Facile Synthesis of Baylis-Hillman Adducts Bearing the Carbamate or Amide Functional Group at the Secondary Position

Abstract

Recently, we and other groups have reported on the selective introduction of various nucleophiles onto the secondary position of the Baylis-Hillman adducts. Introduction of nucleophile at the secondary position of the Baylis-Hillman adducts was carried out in aqueous THF via the corresponding DABCO salt, which was generated in situ from the corresponding acetate or bromides. The nucleophiles include hydride (NaBH4), p-toluenesulfonamide, cyanide (KCN), water surrogate (NaHCO3), primary nitro alkane, 2,4-pentanedione, allyl alcohol, and various kinds of N-containing heterocyclic compounds such as isatin, benzotriazole, phthalimide, and barbituric acid. But, we failed to introduce somewhat weaker nucleophiles such as ethyl carbamate, acetamide, or 2-amino-4-methoxy-6methylpyrimidine in aqueous THF medium. The introduction of such nucleophiles is highly required in view of the usefulness of the products toward various types of chemical transformations. We thought the nucleophilicity of ethyl carbamate or diethyl phosphoramidate could be increased in polar and aprotic solvent such as CH3CN, DMSO, or DMF. Thus, we reasoned that if the DABCO salt formation in non-aqueous solvent could be successfully carried out, we might use the solvent as the reaction medium. In the same contexts, we reasoned that we can use NaOH or KOH in order to deprotonate partially the hydrogen atom of ethyl carbamate of diethyl phosphoramidate and increase the nucleophilicity of them as a result. In this paper, we wish to disclose the results for the successful introduction of some nucleophiles at the secondary position of Baylis-Hillman adducts regioselectively. The nucleophiles included ethyl carbamate (2a), diethyl phosphoramidate (2b), diacetamide (2c), acrylamide (2d), and 2-amino-4-methoxy-6-methylpyrimidine (2e). Our synthetic rationale for 3a is depicted in Scheme 1 as a representative example. As a first trial, we examined the salt formation between DABCO and 1a in different solvents and we found that the salt formation could be carried out in CH3CN, DMSO, or DMF although the rates were different according to the solvent. The corresponding DABCO salt formation occurred at room temperature within 30 min completely in all cases (TLC observation). As a next, we examined the SN2' type reaction of the DABCO salt and ethyl carbamate (2a) under various conditions (Table 1). The use of aqueous THF as solvent did not produce desired product 3a at all irrespective of the base, DABCO (entry 1), K2CO3 (not shown), NaOH (entry 2). Moderate yields of products were obtained when we used CH3CN, DMF, or DMSO as shown in Table 1. Best result was obtained (48%) when we carried out the reaction in