Nickel peroxide as a selective oxidant in the pyrimidine series. The synthesis of N1-substituted orotic and 2-thioorotic acids

Abstract

A versatile route to the synthesis of iV1-substituted orotic or 2-thioorotic acids is described. The method involves three st>eps: (i) Preparation of 6-hydroxy- methyl-2-thio-1,3-thiazine (24); (ii) conversion of the 1,3-thiazine into the 1- substituted 2-thiouracil by reaction with a primary amine (see Scheme 8); (iii) oxidation of the 6-hydroxymethyl group to a carboxyl group. 3,4-Dihydro-6-hydroxymethyl-4-oxo-2-thio-2H-1,3-thiazine was prepared directly from the reaction of dithiocarbamio acid with ethyl γ-hydroxytetrolate (an improved synthesis of this ester is described). Reaction of the thiazine with primary Bmines was straightforward and produced the related 6-hydroxymethyl-2-thio- uracils in high yield (see Table 2). Similar reactions with O-benzylhydroxylamine formed the 0-benzyl derivative of the Nl-hydroxy-2-thiopyrimidine (40). Nickel peroxide has served as a very selective oxidant in the pyrimidine series. Smoot'h oxidation of the hydroxymethyl group to carboxyl is demonstrated by the conversion of the 6-hyclroxymethyluracils into the corresponding orotic acids. The same products result from the 2-thiouracils on treatment with excess reagent because additional oxidative desulphurization of the 2-thione group occurs. More interestingly, seleotive oxidation of the 6-hydroxymethyl group can be achieved in the presence of the 2-thione group using two equivalents of nickel peroxide, to form a 1-substituted 2-thioorotic acid (Scheme 9). Application of this method to the preparation of I-hydroxyorotic acid mas successful, but only in the presence of excess nickel peroxide reagent. Under other conditions rapid decarboxylation occurred to form either 1-benzyloxyuracil or 1-benzyloxy-2-thiouracil and this has been developed into a useful synthetic route to these products. The role of nickel complexes in this deoarboxylation is discussed in terms of the hard/soft, acid/base theory. P.m.r. data on all compounds are reported.