Development and Execution of an Ni(II)-Catalyzed Reductive Cross-Coupling of Substituted 2-Chloropyridine and Ethyl 3-Chloropropanoate

Abstract

We describe the development and scale-up of a nickel-catalyzed reductive cross-electrophile coupling reaction between a substituted 2-chloropyridine and ethyl 3-chloropropanoate using manganese dust as the terminal reductant. Several additives were screened for the activation of the manganese reductant in situ, and chlorotriethylsilane (TESCl) was found to provide the optimal conversion. A focused beam reflectance measurement (FBRM) probe was utilized to monitor particle attrition as well as manganese activation during the reaction. Modeling was employed to garner an understanding of mixing requirements that would ensure effective suspension of the manganese during scale-up. The process was successfully demonstrated on a 7 kg scale and afforded 2 in 64% yield.

Controlling Ni redox states by dynamic ligand exchange for electroreductive Csp3–Csp2 coupling

“…A dvances in Ni-based catalysis have enabled new C-C bond-forming methodologies that directly couple two C electrophiles in a net-reductive process without the need to preform a nucleophilic coupling partner (1)(2)(3)(4). The ubiquity of simple organohalides or other C electrophiles has caused Ni-catalyzed cross-electrophile coupling (XEC) to become one of the most common strategies for C-C coupling in industry, particularly to form C(sp 3 )-C(sp 2 ) bonds (5)(6)(7)(8)(9)(10)(11). Although chemical (3), photoredox (12), and electrochemical (13) approaches have been developed to deliver the reducing equivalents needed for XEC, all three reductive strategies are limited to couplings of similar classes of alkyl and aryl halides.…”

Nickel-catalyzed reductive coupling of unactivated alkyl bromides and aliphatic aldehydes

“…Benzyl ethers and straight-chain aldehydes were shown to couple effectively. Substrates with b-branching, such as citronellal (7) and isovaleraldehyde (8), delivered the desired products in good yield. Aldehydes bearing protected amines such as carbamates were well tolerated, showing no activation or cleavage of the Boc group in 9. a-Branched aldehydes showed comparable reactivity to linear substrates (10-13), however, aldehydes bearing a-quaternary centers did not afford meaningful amounts of coupled product.…”

“…These processes are attractive due to the generation of metalated intermediates of lower nucleophilicity, a higher control of selectivity by tuning the catalytic systems, and ability to be applied on process scales. [6][7][8] Net reductive couplings using organohalide feedstocks have been developed using stoichiometric reductants to enable catalyst turnover, obviating the need for pre-generation of the organometallic nucleophile. [9][10][11][12][13][14][15][16] Among the most common systems are Rh 10 , Ni 11,[14][15][16] and Cr [17][18][19][20][21][22][23][24] -catalyzed couplings of aldehydes and organohalides.…”

Recent Advances in Nonprecious Metal Catalysis

“…Exemplifying the utility of the cross-electrophile coupling, this reaction was used to produce a pharmaceutical intermediate on 7 kg scale by the process chemists at Bristol-Myers Squibb (BMS) (Scheme 4). 13 Prior to the use of the cross-electrophile coupling, Suzuki and Heck coupling approaches yielded no desired product. While Negishi coupling was initially successful, bulk availability of the organozinc reagent derived from ethyl 3-chloropropanoate was a concern.…”