BIAN–NHC Ligands in Transition-Metal-Catalysis: A Perfect Union of Sterically-Encumbered, Electronically-Tunable N–Heterocyclic Carbenes?

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)acenaphtene) 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.

Graphical Abstract

1. Introduction

N-Heterocyclic carbenes (NHCs) have found extraordinary utility in organic synthesis and catalysis.^[1] Classical NHCs feature at least one nitrogen atom within the heterocyclic system that is directly connected to the carbene center, which renders them powerful ligands in transition-metal-catalysis.^[1] Following early studies by Wanzlick and Öfele in the 1960s, resulting in isolation of the first NHC–transition-metal-complexes,^[2,3] it was the seminal work by Arduengo and co-workers in 1991 on the stability of a free NHC, 1,3-di(adamantyl)imidazol-2-ylidene,^[4,5] that has sparked interest of the chemical community and resulted in a raise of NHCs from academic curiosities to broadly employed species in various fields of science ranging from catalysis to medicine.^[6]

In the last two decades, the organometallic chemistry of N-heterocyclic carbenes has been rapidly developed and a variety of NHC–metal complexes have been explored.^[7–10] From a fundamental perspective, N-heterocyclic carbenes represent the most important class of strong σ-donor ligands superseding phosphines^[11–20] that have been widely employed in metal coordination chemistry, catalysis, and polymer science. Major advantages of NHCs as ligands include (1) NHC ligands are easy to synthesize and functionalize, in particular in comparison with phosphines, which allows for rapid tuning and modification of catalytic performance; (2) strong NHC–metal bonds provide high complex stability during catalysis and enable isolation of novel metal complexes, including main metals and f-block elements; (3) large structural and stereo-electronic diversity of NHC ligands is available, wherein the ligand properties can be tuned by the backbone or N-wingtip modification; (4) steric shielding of the N-wingtip substituents around the metal center provides efficient control of the catalytic pocket; (5) high stability to oxidative conditions permits for highly successful catalytic applications with metals at higher oxidation state.^[21,22]

In this context, although the research has predominantly focused on the classical NHCs based on imidazolylidene and imidazolinylidene ring systems (Figure 1), recently tremendous progress has been made in the development and catalytic applications of BIAN–NHC (BIAN = bis(imino)acenaphtene) class of NHC ligands (Figure 2). These carbene ligands were first reported by the Çetinkaya group in 2006^[23] and feature a naphthalene ring fused to the imidazolylidene ring system. The unique geometric arrangement results in a number of distinct properties of BIAN–NHC ligand resulting from the combination of electronic and steric properties (Figure 2),^[24–30] such as (1) stronger σ-donor and better π-acceptor character than the classical imidazolylidenes, which results in enhanced reactivity in both oxidative addition and electrophilic functionalization; (2) the presence of an extended π-system and the rigid backbone that pushes the N-wingtip substituents closer to the metal center by buttressing effect and affords improved control of the catalytic center; (3) significantly improved air-stability of BIAN–NHC–metal complexes at low oxidation state; (4) potential for scaffold modification by naphthalene functionalization, including a related class of perylene-type NHCs; (5) acenaphthoquinone as an NHC precursor enables for the first time for a high yielding synthesis of unsymmetrical NHCs with unique catalytic properties. Overall, these properties result in a highly attractive, easily accessible class of NHC ligands that bring advances in transition-metal-catalysis using various metals and emerge as a leading practical alternative to the classical imidazolylidene and imidazolinylidene NHC ligands. Structures of the most common BIAN–NHC ligands used in catalysis are summarized in Figure 3.

Figure 1.

Structures of Classical NHC Ligands.

Figure 2.

Structural Features of BIAN-NHC Ligands and their Impact on Catalysis.

Figure 3.

Structures of the Most Common BIAN–NHC Ligands in Transition-Metal-Catalysis.

In this context, an important difference between saturated and unsaturated BIAN–NHC catalysts (e.g. BIAN–IMes vs. BIAN–SIMes) should be noted (Figure 3). In analogy to imidazolinylidenes, saturated BIAN–NHCs are stronger σ-donors,^[23] while geometrically the saturated acenaphthylene framework creates a bend-like geometry placing the steric bulk away from the metal center.^[24]

It also worth noting that BIAN–NHC backbone is unique from other benzofused NHC analogues^[1–22] due to (1) vastly accessible methods of synthesis, (2) diversity and ease of scaffold functionalization, (3) structural buttressing effects enabled by the acenaphthoimidazolylidene framework, (4) electronic properties enabled by the fused naphthalene system. The closest structural analogue, pyrene-containing ligands, are also included in the review for comparison purposes; however, it should be noted that these systems are less developed than BIAN–NHCs. Since the catalytic performance is the most important aspect of BIAN–NHCs in chemistry, the review covers a detailed description of catalytic results. Comparative studies vs. the classical imidazolylidene NHC ligands have been included in all examples when available. For clarity, all these examples are presented in italicized text. It should be noted that in all these published studies, BIAN–NHCs show superior reactivity to typical NHCs across various reactions, catalytic cycles and metals as demonstrated in this review, establishing broad generality of this ligand class.

Intriguingly, BIAN–NHCs represent one of the most striking examples of the “flexible steric bulk” concept owing to the buttressing effect of the ring, wherein the ligand can adjust to the steric substrate requirements during catalysis, while enabling high stabilization of the metal center.^[22] It is further important to note that during the last decade, a large number of BIAN–NHC ligands^[24] and transition-metal-BIAN–NHC complexes, including Ag,^[25] Au,^[26] Pd,^[27] Ni,^[28] Ir,^[29] Rh,^[29] and Pt^[30] complexes have been successfully developed, thus demonstrating the facility of synthesis of a broad range of novel BIAN–NHC complexes.

Herein, we provide a comprehensive overview of BIAN–NHC ligands in transition-metal-catalysis with a focus on both the catalyst structure and the scaffold’s role in catalysis. The review is organized by the type of metal used and further by the type of bond being formed. We hope that this review will stimulate the additional use of BIAN–NHC ligands by a range of chemists. In particular, we believe that a combination of the unique stereo-electronic properties, the facile synthesis of novel NHCs and the high air-stability engendered by the BIAN scaffold provide an attractive entryway to applying well-defined metal-BIAN–NHC complexes in modern catalytic processes that are difficult or impossible to achieve using other NHC ancillary ligands.

2. Palladium–BIAN–NHC Complexes

2.1. Palladium–BIAN–NHC-Catalyzed C–C Cross-Coupling

2.1.1. Heck Cross-Coupling

In 2006, the Çetinkaya group reported the first example of a BIAN-NHC-Pd complex based on naphthyl-fused imidazolinylidene scaffold (Scheme 1).^[23] The BIAN–NHC ligand was readily prepared by the sequential reduction-cyclization sequence of the corresponding IMes-BIAN di-imine. The electronic properties indicated that this BIAN–NHC ligand is a stronger σ-donor (ν_av = 2034 cm⁻¹; TEP = 2047 cm⁻¹ characterized as [RhCl(CO)₂(NHC)] complex) than the corresponding SIMes and IMes ligands (SIMes: ν_av = 2039 cm⁻¹; TEP = 2051 cm⁻¹; IMes: ν_av = 2041 cm⁻¹; TEP = 2053 cm⁻¹). The catalytic activity of 1 was evaluated in the Heck cross-coupling of aryl halides with alkenes.

Scheme 1.

Heck Cross-Coupling of Aryl Bromides Catalyzed by in Situ Formed BIAN–NHC–Pd or Preformed (BIAN–NHC)₂PdCl₂ Reported by Çetinkaya.

