No abstract

Solvent-free mechanochemical conditions have been developed to investigate the significance of ion pairing and the use of weak bases for driving forward nucleophilic substitution reactions.

Base (NaOMe)-catalyzed condensation of 3,3-dimethoxypropionitrile with aldehydes followed by hydrolysis with 6 N HCl gives the unsaturated cyano aldehydes 5. Catalytic reduction of the double bond followed by reaction with diethyl aminomalonate affords the enamines 7, which cyclize to the aminopyrroles 2 on treatment with NaOMe. While the amino group in 2 is unreactive toward many guanylating reagents, acid (AcOH)-catalyzed guanylation occurs easily with 10 to give 12 along with methyl mercaptan as a byproduct. Subsequent facile removal of the carbamate groups and ring closure to the pyrrolo[3,2-d]pyrimidine ring system occurs on treatment with base. The use of HgCl(2) in place of AcOH ties up the mercaptan and eliminates the odor problem. For larger scale reactions where the mercaptan odor and the use of Hg salts are undesirable, the use of the methoxy analogue 11 is preferred. Using this procedure, benzaldehyde has been converted to the 7-(phenylmethyl)pyrrolo[3,2-d]pyrimidine (1a), a potent inhibitor of the enzyme purine nucleoside phosphorylase, in 31% overall yield with only three isolation steps.

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The bromination of 4-, 5-, 6-, and 7-aminobenzothiazoles in chloroform has been studied. Whilst the p-ortho-positions in 5-and 6-aminobenzothiazole appear to be more reactive than in the corresponding naphthalenes, quinolines, or 1,2,3-benzothiadiazoles, 4-and 7-aminobenzothiazole show decreased reactivity relative to l-naphthylamine.Improved methods are described for the preparation of 7-nitro-and 4amino-benzothiazole.