New asymmetric ferrocene-based ligands bearing the bulky di(adamantyl)phosphino motif and their metal catalysts

Abstract

The ferrocenyl-based unsymmetric ligands have the general formula Fc(Ad2P)(R2P) and contain a di(1-adamantyl)phosphino group. Corresponding metal complexes useful as catalysts include metal halide complexes, N-biphenyl metal cation complexes, and R-allyl metal cation complexes. These ligands and complexes solve the problems associated with traditional catalysts and provide new routes to previously difficult cross-coupling reactions, including C-P coupling, C-C coupling, and C-C coupling. sp2 -C sp3 The applications of the present invention include cross-coupling and other conventional cross-coupling, while being scaleable, so that they can provide sufficient quality and purity for industrial applications.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 166,094 (filed March 25, 2021), the entire contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] (background) A new class of ferrocenyl (or ferrocene) based unsymmetric ligands (or ferrocenyl-based (or ferrocene-based) or ferrocenyl-based (or ferrocene-based) unsymmetric ligands) and corresponding metal complexes are provided. Such ligands contain a di(1-adamantyl)phosphino group and have the general formula: Fc(Ad2P)(R2P). The metal complexes include metal halide complexes, N-biphenyl metal cation complexes and R-allyl metal cation complexes, as shown in FIG. 1, which are useful in catalysis.

[0003] Ferrocenyl-based bidentate ligands and their corresponding metal catalysts are the most attractive bidentate systems in metal-catalyzed organic transformations due to their flexible bite angles and tunability of steric and electronic features (1). With the introduction of 1,1'-bis(diphenylphosphino)ferrocene (dppf) (2) and its corresponding (dppf)PdCl2 (Hayashi and Kumada (1972)) (3), much effort has been devoted to its commercialization and newer applications in process chemistry and drug discovery (4). Further work by Colacot's group first led to the discovery of Fc(PR2)2PdCl2 (R = i Pr,Cy, t Complexes of bis(phosphine)(III) have been identified as air-stable and highly active catalysts for difficult CC coupling and α-arylation reactions (5). Such “privileged” bis(phosphine) ligands and catalysts are now commercially available in multi-kilogram quantities for a variety of organic processes (6).

[0004] Among the new generation of ligands, the adamantyl-based phosphine ligands are a special class of ligands that offer very unique characteristics (e.g., electron release properties that have been beyond the boundaries of organophosphines for decades) (8)(9). Examples include the unique cross-coupling applications of Ad3P (Carrow group) (10), Adamantyl Brettphos (Buchwald et al.) (11), the Dalphos class of ligands (Stradiotto group) (12), and Ad2(n-Bu)P (Cataxium) (Beller et al.) (13) (Figure 2). However, the synthesis of such ligands is not a conventional synthesis and allows for isolation and purification, and therefore industrial applications (or uses) are limited to providing the ligands in bulk quantities. Summary of the Invention [Problem to be solved by the invention]

[0005] Despite these advantages, there remains a need for new ligands that meet the following criteria: (1) and (2) (1) A ligand that can solve some of the difficult problems that exist in cross-coupling (2) A synthetic ligand that is sufficient in production (or production) to be produced (or prepared) in sufficient quantity with a purity suitable for industrial use (or application or use) and is amenable to scale-up. [Means for solving the problem]

[0006] (Abstract) Diadamantylphosphino-containing compounds are provided that are useful as ligands and in precatalysis (or precatalysts or precursor catalysts or precatalysts) for coupling reactions. In a first embodiment, there is provided a compound having Formula I: [ka] I [In the formula, R1 and R2 are independently C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C1-C 12 It is selected from alkoxy, -NR4R5, and optionally substituted phenyl. R4 and R5 are H and C1-C 12 Alternatively, R4 and R5 together can form a saturated or unsaturated 5- or 6-membered ring, which optionally contains one or more additional heteroatoms selected from O, S and N, and one or more optional substituents. Each optional substituent, when present, is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy.

[0007] There is also provided a precatalyst (or precatalyst or precursor catalyst or precatalyst) having the following Formula II: [ka] II [In the formula, Ad is adamantyl. R1 and R2 are independently C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C1-C 12It is selected from alkoxy, -NR4R5, and optionally substituted phenyl. R4 and R5 are H and C1-C 12 Alternatively, R4 and R5 together can form a saturated or unsaturated 5- or 6-membered ring, which optionally contains one or more additional heteroatoms selected from O, S and N, and one or more optional substituents. Each optional substituent, when present, is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. M is a transition metal selected from Group 9 or 10. Y is halo.]

[0008] There is also provided a precatalyst (or precatalyst or precursor catalyst or precatalyst) having the following Formula III: [ka] III [In the formula, Ad is adamantyl. R1 and R2 are independently C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C1-C 12 It is selected from alkoxy, -NR4R5, and optionally substituted phenyl. R4 and R5 are H and C1-C 12 Alternatively, R4 and R5 together can form a saturated or unsaturated 5- or 6-membered ring, which optionally contains one or more additional heteroatoms selected from O, S and N, and one or more optional substituents. Each optional substituent, when present, is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. M represents a transition metal selected from Group 9 or 10. X is selected from H, C1-C4 alkyl and phenyl. Y - is a halide, triflate ( - OTf), tetrafluoroborate ( - BF4), hexafluorophosphate ( - PF6), mesylate ( - OMs), tosylate ( - OTs), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate ( - BArF), hexafluoroantimonate ( - SbF6), and combinations thereof.]

