Collaboration as a Key to Advance Capabilities for Earth-Abundant Metal Catalysis

Abstract

Earth-abundant metal (EAM) catalysis can have profound impact in the pharmaceutical industry in terms of sustainability and cost improvements from replacing precious metals like palladium as well as harnessing the differential reactivity of first-row metals that allows for novel transformations to enable more efficient routes to clinical candidates. The strategy for building these capabilities within the process group at Bristol Myers Squibb is described herein, with the general plan of building a reaction screening platform, demonstrating scalability, and increasing mechanistic understanding of the reaction and catalyst activation. The development of catalytic transformations utilizing nickel, cobalt, and iron is described while highlighting the importance of collaboration with internal and external groups to advance EAM catalysis and impact our portfolio. The challenges and benefits of working with first-row transition metals, including metrics for the implementation of EAM catalysis, such as cost, process mass intensity, and commercial availability of catalysts and ligands, are discussed.

General Method for Ni-Catalyzed C–N Cross-Couplings of (Hetero)Aryl Chlorides with Anilines and Aliphatic Amines under Homogeneous Conditions Using a Dual-Base Strategy

“…Yet, despite its success in catalyzing Buchwald–Hartwig aminations, palladium has tangible liabilities . Most notable of these is its relative cost compared to earth-abundant metal (EAM) catalysts , that have also been utilized in catalytic C–N bond construction including copper (i.e., Ullmann and Chan–Lam reactions), − iron, and nickel . Of these EAMs, nickel is perhaps the most promising catalyst due to its demonstrated compatibility with a broad range of coupling partners that in many cases complements Pd-catalyzed aminations and in some cases, has the potential to replace its more expensive second-row cousin. − …”

Organopalladium Catalysis as a Proving Ground for Data-Rich Approaches to Reaction Development and Quantitative Predictions

“…No other examples of homogeneous organometallic catalysis are in this set. Certainly, the plethora of excellent research into nonprecious metal catalysis for cross-coupling and related transformations means that these systems are emerging as viable alternatives. − However, the sheer number and variety of documented examples of Pd catalysis in complex molecule synthesis attests to its enduring importance as a reliable and effective means to access new chemical matter.…”

Nickel-Catalyzed O-Arylation of Primary or Secondary Aliphatic Alcohols with (Hetero)aryl Chlorides: A Comparison of Ni(I) and Ni(II) Precatalysts

“…The metal-catalyzed C–O cross-coupling of ROH nucleophiles with (hetero)aryl electrophiles, traditionally involving palladium or copper catalysis, offers a useful route to the alkyl (hetero)aryl ether motif found in biologically active compounds such as active pharmaceutical ingredients that is complementary to alternative synthetic protocols (e.g., Mitsunobu, Williamson, S N Ar, and others). More recently, the development of nickel catalysts for such cross-couplings has received attention in the pursuit of an expanded reaction scope within a base–metal catalyst system . In this effort, two parallel approaches have emerged: (a) photochemical, electrochemical, or alternative redox strategies operating within Ni(I/III) catalytic cycles, typically employing nitrogen donor ligands, and (b) the use of bisphosphine-ligated species under thermal conditions, operating within presumptive Ni(0/II) cycles.…”