Methyl groups condensation

For less reactive methyl groups, condensation with the aldehyde anils, rather than the aldehydes themselves, can be more effective <78AHC(23)l7l). 

A good example is in the comparison of methyl group reactivity in 538 the S-methyl group condenses with aldehydes easily, whereas the 3-methyl group does not. However, quaternization at nitrogen renders the 3-methyl group reactive. 

A ring methyl group condenses with benzaldehydes to yield styryl compounds, but the condensation needs an auxiliary reagent such as acetic anhydride <87S638> or zinc halide, and forcing reaction conditions at reflux or temperatures above 200 °C. In contrast, the condensation of methyl-pyrazine 7V-oxides with benzaldehyde proceeds smoothly by treatment with sodium methoxide in refluxing methanol (Scheme 27) <83JHC169>. 

By contrast, in Woodward s synthesis of the supposed structure (35) of the antibiotic patulin, analysis of intermediate (36) by the standard 1,3-dicarbonyl disconnection reveals reactive non-enolisable (37) and unsym metrical ketone (38), required to enolise at the methyl group. Condensation in base ensured kinetic control (page 154). 

Allyl aryl ethers are used for allylation under basic conditionsfh], but they can be cleaved under neutral conditions. Formation of the five-membered ring compound 284 based on the cyclization of 283 has been applied to the syntheses of methyl jasmonate (285)[15], and sarkomycin[169]. The trisannulation reagent 286 for steroid synthesis undergoes Pd-catalyzed cyclization and aldol condensation to afford CD rings 287 of steroids with a functionalized 18-methyl group 170]. The 3-vinylcyclopentanonecarboxylate 289, formed from 288, is useful for the synthesis of 18-hydroxyestrone (290)[I7I]. 

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. 

An Organic Syntheses preparation of 4-nitroindole may involve a related reaction. The condensation occurs in the presence of diethyl oxalate which may function by condensation at the methyl group. If this is the case, it must subsequently be lost by deacylation[17]. 

The monomethine cyanines with a methyl group on the chain (Table 2113) are prepared in a basic medium from a 2-alkyl-substituted thiazolium by condensation of an electrophilic reagent. 

Mills and Smith (504) were the first, in 1922, to develop a systematic study of the reactivity of methyl groups fixed on nitrogen-containing heterocycles. While in alkylpyridines the 2- (or 6) and 4-positions are activated, only the 2-position in thiazole corresponds to an enhanced reactivity of the methyl groups in condensation with aldehydes 4- and 5-methylthiazoles bear inert methyl groups. Quatemization of the thiazole nitrogen enhances still further the reactivity of the methyl in the 2-position (cf. Chapter IX), but it does not increase the reactivity of a methyl group in the 4-position (504). The authors invoke the possibility for 2- (and 6) methylpyridine and 2-methylthiazole to pass, to some extent, into the reactive enamine form (245), while 4-methylthiazole could adopt such a structure only with the participation of an unusual formula such as 247 (Scheme 112). 

In 1937, Kondo and Nagasawa confirmed the reactivity of the sole 2-methyl group in the condensation of 2,4-dimethylthiazole with benzal-dehyde (505) and in the cyclizafion to tbiazolopyrrole in the reaction with phenacyl bromide (506) (Scheme 113). 

Erlenmeyer et al. also examined the behavior of 4-methyl-, 4,5-dimethyl-, and 5-methylthiazole in the reaction with benzaldehyde at 160°C in the presence of ZnClj (439, 510) they were able to show that neither the 4- nor 5-methyl groups reacted under these conditions and that the condensation occurred at the sole unsubstituted 2-position (Scheme 114). 

Reactions of the Methyl Groups. These reactions include oxidation, polycondensation, and ammoxidation. PX can be oxidized to both terephthahc acid and dimethyl terephthalate, which ate then condensed with ethylene glycol to form polyesters. Oxidation of OX yields phthaUc anhydride, which is used in the production of esters. These ate used as plasticizers for synthetic polymers. MX is oxidized to isophthaUc acid, which is also converted to esters and eventually used in plasticizers and resins (see Phthalic acids and otherbenzenepolycarboxylic acids). 

The salts (29) condense with quartenary salts of heterocycHc bases containing an activated methyl group to yield the polycarbocyanines (30), where = 4 or 5 (73). Higher vinylogous dyes (30), hexa- and heptacarbocyanines (n = 6 or 7), have been synthesized by analogous methods (106). 

Alkyl Isoquinolines. Coal tar contains small amounts of l-methylisoquinoline [1721-93-3] 3-methylisoquinoline [1125-80-0] and 1,3-dimetliylisoquinoline [1721-94-4J. The 1- and 3-methyl groups are more reactive than others in the isoquinoline nucleus and readily oxidize with selenium dioxide to form the corresponding isoquinoline aldehydes (174). These compounds can also be obtained by the hydrolysis of the dihalomethyl group. The 1- and 3-methyhsoquinolines condense with benzaldehyde in the presence of zinc chloride or acetic anhydride to produce 1- and 3-styryhsoquinolines. Radicals formed by decarboxylation of carboxyUc acids react to produce 1-aIkyhsoquinolines. 

Aldol reaction of the campholenic aldehyde with 2-butanone gives the intermediate ketones from condensation at both the methyl group and methylene group of 2-butanone (Fig. 6). Hydrogenation results in only one of the two products formed as having a typical sandalwood odor (160). 

Because of the electron-attracting properties of the ring nitrogen atoms, methyl groups undergo aldol-like condensations. For example, 3- and 4-methylpyridazine react with chloral to give 3- or 4-(2-hydroxy-3,3,3-trichloropropyl)pyridazine, and 4-methylpyridazine reacts with anisaldehyde to yield 4-(p-methoxystyryl)pyridazine. 

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