethyl cyanoacetate (4a, 283 mg, 2.5 mmol) in EtOH (8 mL). One drop of piperidine was added, and the reaction mixture was allowed to stir at r.t. for 30 min. The reaction mixture was kept inside the freezer overnight. The yellow solid which appeared in the reaction mixture was filtered, washed with cold EtOH and dried. Yield 508 mg (75%); mp 87-88 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 1.43 (t, J = 3.6 Hz, 2 H), 1.72 (s, 9 H), 4.36-4.44 (m, 2 H), 7.20-8.10 (m, 4 H), 8.49 (s, 1 H).

22

Synthesis of α-Carboline 6a from [A] The condensed product [A] (339 mg, 1 mmol) was mixed with NaN3 (5, 80 mg, 1.24 mmol) in DMF (5 mL) and 2 drops of H2O were added. A catalytic amount (1-2 drops) of Et3N was then added to the reaction mixture, and the whole was stirred for 3 h at 50-60 ˚C After completion of reaction, the mixture was cooled to r.t. and poured into H2O with stirring. A yellow-brownish solid was formed after keeping the mixture inside the freezer overnight. Product 6a was purified by preparative TLC using EtOAc-hexane (3:7); yield 251 mg (66%); mp 221-223 ˚C.