IPr (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) represents the most important NHC (NHC = N-heterocyclic carbene) ligand throughout the field of homogeneous catalysis. Herein, we report the synthesis, catalytic activity, and full structural and electronic characterization of novel, sterically-bulky, easily-accessible NHC ligands based on the hash peralkylation concept, including IPr#, Np# and BIAN-IPr#. The new ligands have been commercialized in collaboration with Millipore Sigma: IPr#HCl, 915653; Np#HCl; 915912; BIAN-IPr#HCl, 916420, enabling broad access of the academic and industrial researchers to new ligands for reaction optimization and screening. In particular, the synthesis of IPr# hinges upon cost-effective, modular alkylation of aniline, an industrial chemical that is available in bulk. The generality of this approach in ligand design is demonstrated through facile synthesis of BIAN-IPr# and Np#, two ligands that differ in steric properties and N-wingtip arrangement. The broad activity in various cross-coupling reactions in an array of N–C, O–C, C–Cl, C–Br, C–S and C–H bond cross-couplings is demonstrated. The evaluation of steric, electron-donating and π-accepting properties as well as coordination chemistry to Au( i ), Rh( i ) and Pd( ii ) is presented. Given the tremendous importance of NHC ligands in homogenous catalysis, we expect that this new class of NHCs will find rapid and widespread application.
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Thiazol-2-ylidenes as N-Heterocyclic carbene ligands with enhanced electrophilicity for transition metal catalysis
Over the last 20 years, N-heterocyclic carbenes (NHCs) have emerged as a dominant direction in ligand development in transition metal catalysis. In particular, strong σ-donation in combination with tunable steric environment make NHCs to be among the most common ligands used for C–C and C–heteroatom bond formation. Herein, we report the study on steric and electronic properties of thiazol-2-ylidenes. We demonstrate that the thiazole heterocycle and enhanced π-electrophilicity result in a class of highly active carbene ligands for electrophilic cyclization reactions to form valuable oxazoline heterocycles. The evaluation of steric, electron-donating and π-accepting properties as well as structural characterization and coordination chemistry is presented. This mode of catalysis can be applied to late-stage drug functionalization to furnish attractive building blocks for medicinal chemistry. Considering the key role of N-heterocyclic ligands, we anticipate that
- Award ID(s):
- 1650766
- NSF-PAR ID:
- 10381864
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Communications Chemistry
- Volume:
- 5
- Issue:
- 1
- ISSN:
- 2399-3669
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract The discovery of NHCs (NHC = N‐heterocyclic carbenes) as ancillary ligands in transition‐metal‐catalysis ranks as one of the most important developments in synthesis and catalysis. It is now well‐recognized that the strong σ‐donating properties of NHCs along with the ease of scaffold modification and a steric shielding of the N‐wingtip substituents around the metal center enable dramatic improvements in catalytic processes, including the discovery of reactions that are not possible using other ancillary ligands. In this context, although the classical NHCs based on imidazolylidene and imidazolinylidene ring systems are now well‐established, recently tremendous progress has been made in the development and catalytic applications of BIAN‐NHC (BIAN = bis(imino)acenaphthene) class of ligands. The enhanced reactivity of BIAN‐NHCs is a direct result of the combination of electronic and steric properties that collectively allow for a major expansion of the scope of catalytic processes that can be accomplished using NHCs. BIAN‐NHC ligands take advantage of (1) the stronger σ‐donation, (2) lower lying LUMO orbitals, (3) the presence of an extended π‐system, (4) the rigid backbone that pushes the N‐wingtip substituents closer to the metal center by buttressing effect, thus resulting in a significantly improved control of the catalytic center and enhanced air‐stability of BIAN‐NHC‐metal complexes at low oxidation state. Acenaphthoquinone as a precursor enables facile scaffold modification, including for the first time the high yielding synthesis of unsymmetrical NHCs with unique catalytic properties. Overall, this results in a highly attractive, easily accessible class of ligands that bring major advances and emerge as a leading practical alternative to classical NHCs in various aspects of catalysis, cross‐coupling and C−H activation endeavors.