Two classes of catalysts were tested: (1) in situ formed Pd–BIAN–NHC complex generated from Pd(OAc)₂ (3 mol%)/1 (3 mol%) in the presence of Cs₂CO₃; and (2) bis-carbene precatalyst trans-(BIAN–NHC)₂PdCl₂ (3 mol%). The in situ formed Pd–BIAN–NHC complex showed high reactivity in the cross-coupling of aryl bromides (Scheme 1). Importantly, this seminal study demonstrated the beneficial effect of the BIAN ligand on the Heck cross-coupling as the use of SIMesHCl under the same reaction conditions resulted in lower yields.

2.1.2. Suzuki-Miyaura Cross-Coupling

In 2010, Green and co-workers reported the synthesis of allyl-supported [Pd(BIAN–NHC)(allyl)Cl] complexes based on naphthyl-fused saturated imidazolinylidene scaffold (2 and 3) (Scheme 2).^[31] Interestingly, the X-ray structure of 3 indicated unsymmetrical σ-π bonding of the allyl throw-away ligand, while temperature dependent NMR studies showed η³–η¹–η³ isomerisation of the allyl group. The catalytic activity of Pd–BIAN–NHC complexes 2 and 3 was tested in the Suzuki–Miyaura cross-coupling (Scheme 2). It was found that both 2 and 3 are highly active as Pd(II)–NHC precatalysts in the cross-coupling, including highly deactivated and sterically-hindered aryl halides. Impressively, quantitative conversions were obtained even for the challenging cross-coupling between sterically-hindered boronic acids and deactivated aryl chlorides.

Scheme 2.

Suzuki Cross-Coupling of Aryl Chlorides and Aryl Bromides Catalyzed by BIAN–NHC–Pd Reported by Green.

In 2012, Tu and co-workers reported the Suzuki–Miyaura cross-coupling to afford sterically-hindered biaryls using Pd–BIAN–IPr complex 4 (Scheme 3).^[32] The most striking feature of this chemistry is that the electronic-modification of the BIAN ligand permitted for a significantly improved reactivity at low catalyst loadings (0.05–0.5 mol%) as compared to the traditional imidazolylidene-based Pd–PEPPSI–IPr catalysts. The reaction was used to prepare extremely sterically-hindered biaryls, including the challenging tetra-ortho-substituted biaryls. This protocol is performed in the presence of t-BuOK as base and dioxane as solvent at 80 °C. The authors proposed that the high reactivity of the Pd–BIAN–IPr complex results from its stronger σ-donor properties than the related Pd–PEPPSI–IPr. The superb efficiency of the method was showcased in multiple one-pot cross-couplings. Furthermore, the protocol showed excellent functional group tolerance, including free hydroxyl and amino groups.

Scheme 3.

Synthesis of Sterically-Hindered Biaryls by Suzuki Cross-Coupling of Aryl Chlorides and Bromides Cata-lyzed by BIAN–NHC–Pd Reported by Tu.

In 2013, the Peris group reported pyracene-based [Pd(NHC)(allyl)Cl] and Pd–NHC–PEPPSI complexes 6–7 (Scheme 4).^[33] These bi-metallic complexes feature a π-extended pyracene-type bis-imidazolylidene group (pyrabim) and are structurally-related to Pd–BIAN complexes, such as Pd–BIAN–PEPPSI complex 4 (Scheme 3) and [Pd(BIAN–IPr)(allyl)Cl] 5 also prepared by the authors. The catalytic properties of complexes 4–7 were evaluated in the Suzuki–Miyaura cross-coupling of aryl bromides under the same reaction conditions. Intriguingly, it was found that bi-metallic complexes 6–7 showed much higher reactivity than their monometallic congeners 4–5, while allyl-based complex 6 [Pd(NHC)(allyl)Cl] was more reactive than PEPPSI-based complex 7. The reactions were performed in the presence of Cs₂CO₃ at 80 °C in dioxane at 2 mol% Pd loading. The authors proposed that the superior reactivity of bi-metallic complexes results from higher local concentration of palladium, while the extended π-system could be beneficial for substrate preorganization. This interesting study opened up the vistas for the use of polytopic^[34] π-extended BIAN-type complexes in catalysis.

Scheme 4.

Suzuki Cross-Coupling of Aryl Bromides Catalyzed by BIAN–NHC–Pd Reported by Peris.

In 2014, Humphrey and co-workers reported mixed NHC/phosphine [Pd(BIAN–NHC)(PPh₃)Cl₂] complexes 8–9 and evaluated their reactivity in the Suzuki–Miyaura cross-coupling of aryl halides under aqueous conditions (Scheme 5).^[35] The performance of catalysts 8–9 was also evaluated in non-polar solvents. Interestingly, it was found that water and toluene promoted catalyst decomposition to yield a new heterogeneous species, while both catalysts were considerably more stable in dichloromethane. Kinetic studies revealed that water significantly enhanced the catalyst activity. As expected, IPr–BIAN catalyst 9 showed higher reactivity than the corresponding IMes–BIAN complex 8.

Scheme 5.

Suzuki Cross-Coupling of Aryl Halides Catalyzed by BIAN–NHC–Pd Reported by Humphrey.

In 2016, one of us (F.S.L.) reported the Suzuki–Miyaura cross-coupling of aryl chlorides catalyzed by the backbone modified Pd–BIAN–IPr complex 10 (Scheme 6).^[36] In this study, we found that 1,2-di-tert-butyl-substitution of the acenaphthyl group results in a major catalytic improvement over the unsubstituted Pd–BIAN–IPr complex 4. Structural characterization of complex 10 by X-ray crystallography revealed that the bulky t-Bu groups intersect the coordination plane, which likely slows down rotation of N-wingtip substituents. Moreover, the BIAN scaffold leads to the perpendicular arrangement of the N-wingtip substituents. Altogether, these effects result in an enhanced stabilization of the monoligated NHC–Pd(0) and permit to conduct the cross-coupling under aerobic conditions. The catalytic performance was studied by kinetic studies. Interestingly, kinetic profiles showed comparable catalytic efficiency of complexes 10 and 4 at the initial t = 5 min. However, the backbone-modified complex 10 showed much longer life-time than Pd–BIAN–IPr complex 4 and the classical Pd–PEPPSI–IPr, which further confirmed the positive effect of sterically encumbered substituents on the BIAN-backbone. Impressively, this Suzuki–Miyaura cross-coupling could be performed at very low catalyst loading of 0.01–0.05 mol% in the presence of K₃PO₄ as a weak base in ethanol at 80 °C, and showed excellent functional group tolerance. It is noteworthy that the challenging cross-coupling of 2,6-dimethyl chlorobenzene with ortho-substituted boronic acids was smoothly accomplished to afford tri-ortho-substituted biaryls in close to quantitative yields. The scope was highlighted by the facile synthesis of Boscalid and sartan intermediates.

Scheme 6.

Suzuki Cross-Coupling of Aryl Chlorides Catalyzed by BIAN–NHC–Pd in Air Reported by Liu.

The synthesis of tetra-ortho-substituted biaryls has been recognized as one of the most challenging transformations in the field of Pd-catalyzed cross-coupling reactions.^[37] Although elegant examples demonstrated the feasibility of the synthesis of tetra-ortho-substituted biaryls using NHCs as ancillary ligands, these reactions have been limited by the necessity for strict air- and moisture-free conditions.^[38] In general, the oxidative addition step of di-ortho-substituted aryl halides requires a combination of (1) an electron-rich ancillary ligand, and (2) steric flexibility around the palladium center. Furthermore, while transmetalation using di-ortho-substituted arylboronic acids requires less hindered ligands, it is well established that these less sterically NHC–Pd(0) active species readily decompose to afford unreactive NHC–Pd(O₂) complexes in the presence of atmospheric oxygen.^[39] Moreover, aerobic conditions favor the formation of homocoupling and oxidation products. Thus, a delicate balance of the flexible steric environment and the use of strongly σ-donating ligands are implicated in the successful design of NHC ligands for the synthesis of tetra-ortho-substituted biaryls.

