Process for the preparation of 2-substituted-5-(1-alkylthio)alkylpyridines
View Patent ↗2-Substituted-5-(1-alkylthio)alkylpyridines are produced efficiently and in high yield by cyclization and thioalkylation.
1. A process for the preparation of 2-substituted-5-(1-alkylthio)alkylpyridine (I),
wherein
R 1 and R 2 independently represent H, or C 1 -C 4 alkyl; and
R 3 represents C 1 -C 4 alkyl; and
R 4 represents C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;
which comprises:
a) condensing a substituted enone (II)
wherein
R 4 is as previously defined; and
R 5 represents C 1 -C 4 alkyl;
with an enamine (III)
wherein
R 1 and R 2 are as previously defined; and
R 6 and R 7 independently represent C 1 -C 4 alkyl or R 6 and R 7 taken together with N represent a 5-membered saturated ring; and
cyclizing in the presence of ammonia or a reagent capable of generating ammonia to produce a 2,5-disubstituted pyridine (IV)
wherein R 1 , R 2 and R 4 are as previously defined;
b) chlorinating or brominating the 2,5-disubstituted pyridine (IV) to provide a haloalkylpyridine (V)
wherein
R 1 , R 2 and R 4 are as previously defined; and
X represents Cl or Br; and
c) treating the haloalkylpyridine (V) with mercaptan salt (VI)
R 3 S − M + (VI)
wherein
R 3 as previously defined; and
M represents an alkali metal
to give 2-substituted-5-(1-alkylthio)alkylpyridine (I).
2. The process of claim 1 in which R 4 represents CF 3 .
3. The process of claim 2 in which R 1 represents H, R 2 represents CH 3 , and R 3 represents CH 3 .
4. A process for the preparation of 2-substituted-5-(1-alkylthio)alkylpyridine (I),
wherein
R 1 and R 2 independently represent H, C 1 -C 4 alkyl, or R 1 taken together with represent a 3- to 6-membered saturated ring optionally substituted with an O or a N atom; and
R 3 represents C 1 -C 4 alkyl; and
R 4 represents C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;
which comprises:
a) condensing a substituted enone (II)
wherein
R 4 is as previously defined; and
R 5 represents C 1 -C 4 alkyl;
with an enamine (III)
wherein
R 1 and R 2 are as previously defined; and
R 6 and R 7 independently represent C 1 -C 4 alkyl or R 6 and R 7 taken together with N represent a 5-membered saturated or unsaturated ring; and cyclizing in the presence of ammonia or a reagent capable of generating ammonia to produce a 2,5-disubstituted pyridine (IV)
wherein
R 1 , R 2 and R 4 are as previously defined; and
b) treating the 2,5-disubstituted pyridine (IV) with dialkyl disulfide (VII) and strong base,
R 3 SSR 3 (VII)
wherein
R 3 as previously defined;
to give 2-substituted-5-(1-alkylthio)alkylpyridine (I).
5. The process of claim 4 in which R 4 represents CF 3 .
6. The process of claim 5 in which R 1 represents H, R 2 represents CH 3 , and R 3 represents CH 3 .