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ItBu (ItBu = 1,3-di- tert -butylimidazol-2-ylidene) represents the most important and most versatile N -alkyl N-heterocyclic carbene available in organic synthesis and catalysis. Herein, we report the synthesis, structural characterization and catalytic activity of ItOct (I t Octyl), C 2 -symmetric, higher homologues of ItBu. The new ligand class, including saturated imidazolin-2-ylidene analogues has been commercialized in collaboration with MilliporeSigma: ItOct, 929 298; SItOct, 929 492 to enable broad access of the academic and industrial researchers within the field of organic and inorganic synthesis. We demonstrate that replacement of the t -Bu side chain with t -Oct results in the highest steric volume of N -alkyl N-heterocyclic carbenes reported to date, while retaining the electronic properties inherent to N-aliphatic ligands, such as extremely strong σ-donation crucial to the reactivity of N -alkyl N-heterocyclic carbenes. An efficient large-scale synthesis of imidazolium ItOct and imidazolinium SItOct carbene precursors is presented. Coordination chemistry to Au( i ), Cu( i ), Ag( i ) and Pd( ii ) as well as beneficial effects on catalysis using Au( i ), Cu( i ), Ag( i ) and Pd( ii ) complexes are described. Considering the tremendous importance of ItBu in catalysis, synthesis and metal stabilization, we anticipate that the new class of ItOct ligands will find wide application in pushing the boundaries of new and existing approaches in organic and inorganic synthesis.more » « less
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Abstract IMes (IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazol‐2‐ylidene) and IPr (IPr=1,3‐ bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene) represent by far the most frequently used N‐heterocyclic carbene ligands in homogeneous catalysis, however, despite numerous advantages, these ligands are limited by the lack of steric flexibility of catalytic pockets. We report a new class of unique unsymmetrical N‐heterocyclic carbene ligands that are characterized by freely‐rotatable N‐aromatic wingtips in the imidazol‐2‐ylidene architecture. The combination of rotatable N−CH2Ar bond with conformationally‐fixed N−Ar linkage results in a highly modular ligand topology, entering the range of geometries inaccessible to IMes and IPr. These ligands are highly reactive in Cu(I)‐catalyzed β‐hydroboration, an archetypal borylcupration process that has had a transformative impact on the synthesis of boron‐containing compounds. The most reactive Cu(I)‐NHC in this class has been commercialized in collaboration with MilliporeSigma to enable broad access of the synthetic chemistry community. The ligands gradually cover %Vburgeometries ranging from 37.3 % to 52.7 %, with the latter representing the largest %Vburdescribed for an IPr analogue, while retaining full flexibility of N‐wingtip. Considering the modular access to novel geometrical space in N‐heterocyclic carbene catalysis, we anticipate that this concept will enable new opportunities in organic synthesis, drug discovery and stabilization of reactive metal centers.
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Abstract IMes (IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazol‐2‐ylidene) and IPr (IPr=1,3‐ bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene) represent by far the most frequently used N‐heterocyclic carbene ligands in homogeneous catalysis, however, despite numerous advantages, these ligands are limited by the lack of steric flexibility of catalytic pockets. We report a new class of unique unsymmetrical N‐heterocyclic carbene ligands that are characterized by freely‐rotatable N‐aromatic wingtips in the imidazol‐2‐ylidene architecture. The combination of rotatable N−CH2Ar bond with conformationally‐fixed N−Ar linkage results in a highly modular ligand topology, entering the range of geometries inaccessible to IMes and IPr. These ligands are highly reactive in Cu(I)‐catalyzed β‐hydroboration, an archetypal borylcupration process that has had a transformative impact on the synthesis of boron‐containing compounds. The most reactive Cu(I)‐NHC in this class has been commercialized in collaboration with MilliporeSigma to enable broad access of the synthetic chemistry community. The ligands gradually cover %Vburgeometries ranging from 37.3 % to 52.7 %, with the latter representing the largest %Vburdescribed for an IPr analogue, while retaining full flexibility of N‐wingtip. Considering the modular access to novel geometrical space in N‐heterocyclic carbene catalysis, we anticipate that this concept will enable new opportunities in organic synthesis, drug discovery and stabilization of reactive metal centers.
