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Challenging nickel-catalysed amine arylations enabled by tailored ancillary ligand design

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ABSTRACT

Palladium-catalysed C(sp2)–N cross-coupling (that is, Buchwald–Hartwig amination) is employed widely in synthetic chemistry, including in the pharmaceutical industry, for the synthesis of (hetero)aniline derivatives. However, the cost and relative scarcity of palladium provides motivation for the development of alternative, more Earth-abundant catalysts for such transformations. Here we disclose an operationally simple and air-stable ligand/nickel(II) pre-catalyst that accommodates the broadest combination of C(sp2)–N coupling partners reported to date for any single nickel catalyst, without the need for a precious-metal co-catalyst. Key to the unprecedented performance of this pre-catalyst is the application of the new, sterically demanding yet electron-poor bisphosphine PAd-DalPhos. Featured are the first reports of nickel-catalysed room temperature reactions involving challenging primary alkylamine and ammonia reaction partners employing an unprecedented scope of electrophiles, including transformations involving sought-after (hetero)aryl mesylates for which no capable catalyst system is known.

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Approaches to metal-catalysed C–N cross-coupling.(a) Generic equation for Buchwald–Hartwig amination and Ullmann C–N coupling to form a (hetero)aniline. (b) Ancillary ligand design strategies for palladium and nickel, along with the new ancillary ligand L1 (PAd-DalPhos).
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f1: Approaches to metal-catalysed C–N cross-coupling.(a) Generic equation for Buchwald–Hartwig amination and Ullmann C–N coupling to form a (hetero)aniline. (b) Ancillary ligand design strategies for palladium and nickel, along with the new ancillary ligand L1 (PAd-DalPhos).

Mentions: Homogeneous transition metal catalysis is employed broadly in synthetic organic chemistry, including in the pharmaceutical industry for the preparation of active pharmaceutical ingredients on bench-top and production scales1. The development of useful catalysts of this type that offer broad substrate scope is often made possible through the application of appropriately designed ancillary ligands; when coordinated to the reactive metal of interest, such ligands can dramatically enhance catalytic performance (for example, activity, selectivity and lifetime). The palladium-catalysed cross-coupling of NH substrates and (hetero)aryl (pseudo)halides (that is, Buchwald–Hartwig amination23456, BHA; Fig. 1a) is a well-established C(sp2)-N bond-forming methodology whose rapid evolution can be attributed in large part to advances in ancillary ligand design. Indeed, BHA chemistry is now employed widely the synthesis of biologically active molecules and functional materials, including in the pharmaceutical industry with applications ranging from the rapid diversification of small-molecule libraries to larger-scale production1789.


Challenging nickel-catalysed amine arylations enabled by tailored ancillary ligand design
Approaches to metal-catalysed C–N cross-coupling.(a) Generic equation for Buchwald–Hartwig amination and Ullmann C–N coupling to form a (hetero)aniline. (b) Ancillary ligand design strategies for palladium and nickel, along with the new ancillary ligand L1 (PAd-DalPhos).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4814586&req=5

f1: Approaches to metal-catalysed C–N cross-coupling.(a) Generic equation for Buchwald–Hartwig amination and Ullmann C–N coupling to form a (hetero)aniline. (b) Ancillary ligand design strategies for palladium and nickel, along with the new ancillary ligand L1 (PAd-DalPhos).
Mentions: Homogeneous transition metal catalysis is employed broadly in synthetic organic chemistry, including in the pharmaceutical industry for the preparation of active pharmaceutical ingredients on bench-top and production scales1. The development of useful catalysts of this type that offer broad substrate scope is often made possible through the application of appropriately designed ancillary ligands; when coordinated to the reactive metal of interest, such ligands can dramatically enhance catalytic performance (for example, activity, selectivity and lifetime). The palladium-catalysed cross-coupling of NH substrates and (hetero)aryl (pseudo)halides (that is, Buchwald–Hartwig amination23456, BHA; Fig. 1a) is a well-established C(sp2)-N bond-forming methodology whose rapid evolution can be attributed in large part to advances in ancillary ligand design. Indeed, BHA chemistry is now employed widely the synthesis of biologically active molecules and functional materials, including in the pharmaceutical industry with applications ranging from the rapid diversification of small-molecule libraries to larger-scale production1789.

View Article: PubMed Central - PubMed

ABSTRACT

Palladium-catalysed C(sp2)–N cross-coupling (that is, Buchwald–Hartwig amination) is employed widely in synthetic chemistry, including in the pharmaceutical industry, for the synthesis of (hetero)aniline derivatives. However, the cost and relative scarcity of palladium provides motivation for the development of alternative, more Earth-abundant catalysts for such transformations. Here we disclose an operationally simple and air-stable ligand/nickel(II) pre-catalyst that accommodates the broadest combination of C(sp2)–N coupling partners reported to date for any single nickel catalyst, without the need for a precious-metal co-catalyst. Key to the unprecedented performance of this pre-catalyst is the application of the new, sterically demanding yet electron-poor bisphosphine PAd-DalPhos. Featured are the first reports of nickel-catalysed room temperature reactions involving challenging primary alkylamine and ammonia reaction partners employing an unprecedented scope of electrophiles, including transformations involving sought-after (hetero)aryl mesylates for which no capable catalyst system is known.

No MeSH data available.