O-Methyl groups

A variation of the Madelung cyclization involves installing a functional group at the o-methyl group which can facilitate cyclization. For example, a triphenylphosphonio substituent converts the reaction into an intramolecular Wittig condensation. The required phosphonium salts can be prepared by starting with o-nitrobenzyl chloride or bromide[9]. The method has been applied to preparation of 2-alkyl and 2-arylindoles as well as to several 2-alkenylindoles. Tabic 3.2 provides examples. 

Further support for this pathway was provided by competition feeding studies. If 104 were not a true biosynthetic intermediate and were incorporated due to some flexibility in the biosynthetic enzymes, then its incorporation would be expected to be reduced by an equivalent concentration of the true substrate 102 or 103. If it were a real intermediate, then it would be expected that incorporation of earlier intermediates would be reduced by an equivalent concentration of 104. Precursor 104, labeled with deuterium at the O-methyl group, was co-fed with an approximately equal concentration of either 102 or 103 labeled with deuterium at the C-5 methyl group, and relative incorporation levels were compared by measurement of the CD3 peak intensities in the 2H NMR spectrum of the labeled azinomycin B. In each case, there was approximately twice as much deuterium labeling at the O-methyl group as at the other methyl group, consistently with 104 being a true biosynthetic intermediate. 

FIGURE 53. Molecular structure of Pl>2 (o>-tolyI )o illustrating the twisting of the o-methyl groups. Reprinted with permission from Reference 163. Copyright (1990) American Chemical Society... 

Methylhydroxyurea (28, Fig. 7.5) oxidizes oxyHb to metHb and reduces metHb to deoxyHb but neither of these reactions produces HbNO, further supporting the mechanism depicted in Scheme 7.16 for the formation of NO and HbNO from the reactions of hydroxyurea and hemoglobin [115]. The O-methyl group of 27 prevents the association and further reaction of 27 with the heme iron [115]. Scheme 7.16 predicts the redox chemistry observed during the reaction of 28 with hemoglobin and the failure to detect HbNO shows the inability of 28 or any derivative radicals to transfer NO during these reactions [115]. These results indicate that nitric oxide transfer in these reactions of hydroxyurea requires an unsubstituted acylhydroxylamine (-NHOH) group. 

B.2.9-12.) The interaction between an o-methyl group and an a cr-di-methyl-substituted chain is particularly severe, and undoubtedly leads to restricted rotation about the ring-chain bond (see Lomas and Dubois, 1978). This is not itself a major source of high effective molarities, however, as shown by the moderate EM s for compounds like [20] and [21] which have naturally restricted conformations (Danforth et ai, 1976). 

The behavior of the ort/io-methyl resonances of diarylsulfoxides is also exceptional (48). For example, both methyls of o-tolyl-p-tolylsulfoxide show nonequivalence of the same sense as that expected for the p-methyl group on the basis of the general sulfoxide model. The senses observed for o-methyl groups in several other o-tolyl-sulfoxides are also inverted, whereas those of other resonances are normal. This behavior, which may result from an intramolecular shielding of these groups by either sulfinyl or aromatic moieties in rotamers whose populations are affected by the CSA, is not well understood. 

A lipophilic gel, namely, Sephadex LH-20, has found application in studies of partially acetylated dextrans. In describing a modified procedure for the replacement of the O-acetyl groups in such dextrans by O-methyl groups prior to acid hydrolysis and identification of the fragments (which indicates the distribution of the substituents in... 

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