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Facile preparation of a 4‐substituted [2,6‐ 14 C]pyridine: Synthesis of [ 14 C]SK&F 105809
Author(s) -
Heys J. Richard,
Villani A. J.,
Mastrocola A. R.
Publication year - 1996
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/(sici)1099-1344(199608)38:8<761::aid-jlcr887>3.0.co;2-2
Subject(s) - chemistry , iminium , hydrogenolysis , pyridine , medicinal chemistry , nucleophile , formaldehyde , organic chemistry , ion , catalysis
[ 14 C]Formaldehyde was used in a nucleophile‐assisted iminium ion cyclization with N‐benzyl‐3‐butynylamine to provide N‐benzyl‐4‐iodo‐1,2,5,6‐tetrahydro[2,6‐ 14 C 2 ]pyridine. Palladium‐catalyzed coupling of this vinyl iodide with the organozinc derivative 2 gave the corresponding 4‐arylated tetrahydropyridine. Treatment of this compound at elevated temperatures with Pd/Al 2 O 3 in nitrobenzene solution caused hydrogenolysis of the benzyl group and aromatization, generating the 4‐substituted [2,6‐ 14 C 2 ]pyridine 4 in good overall radiochemical yield from [ 14 C]formaldehyde. In high yields, compound 4 was converted via the methylsulfide [ 14 C]SK&F 105561 ( 1b ) to the methylsulfinyl compound [ 14 C]SK&F 105809 ( 1a ). It is proposed that, during the iminium ion cyclization, randomization of label between the 2‐ and 6‐positions of the tetrahydropyridine ring occurs as the result of rapid equilibration between alkynyl and allenyl iminium ions, prior to cyclization.