On DABAL-Me3 promoted formation of amides

Abstract

Abstract. The range and utility of DABAL-Me 3 couplings of methyl esters and free carboxylic acids with primary and secondary amines under a variety of conditions (reflux, sealed tube, microwave) has been compared for a significant range of coupling partners of relevance to the preparation of amides of interest in pharmaceutical chemistry. Commercial microwave reactors promote the fastest couplings and allow the use of significantly sterically hindered amines (primary and secondary) and carboxylic acids derivatives. The influence of microwave energy on the reaction system was shown to be typically related to thermal effects (over-pressuring and superheating).

Rhenium Complexes Based on an N2O Tridentate Click Scaffold: From Synthesis, Structural and Theoretical Characterization to a Radiolabelling Study

“…of DABAL‐Me 3 , the desired coupling products 7b and 7a were obtained in yields of 76 and 25 %, respectively. Although the direct coupling of amines with esters containing a free alcohol group has previously been reported to give high yields, in this case, the protection of the OH group is mandatory for obtaining a good coupling yield (76 % for the OTBS group vs. 25 % for the OH group). It is noteworthy that TBS deprotection of 7b with ammonium bifluoride gave 7a in good yield…”

“…The formation of amide linkages from carboxylic acid derivatives and amines is the most employed synthetic process and requires the presence of an activating coupling agent. In our case, a different strategy was adopted, based on the direct coupling of methyl ester compounds and amines using DABAL‐Me 3 [bis(trimethylaluminium)–1,4‐diazabicyclo[2.2.2]octane adduct] as the activating coupling agent . By treating 4 or 5 with propargylamine in the presence of 2 equiv.…”

Investigating Scale-Up and Further Applications of DABAL-Me3 Promoted Amide Synthesis

“…6 One solution to this problem was use of microwave reactors (which reduced the conversion times to 8−16 min). 7 However, the use of microwave heating at large scales is expensive and requires specialist equipment.…”

“…15 The scope of DABAL-Me 3 1 couplings has typically been limited to esters/ carboxylic/amines combinations 4,6,7 and some limited use in heterocycle formation. 6,16 Use of nitriles with 1 is expected to allow easy access to amidines and related compounds as related AlMe 3 transformations are known. 17,24a Brief optimization of conditions (Table 2) focused on our previous microwave reactions (used for amide formation).…”

“…NMR spectra ( 1 H, 13 C) were recorded with Bruker AV400, DPX400, AV(III)400, AV(III)500, and JEOL EX 270 spectrometers at ambient temperatures unless otherwise specified. Chemical shift values are reported in ppm, and solvent resonances were used as internal standards (CHCl 3 : δ = 7.26 ppm for 1 H, δ = 77.16 ppm for 13 C; DMSO-d 6 : δ = 2.50 ppm for 1 H, δ = 39.52 ppm for 13 C; MeOD: δ = 3.31 ppm for 1 H, δ = 49.00 ppm). Coupling constants (J) are quoted in Hertz.…”