In 2017, we reported (F.S.L.) the Suzuki–Miyaura cross-coupling for the synthesis of sterically-hindered biaryls in air using a sterically-flexible Pd–BIAN–IPent catalyst 11 (Scheme 7).^[40] The Ir(I) complex [IrCl(CO)₂(NHC)] was used to gauge the electronic properties of this new BIAN–NHC carbene ligand, which indicated that both BIAN–IPent (TEP = 2042 cm⁻¹) and BIAN–IPr (TEP = 2042 cm⁻¹) are stronger σ-donors than the corresponding imidazolylidene-based IPent (TEP = 2049 cm⁻¹) and IPr (TEP = 2052 cm⁻¹) ligands. The structure of the Pd–BIAN–IPent complex 11 was confirmed by the X-ray crystallography (% V_bur = 38.2%), implying flexibility of the ligands around to the metal center. We proposed that the high reactivity of BIAN–IPent complex 11 resulted from the strong σ-donation and N-wingtip flexibility to accommodate different steric environment during oxidative addition and transmetallation steps, thus allowing for the synthesis of challenging tetra-ortho-substituted biaryls. The optimized protocol involved 1.0 mol% Pd loading in the presence of t-BuOK in t-BuOH at 80 °C. Notably, other Pd–NHC catalysts, such as Pd–PEPPSI–IPr*, Pd–PEPPSI–IPent or Pd–PEPPSI–IPr resulted in low reactivity, thus clearly showcasing the benefits of the BIAN framework. Importantly, these reaction conditions are also compatible with a range of medicinally-relevant heterocycles, including pyrazines, quinolines, pyridines, thiophenes and furans.

Scheme 7.

Suzuki Cross-Coupling of Aryl Chlorides Catalyzed by BIAN–NHC–Pd in Air Reported by Liu.

In 2018, we developed (F.S.L.) a new class of sterically-flexible Pd–BIAN–NHC catalysts such as 12 and applied them in the Suzuki–Miyaura cross-coupling of aryl chlorides at very low catalyst loading in air (Scheme 8).^[41] By systematic investigation of the structure-reactivity relationship, we identified complex 12 bearing unsymmetrical 2,4-(CHPh₂)₂-6-Me-C₆H₂ N-wingtip substitution as the excellent precatalyst for the Suzuki–Miyaura cross-coupling. The high reactivity of complex 12 was proposed to arise from high N-wingtip flexibility (% V_bur = 41.1%), while leaving significant open space for oxidative addition and transmetallation steps in combination with the strong σ-donation (TEP = 2047 cm⁻¹, Ir(I) complex [IrCl(CO)₂(NHC)]. These cross-couplings were conducted at very low 0.025 mol% Pd loading in the presence of K₂CO₃ as a mild carbonate base in EtOH at 80 °C. Notably, other Pd–NHC precatalysts, including Pd–PEPPSI–IPr, Pd–PEPPSI–IPr* or Pd–PEPPSI–IPent gave no or low yields under the reaction conditions, clearly demonstrating the advantage of BIAN-type backbone and unsymmetrical N-wingtip substitution on the catalytic reactivity. The facile synthesis of NHC salts such as in 12, excellent catalytic efficiency and broad functional group compatibility, including installation of biologically relevant heterobiaryls are attractive features of this class of catalysts.

Scheme 8.

Suzuki Cross-Coupling of Aryl Chlorides Catalyzed by BIAN–NHC–Pd in Air Reported by Liu.

In 2017, the Tu group reported the Suzuki–Miyaura cross-coupling of 9-chloroacridines catalyzed by a BIAN-type Pd–NHC precatalyst 13 supported on magnetic nanoparticles (Scheme 9).^[42] This reaction showed excellent functional group tolerance to yield biaryl acridine derivatives with potential applications in polymer science and medicinal chemistry at 0.5 mol% Pd loading. An advantage of this approach is that this method allows for catalyst recycling up to 5 times without any loss of catalytic activity.

Scheme 9.

Suzuki Cross-Coupling of 9-Chloroacridine Catalyzed by Nanoparticles supported BIAN–NHC–Pd Reported by Tu.

2.1.3. Negishi Cross-Coupling

The Negishi cross-coupling between aryl halides and organozinc reagents catalyzed by the Pd–BIAN–NHC complex 4 was reported by Tu and co-workers in 2013 (Scheme 10).^[43] The reaction was catalyzed by Pd–BIAN–IPr PEPPSI-type catalyst, which showed much higher reactivity than the analogous Pd–BIAN–IMes complex as well as the classical imidazolylidene Pd–PEPPSI–IPr. Both aryl bromides and chlorides could be utilized in this process. Likewise, a variety of alkyl and aryl organozinc reagents were compatible, including sterically-hindered and challenging α-branched substrates prone to isomerization. Mild room temperature reaction conditions, low catalyst loading (0.25 mol%) and excellent functional group tolerance, including aldehydes, amines, carbamates, nitriles, are notable features of this protocol. It is especially noteworthy that this protocol efficiently prevents isomerization of 2° alkyl organozinc reagents to the linear products, which could be attributed to the fast reductive elimination vs. the competing β-hydride elimination in the presence of the sterically-encumbered BIAN scaffold.

Scheme 10.

Negishi Cross-Coupling of Aryl Chlorides and Bro-mides Catalyzed by BIAN–NHC–Pd Reported by Tu.

Moreover, Browne demonstrated superior reactivity of Pd–BIAN–IPr complex 4 over the classical imidazolylidene Pd–PEPPSI–IPr in the Negishi cross-coupling between aryl bromides and alkyl organozinc reagents under mechanochemical ball milling conditions (not shown).^[44]

2.1.4. Sonogashira Cross-Coupling

In 2018, Tu and co-workers reported the Sonogashiracross-coupling of aryl bromides with phenylacetylenes catalyzed by a combination of Pd–BIAN–NHC PEPPSI-type catalyst 4 and the imidazolylidene IPr–Cu–Cl complex 14 (Scheme 11).^[45] The reaction was performed at very low Pd loading (0.01 mol%) in the presence of mild carbonate base and 1.0 mol% of Cu in DMSO at 120 °C. Interestingly, the authors found that the BIAN complex 4 gave much higher yields that the analogous allyl complex, [Pd(BIAN–IPr)(allyl)Cl] 5, suggesting non-innocent role of the pyridine throw-away ligand. Similarly, the IPr–Cu–Cl complex 14 showed higher reactivity than CuI and BIAN–IPr–Cu–Cl. The proposed mechanism involves the following steps: (1) oxidative addition of the aryl halide to NHC–Pd(0) to generate NHC–Pd(II)–Ar; (2) transmetallation with NHC–Cu–acetylide; (3) reductive elimination. This important study introduced the use of cooperative catalysis by two distinct transition-metal-NHC complexes involving BIAN scaffold.

Scheme 11.

Sonogashira Cross-Coupling of Aryl Halides Catalyzed by BIAN–NHC–Pd/NHC–Cu Reported by Tu.

2.1.5. Murahashi Cross-Coupling

In 2019, Feringa, Organ and co-workers reported Murahashi cross-coupling of aryl bromides with alkyl and aryl organolithium reagents catalyzed by Pd–BIAN–IPent catalyst 11 (Scheme 12).^[46] Interestingly, this catalyst showed higher reactivity than the classical imidazolylidene-based Pd–PEPPSI–IPr, Pd–PEPPSI–IPent and Pd–PEPPSI–IPent^Cl, permitting for the first example of the Murahashi coupling at temperatures below −65 °C. The beneficial effect of the BIAN scaffold was also evident in the efficient cross-coupling at very low catalyst loading (0.1 mol%). This chemistry is compatible with a variety of organolithium nucleophiles, including 1° and 2° alkyl organolithium as well as aryl and heteroaryl organolithium reagents. In terms of the electrophile, the cross-coupling is fully selective for bromides in the presence of chlorides. This exquisite selectivity allowed to achieve highly practical one-pot sequential cross-couplings for the synthesis of polyfunctionalized building blocks containing biaryls, amines or sulfides.

