Mark Stradiotto

Reported herein is the first nickel‐catalyzed N ‐arylation of sulfonimidamides at the imine position employing (hetero)aryl chloride reaction partners with useful substrate scope. Such otherwise challenging transformations are enabled under mild conditions and in synthetically useful isolated yields by use of a PAd‐DalPhos/Ni catalyst system, including N ‐arylation of the active pharmaceutical ingredient chlorpromazine.

While base metal-catalyzed cross-couplings of alcohols and (hetero)aryl chlorides have emerged over the past decade, the development of a single pre-catalyst capable of promoting such transformations spanning all of primary, secondary, and tertiary (aliphatic) alcohols remains an enduring challenge. Herein we disclose the easily prepared, air-stable 4-cyanophenyl pre-catalyst (L2)Ni(4-CN-Ph)Cl (L2 = CgPhen-DalPhos), which is shown to be capable of promoting, with useful reaction scope, the C–O cross-coupling of all such alcohol classes with (hetero)aryl chlorides.

Palladium-catalyzed thermal C–O cross-coupling reactions represent first-choice methodologies for alkyl (hetero)aryl ether formation in both academia and industry, especially when commencing from otherwise challenging (hetero)aryl chloride or bromide electrophiles and aliphatic alcohol coupling partners. While highly effective thermal nickel-catalyzed processes of this type have emerged owing to advances in ancillary ligand design, their use as competitive drop-in alternatives to palladium in such applications in the context of high-throughput experimentation (HTE) has not been demonstrated. In targeting the formation of alkyl heteroaryl ethers of biological relevance, we disclose herein a comparative HTE screening study focused on thermal palladium- or nickel-catalyzed C–O cross-couplings of primary, secondary, or tertiary aliphatic alcohols with heteroaryl chlorides or bromides. We demonstrate that appropriate DalPhos-ligated nickel precatalysts can offer catalytic performance in such transformations that is competitive with (e.g., for primary and secondary alcohols) or superior to (e.g., for tertiary alcohols) that achieved by use of otherwise best-in-class palladium catalysts (e.g., featuring biarylmonophosphine, JosiPhos, or other ligation).

The evolution of palladium‐catalyzed C─N and C─O cross‐coupling chemistry into first‐choice methods for the synthesis of aniline and phenol derivatives can be attributed to innovations in ancillary ligand design that facilitate challenging elementary steps of thermal catalysis. Inspired by this strategy, and in the quest to establish more sustainable thermal base metal catalysis that is competitive with and complementary to such precious metal protocols, several successful mechanism‐inspired ancillary ligand classes for use in enabling high‐performing copper and nickel catalysts have emerged over the last decade. In this Review we document key ancillary ligand advances of this type, with a focus on superlative copper and nickel catalysts that enable C─N or C─O cross‐couplings of cheap and abundant (hetero)aryl chloride electrophiles under operationally simple conditions of relevance to end‐users in academia and industry.

Reported herein is the palladium‐catalyzed allylation of (hetero)aryl fluorosulfates. When employing a [Pd(cinnamyl)Cl]₂/XantPhos catalyst system and using either allyl pinacolboronate or potassium allyltrifluoroborate, allyl (hetero)arene products were successfully prepared and isolated in synthetically useful yields, including examples featuring potentially reactive chloro groups. (Pseudo)halide chemoselectivity was further probed in intermolecular competition experiments, which revealed a preferred reactivity trend of Br > OFs >> Cl in the test system examined.

The palladium-catalyzed Sonogashira cross-coupling of (hetero)aryl fluorosulfates and terminal alkynes, featuring a synthetically useful scope and yields, is reported herein. Such transformations involving a diversity of (hetero)aryl fluorosulfate coupling partners, including chemoselective examples where contending chloro functionalities are present, are achieved using a DPPF/[Pd(cinnamyl)Cl]₂ catalyst system without the requirement of a copper additive.

The aryloxyamine motif is a prominent pharmacophore in drug design and development. While these biologically relevant structures could in principle be sustainably assembled from the base metal‐catalyzed O‐arylation of inexpensive and abundant amino alcohols with (hetero)aryl chlorides, reports of such challenging C−O bond formations with useful scope are lacking. In response, we report herein the hitherto unknown Ni‐catalyzed C−O cross‐coupling of N‐protected amino alcohols (primary, secondary, and tertiary) with (hetero)aryl chlorides. Also presented are chemoselective sequential/telescoped C−N and C−O cross‐couplings of the unprotected amino alcohol prolinol to afford an unsymmetrical diarylated product.

We disclose herein our evaluation of competitive (hetero)aryl‐X (X: Br>Cl>OTf) reactivity preferences in bisphosphine/Ni‐catalyzed C−N cross‐coupling catalysis, using furfurylamine as a prototypical nucleophile, and employing DalPhos and DPPF as representative ancillary ligands with established efficacy. Beyond this general (pseudo)halide ranking, other intriguing structure‐reactivity trends were noted experimentally, including the unexpected observation that bulky alkyl (e. g., R=tBu) substitution in para‐R‐aryl‐X electrophiles strongly discourages (pseudo)halide reactivity relative to smaller substituents (e. g., nBu, Et, Me), despite being both remote from, and having a similar electronic influence on, the reacting C−X bond; such effects on nickel oxidative addition have not been documented previously and were not observed in our comparator reactions presented herein involving palladium. Density functional theory modeling of such PhPAd‐DalPhos/Ni‐catalyzed C−N cross‐couplings revealed the origins of competitive turnover of C−Br over C−Cl, and possible ways in which bulky para‐alkyl substitution might discourage net electrophile uptake/turnover, leading to inversion of halide selectivity.

The development of the DalPhos cage ligand family and application in developing state-of-the-art nickel-catalyzed cross-coupling chemistry is described.