Palladium(II)-Promoted Directing Group-Enabled Regioselective C-H Arylation of The C-3 Position of 2- or 3-(Aminoalkyl)-Thiophene and Furfurylamine Derivatives

Abstract

The palladium(II)‐promoted, bidentate ligand‐assisted regioselective C−H activation/arylation of the C‐3 position of 2‐ or 3‐(aminoalkyl)‐thiophene and furfurylamine derivatives with various aryl‐/heteroaryl iodides was reported. Various aryl‐/heteroaryl iodides and bidentate ligands, such as, picolinamide, quinoline‐2‐carboxamide, pyrazine‐2‐carboxamide and oxalylamide were examined for accomplishing the regioselective palladium(II)‐promoted C−H arylation and C−C bond formation at the C‐3 position of the 2‐/3‐(aminoalkyl)‐thiophene and furfurylamine derivatives. The X‐ray structures of the regioisomers 8 c and 9 c confirmed the observed regiselectivity. This C−H activation/arylation method gave an access to several C3‐arylated 2/3‐(aminoalkyl)‐thiophene‐ and furfurylamine based biaryl scaffolds that are analogous to biologically active C3‐arylated 2/3‐(aminoalkyl)‐thiophenes and furfurylamines.

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

“…In 2016, Babu and co-workers disclosed picolinamide-directed arylation of the C3-position of 2-(aminoethyl)thiophenes with aryl iodides and heteroaryl iodides in low to good yields and in a regioselective manner ( Scheme 93A ). 568 The same group used a similar catalytic system for arylation of allylamines at the γ-position leading to the corresponding cinnamylamines with good to high E / Z ratios (up to 2 : 98) in the favour of the challenging Z isomers ( Scheme 93B ). 569 Note that substrates bearing a primary γ-C(sp 3 ) center and a γ-C(sp 2 ) center led to di-arylated products.…”

“…A two steps sequence ( N -Boc) protection/hydrazinolysis (NH 4 I, NH 2 NH 2 ·H 2 O) under microwave irradiation afforded the Boc-protected MBIPNH 2 and the corresponding N -acylhydrazide in good yield. 568 …”

“…In the course of their investigation for the Pd-catalysed arylation of 3-(aminoethyl)thiophene derivatives, the group of Babu showed that among the possible DGs for this transformation, the NHOA DG turned out to be efficient affording the products in 57 to 75% yields and the reaction was also performed on a gram scale ( Scheme 105C ). 568 …”

4-Amino-2,1,3-benzothiadiazole as a Removable Bidentate Directing Group for the Pd(II)-Catalyzed Arylation/Oxygenation of sp2/sp3 β-C–H Bonds of Carboxamides

“…The first paper by Daugulis , dealing with the Pd­(II)-catalyzed, bidentate directing group 8-aminoquinoline ( DG-a )-assisted arylation of unactivated sp 3 C­(β)–H bonds of aliphatic and aromatic carboxamides has provided an inspiring direction to the research area pertaining to the sp 3 C–H activation/functionalization reactions (Figure ). − ,, Concurrently, Yu’s work dealing with the Pd­(II)-catalyzed, monodentate directing group 2,3,5,6-tetrafluoro-4-(trifluoromethyl)­aniline ( DG-b )-assisted functionalization of unactivated sp 3 C–H bonds of organic molecules has provided motivation for synthetic organic chemists (Figure ). Consequently, while the directing group-free C–H activation/functionalization transformation still remains a challenging and less explored area, the directing group-assisted C–H activation/functionalization tactic has emerged as a dependable method for functionalizing organic molecules with a high degree of site-selectivity. − …”

Pd(II)-Catalyzed Bidentate Directing Group-Aided Chemoselective Acetoxylation of Remote ε-C(sp2)–H Bonds in Heteroaryl–Aryl-Based Biaryl Systems

“…Transition metal-catalyzed sp 2 /sp 3 C–H activation/functionalization is one of the remarkable synthetic transformations in organic synthesis. − While the directing group-free C–H activation/functionalization is well documented, the directing group-aided C–H activation/functionalization has become a powerful synthetic strategy for accomplishing the site-selectivity. − Especially, the use of the bidentate directing groups (BDGs) has offered a new zeal for achieving the site-selective C–H functionalization (e.g., arylation, alkylation, and acetoxylation) of organic molecules. − The 8-aminoquinoline (8AQ)-type BDGs have preferentially assisted the functionalization of sp 2 /sp 3 β-C–H bonds of carboxylic acid substrates. − The picolinamide (PA)-type BDGs have assisted the functionalization of sp 2 /sp 3 γ- and δ-C–H bonds of amine systems. − The BDG-aided functionalization of sp 2 /sp 3 β- and γ-C–H bonds of appropriate carboxamide systems was well documented, − and there also have been some outstanding efforts on the BDG-aided functionalization of remote sp 2 /sp 3 δ- and ε-C–H bonds of appropriate carboxamide systems. ,− In particular, to the best of our knowledge, there exist only rare reports dealing on the BDG-aided functionalization of remote sp 2 /sp 3 ε-C–H bonds …”