Scheme 12.

Murahashi Cross-Coupling of Aryl Bromides Cata-lyzed by BIAN–NHC–Pd Reported by Feringa and Organ.

2.1.6. C–H Arylation

In 2018, one of us (F.S.L.) reported the direct C–H arylation of azoles with aryl bromides catalyzed by Pd–BIAN–NHC complex 15 under aerobic conditions (Scheme 13).^[47] Interestingly, we found that remote modification of the N-wingtip group by the bulky CHPh₂ substitution at the 4-position led to significant improvement in the catalytic reactivity. It was proposed that the strong σ-donation of BIAN-type catalysts would lead to a facile oxidative addition, while the remote N-wingtip substitution would stabilize the reactive Pd species by increased bulk. These C–H activation reactions are performed in air at very low catalyst loading (0.05–0.5 mol%) in the presence of PivOH in DMAc at 130 °C. Complex 15 showed much higher reactivity than the classical imidazolylidene Pd–PEPPSI–IPr or unfunctionalized BIAN-IPr complex 4. Another noteworthy feature is fully regioselective C–H arylation of several classes of heterocycles and excellent functional group tolerance, including aryl bromides and various medicinally-relevant scaffolds, such as imidazoles, pyrazoles, thiazoles, isoxazoles, triazoles, pyridines, pyrimidines and quinolines.

Scheme 13.

Direct C–H Arylation of Azoles with Aryl Bromides Catalyzed by BIAN–NHC–Pd in Air Reported by Liu.

2.1.7. C–H Acylation

In 2013, the Peris group reported C–H acylation of hydrocinnamaldehyde with aryl halides catalyzed by their bi-metallic pyracene-type Pd–NHC complexes 6–7 and Pd–BIAN–PEPPSI and [Pd(BIAN–IPr)(allyl)Cl] complexes 4-5 (Scheme 14, cf. Scheme 4).^[33] The PEPPSI-based catalyst 4 showed the highest reactivity in this acylation. In contrast to the Suzuki–Miyaura cross-coupling (Scheme 4), the mono-metallic catalysts were more reactive than their bi-metallic counterparts.

Scheme 14.

Acylation of Aryl Halides with Hydrocinnamaldehyde Catalyzed by BIAN–NHC–Pd Reported by Peris.

2.1.8. Miscellaneous

In addition to the studies outlined above, it is important to note that chiral BIAN-type complexes (see, Section 3.1. and Section 8) have been tested in the Pd-catalyzed enantioselective Suzuki–Miyaura cross-coupling for the synthesis of atropoisomeric biaryls.^[48] These Pd–BIAN-ANIPE catalysts showed excellent reactivity; however, resulted in slightly lower enantioselectivity than the analogous imidazolinylidene complexes (80% ee vs. 96% ee). Considering the lower hydrolytic stability of imidazolinylidenes,^[1a–d] the use of more stable BIAN-type NHC ligands could provide an attractive avenue for future developments.

2.2. Palladium–BIAN–NHC-Catalyzed C–N Cross-Coupling

2.2.1. Buchwald-Hartwig Amination

In comparison with the numerous phosphine-based ligands in the Pd-catalyzed Buchwald-Hartwig cross-coupling, the development of Pd–NHCs for amination reactions is still in its infancy.^[49] In 2010, Green and co-workers reported Buchwald-Hartwig amination of aryl chlorides and bromides using their [Pd(BIAN–NHC)(allyl)Cl] complexes 2–3 based on BIAN imidazolinylidene scaffold (Scheme 15).^[31] These reactions were performed using morpholine and N-methylaniline as nucleophiles at 1.0 mol% palladium loading. The use of t-BuOK and dioxane gave optimal results. Impressively, this catalytic system permitted the cross- coupling of deactivated aryl chlorides in excellent yields at room temperature.

Scheme 15.

Buchwald-Hartwig Cross-Coupling of Aryl Chlorides and Bromides Catalyzed by BIAN–NHC–Pd Reported by Green.

In 2011, Tu and co-workers reported Buchwald-Hartwig amination of aryl chlorides using their Pd–BIAN–NHC catalyst 4 featuring the 3-Cl-pyridine throw-away ligand (Scheme 16).^[50] The structure of 4 was confirmed by the X-ray crystallography for the first time, and indicated a shorter Pd–C bond (1.960 Å) than in the classical imidazolylidene-based Pd–PEPPSI–IPr (1.969 Å), consistent with the stronger σ-donor character of the BIAN scaffold. The cross-coupling was performed at very low catalyst loading (0.075–0.5 mol%) using t-BuOK in dioxane at 80 °C. Catalyst poisoning studies indicated that the reaction follows the homogenous mechanism, as expected from the reaction conditions. Notably, the authors demonstrated excellent scalability of the protocol in that the synthesis of 2-(4-morpholinyl)pyridine was performed on 100 mmol scale (16 gram) at 0.075% catalyst loading.

Scheme 16.

Buchwald-Hartwig Cross-Coupling of Aryl Chlorides Catalyzed by BIAN–NHC–Pd Reported by Tu.

In 2017, Tu and co-workers reported Buchwald-Hartwig amination catalyzed by Pd–BIAN–NHC catalysts 16a-c supported by the ortho-metallated N,N-dimethylbenzylamine palladacycle throw-away ligand (Scheme 17).^[51] They found that the palladacycle catalysts 16a-c showed much higher reactivity in the amination than the PEPPSI-based Pd–BIAN–IPr catalyst 4 and the analogous imidazolylidene-based catalyst 16d. Unexpectedly, both N-mesityl and N-phenyl catalysts 16b-c afforded similar yields to the more sterically-demanding N-2,6-diisopropylphenyl catalyst 16a. The authors proposed that the high activity of complexes 16 results from a high stability of the palladacycle under the reaction conditions; however, kinetic studies were not performed to support this hypothesis. This protocol is compatible with a variety of 3-chloropyridines and related N-heterocycles to provide the cross-coupling products in high yields at 0.50 mol% catalyst loading. Importantly, the use of 16a is highly selective for mono-N-amination under these conditions.

Scheme 17.

Buchwald-Hartwig Cross-Coupling of Aryl Chlorides Catalyzed by BIAN–NHC–Pd Reported by Tu.

In 2017, one of us (F.S.L.) reported Buchwald-Hartwig amination of aryl chlorides under practical aerobic conditions catalyzed by unsymmetrical Pd–BIAN–NHC catalyst 17 featuring sterically-differentiated N-Dipp and N-4-MeO-((2,6-Ph₂CH)₂-C₆H₂) wingtips (Scheme 18).^[52] In general, the synthesis of unsymmetrical imidazolylidene NHC ligands is notoriously challenging due to selectivity issues, the BIAN scaffold enables high yielding introduction of differentiated N-substituents by step-wise condensation with acenaphthoquinone. Kinetic studies established that catalyst 17 is significantly more effective than the classical imidazolylidene-based Pd–PEPPSI–IPr and the analogous Pd–BIAN–IPr catalyst 4 with symmetrical N-Dipp wingtips. Under the tested conditions, Pd–PEPPSI–IPr* was also an efficient catalyst; however, it resulted in lower conversions than that of 17. The electron-donating 4-MeO group in 17 enhances σ-donation of the NHC ligand, while the unsymmetrical arrangement of the N-substituents enables gradual variation of flexible steric bulk protecting monoligated NHC–Pd(0). This combination permits for the highly efficient cross-coupling under aerobic conditions. The optimum conditions involve 17 at 0.1 mol% catalyst loading in the presence of t-AmOK in dioxane at 100 °C. This protocol was compatible with a wide range of sterically-hindered aryl and heteroaryl chlorides, including with 1° and 2° aliphatic and aromatic amines. Furthermore, DFT studies of the catalytic cycle established that oxidative addition is the rate-determining-step.

