2-Substituted benzaldehydes are useful intermediates for preparing pharmaceutically active compounds. For example, certain compounds which are leukotriene antagonists and useful in the treatment of asthma may be prepared from 2-substituted benzaldehydes of the general formula(Ia): ##STR2## wherein:
R.sub.x is (L).sub.a --(CH.sub.2).sub.b --(T).sub.c --M;
a is 0or 1;
b is 3 to 14;
c is 0 or 1;
L and T are independently sulfur, oxygen, or CH.sub.2 ; and
M is C.sub.1-4 alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl optionally mono substituted with Br, Cl, CF.sub.3, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, methylthio, or trifluoromethylthio;
R.sub.2 and A are independently selected from H, CF.sub.3, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, F, Cl, Br, I, OH, NO.sub.2 or NH.sub.2 ;
or R.sub.1 and A are H and R.sub.2 is (L).sub.a --(CH.sub.2).sub.b --(T).sub.c --M wherein a, b, c, L, T, and M are as defined above.
Such compounds are disclosed, for instance in U.S. Pat. No. 4,820,719, U.S. Pat. No. 4,874,792 and EP-A 0 296 732, the disclosures of which are incorporated herein by reference. Accordingly, two general methods for preparing the 2-substituted benzaldehydes are reported therein: 1) palladium catalyzed addition of a substituted 1-alkynyl compound to a 2-halo benzaldehyde effects a coupling to provide a 2-(1-alkynyl)benzaldehyde directly, and 2) a 2-methoxy-benzoic acid may be converted to 2-(2-methoxy-phenyl)-4,4-dimethyl-oxazoline and treated with an alkyl or aralkyl Grignard reagent to prepare the corresponding 2-(2-alkyl phenyl)-4,4-dimethyl-oxazoline or 2-(2-aralkyl phenyl)4,4-dimethyl-oxazoline (subsequent treatment of the 2-substituted oxazoline with methyl iodide, reduction with sodium borohydride and subsequent acid hydrolysis produces the corresponding 2-substituted benzaldehyde). The latter method is based upon methods disclosed by Meyers et at., J. Org. Chem., 43, 1372(1978). Similar methods for preparing 2-substituted benzaldehydes are disclosed by Perchonock et al., J. Med. Chem., 28, 1145 (1985). In general, these methods employ reagents which functionally displace substituents upon the aryl ring.
Methods for adding an ortho substituent to an aryl ring by rendering the aryl ring nucleophilic are also known. Org. Reactions, 26, 43-61 (1979) discloses that certain functional groups which contain nitrogen heteroatoms and are attached to phenyl rings can stabilize a phenyl ring toward lithiation, preferably in the ortho position. The lithiated site may then be treated with a suitable electrophilic reagent to effect substitution. Functional groups which are reported therein to be particularly effective for this purpose are mono- or di-alkyl amides, amines, N,N-dialkyl hydrazones, imidazolines and oxazolines. De Silva et at., Tetrahedron Lett., 5107 (1978), report an ortho-lithiation of a benzamide using sec-butyllithium and a diisopropyl amine, and Trecourt et al., J. Org. Chem., 53, 1367 (1988), report ortho-lithiation of 2-methoxy-pyridine with methyllithium and a catalytic mount of diisopropylamine. Arylcarbimines, however, are reported to have limited synthetic utility due to their tendency to suffer from reaction at the azomethine linkage and alpha-deprotonation. See Org. Reactions, 26, 57-58 (1979). Zeigler et at., J. Org. Chem., 41, 1564 (1976) report that arylcarbimines may be induced to undergo ortho-lithiation if an adjacent ether substituent is present.
In addition, it has been reported that methyl groups can be lithiated if located in the ortho position of benzamides, 2-phenyl imidazolines and 2-phenyl oxazolines. Thus, Watanabe et al., J. Org. Chem., 49, 742 (1984) report chain extension via an ortho-toluamide in the synthesis of isocoumarins; Gschwend, et al., J. Org. Chem., 40, 2008 (1975), report benzylic chain extension via lithiation of 2-(o-tolyl)oxazolines; and Houlihan, U.S. Pat. No. 4,100,165, reports condensation of a dilithiated 2-(o-tolyl)imidazoline with esters and acyl halides.
Current methods for the synthesis of the 2-substituted benzaldehydes of this invention employ expensive reagents or multiple process steps which make them unattractive for commercial preparation of 2-substituted benzaldehydes. There is therefore a need for an efficient alternative method for the preparation of 2-substituted benzaldehydes.
USPTO Backgrounds
USPTO Backgrounds