1,2,4‐ and 1,3,4‐Oxadiazole Synthesis by Palladium‐Catalyzed Carbonylative Assembly of Aryl Bromides with Amidoximes or Hydrazides

Abstract

Aryl bromides were successfully transformed into their corresponding N,N'-diacylhydrazines via a Pd-catalyzed carbonylative coupling with acylhydrazines. These reactions employed near-stoichiometric amounts of carbon monoxide generated ex situ from a non-gaseous precursor. A range of di-A C H T U N G T R E N N U N G (hetero)aryl diacylhydrazines was isolated in good to excellent yields. Furthermore, dehydration conditions were identified that could be used in a compatible one-pot synthesis of 1,3,4-oxadiazoles. The applicability of this method towards 13 C-isotope labeling was also demonstrated, with the production of symmetrical and non-symmetrical doubly isotopically labeled 1,3,4-oxadiazoles. Finally, experimental conditions were identified for the carbonylative coupling of aryl bromides with amidoximes and CO producing 1,2,4-oxadiazoles after spontaneous dehydration.

Scalable carbon dioxide electroreduction coupled to carbonylation chemistry

“…The active ingredient in three commercially available pharmaceutical drugs could be effectively prepared via an aminocarbonylation with CO produced from the electrochemical reduction of CO 2 , including the PARP inhibitor, olaparib ( 4 , 86% yield), the tyrosine-kinase inhibitor, sunitinib ( 5 , 66% yield) and the D 2 -receptor antagonist, itopride ( 6 , 63% yield). Other compounds successfully prepared from an aminocarbonylative step include thiophene carboxamide 7 (84% yield), the H3-receptor antagonist 8 (79% yield), oxadiazole 9 (73% yield) prepared from a dehydrative cyclisation of the intermediate diacyl hydrazide 33 , and the melanoma positron emission tomography tracer 10 (83% yield). Resorting to a Pd-catalysed alkoxycarbonylation also proved viable providing the local anesthetic, butoxycaine ( 11 ) and the cyclopropyl ester 12 in good yields, 98 and 69%, respectively.…”

Recent developments in carbonylation chemistry using [13C]CO, [11C]CO, and [14C]CO

“…This concept is shown in Scheme 8C, where an acyl hydrazine 35 can be formed in an excellent yield with N ‐Boc protected hydrazine, and then undergoes an additional aminocarbonylation forming 36 after a deprotection step. The benzoylated hydrazine can then be cyclized to form the 13 C 2 ‐labeled 1,3,4‐oxadiazole 37 …”

Recent developments in heterocycle labeling with carbon isotopes

“…In the same year, the Skrydstrup group expanded even further the scope of heterocycles with benzothiophene, 77 1,2,4-oxadiazole, and 1,3,4-oxadiazole derivates. 78 In the first report, the aryl bromide 105 was coupled with 2-SCHEME 29 Synthesis of drug-like heterocycles via palladium-catalyzed carbonylation SCHEME 30 Carbon-13 labeling of thiazolamine and pyrazolopyridine derivatives SCHEME 31 Synthesis of benzothiophene derivate via palladium carbonylation and McMurry coupling mercaptobenzophenones 106 via palladium carbonylation to obtain the thioester [ 13 C]-107 with 70% yield; then, under McMurry coupling conditions, the thioester was cyclized to obtain [ 13 C]-108 in good yield, as depicted in Scheme 31.…”

“…In the same year, the Skrydstrup group expanded even further the scope of heterocycles with benzothiophene, 1,2,4‐oxadiazole, and 1,3,4‐oxadiazole derivates . In the first report, the aryl bromide 105 was coupled with 2‐mercaptobenzophenones 106 via palladium carbonylation to obtain the thioester [ 13 C]‐ 107 with 70% yield; then, under McMurry coupling conditions, the thioester was cyclized to obtain [ 13 C]‐ 108 in good yield, as depicted in Scheme 31.…”