Scheme 18.

Buchwald-Hartwig Cross-Coupling of Aryl Chlorides Catalyzed by Unsymmetrical BIAN–NHC–Pd in Air Reported by Liu.

In 2018, we reported (F.S.L.) Buchwald-Hartwig amination of sterically-hindered and electronically-deactivated substrates catalyzed by Pd–BIAN–IPent catalyst 18 (Scheme 19).^[53] This highly practical cross-coupling was conducted under aerobic conditions using KOt-Bu as a base in dioxane at 100 °C.

Scheme 19.

Buchwald-Hartwig Cross-Coupling of Aryl Chlorides Catalyzed by Bulky BIAN–IPent–Pd in Air Reported by Liu.

Extensive screen of various Pd–NHC precatalysts indicated that 18 was significantly more reactive than the classical Pd–PEPPSI–IPr, the imidazolylidene-based, sterically-hindered Pd–PEPPSI–IPr* as well as the symmetrical Pd–BIAN–IPr 4 with N-Dipp wingtips and the unsymmetrical Pd–BIAN–NHC 17. Furthermore, pyridine throw-away ligand was found to be more effective than 3-chloro-pyridine. The structure of the catalyst 18 was confirmed by the X-ray crystallography. This allowed to determine % V_bur of this BIAN–IPent ligand (38.2%) to be larger than that of BIAN–IPr (34.7%) and IPr (34.3%) (determined for Pd–PEPPSI complexes), which suggests a more comprehensive protection of the metal center during the cross-coupling. The significant σ-donation is suggested to facilitate oxidative addition. This reaction was compatible with a remarkably broad scope of sterically-hindered aryl chlorides and electron deficient anilines, providing medicinally-relevant heteroaryl amines in excellent yields, including chelating heterocyclic substrates that typically shut down the catalytic cycle through coordination to palladium. It is noteworthy that the use of Pd–BIAN–NHC 18 fully suppressed the formation of diarylated products. However, it should be noted that a limitation of this class of catalysts is the lengthy synthesis of N-IPent aniline (IPent = 2,6-di-isopentyl), which leaves room for future improvements.

More recently, we reported another strategy for Buchwald-Hartwig cross-coupling of aryl chlorides catalyzed by the sterically-bulky Pd–BIAN–IPr*^OMe complex 19 under aerobic conditions (Scheme 20).^[54] In contrast to ‘bulky-yet-flexible’ catalyst design, the most important variation in this class of catalysts is the combination of the π-extended electron-rich BIAN scaffold with the rigid and electron-rich classical IPr*^MeO imidazolylidene catalysts. This merger leads to strong σ-donation (TEP = 2048 cm⁻¹, measured for [IrCl(CO)₂(NHC)] and large buried volume (% V_bur = 42.6%, measured for Pd–PEPPSI complex) of the BIAN–IPr*^OMe ligand in 19. This catalyst allowed for the efficient cross-coupling of deactivated five-membered and six-membered heterocycles, such as thiazoles, benzothiazoles, benzoxazoles, pyridines, quinolines and diazines with heteroaryl amines. The utility of this protocol was showcased in the synthesis of pharmaceuticals, Brexpiprazole and Piribedil. It is important to point out that this class of BIAN–IPr*^OMe catalysts benefits from the facile synthesis of N-wingtip anilines as compared with N-IPent-type precursors, while the introduction of strong σ-donor, rigid ligands has a key role in the success of challenging Buchwald-Hartwig aminations.

Scheme 20.

Buchwald-Hartwig Cross-Coupling of Aryl Chlorides Catalyzed by Bulky BIAN–IPr*MeO–Pd in Air Reported by Liu.

In 2017, Bazzi and co-workers reported another approach to Buchwald-Hartwig amination using polyisobutylene-supported Pd–BIAN–NHC catalyst 20 (Scheme 21).^[55] A practical advantage of polyisobutylene-tagging is facile catalyst separation in biphasic heptane/acetonitrile mixture. However, under the tested reaction conditions, Pd–BIAN–NHC catalyst 20 showed slightly lower reactivity than the analogous imidazolylidene-based catalyst.

Scheme 21.

Buchwald-Hartwig Cross-Coupling of Aryl Chlorides Catalyzed by BIAN–NHC–Pd Reported by Bazzi.

2.2.2. Aminocarbonylation.

In 2013, Tu and co-workers reported aminocarbonylation of aryl iodides catalyzed by [Pd(BIAN–IPr)(allyl)Cl] complex 5 (Scheme 22).^[56[ The X-ray structure of 5 was determined and indicated Pd– C(carbene) bond of 2.048 Å, which can be compared with the Pd–C(carbene) bond of 2.040 Å for the analogous imidazolylidene complex [Pd(IPr)(allyl)Cl].^[7] This catalyst showed higher reactivity than BIAN–IPr–PEPPSI complex 4 and the classical imidazolylidene complex [Pd(IPr)(allyl)Cl]. An attractive feature of this protocol is atmospheric pressure of CO, low Pd loading (0.5–1.0 mol%) and broad substrate scope, including the synthesis of medicinally-relevant amides, such as pharmaceutical Tamibarotene. The authors proposed that the strong σ-donation of the BIAN scaffold facilitates oxidative addition in the presence of a large excess of CO.

Scheme 22.

Aminocarbonylation of Aryl Iodides Catalyzed by BIAN–NHC–Pd Reported by Tu.

Subsequently, the Tu group developed a mild protocol for the double aminocarbonylation of o-dihaloarenes catalyzed by BIAN–IPr–PEPPSI complex 4 at atmospheric CO pressure (Scheme 23).^[57] Interestingly, in this reaction the BIAN-supported catalyst 4 showed much higher reactivity than the classical Pd–PEPPSI–IPr, allowing to achieve a TON of 5,000 at 0.10 mol% catalyst loading; however, a very similar reactivity between PEPPSI and allyl-supported BIAN complexes 4 and 5 was reported. This method represents a highly practical approach to various N-substituted phtalimides, including pharmaceuticals Thalidomide and Alrestatin as well as to fluorescent imides.

Scheme 23.

Double Aminocarbonylation of o-Diiodobenzene Catalyzed by BIAN–NHC–Pd Reported by Tu.

2.3. Palladium–BIAN–NHC-Catalyzed C–S Cross-Coupling

In 2017, Tu and co-workers reported the direct alkylsulfonylation of boronic acids with halides and potassium metabisulfite (K₂S₂O₅) catalyzed by [Pd(BIAN–IPr)(allyl)Cl] complex 5 (Scheme 24, see also Scheme 36).^[58] This transformation represents a rare example of C–S bond cross-coupling catalyzed by BIAN–NHC-metal complexes. In the optimization study, the authors showed that [Pd(BIAN–IPr)(allyl)Cl] complex 5 showed comparable reactivity to its cinnamyl analogue, [Pd(BIAN–IPr)(cin)Cl], and higher than BIAN–IPr–PEPPSI complex 4 and imidazolylidene complex [Pd(IPr)(allyl)Cl]. The scope of this reaction is broad using a-halo-carbonyl, benzylic and even 1° alkyl electrophiles. In terms of the boronic acid component, the reaction tolerates aromatic, heteroaromatic and alkenyl boronic acids; however, a disadvantage of this protocol is the requirement for 5 mol% catalyst loading. A mechanism involving transmetallation between Pd(II) and boronic acid, SO₂ insertion to give a dimeric Pd(II) complex, and alkylation was proposed. The authors suggested that TBAF might facilitate the formation of sulfinate from the dimeric Pd(II) species. This transformation appears to be broader in scope than the analogous Au–BIAN–NHC-catalyzed protocol reported by the same group (see Scheme 36).

Scheme 24.