[0009] There is further provided a precatalyst (or precatalyst or precursor catalyst or precatalyst or precatalyst) having the following formula IV: [ka] IV [In the formula, Ad is adamantyl. R1 and R2 are independently C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C1-C 12 It is selected from alkoxy, -NR4R5, and optionally substituted phenyl. R4 and R5 are H and C1-C 12 Alternatively, R4 and R5 together can form a saturated or unsaturated 5- or 6-membered ring, which optionally contains one or more additional heteroatoms selected from O, S and N, and one or more optional substituents. Each optional substituent, when present, is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. M represents a transition metal selected from Group 9 or 10. X is selected from H, C1-C4 alkyl and phenyl. Y - is a halide, triflate ( - OTf), tetrafluoroborate ( - BF4), hexafluorophosphate ( - PF6), mesylate ( - OMs), tosylate ( - OTs), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate ( - BArF), hexafluoroantimonate ( - SbF6), and combinations thereof.]

[0010] Additionally, a method is provided for carrying out metal-catalyzed cross-coupling reactions of PCs. The method includes the following steps: contacting a ligand having formula I (as described above) with a metal catalyst in a reaction vessel in the presence of an aromatic solvent and a base; A first substrate (or base or substrate or substrate) of the formula: Ar-X', where Ar is aryl and X' is halo, and a compound of the formula: R'2PH, where R' is C1-C 10 Alkyl and C3-C 10 adding a second substrate to the reaction vessel, Heating the reaction vessel to a temperature in the range of 100° C. to 200° C. for a period of time sufficient to form carbon (C)-phosphorus (P) bonds.

[0011] In addition, metal-catalyzed C sp2 -C sp3 The present invention provides a method for carrying out the cross-coupling reaction of the formula: contacting a precatalyst (or pre-catalyst or precursor catalyst or precatalyst) of formula II (as described above) with a first substrate (or base or substrate or substrate) and a second substrate (or base or substrate or substrate) in a reaction vessel in the presence of a solvent, optionally heating the reaction vessel; and C sp2 -C sp3 reacting the first substrate and the second substrate in the presence of the pre-catalyst described above for a period of time sufficient for cross-coupling of In various embodiments of this method, the first substrate has the formula: Ar-X', where Ar is an optionally substituted aryl or an optionally substituted heteroaryl, and X' is chloro or bromo or iodo. The second substrate has the formula: R'[M], where R' is a C1-C 10 Alkyl and C3-C 10 [M] is selected from Li, MgX', ZnX', and B(OH)2 and related boron reagents, and X' is selected from chloro, bromo, and iodo. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 is an illustration of ferrocenyl-based unsymmetrical phosphines and their PdCl2, G3-Palladacycles, and (R-allyl)PdCl complexes (described in this disclosure). [Figure 2A] FIG. 2A shows Ad3P, a conventional phosphine containing a di-1-adamantylphosphino (Ad2P) moiety. [Figure 2B] FIG. 2B shows Dalphos, a conventional phosphine containing a di-1-adamantylphosphino (Ad2P) moiety. [Figure 2C]Figure 2C shows Adamantyl Brettphos, a conventional phosphine containing a di-1-adamantylphosphino (Ad2P) moiety. [Figure 2D] FIG. 2D shows Ad2(n-Bu)P (Cataxium), a conventional phosphine containing a di-1-adamantylphosphino (Ad2P) moiety. [Figure 3A] FIG. 3A shows Reaction Scheme 1 (synthesis of ferrocenyl-based unsymmetric bidentate (or bidentate) phosphine ligands using the method of Cullen). [Figure 3B] FIG. 3B shows reaction scheme 1 using the method of Stepnicka (compare with FIG. 3C). [Figure 3C] FIG. 3C shows Reaction Scheme 1 using the methods described in this disclosure. [Figure 4A] FIG. 4A shows the synthesis of ferrocenyl-based unsymmetric bidentate (or bidentate) ligands (L1-4). [Figure 4B] FIG. 4B shows the corresponding Pd complexes (Pd(1-4)-a to Pd(1-4)-c). [Diagram 5] FIG. 5 is an X-ray plot of the molecular structure of (L1)PdCl2,Pd1-a. [Figure 6] FIG. 6 is an X-ray plot of the molecular structure of (L3)PdCl2,Pd3-a. [Figure 7] FIG. 7 is an X-ray plot of the molecular structure of (L4)PdCl2,Pd4-a. [Figure 8] FIG. 8 is an X-ray plot of the molecular structure of (L1)Pd G3,Pd1-b. [Figure 9] FIG. 9 is an X-ray plot of the molecular structure of (L2)Pd G3,Pd2-b. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] (Detailed Description) This disclosure describes new ligands and precatalysts, such as those shown in FIG. 1. The new ligands and precatalysts solve the problems of conventional catalysts and provide new and powerful routes to cross-coupling reactions that were previously difficult. Meanwhile, the new ligands and precatalysts can be scaled to provide sufficient quality and purity for industrial use. These new ligands and precatalysts utilize a ferrocenyl (or ferrocene) backbone and a di(adamantyl)phosphino moiety. As described in this disclosure, these backbones and moieties provide significant advantages over existing ligands and precatalysts.

[0014] Conventional methods for preparing ferrocenyl (or ferrocene)-based asymmetric ligands (as shown in Figures 3A and 3B) are not suitable for incorporating the Ad2P site to prepare Fc(Ad2P)(R2P) ligands (14).

