An improved and practical procedure for the synthesis of substituted phenylacetylpyridines

Tetrahedron Letters

Volumn 39, Issue 13, 1998, Pages 1717-1720

  Journet, Michel ^a   Cai, Dongwei ^a   Larsen, Robert D ^a   Reider, Paul J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

PYRIDINE DERIVATIVE;

ARTICLE; CONFORMATIONAL TRANSITION; DRUG CONFORMATION; DRUG SYNTHESIS; METHODOLOGY;

EID: 0032568279     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(98)00140-3     Document Type: Article

References (13)

1. (1) a) Burger, A.; Walter, C. R. J. Am. Chem. Soc. 1950, 72, 1988-1990.
2. b) Zimmer, H.; Bercz, J. P. Justus Liebigs Ann. Chem. 1965, 686, 107-114.
3. c) Bond, C. C.; Hooper, M. Synthesis 1974, 443-443.
4. d) Bunting, J. W.; Stefanidis, D. J. Am. Chem. Soc. 1988, 110, 4008-4017.
5. e) Sheldrake, P.W. Synth. Commun. 1993, 23, 1967-1971.
6. f) Pal, K.; Behnke, M. L.; Tong, L. Tetrahedron Lett. 1993, 34, 6205-6210.
7. g) Katritzky, A. R.; Lang, H.; Wang, Z.; Zhang, Z.; Song, H. J. Org. Chem. 1995, 60, 7619-7624.
8. h) Clader, J. W.; Berger, J. G.; Burrier, R. E.; Davis, H. R.; Domalski, M.; Dugar, S.; Kogan, T. P.; Salisbury, B.; Vaccaro, W. J. Med. Chem. 1995, 38, 1600-1607.
9. (2) For reviews, see ref. 1g.
10. (3) The N,P-acetals 5a-c were prepared by mixing the respective pyridinecarboxaldehyde 4a-c with aniline (1.2 equiv) and diphenylphosphite (1.6 equiv) in a variety of solvents, such as ethanol, i-PrOH, isopropyl acetate, methyl tert-butylether, or acetonitrile. Isopropyl alcohol was preferable and allowed a good recovery of product. Attempts at using the crude N,P-acetal without isolation by adding the base directly failed to give good quality product. A general procedure for the N,P-acetal follows: 3-pyridinecarboxaldehyde (4b) (32.1 g, 0.3 mole) was dissolved in 650 mL of i-PrOH and stirred at room temperature. Aniline (32.8 mL, 0.36 mole) was added in one portion followed by the addition of diphenylphosphite (102 mL of 85-90 wt%, ca. 0.48 mole) in one portion. The temperature gradually raised to 35 °C over 15 minutes and the N,P-acetal started to crystallize after 30-45 minutes. The slurry was aged for 4 hours at room temperature, cooled to 0 °C, filtered and washed with 100 mL of cold i-PrOH to give 107 g of a white solid (86% yield, >99% purity). The same procedure gave the 2-pyridyl isomer 5a (precipitated as a thick heavy white solid) in 88% yield (110 g; >99% purity). The 4-pyridyl isomer 5c was prepared in a 4/1 mixture of MTBE/i-PrOH to give 103.5 g of a pale yellow solid (83% yield; >99% purity).
11. 4), B: acetonitrile; gradient elution: 85% A at 0.0 min., 65% A at 10.0 min., 30% A at 20.0 min; 5b, 16.75 min.; 5c, 16.25 min. The HPLC conditions for the 2-pyridyl N,P-acetal 5a : 70% A at 0.0 min., 40% A at 10.0 min.; 5a, 15.35 min.
12. (5) Other bases tested were n-butyllithium in THF, DBU, potassium tert-butoxide, and NaOH.
13. 2O/mL) were crucial in preventing the formation of the unreactive monosaponified phosphonate. Cesium carbonate was dried at 150 °C under vacuum (~1 mm Hg) for 16 h.