Dimethylamine, reaction with Subject

Some methods for the synthesis of thiophene-substituted 1,4-diketones begin with the transformation of acetylthiophene. 2-Acetylthiophene 61 is reacted in a Mannich reaction with formaldehyde and dimethylamine to yield the corresponding Maimich base 62 in 70% yield. The Mannich base 62 is then subjected to a Stetter reaction [109] which results in l,4-di-(2 -thienyl)-l,4-butanedione 63 in 70% yield via the cyanhydrine of 2-thiophenecarbaldehyde [110]. Reaction of Mannich base 62 with the isomeric 3-thiophenecarbaldehyde under the same conditions results in l-(2 -thienyl)-4-(3 -thienyl)-l,4-butanedione 64 in lower (35%) yield [Eq. (27)] [110]. 

The Mannich reaction proceeded in nearly quantitative yield for the pyrrolopyridines (1) and (4). A somewhat lower yield was obtained from the isomer (3). A number of derivatives of compound (1) have also been subjected to the Mannich reaction. The typical reaction conditions include treatment with excess paraformaldehyde and dimethylamine hydrochloride in butanol. Results are summarized in Table 41 <69TL1909>. 

The heterocyclic ring, also, has been subjected to aminomethylation, as reported for the reaction of the furane sub.strate 454 (Fig. 172) with dimethylamine and formaldehyde, which represents a key step in the synthesis of muscarines. This is one of the few examples in alkaloid chemistry of the Mannich reaction not involving cyclization. 

Before leaving the subject of 3,5-cyclosteroids, comment must be made about unusual situations where inverted 3 a-substituted products are formed from cholesteryl tosyiate and similar steroids. Several authors have recorded the occurrence of Sjt2 substitutions, with Walden inversion at C 3>, by powerful nucleophiles. These reactions occur particularly in solvents of low dielectric constant, where ionisation processes become relatively unfavourable. Ammonia, methylamine, and benzyl-amine are sufficiently reactive as nucleophiles to give moderate yields of the corresponding AS-3a-amines [33,36], and the more powerfully nucleophilic dimethylamine is reported to give virtually complete conversion into the ga-dimethyl-amino-A -derivative [36]. Other reactive nucleophiles which... 

In addition to the side reactions mentioned above, deamination of Mannich bases can occur, especially at elevated temperature, to give a,p-unsaturated derivatives. This route of decomposition of Mannich bases has been exploited as a means of in situ generation of a,p-unsaturated ketones in the Michael reaction and for the direct synthesis of a,3-unsaturated ketones several reviews of the Mannich reaction have discussed aspects of these applications.Recently, a direct one-pot synthesis of a-methylene ketones has been reported involving condensation of ketones with formaldehyde and A -methylaniline tri-fluoroacetate in aptotic solvents. Also, a less direct method has been described in which Mannich bases prepared from 3-keto esters, formaldehyde and dimethylamine are subjected to quatemarization and thermal fragmentation to yield a-methylene ketones.This method is particularly useful for the regios-pecific synthesis of a-methylene ketones because the aminomethylation reaction always takes place at the most activated position flanked by the ketone and ester groups. 

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