2,2,5,5-Tetramethyloxolane (TMO) as a Solvent for Buchwald–Hartwig Aminations

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.