[0015] In this disclosure, we describe a new class of ferrocenyl (or ferrocene)-based unsymmetrical phosphines, containing the Ad2P moiety (Figure 3C), and the synthesis of their corresponding metal complexes. We also describe convenient synthetic protocols for the preparation of such ligands. We also provide methods for using new ligands and precatalysts. These include the C sp2 -C sp3(e.g., Kumada, Negishi, Suzuki and Murahashi) and the use of CP couplings with a wide range of substrates are described in this disclosure because these classes of coupling reactions are challenging and underrepresented in the literature. It would be further desirable for such ligands and precatalysts to be commercially available.

[0016] First, diadamantylphosphino-containing compounds are provided. Such compounds are useful as ligands and precatalysts for coupling reactions. In a first embodiment, there is provided a compound having formula I: [ka] I wherein R1 and R2 are independently C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C1-C 12 It is selected from alkoxy, -NR4R5, and optionally substituted phenyl. R4 and R5 are H and C1-C 12 alkyl, or R4 and R5 taken together form a saturated or unsaturated 5- or 6-membered ring, such ring optionally containing one or more additional heteroatoms selected from O, S and N, and one or more optional substituents. Some representative -NR4R5 ring structures include, but are not limited to, pyrrolo, pyrrolidino, pyrazolo, piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, and the like. Each optional substituent, when present, is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. In some embodiments of Compound I, R1 and R2 are independently selected from phenyl, optionally substituted phenyl, cyclohexyl, isopropyl, and tert-butyl. In some embodiments, R1 and R2 are each substituted phenyl.

[0017] In some embodiments, R1 and R2 are substituted phenyl. The substituted phenyl can have 1 to 5 substituents. The substituents can be the same or different. In one embodiment, the substituted phenyl contains one substituent at the para position. In other embodiments, the substituted phenyl contains one substituent at the ortho position. In other embodiments, the substituted phenyl contains one substituent at the meta position. In some embodiments, the substituted phenyl contains two substituents at both ortho positions. In other embodiments, the substituted phenyl contains two substituents at both meta positions. In other embodiments, the two substituents are at the ortho and para positions. In yet other embodiments, two substituents are at the meta and para positions. In yet other embodiments, the substituted phenyl comprises three substituents. The substituents may be the same or different. In some embodiments, three substituents are at the para position and two at the ortho positions. In other embodiments, three substituents are at the para position and two at the meta position. In yet other embodiments, substituents are at one ortho position, one meta position and the para position(s). In other embodiments, the substituted phenyl comprises four substituents. Each substituent may be the same or different. The substituents may be in the ortho and meta positions. Alternatively, the substituents may be in a combination of the ortho, meta and para positions. In yet other embodiments, the substituted phenyl may include five substituents, each of which may be the same or different.

[0018] In some preferred embodiments, -PR1R2 is selected from the following:

[0019] [ka]

[0020] In some preferred embodiments, the compound having formula I is a ligand selected from the following:

[0021] [ka]

[0022] The present disclosure also provides a precatalyst (or precatalyst or precursor catalyst or precatalyst) having Formula II: [ka] II In the formula, Ad is adamantyl. R1 and R2 are independently C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C1-C 12 It is selected from alkoxy, -NR4R5, and optionally substituted phenyl. R4 and R5 are H and C1-C 12alkyl, or R4 and R5 taken together form a saturated or unsaturated 5- or 6-membered ring, which optionally contains one or more additional heteroatoms selected from O, S and N, and which may further optionally contain one or more substituents. Some representative -NR4R5 ring structures include, but are not limited to, pyrrolo, pyrrolidino, pyrazolo, piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, and the like. Each optional substituent, when present, is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy. In some embodiments, R1 and R2 are independently selected from phenyl, substituted phenyl, cyclohexyl, isopropyl, and tert-butyl. In a preferred embodiment, R1 and R2 are each substituted phenyl (as described above).

[0023] In formula II, M is a transition metal selected from Group 9 or Group 10. In some embodiments, M is selected from Pd, Ni, Rh, Co, Ir, and Pt. In a preferred embodiment, M is Pd.

[0024] In formula II, Y is halo, i.e., in various embodiments, Y can be chloro, bromo, or iodo. In a preferred embodiment, Y is chloro.

[0025] Some preferred embodiments of the pre-catalyst having formula II include the following:

[0026] [ka]

[0027] There is also provided a precatalyst (or precatalyst or precursor catalyst or precatalyst or precatalyst) having formula III. [ka] III In the formula, Ad is adamantyl. R1 and R2 are independently C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C1-C 12 It is selected from alkoxy, -NR4R5, and optionally substituted phenyl. R4 and R5 are H and C1-C 12 alkyl, or R4 and R5 taken together form a saturated or unsaturated 5- or 6-membered ring, which optionally contains one or more additional heteroatoms selected from O, S and N, and may further contain one or more optional substituents. Some representative -NR4R5 ring structures include, but are not limited to, pyrrolo, pyrrolidino, pyrazolo, piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, and the like. Each optional substituent, when present, is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy. In some embodiments, R1 and R2 are independently selected from phenyl, cyclohexyl, isopropyl, and tert-butyl.

[0028] In formula III, M represents a transition metal selected from Group 9 or 10. In some embodiments, M is selected from Pd, Ni, Rh, Co, Ir, and Pt. In a preferred embodiment, M is Pd.

[0029] X in formula III may be selected from H, C1-C4 alkyl, and phenyl. In some embodiments, X is selected from H, methyl and phenyl.

