Two Pathways for the Reaction of Ethyl 4-Chloromethyl-6-methyl- 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with Thiophenolates: Ring Expansion versus Nucleophilic Substitution

Ethyl 4-methyl-2-oxo-7-phenylthio-2,3,6,7-tetrahydro-1H-1,3-diazepine-5-carboxylate and/or ethyl 6-methyl-2-oxo-4-(phenylthiomethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate were obtained in the reaction of ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with PhSNa or PhSK with or without PhSH, depending on the reagent ratio, reaction time or temperature, as a result of ring expansion and/or nucleophilic substitution. The reaction pathway was affected strongly by the basicity-nucleophilicity of the reaction media. The results obtained were confirmed by reactions of 4-mesyloxymethyl-6methyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-2-one with PhSNa/PhSH and ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with NaCN/HCN or NaCH(COOEt)2/CH2(COOEt)2.


Introduction
Ring expansion reactions are widely used in organic chemistry, 1 particularly in the synthesis of nitrogen-containing heterocycles. 1,2 An important example of one-carbon ring expansion is the transformation of tetrahydropyrimidines 1 into tetrahydro-1,3-diazepin-2ones 2 by treatment with nucleophilic reagents (Scheme 1). 3 Scheme 1. Two possible pathways for the reaction of pyrimidines 1 with nucleophilic reagents: ring expansion or nucleophilic substitution.
It was postulated 3 that diazepinones 2 form via the cyclopropane-containing bicyclic intermediates 4 (Scheme 1) which result from proton abstraction from the N(1)H group under the action of nucleophiles followed by intramolecular nucleophilic substitution of chlorine in anions 3. Clearly, this reaction depends not only on nucleophilicity, but also on the basicity of the nucleophile. For example, direct nucleophilic substitution of chlorine resulting in pyrimidines 5 cannot be excluded a priori under certain reaction conditions. However, the influence of reaction conditions on the reaction of compounds 1 with nucleophiles remained unexplored. 3 Therefore, study of the effect of the nucleophilicity and basicity of the nucleophile, the reagent ratio, the solvent, time and temperature on the reaction of compounds 1 with nucleophiles is interesting. In this research we used readily available pyrimidinone 6 as the starting material and PhSNa or PhSK as nucleophiles which demonstrate strong nucleophilicity and relatively low basicity. 4 The nucleophiles were generated by treatment of PhSH with NaH or KOH in an appropriate solvent.

Results and Discussion
The reaction of 6 with PhSNa (1.08 equiv) in dry MeCN at rt for 7 hours yielded diazepinone 7 as the product of ring expansion (Scheme 2). According to the 1 H NMR spectrum, the crude material contained 3 mol% of tetrahydropyrimidinone 8, a product of nucleophilic substitution of chlorine in 6 ( Table 1, entry 1). Diazepinone 7 formed with complete selectivity under similar conditions in the reaction of 6 with PhSNa (1.10 equiv) in dry THF (rt, 7 h) (entry 2), however, 9 mol% of starting material 6 was recovered. When EtOH was used as the solvent, the rate of the reaction of 6 with PhSK (1.10 equiv) decreased dramatically (conversion of 6 was only 8% after 7 h at rt), and the selectivity also decreased (7:8 = 7:1) (entry 3).

Scheme 2.
Reaction of pyrimidine 6 with PhSNa or PhSK.  However, the selectivity remained high at rt and over long reaction times (entries 8 and 9).
A relationship between the ratio of 7:8 and the amount of PhSH was also observed at rt and over long reaction times (entry 8 vs entry 10), refluxing the reaction mixture (entry 11 vs entry 12 vs entry 13), and when EtOH was used as the solvent (entry 3 vs entry 14).
Under the optimal conditions diazepinone 7 was obtained in the reaction of 6 with PhSNa (1.08 equiv) in MeCN at rt for 7 hours (entry 1), and pyrimidinone 8 was prepared by reaction From the results obtained we suggest that the reaction of 6 with PhSNa and PhSK proceeds via two possible mechanisms. In aprotic solvents (MeCN or THF) and a highly basic reaction media without PhSH, the thiophenolate-anion acts as a base and abstracts a proton from N(1)H to give anion 3 (R = Et, R 1 = Me) (see Scheme 1), which further affords diazepinone 7. Addition of PhSH inhibits anion 3 formation and therefore causes a decrease in the amount of diazepinone 7. Probably, in this case, compound 6 reacts with PhSNa via an S N 2 mechanism, resulting in pyrimidine 8. Since chlorine is a rather poor leaving group, the rate of reaction is low, and heating at reflux or a long reaction time is necessary for completion of the reaction. The low rate of reaction of 6 with PhSK in EtOH can be explained by the decreased basicity and nucleophilicity of PhSK in a polar protic solvent.
However, the reaction of 6 and 10 with PhSNa or PhSK in the presence of their conjugate acid (PhSH) gave diazepinones 7 and 11 along with the respective pyrimidines 8 and 12. An increase in the amount of PhSH led to a significant increase in pyrimidine formation, while the rate of the conversion of starting materials into products decreased. In aprotic solvents, almost pure pyrimidines 8 and 12 were obtained when more than 2 equivalents of PhSH were used. However, the reaction of 6 with more basic nucleophiles, NaCN or NaCH(COOEt) 2 (pK a = 12.9 and 15.9, respectively, in DMSO) with or without their conjugate acids yielded only the diazepinones 13a,b.
We envisage that our findings may be of value for other similar one-carbon ring expansion reactions. 1,2