Nickel-catalysed direct alkylation of thiophenes via double C(sp³)–H/C(sp²)–H bond cleavage: the importance of KH₂PO₄

Abstract

A Ni-catalyzed oxidative C-H/C-H cross-dehydrogenative coupling (CDC) reaction was developed for constructing various highly functionalized alkyl (aryl)-substituted thiophenes. This method employs thiophenes and aliphatic (aromatic) amides that contain an 8-aminoquinoline as a removable directing group in the presence of a silver oxidant. The approach enables the facile one-step synthesis of substituted thiophenes with high functional group compatibility via double C-H bond cleavage without affecting C-Br and C-I bonds. DFT calculations verify the importance of KHPO as an additive for promoting C-H bond cleavage and support the involvement of a Ni(iii) species in the reaction.

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

“…466 Thiophene derivatives were also used by Xu and Qiu ( Scheme 77F ) 467 as well as by Xia and Yin ( Scheme 77G ). 468 In the last cases, the heteroarylation did tolerate several FGs on the heteroaromatic ring (Cl, Br, I, OR, C(O)R, CO 2 R, aryl) and was carried out under Ni catalysis. 469 , 470 …”

Nickel‐Catalyzed Dehydrogenative Couplings

“…Yin group in 2017 reported cross dehydrogenative coupling between C(sp 2 )−H bond of thiophene and unactivated C(sp 3 )−H bond of pivalamide substrates with the help of 8‐aminoquinoline as a directing group (Scheme ) . Equivalent amount of silver carbonate is necessary to oxidize the Ni(II)‐intermediate to Ni(III) in the course of the reaction (Scheme ).…”

Base Metal Catalysis in Directed C(sp3)−H Functionalisation

“…Nickel catalyzed dehydrogenative coupling of aminoquinoline amides with electron-rich aromatics was later exemplified by Xia and Yin (Scheme 17b). [51] A variety of thiophenes and furans could be introduced in good yields throughout, and full α-substitution of the propanamide was required for reactivity. Interestingly, when using 2-bromothiophene, in the absence of silver, arylation occurred through the C-Br bond in good yields, however when Ag2CO3 was used, the arylation occurred via dehydrogenative coupling leaving the C-Br bond intact.…”