[0030] In the pre-catalyst having formula III, Y - is a halide, triflate ( - OTf), tetrafluoroborate ( - BF4), hexafluorophosphate ( - PF6), mesylate ( - OMs), tosylate ( - OTs), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate ( - BArF), hexafluoroantimonate ( - SbF6), and combinations thereof. In various embodiments, Y - is Cl - , Br - , I - , - OTF, - BF4, - OMS, - O.T.s., - PF6, - BArF and - SbF6.

[0031] In some preferred embodiments, the pre-catalyst having formula III is:

[0032] [ka]

[0033] Further provided is a precatalyst (or precatalyst or precursor catalyst or precatalyst or precatalyst) having formula IV. [ka] IV In the formula, Ad is adamantyl. R1 and R2 are independently C1-C12 Alkyl, C3-C 12 Cycloalkyl, C1-C 12 It is selected from alkoxy, -NR4R5, and optionally substituted phenyl. R4 and R5 are H and C1-C 12 alkyl, or R4 and R5 taken together form a saturated or unsaturated 5- or 6-membered ring, such ring optionally containing one or more additional heteroatoms selected from O, S and N, and one or more optional substituents. Some representative -NR4R5 ring structures include, but are not limited to, pyrrolo, pyrrolidino, pyrazolo, piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, and the like. Each optional substituent, when present, is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. In some preferred embodiments, R1 and R2 are independently selected from phenyl, cyclohexyl, isopropyl, and tert-butyl.

[0034] In formula IV, M represents a transition metal selected from Group 9 or Group 10. In some embodiments, M is selected from Pd, Ni, Rh, Co, Ir, and Pt. In a preferred embodiment of Formula IV, M is Pd.

[0035] X in formula IV is selected from H, C1-C4 alkyl, and phenyl. In some preferred embodiments, X is selected from H, methyl, and phenyl.

[0036] Y - is a halide, triflate ( - OTf), tetrafluoroborate ( - BF4), hexafluorophosphate ( - PF6), mesylate ( -OMs), tosylate ( - OTs), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate ( - BArF), hexafluoroantimonate ( - SbF6), and combinations thereof. In some preferred embodiments, Y - is Cl - , Br - , I - , - OTF, - BF4, - OMS, - O.T.s., - PF6, - BArF and - SbF6.

[0037] In some preferred embodiments, the pre-catalyst having formula IV is selected from the following:

[0038] [ka]

[0039] Additionally, a method is provided for carrying out a metal-catalyzed PC cross-coupling reaction. The method includes the following steps: contacting a ligand having formula I (as described above) with a metal catalyst in a reaction vessel in the presence of an aromatic solvent and a base; A first substrate (or base or substrate or substrate) of the formula: Ar-X', where Ar is aryl and X' is halo, and a second substrate (or base or substrate or substrate) of the formula: R'2PH, where R' is C1-C 10 Alkyl and C3-C 10 adding a second substrate to the reaction vessel, Heating the reaction vessel to a temperature in the range of 100° C. to 200° C. for a period of time sufficient to form carbon (C)-phosphorus (P) bonds.

[0040] In a preferred embodiment of this method of metal-catalyzed PC cross-coupling reaction, the ligand is selected from:

[0041] [ka]

[0042] And the catalyst is a Pd catalyst.

[0043] In addition, metal-catalyzed C sp2 -C sp3 Cross-coupling reaction of (metal-catalyzed C sp2 -C sp3 The present invention provides a method for performing a cross-coupling reaction. The method includes the following steps: contacting a pre-catalyst having formula II (as described above) with a first substrate (or a substrate or a base material or a substrate) and a second substrate (or a substrate or a base material or a substrate) in a reaction vessel in the presence of a solvent, and optionally heating the reaction vessel; C sp2 -C sp3 reacting a first substrate (or base or substrate) and a second substrate (or base or substrate) in the presence of a pre-catalyst for a period (or time) sufficient for cross-coupling of

[0044] In various embodiments of this method, the first substrate has the formula: Ar-X', where Ar is an optionally substituted aryl or an optionally substituted heteroaryl, and X' is chloro or bromo or iodo. In some embodiments of this method, the first substrate is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thiophene, and optionally substituted furan.

[0045] In various embodiments, the second substrate has the formula R'[M], where R' is a C1-C 10 Alkyl and C3-C 10 [M] is selected from Li, MgX′, ZnX′, and B(OH)2, and X′ is selected from chloro, bromo, and iodo.

[0046] In certain embodiments according to this method, [M] is Li, the solvent is toluene, and the reaction vessel is not heated.

[0047] In certain embodiments according to this method, [M] is selected from MgX' and ZnX', the solvent is tetrahydrofuran, and the reaction vessel is heated to 50°C.

[0048] In yet another embodiment according to this method, [M] is B(OH), the solvent is toluene, and the reaction vessel is heated to 100°C.

[0049] The synthesis and use (or methods of use) of the ligands and pre-catalysts described in this disclosure are now described in more detail. Table 1 shows the unsymmetrical phosphines based on ferrocenyl (or ferrocene) and their PdCl2, G3-Palladacycles and (R-allyl)PdCl complexes.

