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DOI: 10.1055/s-0030-1260787
An Efficient One-Pot, Three-Component Reaction: Synthesis of Complex-Annelated α-Carbolines via an Intramolecular [3+2]-Dipolar Cycloaddition Reaction
Publication History
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.
Key words
α-carboline - oxindole - [3+2]-dipolar cycloaddition reaction - β-halo aldehyde - multicomponent reaction
- Supporting Information for this article is available online:
- Supporting Information
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References and Notes
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-¹. Similar
compounds 6b-i were synthesized
and characterized.
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).
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).
22Synthesis 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.