Synthesis of cis-3-arylated cycloalkylamines through palladium-catalyzed methylene sp3 carbon–hydrogen bond activation

Bidentate Directing Groups: An Efficient Tool in C–H Bond Functionalization Chemistry for the Expedient Construction of C–C Bonds

“…Since the first use of a picolinamide derivative as a bidentate directing group in 2005 by Daugulis, a variety of functionalization reactions using this directing group have been reported. In terms of C–C bond formation, arylation, ,,− alkylation, ,− alkenylation, ,− alkynylation, ,, oxidative annulation, , carbonylation, carboxyarylation, cyanation, − and trifluoromethylation, reactions have all been reported with the aid of a picolinamide moiety. This auxiliary has been used for the functionalization of amine derivatives because functionalized amine derivatives generate the desired product after removal of the picolinamide auxiliary.…”

“…348 The authors designed a new picolinamide directing group by introducing a silyl protected methylene hydroxyl group at the ortho-position of picolinamide (as shown in 39 and 40), which could then be used to facilitate amide cleavage through an intramolecular acyl transfer under mildly acidic conditions to form the functionalized amine 41 and the auxiliary precursor 42 (Scheme 71). 348 Because of the importance of C(sp 3 )−H functionalization, arylation reactions involving various other aliphatic amine derivatives, such as, the C(sp 3 )−H arylation of cyclopropyl methylamine (Scheme 70c), 353 the δ-C(sp 3 )−H arylation of pinanamine derivatives (Scheme 70d), 339 the γ-C(sp 3 )−H arylation of cycloalkylamines (Scheme 70e), 355 the β-C(sp 3 )− H arylation of amides (Scheme 70f), 359 the C(sp 3 )−H diarylation of rimantadine derivatives (Scheme 70g), 342 the C(sp 3 )−H arylation of 3-aminopiperidine derivatives (Scheme 70h), 345 the γ-C(sp 3 )−H arylation of macrocyclic amines (Scheme 70i), 354 the γ-C(sp 3 )−H monoarylation of amino acid derivatives (Scheme 70j), 341 the unsymmetrical diarylation of amino acid derivatives (Scheme 70k), 341 C(sp 3 )−H arylation of saturated bicyclic amine scaffolds (Scheme 70l), 338 and the γ-C(sp 3 )−H arylation of quinuclidine derivatives (Scheme 70m) 343 have been reported. All of the above arylation reactions involved the use of aryl halides and a Pd-catalyst with the aid of a picolinamide as an efficient bidentate directing group.…”

Transition-Metal-Catalyzed, Coordination-Assisted Functionalization of Nonactivated C(sp3)–H Bonds

“…Palladium-catalyzed, picolinamide-directed γ-C­(sp 3 )–H arylation of a variety of cycloalkyl amine derivatives, such as cyclopropyl methylamines, 3-pinanamine, cycloalkylamines, rimantadine, and saturated bicyclic amines, have been developed, further demonstrating the robustness of the picolinamide DG (Scheme ).…”

“…Peptide 444, which contains unprotected polar side chains, can also cyclize well in aqueous solution to give the corresponding cyclic peptide 445 (Scheme 76). 225 Palladium-catalyzed, picolinamide-directed γ-C(sp 3 )−H arylation of a variety of cycloalkyl amine derivatives, such as cyclopropyl methylamines, 226 3-pinanamine, 227 cycloalkylamines, 228 rimantadine, 229 In 2016, the Maes group reported picolinamide-directed, palladium-catalyzed C5-arylation of 3-aminopiperidine (Scheme 78a). 231 Upon use of catalytic 2,6-dimethylbenzoic acid as additive and a high reaction concentration, the yield of the products was improved significantly.…”

Remote Functionalization: Palladium-Catalyzed C5(sp3)-H Arylation of 1-Boc-3-aminopiperidine through the Use of a Bidentate Directing Group

“…As a starting point, a literature protocol involving the use of a picolinoylamino DG was selected, because of its previously reported success on saturated carbocycles, namely, cyclohexylamine 1 . Interestingly, no directed C5­(sp 3 )-H functionalization on 3-substituted saturated heterocycles, such as cyclic amines, has hitherto been reported.…”