Regioselective halogen-metal exchange reaction of 3-substituted 1,2-dibromo arenes: The synthesis of 2-substituted 5-bromobenzoic acids

Synlett

Volumn , Issue 12, 2006, Pages 1948-1952

  Menzel, Karsten ^a   Dimichele, Lisa ^a   Mills, Paul ^a   Frantz, Doug E ^a,b   Nelson, Todd D ^a   Kress, Michael H ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

1,2 dibromobenzene; Carboxylic acids; Grignard reactions; Regioselectivity; Substitutent effect

Indexed keywords

1,2 DIBROMO 3 CHLOROBENZENE; 1,2 DIBROMOARENE DERIVATIVE; 2 BROMO 6 CHLOROBENZOIC ACID; 2 BROMO 6 FLUOROBENZOIC ACID; 2 BROMO 6 METHOXYBENZOIC ACID; 2 BROMO 6 METHYLBENZOIC ACID; 2 BROMO 6 TRIFLUOROMETHYLBENZOIC ACID; 2,6 DIBROMOBENZOIC ACID; 5 BROMOBENZOIC ACID DERIVATIVE; BENZENE DERIVATIVE; BENZOIC ACID DERIVATIVE; HALOGEN; ISOPROPYLMAGNESIUM CHLORIDE; MAGNESIUM CHLORIDE; METAL; POLYCYCLIC AROMATIC HYDROCARBON DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL REACTION; SYNTHESIS;

EID: 33747056348     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2006-947362     Document Type: Article

References (51)

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30. Major by-products of the halogen-metal exchange reaction were debrominated chlorobenzene derivatives and polyhalogenated biphenyls. The debrominated chloro arene may be indicative of a benzyne side reaction.
31. The decomposition was accompanied by copious amounts of chlorobenzene and biphenyl derivatives, which can be generated by a dehydrobenzene pathway.
32. Significant amounts of debrominated arenes and biphenyl derivatives had been identified by GC-MS. The impurity profiles of theses reaction conditions and using n-BuLi were similar.
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41. The ratio of 94:6 corresponds to the protonated products of A and B. The regioselectivity was confirmed by commercially available samples of 2- and 3-bromobenzonitrile.
42. Chou, T.; Chen, S.; Chen, Y. Tetrahedron 2003, 59, 9939.
43. (a) 1,2-dibromo-3-methoxybenzene (1g) was prepared following a modified procedure of: Shnur, R. C.; Morvilee, M. J. Med. Chem. 1986, 29, 770.
44. 3): δ = 157.5, 128.8, 126.3, 125.6, 114.9, 110.3, 56.6.
45. 3): δ = 25.0, 125.6, 127.1, 128.0, 129.3, 131.2, 140.8.
46. 1,2-Dibromo-3-methylbenzene underwent the halogen-metal exchange with complete consumption in the presence of 7 equiv of isopropylmagnesium chloride. If 1.1 equiv are used, only a 50% conversion is observed at -25 °C after 24 h.
47. 1H NMR.
48. The regioselective assignments were done by proton-carbon coupling constants along the aromatic ring structure which are different for the regioisomeric structure of 4 and 5, see: Dimichele, L.; Menzel, K.; Mills, P.; Frantz, D. E.; Nelson, T. D. Magn. Reson. Chem. 2006, 44, submitted.
49. 3): δ = 125.4, 126.3, 128.0, 128.1 (2 C), 128.2, 129.2 (2 C), 129.8, 132.8, 141.8, 145.5.
50. 3): δ = 156.3, 142.5, 132.5, 130.8,130.4, 130.0, 129.6, 127.9, 126.7, 125.6, 120.3, 110.9, 55.5. GC-MS: m/z = 342, 261, 246, 182, 152, 139.
51. 2): δ = 125.4, 126.3, 128.0, 128.1 (2 C), 128.2, 129.2 (2C), 129.8, 132.8, 141.8, 145.5.