Azobisisobutyronitrile → 3-(Bromomethyl)-5-methylbenzoic acid
Reaction equation
[CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=O)[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CC1C=C(C=C(C)C=1)C(O)=O.[Br:24]Br.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:24][CH2:11][C:4]1[CH:5]=[C:6]([CH:10]=[C:2]([CH3:1])[CH:3]=1)[C:7]([OH:9])=[O:8]Participants
Procedure
In general, 5-alkyl-3-formyl-benzoic acids may be prepared from 5-bromo-3-formyl-benzoic acid which in turn is prepared from 3-formyl-benzoid acid according to literature procedures (e.g. D. Zhao, J. S. Moore, J. Org. Chem. (2002), 67, 3548-3554). Thus, a 5-bromo-3-formyl-benzoic acid ester is reacted with the appropriate alkenyl boron derivative (e.g. 2,4,6-trivinyl-cyclotriboroxane) under Suzuki conditions (Lit.: e.g. F. Kerins, D. F. O'Shea, J. Org. Chem. (2002), 67, 4968-4971) followed by catalytic hydrogenation and subsequent ester cleavage to give the desired 5-alkyl-3-formyl-benzoic acid. Alternatively, the alkyl group may also be introduced using the appropriate alkyl-Zn reagents under Negishi conditions (e.g. H. Matsushita, E. Negishi, J. Org. Chem. (1982), 47, 4161-4165). The 3-formyl-group may require protection e.g. as an acetal during these transformations. More specifically, 5-methyl-3-formyl-benzoic acid may be prepared by brominating 3,5-dimethylbenzoic acid using Br2 in the presence of 2,2′-azo-bis-isobutyronitrile (Lit. e.g. Y. Sawada, et al. J. Pesticide Sci. (2002), 27, 365-373) to give 3-bromomethyl-5-methyl-benzoic acid which is then oxidised with MnO2 (Lit. e.g. S. Goswami, et al. Chem. Letters 34 (2005), 194-195) to give the desired 5-methyl-3-formyl-benzoic acid.
Workup
- additionAlternatively, the alkyl group may also be introduced
Sources & evidence
- ORD record
- ord-f5fd1c3979c441e3afb52c0fc7c8af5c
- Source dataset
- uspto-grants-2013_04
- Patent number
- US08410151B2
Reaction notes
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