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Synlett 2006(16): 2593-2596  
DOI: 10.1055/s-2006-951477
LETTER
© Georg Thieme Verlag Stuttgart · New York

α-Cyclisation of Tertiary Amines: Synthesis of Some Novel Annelated Quinolines via a Three-Component Reaction under Solvent-Free Conditions

Ipsita Devi, Biswajita Baruah, Pulak J. Bhuyan*
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat 785006, Assam, India
Fax: +91(376)2370011; e-Mail: pulak_jyoti@yahoo.com;
Further Information

Publication History

Received 14 June 2006
Publication Date:
22 September 2006 (online)

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Abstract

Synthesis of some novel classes of quinolizine-, indolizine- and pyrido-1,4-oxazine-fused quinoline derivatives via a three-component reaction under solvent-free conditions by exploring the ‘tertiary amine effect’ reaction strategy.

Key words

quinolines - pyrimidines - tertiary amine effect - solvent-free reaction - multicomponent reaction

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Compound 2a: POCl3 (9 mL, 98.28 mmol) was added drop-wise via dropping funnel to DMF (2.7 mL, 34.65 mmol) at 0-5 °C. The mixture was stirred for about 5 min. Acetanilide (1a; 1.42 g, 10.37 mmol) was then added to the reaction mixture and the resulting solution was heated for 8 h (75-80 °C). The reaction mixture was cooled to r.t. and then poured into crushed ice with stirring. A pale-yellow precipi-tate appeared at once, which was filtered, washed with H2O and dried. The crude compound was then recrystallised from EtOAc. Yield: 80% (1.62 g); mp 142-143 °C. Similarly compounds 2b-d were synthesised and characterised.

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Three-Component Synthesis: 2-Chloro-3-formyl quinoline (2a) (1.92 g, 10 mmol) was mixed thoroughly with freshly distilled piperidine (3a; 0.991 g, 11.66 mmol) and malononitrile (4a; 0.660 g, 10 mmol) in a round-bottom flask. The reaction mixture was allowed to fuse at 110-120 °C for 5 h. The progress of the reaction was monitored by TLC and after its completion the product was separated and purified by preparative TLC (CHCl3-hexane, 2:1) to give 5a. Yield: 540 mg (54%); brown solid; mp 169-170 °C. IR (CHCl3): 2945, 2854, 2225 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.25-1.79 (m, 4 H, CH2), 2.10-2.33 (m, 2 H, CH2), 2.79-2.84 (t, 1 H, CH), 3.54-3.73 (m, 2 H, CH2), 5.3 (s, 2 H, CH2), 7.26-7.75 (m, 5 H, Ar). 13C NMR (CDCl3): δ = 23.79 (C-10), 24.68 (C-11), 30.12 (C-7), 36.74 (C-9), 37.11 (C-12), 45.55 (C-8), 60.06 (C-8a), 112.51 (C-5), 113.63 (CN), 114.75 (CN), 123.84 (C-4), 123.92 (C-2), 127.22 (C-3), 127.36 (C-6), 130.45 (C-6a), 137.03 (C-12b), 147.89 (C-5a), 152.96 (C-1a). MS: m/z = 289 (M + H)+. Similarly compounds 5b-j and 7a-f were synthesised and characterised.

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Compound 8a: 2-Chloro-3-formyl quinoline (2a; 1.92 g, 10 mmol) was mixed thoroughly with freshly distilled piperidine (3a; 0.991 g, 11.66 mmol) and K2CO3 (1.469 g, 11.66 mmol) in DMF (50 mL). The resulting mixture was allowed to reflux for 7 h. After completion of the reaction (monitored by TLC), the mixture was cooled to r.t. and poured into crushed ice under continuous stirring. A light-yellow solid appeared, which was allowed to settle for 2 h under ice cooling. The precipitate was filtered under reduced pressure, dried in a hot-air oven and finally purified by column chromatography (CHCl3-hexane). Yield: 87.5% (2.1 g); light yellow crystals; mp 84-85 °C. IR: 2935.1, 2851.2, 1690.7 cm-1. 1H NMR (60 MHz, CDCl3): δ = 1.5-1.7 (CH2, 6 H), 3.1-3.3 (CH2, 4 H), 6.9-7.6 (Ph, 5 H), 8.2 (CH, 1 H), 9.8 (CHO, 1 H).

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Compound 9a: Compound 8a (1.2 g, 5 mmol) and malononitrile (4a; 0.33 g, 5 mmol) were added to hexane (5 mL) and the resulting solution was stirred at r.t. To this solution piperidine (1 drop) was added and stirring was continued for 90 min. After completion of the reaction (monitored by TLC) the solvent was evaporated to dryness. The orange solid was further purified by column chromatography using (CHCl3-hexane). Yield: 88.5% (1.24 g); orange crystals; mp 127-129 °C. IR: 2938, 2851, 2229 cm-1. 1H NMR (60 MHz, CDCl3): δ = 1.5-1.8 (CH2, 4 H), 3.1-3.3 (CH2, 4 H), 7.0-7.8 (Ph, 5 H), 8.5 (CH, 1 H). Yield: 1.24 g (88.5%). Similarly compounds 9b and 9c were synthesised and characterised.

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Compound 5a: Compound 9a (1 g, 3.47 mmol) was allowed to fuse at 110-120 °C for 5 h. The conversion was monitored by TLC. The new compound was separated by preparative TLC (CHCl3-hexane, 2:1) to give a brown solid. Similarly compounds 5e, 5i and 7a were synthesised and characterised.