Direct Alkylsulfonylation of Aryl Boronic Acids with Alkyl Halides Catalyzed by BIAN–NHC–Pd Reported by Tu.

Scheme 36.

C–H Hydroarylation of Alkenes Catalyzed by Pyrene–NHC–Ru Reported by Peris.

3. Nickel–BIAN–NHC Complexes

Recently, Ni-catalysis has emerged as a powerful reactivity manifold in cross-coupling due to high nucleophilicity of nickel, enabling challenging oxidative additions.^[59] In this context, Ni–BIAN–NHC complexes have seen major progress as a tool for asymmetric C–H functionalization.

3.1. C–C Cross-Coupling

In 2019, the Shi group reported enantioselective C–H alkylation of fluoroarenes with alkenes catalyzed by Ni(cod)₂ in the presence of NaOt-Bu and the chiral BIAN ligand 21 (Scheme 25, see also Scheme 41).^[60] These same group proposed the buttressing effect of the acenaphthoimidazolylidene ring in enantioselective ligand design in the context of Cu–NHC-catalyzed hydroboration (Scheme 41), pushing the chiral N-wingtip groups closer to the metal center.^[79]

Scheme 25.

Enantioselective C–H Alkylation of Fluoroarenes Catalyzed by BIAN–NHC–Ni Reported by Shi.

Scheme 41.

Enantioselective Protoboration of α-Olefins Catalyzed BIAN–NHC–Cu Reported by Shi.

The authors found that in this case, the BIAN-based ligand was more effective for C–H annulation of aryl-substituted olefins, while the analogous imidazolinylidene-based chiral ligand was slightly preferred for cyclization of alkyl-substituted olefins. The chiral ligand 21 showed similar reactivity to BIAN-based (R,R,R,R)-ANIPE ligand (see Scheme 40) developed for a Cu-catalyzed protoboration by the same group (Ar = Ph instead of Ar = 3,5-xyl). Importantly, the authors found that the use of BIAN-based ligand 21 was critical to prevent olefin isomerization, which was the predominant reaction pathway using the classical imidazolinylidene. In this protocol, C–F activation was not observed even though activated polyfluorinated arenes were used as substrates. The authors proposed that the steric-bulk of the ligand accelerates reductive elimination and promotes endo-selective annulation. The scope of this transformation is impressively broad showing tolerance to various functional groups, including alcohols, amides and ketones. It also worth noting that in 2019, Shi and co-workers reported a closely related Ni–NHC catalyzed C–H alkylation of pyridines (not shown).^[60b] In this study, they found that BIAN-based ANIPE-type ligands resulted in a superior enantioselectivity than saturated NHC ligands for select challenging substrates.^[60b]

Scheme 40.

Electrophilic 1-En-6-yne Cyclization Catalyzed by BIAN–NHC–Au Reported by Plenio.

In 2018, Cramer and co-workers reported highly enantioselective C–H annulation of pyridones with alkenes catalyzed by a combination of Ni(cod)₂, MAD as a Lewis acid and a sterically-bulky, chiral BIAN ligand 21 (Scheme 26).^[61a] The authors found that replacement of the imidazolylidene scaffold in the Gawley’s C2-symmetric NHC carbenes^[62] with the BIAN framework resulted in a significant improvement in selectivity. The structures of [Ni(BIAN–NHC)CpCl] and [Au(BIAN–NHC)Cl] complexes with BIAN–NHC ligand related to 21 (Ar = Ph instead of Ar = 3,5-xyl) were determined by the X-ray crystallography. Interestingly, both of these complexes showed lower V_bur than the analogous Ni(II) and Au(I) imidazolylidene complexes (Ni: 35.7% vs. 38.7%; Au: 43.5% vs. 49.4%); this steric differentiation could improve steric access to the metal center in BIAN and further indicates flexibility of the bulky BIAN scaffold in adjusting to steric environment. The scope of this C–H annulation is very broad and encompasses various 2- and 4-pyridones as well as uracils and thiopyridones to afford chiral N-containing heterocycles in an attractive C–H functionalization protocol. A very similar study on the Ni–NHC-catalyzed pyridine C–H alkylation was reported.^[61b]

Scheme 26.

Enantioselective C–H Annulation of Pyridones Catalyzed by BIAN–NHC–Ni Reported by Cramer.

In 2020, Ho and co-workers reported a highly selective cross-dimerizaton of olefins and methylenecyclopropanes catalyzed by Ni–BIAN–NHC complexes (Scheme 27).^[63] The authors found that a combination of [Ni(BIAN–IPr)(allyl)Cl] catalyst 22 and NaBAr^F could be used to achieve high yields and remarkable selectivity in this [3+2] cross-dimerization. The use of BIAN–IPr ligand provided significantly better results than the classical imidazolylidene-based IPr and imidazolinylidene-based SIPr ligands, while the closest, yet lower, reactivity was observed with the difficult to prepare IPent^Me ligand. Furthermore, the more sterically-hindered BIAN–IPent ligand provided inferior results. The use of NaBAr^F as an additive was found necessary for the reaction to occur. The proposed mechanism involves allyl exchange of [Ni(BIAN–IPr)(allyl)BAR^F] with allyl zwitterion derived from methylenecyclopropane. The high selectivity for cross-dimerization was proposed to originate from the fast exchange and slow β-hydride elimination under the reaction conditions. This reaction is particularly noteworthy for the excellent functional group tolerance, high chemoselectivity and the use of simple unactivated olefins as substrates.

Scheme 27.

[3+2] Cross-Dimerization of Olefins and Methylenecyclpropanes Catalyzed by BIAN–NHC–Ni Reported by Ho.

In 2019, the Ye group has reported another attractive approach in their reductive coupling of alkynes with imines catalyzed by Ni(cod)₂ in the presence of BIAN–IPr ligand 23, KOt-Bu as catalytic base and i-PrOH as proton source (Scheme 28).^[64] Direct comparison with a collection of phosphine ligands as well as classical imidazolylidene and imidazolinylidene NHC ligands, such as ICy, IPr, SIPr, IPr* and IPr^Me indicated that BIAN–IPr is a much superior ligand in this transformation. The authors proposed that the strong σ-donation and the sterically-bulky BIAN backbone are the key to the success of the BIAN–IPr ligand in promoting this challenging reductive coupling. Interestingly, the reaction is highly sensitive to the steric environment as the less bulky BIAN– IMes gave only low yield of the coupling product. This reaction has a very broad substrate scope and is conducted using sustainable isopropanol as a reductant, thus showing the promise for its future applications. Furthermore, the authors demonstrated the capacity of this coupling in an enantioselective fashion to yield chiral allylic amines using ligand 21 (see Scheme 26) under very similar reaction conditions. Labelling studies suggested that isopropanol acts as the hydride source in this new C–C bond forming method.

Scheme 28.

Reductive Coupling between Imines and Alkynes Catalyzed by BIAN–NHC–Ni Reported by Ye.

3.2. C–N Cross-Coupling.

In 2014, Tu and co-workers reported Buchwald-Hartwig amination of aryl tosylates catalyzed by Ni–BIAN–NHC at low catalyst loading (Scheme 29).^[65] The active catalyst was formed in situ from NiCl₂·DME and BIAN–IPr salt 23. The use of PhBin and NaOt-Bu as a strong base are required for this reaction. Importantly, BIAN–IPr 23 showed much higher reactivity than the classical imidazolylidene NHCs, such as IPr and IMes. The scope of this amination is broad with respect to the amine component, including 1° and 2° aliphatic as well as aromatic amines; however, the method predominantly requires the use of naphthyl tosylates, which somewhat limits the applicability of this otherwise very interesting transformation. Preliminary results indicated that benzodioxole and even phenyl tosylates might be compatible substrates, which would lead to a more synthetically useful protocol. This reaction could lead to the development of attractive C–O activation methods catalyzed by Ni–BIAN complexes as a practical alternative to Pd.