[0050] [Table 1]

[0051] The synthesis of ligand L1-4 was achieved in two steps from the readily available 1,1'-dibromoferrocene (Figure 3). Following the reported procedure (14b), intermediate (I) was synthesized by selective lithiation of dibromoferrocene with one equivalent of n-BuLi. Subsequent quenching with dialkylchlorophosphines (e.g., Ph2PCl) afforded monobromoferrocenylphosphines (I). Another lithiation could be performed according to Stepnicka. Subsequent quenching with RPCl afforded several examples of mixed ligands (as shown in Figure 3B). By applying the same protocol, the Ad2P moiety was incorporated into intermediate (I), but did not yield the designed products (L1-4). Also, the addition of catalytic (or stoichiometric) amounts of copper(I) salts (e.g., CuCl) (15) did not help either. Instead, Pd-catalyzed PC coupling was used as an alternative approach (Figure 4A) (16). All of the ligands L1–4 were synthesized in two steps in approximately 70% yield (non-optimized yield). 1 H-NMR, 13 C-NMR, 31 Characterization was performed by P-NMR and elemental analysis.

[0052] The corresponding three classes of palladium precatalysts were synthesized in high yields and characterized by NMR and elemental analysis (Figure 4). Some of them ((L1) PdCl2, Pd1-a; (L3) PdCl2, Pd3-a; (L4) PdCl2, Pd4-a; (L1) Pd G3, Pd1-b; (L2) Pd G3, Pd2-b) were clearly characterized by single crystal X-ray studies (see Figures 5-9). X-ray crystal structures of five palladium complexes are also reported in this disclosure. Single crystals were obtained (by slow diffusion of pentane into dichloromethane solution).

[0053] Figure 5 shows the X-Ray plot of the molecular structure of (L1)PdCl2,Pd1-a (selected bond lengths (Å) and bond angles (°)): Pd-P1 2.3370(5),Pd-P2 2.2964(5),Pd-Cl1 2.3484(4),Pd-Cl2 2.3541(4);P1-Pd-P2 100.973(16),Cl1-Pd-Cl2 84.988(15),P1-Pd-Cl1 91.834(16),P1-Pd-Cl2 174.508(16),P2-Pd-Cl1 166.954(17),P2-Pd-Cl2 82.048(16).

[0054] Figure 6 shows the X-Ray plot of the molecular structure of (L3)PdCl2,Pd3-a (selected bond lengths (Å) and bond angles (°)): Pd-P1 2.3365(4),Pd-P2 2.3127(4),Pd-Cl1 2.3519(4),Pd-Cl2 2.3673(4);P1-Pd-P2 103.587(15),Cl1-Pd-Cl2 84.089(14),P1-Pd-Cl1 90.173(14),P1-Pd-Cl2 174.226(15),P2-Pd-Cl1 166.239(15),P2-Pd-Cl2 82.153(15).

[0055] Figure 7 shows the X-Ray plot of the molecular structure of (L4)PdCl2,Pd4-a (selected bond lengths (Å) and bond angles (°)): Pd-P1 2.3679(5),Pd-P2 2.3736(6),Pd-Cl1 2.3370(6),Pd-Cl2 2.3290(6);P1-Pd-P2 106.72(2),Cl1-Pd-Cl2 82.56(2),P1-Pd-Cl1 87.18(2),P1-Pd-Cl2 166.82(2),P2-Pd-Cl1 164.89(2),P2-Pd-Cl2 84.45(2).

[0056] Figure 8 shows the X-Ray plot of the molecular structure of (L1)Pd G3,Pd1-b (selected bond lengths (Å) and bond angles (°)): Pd-P1 2.2791(8),Pd-P2 2.4635(7),Pd-N1 2.147(2),Pd-C43 2.033(3);P1-Pd-P2 102.68(3),N1-Pd-C43 80.64(11),P1-Pd-N1 152.16(7),P1-Pd-C43 86.39(8),P2-Pd-N1 97.22(7),P2-Pd-C43 161.22(9).

[0057] Figure 9 shows the X-Ray plot of the molecular structure of (L2)Pd G3,Pd2-b. Selected bond lengths (Å) and bond angles (°): Pd-P1 2.3094(4),Pd-P2 2.4626(4),Pd-N1 2.1657(14),Pd-C43 2.0454(17);P1-Pd-P2 103.304(17),N1-Pd-C43 80.40(6),P1-Pd-N1 153.33(4),P1-Pd-C43 87.65(5),P2-Pd-N1 95.50(4),P2-Pd-C43 160.31(5).

[0058] In Table 2, the bite angles (°) of selected P-Pd-P as well as other analogues (taken from literature data for comparison purposes) are given. The Pd centers all have a distorted square planar geometry (the two phosphorus atoms are in a cis configuration). Notably, (L4)PdCl2,Pd4-a has a very large P-Pd-P bite angle (106.72°, entry 3). To our best knowledge, this is the largest P-Pd-P bite angle reported in the literature among PdCl2 complexes with ferrocenyl based bidentate ligands. Compared to the bite angle of the “state of the art” catalyst (dtbpf)PdCl2 (104.22°, entry 6), the P-Pd-P bite angle of (L4)PdCl2 is significantly larger.

[0059] [Table 2]

[0060] Due to the bidentate nature and steric bulkiness of the ferrocenyl ligands, all (L)Pd G3 complexes are in cationic form (as shown in the structures of (L1)Pd G3(Pd1-b) and (L2)Pd G3(Pd2-b)). The MsO group in each structure is replaced by the second phosphorus of the ferrocenyl ligand to form a mesylate anion, while the NH2 group remains coordinated to the Pd center. A similar phenomenon has also been reported by Buchwald (17). (BINAP)Pd G3, tBuXPhos Pd G3, and BrettPhos Pd G3 are in cationic form, with the mesylate (MsO) projecting from the coordination sphere. On the other hand, in XPhos Pd G3, even MsO is in a covalent configuration. Both structures derived from Pd1-b and Pd2-b have a significant tetrahedral distortion at the Pd center (28.6° for Pd1-b and 28.2° for Pd2-b).

