Potassium tert-Butoxide Facilitated Amination of Carboxylic Acids with N,N-Dimethylformamide

Abstract

Herein a practical and efficient potassium tert-butoxide (KOtBu)-facilitated amine acyl exchange reaction of N,N-dimethylformamide (DMF) with carboxylic acids is described. In the presence of catalytic amount of KOtBu, a variety of aliphatic and aromatic carboxylic acids are transformed to N,N-dimethylamides using DMF as the dimethylamine reagent with the assistance of trimethylacetic anhydride. The applicability of this protocol is demonstrated by late-stage dimethylamidation of complex drug molecules. A plausible reaction mechanism involving KOtBu-facilitated amine in situ generation from formamide decomposition and anhydride-mediated condensation is proposed on the base of mechanism investigations

Deprotonative Metallation of Benzofuran and Benzothiophene Derivatives for the Formation of Tetracyclic and Pentacyclic Heteroaromatic Compounds

“…N , N ‐dimethylbenzofuran‐ and N , N ‐dimethylbenzothiophene‐2‐carboxamide ( 1 a and 2 a ) can be prepared from the corresponding 2‐carboxaldehydes and dimethylamine in the presence of 1,3‐diiodo‐5,5‐dimethylhydantoin and potassium carbonate in tetrachloromethane [10] . They can also be obtained by amination of the corresponding 2‐carboxylic acids, promoted by potassium tert ‐butoxide, using N , N ‐dimethylformamide (DMF) [11] …”

“…[10] They can also be obtained by amination of the corresponding 2-carboxylic acids, promoted by potassium tert-butoxide, using N,N-dimethylformamide (DMF). [11] While the 2-(morpholinocarbonyl) derivatives 1 b and 2 b were prepared using the first approach, [10] 1 b can also be obtained from ethyl benzofuran-2-carboxylate via nickel-catalysed amide bond formation using morpholine in toluene. [12] Finally, 2-(morpholinocarbonyl)benzothiophene has also been prepared by amidation of the 2-carboxylic acid using morpholine in the presence of 1-hydroxybenzotriazole and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide, [13] or from 2-benzothienoyl chloride.…”

Exploring the Versatility of the Amidation of Aryl Acid Fluorides using the Germylamines R3GeNMe2

“…The synthesis of 7 i and 7 j have both been previously reported but the reported methods for their preparation are not as versatile as the method discussed herein. The synthesis of 7 i was achieved via the photolysis of ortho ‐(2‐dimethylaminoethyl)benzaldehyde in 55 % yield, [60] by the reaction of the corresponding carboxylic acid with DMF promoted by KOBu t in 80 % yield, [61] and also could be prepared in 97 % yield starting with 2‐ethylbenzoic acid via the in situ preparation of the acid chloride [62] . The reaction of 6 i with Ph 3 GeNMe 2 to yield 7 i indicates that the presence of an alkyl substituent at the ortho ‐position of the aromatic ring does not hinder the amidation process.…”

N,N-Dialkyl Amides as Versatile Synthons for Synthesis of Heterocycles and Acyclic Systems

“…Li et al, developed hypervalent iodine mediated reaction between carboxylic acids 43 and N,N-dimethylformamide which occur under mild conditions at room temperature to provide novel O-aroyl-N,N-dimethyl hydroxyl amines 62 in good yields (Figure 33), which are important electrophilic amination reagents. The process shows good functional group compatibility, air and moisture tolerance [62].…”