A new approach to the synthesis of 2-aryl-4-halomethyl-5-methyl-1,3- oxazoles by highly regioselective direct halogenation with NBS or NCS/MeCN

Synthesis

Volumn , Issue 17, 2004, Pages 2825-2832

  Yamane, Taihei ^a   Mitsudera, Hiroyuki ^a   Shundoh, Takatsugu ^a  

^a TAKEDA PHARMACEUTICAL COMPANY LIMITED   (Japan)

Author keywords

Drugs; Halogenation; Heterocycles; Oxazoles; Regioselectivity

Indexed keywords

ACETONITRILE; ISOMERS; REACTION KINETICS; SYNTHESIS (CHEMICAL);

MILD CONDITIONS; REGIOSELECTIVITY;

HALOGENATION;

2 (2,4 DICHLOROPHENYL) 4,5 DIMETHYL 1,3 OXAZOLE; 2 (3 BROMOPHENYL) 4,5 DIMETHYL 1,3 OXAZOLE; 2 (3 CHLOROPHENYL) 4,5 DIMETHYL 1,3 OXAZOLE; 2 (3,4 DICHLOROPHENYL) 4,5 DIMETHYL 1,3 OXAZOLE; 2 (4 BROMOPHENYL) 4,5 DIMETHYL 1,3 OXAZOLE; 2 (4 CHLOROPHENYL) 4,5 DIMETHYL 1,3 OXAZOLE; 2 (4 TERT BUTYLPHENYL) 4,5 DIMETHYL 1,3 OXAZOLE; 2 BIPHENYL 4 YL 4 (BROMOMETHYL) 5 METHYL 1,3 OXAZOLE; 2 BIPHENYL 4 YL 4 (CHLOROMETHYL) 5 METHYL 1,3 OXAZOLE; 2 BIPHENYL 4 YL 4,5 DIMETHYL 1,3 OXAZOLE; 4 (BROMOMETHYL) 2 (2,4 DICHLOROPHENYL) 5 METHYL 1,3 OXAZOLE; 4 (BROMOMETHYL) 2 (3 BROMOPHENYL) 5 METHYL 1,3 OXAZOLE; 4 (BROMOMETHYL) 2 (3 CHLOROPHENYL) 5 METHYL 1,3 OXAZOLE; 4 (BROMOMETHYL) 2 (3,4 DICHLOROPHENYL) 5 METHYL 1,3 OXAZOLE; 4 (BROMOMETHYL) 2 (4 BROMOPHENYL) 5 METHYL 1,3 OXAZOLE; 4 (BROMOMETHYL) 2 (4 CHLOROPHENYL) 5 METHYL 1,3 OXAZOLE; 4 (BROMOMETHYL) 2 (4 TERT BUTYLPHENYL) 5 METHYL 1,3 OXAZOLE; 4 (BROMOMETHYL) 5 METHYL 2 (2 NAPHTHYL) 1,3 OXAZOLE; 4 (BROMOMETHYL) 5 METHYL 2 [4 (TRIFLUOROMETHYL)PHENYL] 1,3 OXAZOLE; 4 (BROMOMETHYL) 5 METHYL 2 PHENYL 1,3 OXAZOLE; 4 (CHLOROMETHYL) 2 (4 TERT BUTYLPHENYL) 5 METHYL 1,3 OXAZOLE; 4 (CHLOROMETHYL) 5 METHYL 2 PHENYL 1,3 OXAZOLE; 4,5 DIMETHYL 2 (2 NAPHTHYL) 1,3 OXAZOLE; 4,5 DIMETHYL 2 (3,4,5 TRIMETHOXYPHENYL) 1,3 OXAZOLE; 4,5 DIMETHYL 2 [4 (TRIFLUOROMETHYL)PHENYL] 1,3 OXAZOLE; 4,5 DIMETHYL 2 PHENYL 1,3 OXAZOLE; ACETONITRILE; N BROMOSUCCINIMIDE; OXAZOLE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ARTICLE; CHEMICAL REACTION; CHEMICAL STRUCTURE; CYCLIZATION; ESTERIFICATION; HALOGENATION; STEREOCHEMISTRY; SYNTHESIS;

EID: 10644284828     PISSN: 00397881     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2004-834862     Document Type: Article

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21. Unoptimized results.
22. 13C NMR and retention time on a HPLC analysis.
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25. The regioselectivity was determined by HPLC analysis (HPLC conditions; YMC Pack-SIL A-002 column with 40:1-10:1 n-hexane-THF as the mobile phase). To investigate regioselectivity, we used HPLC with the normal phase, while the 5-halomethyl-4-methyl regioisomers easily decomposed during a HPLC analysis with the reverse phase.
26. One referee kindly suggested other plausible mechanisms (Schemes 5 and 6).