[0061] In addition, the application (or use) of the ligands and precatalysts described in this disclosure to catalysis (particularly two classes of difficult and underappreciated reactions, namely, C sp2 -C sp3 The application (or application or use) of the coupling reaction of 1-(2-methyl-1,2-diphenyl-2-propanediol and 1-(2-methyl-1,2-diphenyl-2-propanediol) to the coupling reaction of PC was also carried out, as described in detail in the following examples.

[0062] As used herein, the term "Ad" refers to an adamantyl functional group, i.e., a group of the formula: -C 10 H 15 It also can be written as -C(CH)3(CH2)6.

[0063] The term "alkyl" refers to a saturated hydrocarbon chain of 1 to 10 carbon atoms in length. Examples include, but are not limited to, methyl, ethyl, propyl, and butyl. Alkyl groups may be straight or branched chain. For example, as used in this disclosure, propyl includes both n-propyl and iso-propyl. For example, butyl includes n-butyl, sec-butyl, iso-butyl, and tert-butyl.

[0064] The term "aryl" refers to an aromatic hydrocarbon group. Aryl includes, for example, phenyl, biphenyl, naphthyl, anthracenyl, and the like, as well as substituted forms of each. Heteroaryl refers to an aromatic hydrocarbon in which one or more aromatic carbon atoms are replaced with another atom, such as nitrogen (N), oxygen (O), or sulfur (S). Some examples of heteroaryl groups include, but are not limited to, pyridyl (pyridinyl) ((C5H4N)-), furyl (furanyl) (OC4H3-), thienyl ((C4H3S)-), as well as substituted forms thereof.

[0065] "Substituted" as used herein means that one or more hydrogen atoms of the compounds or functional groups described above have been replaced with another functional group (i.e., a substituent). For example, a substituted phenyl may contain one or more substituents in place of any hydrogen atoms of the phenyl ring. In some embodiments, there may be one substituent at the ortho, meta or para position. In other embodiments, there may be substituents at both (2) ortho positions or at both (2) meta positions. In still other embodiments, the optionally substituted phenyl may include substituents at both the ortho and para positions, or both the meta and para positions, for example. In some embodiments having multiple substituents, the substituents are all identical. In other embodiments having multiple substituents, the substituents are different from each other. Exemplary substituents include, but are not limited to, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. When a functional group is described as "optionally substituted," the functional group may have one or more substituents or may have zero or no substituents.

[0066] The precatalyst complexes (or precatalyst complexes or precursor catalyst complexes or precatalyst complexes) described in this disclosure have at least one metal center (or metal center) that includes a transition metal ("M"). Examples of transition metals include, but are not limited to, transition metals from Groups 9 and 10 of the Periodic Table. Group 9 metals include Co, Rh and Ir. Group 10 elements include Ni, Pd and Pt.

[0067] The present disclosure further provides the following embodiments described in Sections {1} to {36} below.

[0068] {1} Compounds having the following formula I [ka] I wherein R1 and R2 are independently C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C1-C 12 It is selected from the group consisting of alkoxy, -NR4R5, and optionally substituted phenyl. R4 and R5 are H and C1-C 12Alternatively, R4 and R5 together can form a saturated or unsaturated 5- or 6-membered ring, which optionally contains one or more additional heteroatoms selected from O, S and N, and one or more optional substituents. Each optional substituent, when present, is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy.

[0069] {2} The compound according to the above item {1}, wherein R1 and R2 are independently selected from the group consisting of phenyl, optionally substituted phenyl, cyclohexyl, isopropyl, and tert-butyl. In some embodiments, R1 and R2 are the same. In other embodiments, R1 and R2 are different. In some embodiments, R1 and R2 are both aryl groups. In some embodiments, R1 and R2 are both alkyl groups. In some embodiments, R1 is an aryl moiety and R2 is an alkyl moiety. In some embodiments, R1 and R2 are both phenyl. In some embodiments, R1 and R2 are both substituted phenyl. In some embodiments, R1 and R2 are both cyclohexyl. In some embodiments, R1 and R2 are both isopropyl. In some embodiments, R1 and R2 are both tert-butyl. In some embodiments, R1 is phenyl and R2 is substituted phenyl. In some embodiments, R1 is phenyl and R2 is cyclohexyl. In some embodiments, R1 is phenyl and R2 is isopropyl. In some embodiments, R1 is phenyl and R2 is tert-butyl. In some embodiments, R1 is substituted phenyl and R2 is cyclohexyl. In some embodiments, R1 is substituted phenyl and R2 is isopropyl. In some embodiments, R1 is substituted phenyl and R2 is tert-butyl. In some embodiments, R1 is cyclohexyl and R2 is isopropyl. In some embodiments, R1 is cyclohexyl and R2 is tert-butyl. In some embodiments, R1 is tert-butyl and R2 is isopropyl.