Scheme 29.

Buchwald-Hartwig Cross-Coupling of Aryl Tosylates Catalyzed by BIAN–NHC–Ni Reported by Tu.

4. Rhodium–BIAN–NHC Complexes

In 2009, Green and co-workers reported the synthesis of Rh(I) complexes [Rh(BIAN-SIMes)(cod)Cl] 24 and [Rh(BIAN-SIPr)(cod)Cl] 25 based on the saturated imidazolinylidene BIAN scaffold and their application in the hydroformylation of 1-octene (Scheme 30).^[66] Both complexes showed similar reactivity at 0.1 mol% loading, favoring aldehyde as the major product. Isomerization to the branched product was observed as the major pathway (l:b = 0.58–0.75), while reduction to the alcohol was typically <5%. The Rh(I) complex 25 was shown to be reactive at 0.01 mol% loading, thus closely matching the most reactive Rh(I)–NHC systems for hydroformylation reactions.

Scheme 30.

Hydroformylation of 1-Octene Catalyzed by BIAN–NHC–Rh Reported by Green.

5. Iridium–BIAN–NHC Complexes

In 2016, Peris and co-workers reported the synthesis of mono- and bi-metallic Ir(III) complexes 26–28 based on pyrene scaffold (Scheme 31).^[67] In these NHCs, the rigid aromatic π-system represents an extended homologue of the BIAN scaffold, while the NHC salt is readily prepared from pyrene-4,5-dione (cf. acenaphthoquinone). These complexes feature chloride [Ir(NHC)Cp*Cl₂] (26) or carbonate ligands [Ir(NHC)Cp*CO₃] (27), [{IrCp*(CO₃)}₂(μ-NHC)] (27) coordinated to Ir. The authors demonstrated the catalytic activity of 26–28 in β-alkylation and H/D exchange reactions (Scheme 30–31). The bi-metallic complex 28 was found to be the most reactive in the model β-alkylation of 1-phenylethanol with 1° alcohols (Scheme 31). These β-alkylation reactions were performed at 0.50 mol% Ir loading in toluene at 100 °C. The intriguing high activity of complex 28 was proposed to arise from cooperative interaction between the two metal centers.

Scheme 31.

β-Alkylation 1-Phenylethanol with 1° Alcohols Cata-lyzed by Pyrene–NHC–Ir Reported by Peris.

The catalytic activity of Ir(III) complexes 26–28 was also tested in H/D exchange reactions (Scheme 32).^[67] Although in H/D exchange of acetophenone and styrene monometallic complexes 26–27 appeared to be more reactive than the bi-metallic complex 28, all three complexes were significantly more reactive than phosphine-based Ir(III) complex [Ir(PMe₃)Cp*Cl],^[68] thus showing the benefit of using π-extended pyrene-based NHC complexes for this process.

Scheme 32.

H/D Exchange Catalyzed by Pyrene–NHC–Ir Report-ed by Peris.

6. Ruthenium–BIAN–NHC Complexes

6.1. Alkene Metathesis

In 2012, Merino and co-workers reported the synthesis of a second generation of Hoveyda-Grubbs catalyst based on BIAN–IMes scaffold 29 (Scheme 33).^[69] Impressively, compared with the classical imidazolinylidene SIMes and imidazolylidene IMes H-G2 catalysts, complex 29 showed higher reactivity in the ring-closing-metathesis of diethyl diallylmalonate, while a comparable reactivity was observed using N,N’-diallyl-4-methyl-benzenesulfonamide. Complex 29 was stable at room temperature for over 15 days. The high activity of BIAN-based complex 29, in particular, in comparison with the typically used SIMes-based H-G2 catalysts provides an attractive entry to the development of more active catalysts for olefin metathesis.

Scheme 33.

Ring Closing Metathesis Catalyzed by BIAN–NHC–Ru Reported by Merino.

In 2016, Bazzi and co-workers reported the synthesis of polyisobutylene-derived BIAN–IMes-based H-G2 catalyst 30 (Scheme 34).^[70] The advantage of polyisobutylene tether is that the catalyst can be recycled by performing the reaction in a non-polar solvent and extraction with acetonitrile. Kinetic studies in the ring-closing-metathesis of 2,2-diallylmalonate demonstrated that BIAN–IMes catalyst 30 is more reactive than the classical imidazolinylidene SIMes H-G2 bearing the same polyisobutylene tether. This finding mirrors the study by Merino and co-workers (cf. Scheme 32) in that the BIAN scaffold has a beneficial effect on alkene metathesis. In addition, complex 30 was applied to ring-opening-polymerization of norbornene derivatives, affording high molecular weight polymers.

Scheme 34.

Ring Closing Metathesis Catalyzed by BIAN–NHC–Ru Reported by Bazzi.

6.2. C–H Arylation

In continuation of their studies on di-metallic transition-metal-NHC complexes based on pyrene scaffold, in 2014, Peris and co-workers reported the synthesis of Ru(II) complexes 31–32 (Scheme 35).^[71] These mono- and di-metallic Ru(II) catalysts were tested in the direct C(sp²)–H arylation of pyridines with aryl halides (Scheme 35) and hydroarylation of alkenes (Scheme 36). Interestingly, both complexes 31–32 showed comparable reactivity in C(sp²)–H arylation, leading exclusively to the formation of bis-arylated products. Likewise, both 31–32 were highly reactive in the hydroarylation of olefins; however, this reaction resulted in the selective mono-hydroarylation of phenylpyridines. This important study demonstrates high activity of π-extended NHC–Ru complexes in the attractive Ru(II)-catalysis C–H activation manifold.^[72,20]

Scheme 35.

C–H Arylation of 2-Arylpyridines Catalyzed by Py-rene–NHC–Ru Reported by Peris.

7. Gold–BIAN–NHC Complexes

7.1. C–S Bond Formation

In 2017, Tu and co-workers reported the direct alkylsulfonylation of boronic acids using BIAN–IPr–Au–Cl complex 33 as a catalyst (Scheme 37).^[73] The reaction is performed with K₂S₂O₅ as the sulfonating reagent. In most examples, activated halides were used; however, a preliminary result indicated the feasibility of 1° alkyl halides as electrophiles. The authors demonstrated that BIAN-based Au(I) catalysts gave significantly higher yields than the classical imidazolylidene-based IPr and IMes (NHC)Au(Cl) complexes. The sterically-demanding BIAN–IPr ligand gave higher yield than the less bulky BIAN–IMes, while both (NHC)Au(Cl) and (NHC)Au(OH) complexes were similarly efficient in this coupling. The authors proposed that the strong σ-donor character of BIAN-scaffold is the key factor in this challenging transformation. The reaction showed broad functional group tolerance, allowing for the convergent synthesis of sulfones. The proposed mechanism involves transmetallation of NHC–Au(I) species with boronic acid, SO₂ insertion to afford NHC–AuSO₂–Ar, and alkylation via arylsulfinate intermediate.

Scheme 37.

Direct Alkylsulfonylation of Aryl Boronic Acids with Alkyl Halides Catalyzed by BIAN–NHC–Au Reported by Tu.

More recently, the Tu group reported the synthesis of diaryl sulfones by the direct arylsulfonylation of boronic acids using the same BIAN–IPr–Au–Cl complex 33 as a catalyst (Scheme 38).^[74] The key finding of this protocol is that diaryliodonium salts can be used as electrophiles under very similar reaction conditions to alkylsulfonylation (cf. Scheme 37). The authors found that BIAN–IPr ligand is preferred over the classical imidazolylidene ligands, such as IPr and IMes. This protocol tolerates a broad range of functional groups, including ketal, chloro, TMS, and indazole. The reaction could be performed on a gram scale as demonstrated in the synthesis of a farnesyl-protein transferase inhibitor; however, the limitation of this protocol is high catalyst loading. Mechanistically, the key steps involve transmetallation of NHC–Au(I) with aryl boronic acid, SO₂ insertion and arylation of the arylsulfinate intermediate by the aryl cation generated from diaryliodonium salt.

