Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp³–sp² Carbon–Carbon Bonds

Abstract

Amines and carboxylic acids are abundant synthetic building blocks that are classically united to form an amide bond. To access new pockets of chemical space, we are interested in the development of amine–acid coupling reactions that complement the amide coupling. In particular, the formation of carbon–carbon bonds by formal deamination and decarboxylation would be an impactful addition to the synthesis toolbox. Here, we report a formal cross-coupling of alkyl amines and aryl carboxylic acids to form C­(sp3)–C­(sp2) bonds following preactivation of the amine–acid building blocks as a pyridinium salt and N-acyl-glutarimide, respectively. Under nickel-catalyzed reductive cross-coupling conditions, a diversity of simple and complex substrates are united in good to excellent yield, and numerous pharmaceuticals are successfully diversified. High-throughput experimentation was leveraged in the development of the reaction and the discovery of performance-enhancing additives such as phthalimide, RuCl3, and GaCl3. Mechanistic investigations suggest phthalimide may play a role in stabilizing productive Ni complexes rather than being involved in oxidative addition of the N-acyl-imide and that RuCl3 supports the decarbonylation event, thereby improving reaction selectivity.

Ligand Relay for Nickel‐Catalyzed Decarbonylative Alkylation of Aroyl Chlorides

“…Although further mechanistic insights are clearly warranted, on the basis of the above results and previous studies, [ 13 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ] a proposed mechanism is outlined ( Scheme 6 ). Initially, the active Ni(0) species A was formed from the reaction Ni(II) catalyst with manganese powder and phosphine ligand.…”

“…Of particular note, the highly hindered aroyl chlorides, such as 2‐formyl‐6‐hydroxybenzoyl chloride and 2,4,6‐trimethylbenzoyl chloride, also worked well ( 3na‐3oa ). [ 33 , 34 ] Notably, the unprotected group ‐SH ( 3ra ) was compatible and valuable ‐TMS ( 3sa ) and ‐Bpin ( 3ta ) groups remained intact. Moreover, heteroatom‐containing aroyl chlorides such as furan, thiophene, indole, carbazole, pyridine, and imidazole were productive in the transformation ( 3ua ‐ 3za ).…”

“…The formation of C(sp 2 )─C(sp 3 ) bonds has been widely studied and become one of the most important processes in organic synthesis chemistry, and many reductive coupling reactions to construct C(sp 2 )─C(sp 3 ) bonds have been developed with cheap transition metals, especially nickel. [ 31 ] Nishihara disclosed a nickel‐catalyzed phosphine ligand promoted decarbonylative cross‐electrophile coupling of aroyl fluorides with alkyl bromides at 140 o C. [ 32 ] Recently, Weix [ 33 ] and Cernak [ 34 ] independently developed nickel‐catalyzed nitrogen ligand promoted decarbonylative coupling of 2‐pyridyl esters or N ‐acyl‐glutarimides with N ‐alkyl pyridinium salts at 80–110 °C, forming C(sp 2 )─C(sp 3 ) bonds (Scheme 1B ). Since the starting materials, aroyl fluorides, esters, and imides, in the above‐mentioned reactions are always prepared in an additional step, a mild protocol of decarbonylative alkylation of aroyl chlorides is highly desirable because aroyl chlorides are commercially available or could be easily prepared from the abundant carboxylic acids in one‐pot protocol.…”

Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling

“…Methods from Weix, − Sevov, and others, − have demonstrated the use of multimetallic catalyst systems, where one catalyst is exclusively responsible for generation of an alkyl radical, and another engages the C­(sp 2 ) coupling partner and facilitates formation of the desired C–C bond (Figure C, part i). , An alternative approach is the addition of stoichiometric additivessuch as phthalimide or pyridine derivativesthat passivate open sites of the arylnickel intermediate, slowing the rate of deleterious disproportionation (Figure C, part ii) . − While these and other modifications have proven effective in many cases, they also introduce complicationssuch as tuning catalyst ratios, decreased atom economy, and new side reactions. A more attractive approach would be the systematic development of a more selective single catalyst.…”

Electrochemical decarboxylative alkylation of β-ketoacids with phenol derivatives

“…Catalytic decarboxylation is a highly effective method for constructing C–C bonds. 16 In contrast to the previously favored malonate hemisulfides (MAHTs), 17 β-ketoacids have received comparatively less attention as 1,3-dicarbonyl compounds. This is primarily attributed to the low melting point of β-ketoacids, their inherent instability and susceptibility to decomposition, as well as their propensity to convert into the corresponding ketones when exposed to heat, acids, or bases.…”