Synthesis of Bulky N‐Acyl Heterocycles by DMAPO/Boc₂O‐Mediated One‐Pot Direct N‐Acylation of Less Nucleophilic N‐Heterocycles with α‐Fully Substituted Carboxylic Acids

Abstract

This report describes a general method for the one‐pot direct N‐acylation of N‐heterocycles using our previously developed 4‐(N,N‐dimethylamino)pyridine N‐oxide (DMAPO)/di‐tert‐butyl dicarbonate (Boc2O) system. This system enables one‐pot N‐acylation reactions to provide bulky N‐acyl heterocycles starting from a wide variety of less nucleophilic N‐heterocycles and sterically hindered α‐fully substituted carboxylic acids in high yields. Moreover, this one‐pot method does not involve pre‐activation of substrates. The protocol has been successfully extended to one‐pot N‐acylation of 7‐azaindoles.

DMAPO/Boc2O‐Mediated One‐Pot Direct N1‐Acylation of Indazole with Carboxylic Acids: A Practical Synthesis of N1‐Functionalized Alkyl Indazoles

“…Initially, the reaction was carried out under the standard conditions for our method (i. e., 1 : 1 substrate ratio, 2 mol% of DMAPO, 1.1 equivalents of Boc 2 O, 2 equivalents of Et 3 N, MeCN as reaction solvent, 22 h at room temperature). [35,36] As a result, an inseparable mixture of N1-acyl indazole 3 and N2-acyl indazole 4 was obtained in 71 % yield with a 9/1 ratio of 3/4 (entry 1). N-tert-Butoxycarbonyl (Boc) indazole 5 was also obtained as a byproduct in 29 % yield.…”

“…The reaction with sterically less demanding but functionalized carboxylic acids proceeded smoothly to yield the desired acylated products (33)(34)(35)(36)(37)(38)(39)(40)(41) in excellent yields. Olefin and ester groups were tolerated under the conditions (34 and 35).…”

“…We chose the challenging reaction substrate 2,2‐diphenylpropionic acid 2 in order to discover conditions with a wider substrate scope. Initially, the reaction was carried out under the standard conditions for our method (i. e., 1 : 1 substrate ratio, 2 mol% of DMAPO, 1.1 equivalents of Boc 2 O, 2 equivalents of Et 3 N, MeCN as reaction solvent, 22 h at room temperature) [35,36] . As a result, an inseparable mixture of N 1‐acyl indazole 3 and N 2‐acyl indazole 4 was obtained in 71 % yield with a 9/1 ratio of 3 / 4 (entry 1).…”

“…Furthermore, the high potential of this reaction was demonstrated in the reaction of less nucleophilic nitrogen compounds with bulky carboxylic acids. [35] Encouraged by this success, we thought to develop the one-pot direct N-acylation of indazole with carboxylic acids utilizing the DMAPO/Boc 2 O system (Scheme 1D, this work). There are several challenges that need to be addressed: 1) direct use of carboxylic acids without prior derivatization; 2) achieving high yields with a 1 : 1 ratio of substrates; 3) high functional group tolerance and wide range of substrate scopes; and 4) high chemoselectivity between N1-acylation and N2-acylation.…”

“…A wide variety of N ‐heterocycles was applicable to this reaction, such as indoles, pyrroles, carbazoles, pyrazoles, and lactams, and the scope of carboxylic acids was also quite wide. Furthermore, the high potential of this reaction was demonstrated in the reaction of less nucleophilic nitrogen compounds with bulky carboxylic acids [35] . Encouraged by this success, we thought to develop the one‐pot direct N ‐acylation of indazole with carboxylic acids utilizing the DMAPO/Boc 2 O system (Scheme 1D, this work).…”