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Synlett 2004(10): 1731-1734  
DOI: 10.1055/s-2004-829547
LETTER
© Georg Thieme Verlag Stuttgart · New York

One-Pot Synthesis of Substituted Pyridines via the Vilsmeier-Haack Reaction of Acyclic Ketene-S,S-acetals

Shaoguang Sun, Yingchun Liu, Qun Liu*, Yulong Zhao, Dewen Dong*
Department of Chemistry, Northeast Normal University, Changchun, 130024, P. R. China
Fax: +86(431)5268966; e-Mail: dongdw663@nenu.edu.cn;
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Publication History

Received 15 May 2004
Publication Date:
15 July 2004 (online)

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Abstract

A one-pot synthesis of substituted pyridines from acyclic ketene-S,S-acetals containing α-acetyl, α-vinyl or α-ethynyl group via the Vilsmeier-Haack reaction has been developed.

Key words

α-oxo ketene-S,S-acetal - substituted pyridine - Vils­meier-Haack reaction - Vilsmeier reagent

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Typical Procedure for 2a: The Vilsmeier reagent was prepared by adding POCl3 (6.0 mmol, 0.56 mL) dropwise to ice cold dry N,N-dimethylformamide (DMF, 10 mL) under stirring. The mixture was then stirred for 10-15 min at 0 °C. To the above Vilsmeier reagent was added 1a (3.0 mmol, 0.49 g) as a solution in DMF (5 mL). The starting material was quickly consumed within 30 min monitored by TLC. The mixture was allowed to warm to r.t. and stirred for about 6 h. Then NH4OAc (3.5 g, 45 mmol) was added as a solid into the reaction system. After stirred at r.t. for 10 min., the mixture was heated to 80 °C under stirring for 30 min. Cooled down to r.t., the reaction mixture was poured into cold sat. K2CO3 aq (50 mL), extracted with Et2O (3 × 10 mL). The combined organic extracts were washed with brine (3 × 20 mL), dried over anhyd Na2SO4, filtered and concentrated under reduced pressure to yield the crude product 2a which was purified by chromatography over silica gel using Et2O/petroleum ether (1:80) as eluent.
Compounds 2b and 2c were synthesized following the same procedure. 2a′-c′ were also synthesized via the similar procedure except that prolonging reaction time (18-24 h) was needed before the feed of NH4OAc.
2-Methylthio-4-chloropyridine 2a (light yellow liquid): 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.56 (3 H, s, -SCH3), 6.98 (1 H, dd, PyH-5, J 1 = 1.6 Hz, J 2 = 5.6 Hz), 7.19 (1 H, d, PyH-3, J = 1.6 Hz), 8.32 (1 H, d, PyH-6, J = 5.6 Hz). IR (KBr, neat): 3046, 2924, 1564, 1541, 1453, 1356, 1150, 793, 689 cm-1. MS: m/z [M - 1]+ = 159.
2-Ethylthio-4-chloropyridine 2b (light yellow liquid): 1H NMR (500 MHz, CDCl3, 25 °C): 1.37 (3 H, t, CH3, J = 7.5 Hz), 3.16 (2 H, q, -SCH2, J = 7.5 Hz), 6.97 (1 H, dd, PyH-5, J 1 = 1.5 Hz, J 2 = 5.5 Hz), 7.17 (1 H, d, PyH-3, J = 1.5 Hz), 8.31 (1 H, d, PyH-6, J = 5.5 Hz). IR (KBr, neat): 3049, 2968, 2926, 1566, 1540, 1452, 1355, 1150, 785, 693 cm-1. MS:
m/z [M - 1]+ = 173.
2-Benzylthio-4-chloropyridine 2c (light yellow liquid): 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.43 (2 H, s, -SCH2), 6.99 (1 H, dd, PyH-5, J 1 = 1.6 Hz, J 2 = 5.6 Hz), 7.17 (1 H, d, PyH-3, J = 1.6 Hz), 7.29 (5 H, m, PhH), 8.33 (1 H, d, PyH-6, J = 5.6 Hz). IR (KBr, neat): 3031, 1678, 1563, 1539, 1452, 1357, 791, 696 cm-1. 2-Methylthio-4-bromopyridine 2a′ (light yellow liquid): 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.55 (3 H, s, -SCH3), 7.13 (1 H, dd, PyH-5, J 1 = 1.5 Hz, J 2 = 5.5 Hz), 7.35 (1 H, d, PyH-3, J = 1.5 Hz), 8.24 (1 H, d, PyH-6, J = 5.5 Hz). IR (KBr, neat): 3039, 2924, 1557, 1537, 1452, 1351, 771, 678 cm-1. 2-Ethylthio-4-bromopyridine 2b′ (light yellow liquid): 1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.37 (3 H, t, CH3, J = 7.5 Hz), 3.15 (2 H, q, -SCH2, J = 7.5 Hz), 7.12 (1 H, d, PyH-5, J = 5.5 Hz), 7.33 (1 H, s, PyH-3), 8.22 (1 H, d, PyH-6, J = 5.5 Hz). IR (KBr, neat): 3049, 2968, 2926, 1558, 1541, 1451, 1350, 1136, 769 cm-1. 2-Benzylthio-4-bromopyridine 2c′ (light yellow liquid): 1H NMR (500 MHz, CDCl3, 25 °C): δ = 4.43 (2 H, s, -SCH2), 7.15 (1 H, d, PyH-5, J = 5.0 Hz), 7.30 (1 H, PyH-3), 7.38 (5 H, m, PhH), 8.26 (1 H, d, PyH-6, J = 5.0 Hz). IR (KBr, neat): 3060, 3029, 2947, 1591, 1545, 1509, 1447, 1355, 765, 697 cm-1. MS: m/z [M - 1]+ = 279 (281).
5-(methylthio)-1,6-naphthyridine 2f (light yellow liquid): 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.48 (3 H, s, -SCH3), 7.45 (2 H, m, NapyH-3, NapyH-8), 7.57 (1 H, m, NapyH-4), 7.97 (2 H, m, NapyH-4, NapyH-7). IR (KBr, neat): 2922, 2857, 1687, 1514, 1401, 771, 678 cm-1. 2-Methylthio-3-(1-chlorovinyl)-4-chloropyridine 2g (light yellow liquid): 1H NMR (400 MHz, CDCl3, 25 °C), 2.54 (3 H, s, -SCH3), 5.55 (1 H, s, =CH2), 5.89 (1 H, s, =CH2), 7.08 (1 H, d, PyH-5, J = 3.6 Hz), 8.30 (1 H, d, PyH-6, J = 3.6 Hz). IR (KBr, neat): 3101, 3036, 2926, 1635, 1545, 1438, 904, 807, 693 cm-1.