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Synlett 2003(13): 1959-1964  
DOI: 10.1055/s-2003-42044
LETTER
© Georg Thieme Verlag Stuttgart · New York

The Vinylogous Mannich Reaction: An Efficient Access to Substituted Nicotinonitriles

Andreas Winter, Nikolaus Risch*
Fakultät für Naturwissenschaften, Department Chemie, Universität Paderborn, Warburger Str.100, 33098 Paderborn, Germany
Fax: +49(5251)603245; e-Mail: nr@chemie.upb.de;
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Publication History

Received 15 July 2003
Publication Date:
08 October 2003 (online)

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Abstract

A straightforward method for the preparation of substituted nicotinonitriles has been developed. Starting from conjugated β-enaminonitriles and iminium salts, this methodology establishes a convenient access to 6-aryl- (5), 6-amino- (16) and 6-carboxylic ester-substituted derivatives 14 and as well to acetic acid-substituted pyrroles 12.

Key words

domino reactions - iminium salts - Mannich bases - β-enaminonitriles - nicotinonitriles - pyrroles - pyridines

7

General Procedure for the Synthesis of Conjugated β-Enaminonitriles 3 and 4: To a solution of β-aminocroto-nonitrile 2 (60 mmol) and Et3N (15.3 mL, 110 mmol) in anhyd CH2Cl2 (60 mL) cooled with an ice bath was added slowly with stirring a solution of TiCl4 (3.3 ml, 30 mmol) in anhyd toluene (40 mL). Subsequently, the ketone 1 (50 mmol) was added in one portion. After the mixture was stirred for 24 h at ambient temperature, the solvent was removed in vacuo and the residue was crushed with a spatula. Then Et2O (200 mL) was added, and the resulting mixture was stirred vigorously until the residue was ground to a fine powder. Subsequently, the powder was sucked off and washed with Et2O (200 mL). Evaporation of the solvent provided the crude conjugated β-enaminonitriles 3 or 4, which were used for preparation of nicotinonitriles without further purification.

10

General Procedure for the Synthesis of Nicotinonitriles 5 and 16: The reactions were conducted in a water-free apparatus under Ar. To a solution of the conjugated β-enaminonitrile 3 or 4 (4 mmol) in anhyd CHCl3 (20 mL) was added the iminium salt 6 or 15 (5 mmol) in one portion. The mixture was stirred and kept at reflux for 15 h. After cooling to r.t., dilute NaOH (2 N, 40 mL) was added, and the resulting mixture was stirred vigorously for 15 min. The organic phase was decanted, and the aq phase was extracted with Et2O (3 × 50 mL). The combined organic phases were dried over MgSO4, and the solvent was removed in vacuo. The crude products were purified either by Kugelrohr distillation or flash column chromatography (SiO2, EtOAc-hexanes 3:1).

14

General Procedure for the Synthesis of Pyrroles 12 and Nicotinonitriles 14: The reactions were conducted under Ar. A solution of ethyl glyoxylate aminal 9 (5 mmol) in anhyd CH2Cl2 (20 mLl) was cooled to 0 °C. Acetyl chloride (0.35 mL, 5 mmol) was added in one portion under stirring to generate the iminium salt 10. After stirring the mixture for 1 h at 0 °C the β-enaminonitrile 3 or 4 (4 mmol) was added and the solution heated under reflux for 15 h. After cooling to r.t., dilute NaHCO3 (4 M, 40 mL) was added, and the resulting mixture was stirred vigorously for 15 min. The organic phase was decanted, and the aq phase was extracted with Et2O (3 × 50 mL). The combined organic phases were dried over MgSO4, and the solvent was removed in vacuo. The crude products were purified by flash column chromatography (SiO2, EtOAc-hexanes 3:1).

15

Carboxylic ester substituted nicotinonitriles 14 derived from β-enaminonitriles such as 3e or 3f (R2 H) could not be isolated. Reaction of 3e and 3f with 10 led to the formation of complex mixtures. However, we were able to identify the desired products 14b,c by GC-MS analysis (Table [4] ).