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Synlett 2007(12): 1873-1876  
DOI: 10.1055/s-2007-982568
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Novel Three-Component Reaction: Synthesis of Some Complex Annelated Quinolines from Simple Acetanilides and via Intramolecular 1,3-Dipolar Cycloaddition of Azide to Nitrile

Biswajita Baruah, Mohit L. Deb, Pulak J. Bhuyan*
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat 785006, Assam, India
Fax: +91(376)2370011; e-Mail: pulak_jyoti@yahoo.com;
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Publication History

Received 9 March 2007
Publication Date:
25 June 2007 (online)

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Abstract

Synthesis of a novel class of tetrazolo[4′,5′:1,6]pyrido[2,3-d]quinolines from simple acetanilides and via intra­molecular 1,3-dipolar cycloaddition of azides to nitriles using a three-component one-pot protocol is reported.

Key words

quinolines - acetanilides - multicomponent reaction - ­cyano-stabilised carbanion - intramolecular 1,3-dipolar cycloaddition reactions

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Three-Component Reaction
To a mixture of 2-chloro-3-formylquinoline (2a, 192 mg, 1 mmol), ethyl cyanoacetate (3a, 140 mg, 1.24 mmol) and NaN3 (4, 80 mg, 1.24 mmol) in DMF (10 mL) were added two drops of water. A catalytic amount (1-2 drops) of Et3N was then added to the reaction mixture and it was allowed to stir for 4 h at 50-60 °C. After completion of the reaction, the mixture was cooled to r.t. and poured into H2O under continuous stirring. A brown solid precipitated that was shown to be almost totally pure 5a. However, it was further purified by preparative TLC using EtOAc-hexane (3:7); mp 205 °C, yield 234 mg (80%). 1H NMR (CDCl3): δ = 1.43 (t, 3 H), 4.32 (q, 2 H), 7.26 (s, 1 H), 7.60-8.05 (m, 4 H), 8.63 (s, 1 H). 13C NMR (CDCl3): δ = 14.50 (CH3), 61.20 (CH2C=O), 112.55 (C-5), 123.75 (C-4), 124.00 (C-2), 126.20 (C-7), 127.45 (C-3), 127.70 (C-6), 131.00 (C-6a), 136.20 (C-11b), 138.36 (C-8), 145.12 (C-8a), 146.67 (C-5a), 151.25 (C-1a), 171.75 (C=O). MS: m/z = 316 [M + Na]+. IR (CHCl3): 2923.70, 2852.60, 1742.80 cm-1. Anal. Calcd for C15N5O2H11: C, 61.43; H, 3.75; N, 23.89. Found: C, 61.43; H, 3.82; N, 23.95.

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2-Chloro-3-formyl quinoline (2a, 384 mg, 2 mmol) was mixed with ethyl cyanoacetate (3a, 260 mg, 2.17 mml) in toluene (10 mL). One drop of piperidine was added and the reaction mixture was allowed to stir at r.t. for 1 h. The solvent was evaporated and the yellow solid obtained was purified by recrystallisation from EtOH.
Compound [Aa] (R1 = H, R2 = CO2Et): mp 110 °C, yield 516 mg (98%). 1H NMR (CDCl3): δ = 1.43 (t, 3 H), 4.43 (q, 2 H), 7.46-815 (m, 4 H), 8.74 (s, 1 H), 9.05 (s, 1 H). IR (CHCl3): 2226.70, 1730.90 cm-1.

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The condensed product [Aa] (286 mg, 1 mmol) was mixed with NaN3 (4, 80 mg, 1.24 mmol) in DMF (10 mL) and 2 drops of H2O were added. The reaction mixture was allowed to stir for 4 h at 50-60 °C. After completion of the reaction the mixture was cooled to r.t. and poured into H2O under continuous stirring. A brown coloured solid which appeared was filtered and purified by preparative TLC using EtOAc-hexane (3:7) to furnish 5a (176 mg, 60%).