[0070] {3} The compound according to the above item {1} or {2}, wherein R1 and R2 are each a substituted phenyl. In some embodiments, the substituent is alkyl. In certain embodiments, the substituent is methyl. In some embodiments, the substituent is alkoxy. In certain embodiments, the substituent is methoxy. In certain embodiments, the substituent is isopropoxy. In some embodiments, the substituent is haloalkyl. In certain embodiments, the substituent is trifluoromethyl. In certain embodiments, multiple substituents are present. In some embodiments, each substituted phenyl has two alkyl substituents. In such embodiments, the alkyl substituent is C1-C4 alkyl or haloalkyl. In some embodiments, the alkyl substituent is a methyl group, an isopropyl group, a tert-butyl group, or a trifluoromethyl group. In other embodiments, each substituted phenyl has three substituents. In such embodiments, the alkyl substituent is C1-C4 alkyl or haloalkyl. In some embodiments, the alkyl substituent is a methyl group, an isopropyl group, a tert-butyl group, or a trifluoromethyl group. In still other embodiments, each substituted phenyl has one or more alkyl substituents and one or more alkoxy substituents. In some embodiments, the substituted phenyl has one or more C1-C4 alkyl or haloalkyl substituents and one or more C1-C4 alkoxy substituents, respectively. In some embodiments, each substituted phenyl has two C1-C4 alkyl substituents and one C1-C4 alkoxy substituent.

[0071] {4} The compound according to any one of the above items {1}, {2} or {3}, wherein -PR1R2 is selected from the following:

[0072] [ka]

[0073] {5} A ligand having the following formula I: [ka] I wherein R1 and R2 are independently C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C1-C 12 It is selected from the group consisting of alkoxy, -NR4R5, and optionally substituted phenyl. R4 and R5 are H and C1-C 12 Alternatively, R4 and R5 together can form a saturated or unsaturated 5- or 6-membered ring, which optionally contains one or more additional heteroatoms selected from O, S and N, and one or more optional substituents. Each optional substituent, when present, is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy.

[0074] {6} The ligand according to item {5} above, wherein R1 and R2 are independently selected from the group consisting of phenyl, optionally substituted phenyl, cyclohexyl, isopropyl and tert-butyl.

[0075] {7} The ligand according to the above item {5} or {6}, wherein R1 and R2 are each a substituted phenyl. In some embodiments, the substituent is alkyl. In certain embodiments, the substituent is methyl. In some embodiments, the substituent is alkoxy. In certain embodiments, the substituent is methoxy. In certain embodiments, the substituent is isopropoxy. In some embodiments, the substituent is haloalkyl. In certain embodiments, the substituent is trifluoromethyl. In certain embodiments, multiple substituents are present. In some embodiments, each substituted phenyl has two alkyl substituents. In such embodiments, the alkyl substituent is C1-C4 alkyl or haloalkyl. In some embodiments, the alkyl substituent is a methyl group, an isopropyl group, a tert-butyl group, or a trifluoromethyl group. In other embodiments, each substituted phenyl has three substituents. In some embodiments, the alkyl substituent is C1-C4 alkyl or haloalkyl. In some embodiments, the alkyl substituent is a methyl group, an isopropyl group, a tert-butyl group, or a trifluoromethyl group. In still other embodiments, each substituted phenyl has one or more alkyl substituents and one or more alkoxy substituents. In some embodiments, the substituted phenyl has one or more C1-C4 alkyl or haloalkyl substituents and one or more C1-C4 alkoxy substituents, respectively. In some embodiments, each substituted phenyl has two C1-C4 alkyl substituents and one C1-C4 alkoxy substituent.

[0076] {8} A ligand according to the above item {5} or {6}, selected from the following:

[0077] [ka]

[0078] {9} A precatalyst (or precatalyst or precursor catalyst or precatalyst or precatalyst) having the following formula II: [ka] II In the formula, Ad is adamantyl. R1 and R2 are independently C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C1-C 12It is selected from the group consisting of alkoxy, -NR4R5, and optionally substituted phenyl. R4 and R5 are H and C1-C 12 Alternatively, R4 and R5 together can form a saturated or unsaturated 5- or 6-membered ring, which optionally contains one or more additional heteroatoms selected from O, S and N, and one or more optional substituents. Each optional substituent, when present, is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. M is a transition metal selected from Group 9 or 10. Y is a halo.

[0079] {10} The pre-catalyst according to item {9} above, wherein R1 and R2 are independently selected from the group consisting of phenyl, optionally substituted phenyl, cyclohexyl, isopropyl and tert-butyl.

[0080] {11} The precatalyst according to the above item {9} or {10}, wherein R1 and R2 are each a substituted phenyl. In some embodiments, the substituent is alkyl. In certain embodiments, the substituent is methyl. In some embodiments, the substituent is alkoxy. In certain embodiments, the substituent is methoxy. In certain embodiments, the substituent is isopropoxy. In some embodiments, the substituent is haloalkyl. In certain embodiments, the substituent is trifluoromethyl. In certain embodiments, multiple substituents are present. In some embodiments, each substituted phenyl has two alkyl substituents. In such embodiments, the alkyl substituent is C1-C4 alkyl or haloalkyl. In some embodiments, the alkyl substituent is a methyl group, an isopropyl group, a tert-butyl group, or a trifluoromethyl group. In other embodiments, each substituted phenyl has three substituents. In such substituents, the alkyl substituent is C1-C4 alkyl or haloalkyl. In some embodiments, the alkyl substituent is a methyl group, an isopropyl group, a tert-butyl group, or a trifluoromethyl group. In still other embodiments, each substituted phenyl has one or more alkyl substituents and one or more alkoxy substituents. In some embodiments, the substituted phenyl has one or more C1-C4 alkyl or haloalkyl substituents and one or more C1-C4 alkoxy substituents, respectively. In some embodiments, each substituted phenyl has two C1-C4 alkyl substituents and one C1-C4 alkoxy substituent.

