Abstract
A protocol for amide coupling by in situ formation of acyl fluorides and reaction with amines at elevated temperature has been developed and found to be efficient for coupling of sterically hindered substrates and electron deficient amines where standard methods failed.
Highlights
View Article OnlineA protocol for amide coupling by in situ formation of acyl fluorides and reaction with amines at elevated temperature has been developed and found to be efficient for coupling of sterically hindered substrates and electron deficient amines where standard methods failed
Amide coupling reactions are common in organic synthesis and the most frequent reaction used in medicinal chemistry.[1]
In our project directed towards the free fatty acid receptor 2 (FFA2/GPR43), we wished to synthesize a compound disclosed in the patent literature via intermediate 1 (Table 1).[4]
Summary
A protocol for amide coupling by in situ formation of acyl fluorides and reaction with amines at elevated temperature has been developed and found to be efficient for coupling of sterically hindered substrates and electron deficient amines where standard methods failed. Solid-phase coupling of sterically hindered amino acids.[13,14,15] Using conditions inspired from solid-phase peptide synthesis,[13] a conversion of only 8% was obtained after 24 hours (Table 2, entry 1). Increasing the temperature above 80 °C did not result in significant improvements (entries 8–10), whereas extending the reaction time to 24 hours using conventional heating in a sealed vial eventually resulted in complete conversion and 85% isolated yield of the desired product (entry 11). Deprotection of the tert-butyl ester by treatment with TFA under anhydrous conditions is
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