Scheme 38.

Direct Arylsulfonylation of Aryl Boronic Acids with Diaryliodonium Salts Catalyzed by BIAN–NHC–Au Reported by Tu.

7.2. C–N Bond Formation

In 2018, Peris and co-workers reported the synthesis of a di-gold(I) complex 34 bearing a π-extended pyrene NHC ligand (Scheme 39).^[75] The catalytic activity of 34 was tested in hydroamination of phenylacetylene with anilines at low catalyst loading. Impressively, up to 900 TON was obtained at 0.05 mol% loading. Interestingly, a further increase in the catalytic efficiency was observed upon addition of coronene. This effect was explained by π-stacking interactions, which could prevent the formation of inactive dimers. This finding represents a potential future direction in enhancing the reactivity of π-extended NHC ligands.

Scheme 39.

Hydroamination of Phenylacetylene Catalyzed by Pyrene–NHC–Au Reported by Peris.

7.3. C–O Bond Formation

In 2018, Zuccaccia showed that BIAN–IPr–Au–X complexes are among the most highly active NHC complexes in hydration of 3-hexyne at 0.10 mol% loading (not shown).^[76] In this manifold, the reactivity closely depends on the counterion, and showed the following order of reactivity: OTf > OTs > Cl; however, this process was not further explored. Additional studies on the structure and reactivity of BIAN–Au–X complexes have been published.^[77,26a,c]

7.4. C–C Bond Formation

In 2016, Plenio and co-workers reported the synthesis of a BIAN-based Au(I) complex 35 featuring extremely bulky N-pentiptycene wingtip substituents (Scheme 40).^[78] This catalyst was tested in the electrophilic cyclization of diethyl 2-allyl-2-(prop-2-ynyl)malonate, affording the desired product in much higher yield and selectivity than the structurally-related (IMes)AuCl.

8. Copper–BIAN–NHC Complexes

In 2018, Shi and co-workers reported an impressive protocol for enantioselective protoboration of terminal olefins catalyzed by a chiral BIAN–NHC–Cu complex 36 (Scheme 41).^[79] The authors proposed that a combination of strong σ-donation and steric buttressing effect afforded by the BIAN scaffold together with the C₂-symmetric chiral wingtip substitution is the key to afford high regio- and enantioselectivity in this process. In agreement with this design, the classical imidazolylidene-based analogue of 36 furnished the product with much lower selectivity. The optimized conditions involve the use of 2 mol% of BIAN–NHC–Cu complex 36 in the presence of B₂dmpd₂ (dmpd = dimethylpentanediol), MeOH as proton source and t-BuONa as base in n-hexane. The scope of this transformation is very broad, including a range of functional groups, such as ethers, ketones, amines and halides. The proposed mechanism involves the regio- and enantioselectivity determining olefin borylcupration, protonation of the alkylcopper intermediate, and σ-metathesis of the copper alkoxide with the diboron reagent. This important transformation demonstrates the beneficial effect of BIAN–NHC complexes in the essential area of enantioselective Cu–NHC catalysis.^[80]

9. Conclusions and Outlook

As demonstrated in this review, the recent years have witnessed tremendous advances using BIAN–NHC ligands as pivotal ancillary ligands to promote catalytic transformations. There are several clear benefits of BIAN–NHCs, including (1) stronger σ-donor character, (2) stronger π-acceptance, (3) steric buttressing effect of the scaffold, (4) ease of synthesis of unsymmetrical N-wingtip precursors, (5) high stability of metal-BIAN–NHC complexes to aerobic conditions, (6) capacity to promote reactions at very low catalyst loading, (7) extended π-aromatic system available for coordination, and (8) scaffold modification that permits for the synthesis of diverse analogues. Importantly, the high activity of BIAN–NHCs as privileged ligands in transition-metal-catalysis has been demonstrated with metals across the periodic table, including Pd, Ni, Ir, Rh, Ru, Au and Cu, which provides an attractive springboard for metal-dependent advantages of each transformation.

Among several exciting developments in this area have been (1) the emergence of asymmetric catalysis by chiral BIAN–NHC ligands; (2) the establishment of Pd-catalyzed cross-coupling reactions at low catalyst loadings; (3) the development of Au- and Pd-catalyzed sulfonation reactions; (4) the discovery of di-metallic complexes with improved selectivity by π-stacking and cooperative catalysis; (5) the development of Pd-catalyzed cross-couplings of challenging electrophiles under exceedingly mild conditions; (6) the establishment of active Ru–BIAN catalysts for alkene metathesis reactions; (7) electrophilic functionalization at low catalyst loading. In these methods, the high catalytic activity of BIAN-transition-metal complexes is retained even at low catalyst loading under aerobic conditions, features improved kinetics, higher selectivity and broader reaction scope compared to the classical imidazolylidene and imidazolinylidene ligands. The “flexible-steric-bulk” BIAN environment established around the metal center allows for adjustment of the ligand architecture to the catalytic reaction pocket. The greater σ-donation of BIAN has been particularly crucial to significantly increase the catalyst activity.

Nevertheless, despite significant progress, there are several challenges that should be addressed: (1) commercialization of BIAN–NHC ligands would make this scaffold readily available to all researchers and facilitate screening of reaction conditions in a modular fashion compared to the classical imidazolylidene ligands; (2) A major focus should be placed on the discovery of more versatile catalysts and generalization of the reactivity trends observed. This point has already been well addressed in asymmetric catalysis, where the ANIPE-type BIAN-ligands emerged as the privileged class in this family of reactions; (3) BIAN–NHC ligands are ideally poised for the development of new reactions; however, with few exceptions thus far, the majority of methods have focused on improving the established protocols. To fully address the high activity of BIAN–NHC ligands, it is imperative that this platform be advanced to new synthetic methods; (4) The majority of current developments is still limited to Pd–BIAN–NHC, Ni–BIAN–NHC and Au–BIAN–NHC complexes. It is essential that the promising reactivity that has already been observed with other metals is advanced to general and robust reaction pathways. (5) Comprehensive mechanistic studies focusing on both the structure-activity-relationship and the mechanisms underlying catalytic cycles would greatly facilitate the design of new generations of catalysts and stimulate widespread application in various areas of catalysis.

Most importantly, the demonstrated reactivity already puts the BIAN–NHC ligand class on the same level as the classical imidazolylidene ligands and it is essential that all researches routinely screen BIAN–NHC ligands when developing new NHC-metal-catalyzed protocols.

Biographies

Changpeng Chen received his Ph.D. degree from Xi’an Jiaotong University, in 2019, under the supervision of Prof. Xiaoming Zeng working on low-valent chromium catalysis. Currently, he is a post-doctoral researcher at Rutgers University in the group of Prof. Michal Szostak. His research interests include base-metal catalysis, organometallic chemistry and NHC catalysis.

Feng-Shou Liu received his Ph.D. degree from Sun Yatsen University, Guangzhou with Prof. Qing Wu in 2009. His doctoral studies focused on alkene polymerization. Currently, he is a Professor of Organic Chemistry at Guangdong Pharmaceutical University. His research group is focused on the development of new ligands for cross-coupling reactions. Particular interest is directed at bulky NHC ligands and their impact on aerobic cross-coupling conditions.

Michal Szostak received his Ph.D. from the University of Kansas with Prof. Jeffrey Aubé in 2009. After post-doctoral stints at Princeton University with Prof. David MacMillan and University of Manchester with Prof. David Procter, in 2014, he joined the faculty at Rutgers University. His research group is focused on the development of new synthetic methodology based on transition-metal-catalysis, amide bond activation, N–C, O–C and C–H activation and cross-coupling. He is the author of over 170 peer-refereed publications.