Tetrahydrofuran → Dicyclohexylcarbodiimide

Participants

Reaction Steps

Ethyl cyanoacetate is alkylated (or dialkylated) by treatment with NaH in an appropriate solvent such as dimethylformamide or tetrahydrofuran at from 0° to 25° C. to give the alkylated nitrile (40). The nitrile is then treated with (n-Bu)3SnN3 in dioxane at reflux for 24 hours to give after acidic hydrolysis the tetrazole (41) which is then alkylated with an alkyl halide (R4Br) in CH3CN employing Et3N as base to give a mixture of regioisomers (42) and (43). The regioisomers are separated by flash chromatography and each ester is reduced by DIBAL-H in CH2Cl2 or toluene at -78° C. to give the corresponding alcohols (44) and (45). The alcohols are treated with methanesulfonyl chloride in CH2Cl2 using triethylamine as a base at 0° C. to give the corresponding mesylates which are then treated with KCN in dimethylformamide or dimethyl sulfoxide at 100° C. to give the corresponding nitriles (46) and (47). These are then hydrolyzed to the corresponding acids (48) and (49) by treatment with ethanolic NaOH (or KOH) at reflux. The acids are then coupled with an appropriate amine employing carbonyldiimidazole in tetrahydrofuran at room temperature or dicyclohexylcarbodiimide in CH2Cl2 at 0° C. to give the amides (50) and (51).

Provenance & Evidence