Buchwald–Hartwig amination is one of the most important methods for the synthesis of N-arylamines and is widely employed for the synthesis of potential pharmaceuticals, natural products, and other fine chemicals. The reaction usually uses a Pd(0) catalyst such as Pd(dba)2 and (±)-BINAP in the presence of a base, and toluene is the most commonly used solvent. However, there are significant safety, toxicological, and environmental hazards associated with the use of toluene. Herein, we demonstrate the successful application of 2,2,5,5-tetramethyloxolane (TMO), a solvent with a similar property profile to toluene, for Buchwald–Hartwig amination reactions for coupling a wide range of primary and secondary amines with aryl bromides. When NaOt-Bu was used as the base, similar yields were obtained in toluene and TMO. In contrast, using Cs2CO3, TMO outperformed toluene significantly for electron-deficient aryl bromides that could be susceptible to nucleophilic attack. To showcase the use of TMO as a solvent for Buchwald–Hartwig aminations, the synthesis of a key intermediate in the route to smoothened (SMO) receptor antagonist drug candidate SEN826 was successfully accomplished in TMO. Improved metrics and reduction in residual palladium in the isolated amines demonstrate further benefits in the substitution of toluene with TMO in Buchwald–Hartwig aminations.