[0081] {12} The pre-catalyst according to any one of the above items {9} to {11}, wherein M is selected from the group consisting of Pd, Ni, Rh, Co, Ir and Pt.

[0082] {13} In the pre-catalyst according to any one of the above items {9} to {12}, M is Pd.

[0083] {14} The pre-catalyst according to any one of the above items {9} to {13}, wherein Y is selected from chloro, bromo and iodo.

[0084] {15} The pre-catalyst according to any one of the above items {9}, {10}, or {12} to {14}, wherein the pre-catalyst is selected from the following:

[0085] [ka]

[0086] {16} A pre-catalyst having the following formula III: [ka] III In the formula, Ad is adamantyl. R1 and R2 are independently C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C1-C 12 It is selected from the group consisting of alkoxy, -NR4R5, and optionally substituted phenyl. R4 and R5 are H and C1-C 12 Alternatively, R4 and R5 together can form a saturated or unsaturated 5- or 6-membered ring, which optionally contains one or more additional heteroatoms selected from O, S and N, and one or more optional substituents. Each optional substituent, when present, is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. M is a transition metal selected from Group 9 or 10. X is selected from the group consisting of H, C1-C4 alkyl and phenyl. Y - is a halide, triflate ( - OTf), tetrafluoroborate ( - BF4), hexafluorophosphate ( - PF6), mesylate ( - OMs), tosylate ( -OTs), tetrakis{3,5-bis(trifluoromethyl)phenyl}borate ( - BArF), hexafluoroantimonate ( - SbF6), and combinations thereof.

[0087] {17} The pre-catalyst according to item {16} above, wherein R1 and R2 are independently selected from the group consisting of phenyl, cyclohexyl, isopropyl and tert-butyl.

[0088] {18} The pre-catalyst according to the above item {16} or {17}, wherein M is selected from the group consisting of Pd, Ni, Rh, Co, Ir and Pt.

[0089] {19} The pre-catalyst according to any one of the above items {16} to {18}, wherein M is Pd.

[0090] {20} The pre-catalyst according to any one of the above items {16} to {19}, wherein X is selected from the group consisting of H, methyl and phenyl.

[0091] {twenty one} The pre-catalyst according to any one of the above items {16} to {20}, - is Cl - , Br - , I - , - OTF, - BF4, - OMS, - O.T.s., - PF6, - BArF and - SbF6.

[0092] {twenty two} The pre-catalyst according to any one of the above items {16} to {21}, wherein the pre-catalyst is selected from the group consisting of:

[0093] [ka]

[0094] {twenty three} A pre-catalyst having formula IV: [ka] IV In the formula, Ad is adamantyl. R1 and R2 are independently C1-C 12 Alkyl, C3-C 12 Cycloalkyl, C1-C 12 It is selected from the group consisting of alkoxy, -NR4R5, and optionally substituted phenyl. R4 and R5 are H and C1-C 12 Alternatively, R4 and R5 together can form a saturated or unsaturated 5- or 6-membered ring, which optionally contains one or more additional heteroatoms selected from O, S and N, and one or more optional substituents. Each optional substituent, when present, is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. M is a transition metal selected from Group 9 or 10. X is selected from the group consisting of H, C1-C4 alkyl and phenyl. Y - is a halide, triflate ( - OTf), tetrafluoroborate ( - BF4), hexafluorophosphate ( - PF6), mesylate ( - OMs), tosylate ( - OTs), tetrakis{3,5-bis(trifluoromethyl)phenyl}borate ( - BArF), hexafluoroantimonate ( -SbF6), and combinations thereof.

[0095] {twenty four} The pre-catalyst according to item {23} above, wherein R1 and R2 are independently selected from the group consisting of phenyl, cyclohexyl, isopropyl and tert-butyl.

[0096] {twenty five} The pre-catalyst according to the above item {23} or {24}, wherein M is selected from the group consisting of Pd, Ni, Rh, Co, Ir and Pt.

[0097] {26} The pre-catalyst according to any one of the above items {23} to {25}, wherein M is Pd.

[0098] {27} The pre-catalyst according to any one of the above items {23} to {26}, wherein X is selected from the group consisting of H, methyl and phenyl.

[0099] {28} The pre-catalyst according to any one of the above items {23} to {27}, - is Cl - , Br - , I - , - OTF, - BF4, - OMS, - O.T.s., - PF6, - BArF and - SbF6.

[0100] {29} The pre-catalyst according to any one of the above items {23} to {28}, wherein the pre-catalyst is selected from the group consisting of:

[0101] [ka]

[0102] {30} A method for carrying out a metal-catalyzed PC cross-coupling reaction, the method comprising the following steps: A step (or a step) of contacting the ligand according to any one of the above items {5} to {8} with a metal catalyst in the presence of an aromatic solvent and a base in a reaction vessel; A first substrate (or base or substrate or substrate) having the formula: Ar-X', where Ar is aryl and X' is halo, and a compound of the formula: R'2PH, where R' is C1-C 10 Alkyl and C3-C 10 adding to the reaction vessel a second substrate having a substituent selected from the group consisting of: Heating the reaction vessel to a temperature in the range of 100° C. to 200° C. for a period of time sufficient to form carbon (C)-phosphorus (P) bonds.

[0103] {31} The method according to the above item {30}, wherein the ligand is the ligand according to the above item {8}, and the catalyst is a Pd catalyst.

[0104] {32} Metal-catalyzed C sp2 -C sp3 The present invention relates to a method for carrying out a metal-catalyzed Csp2-Csp3 cross-coupling reaction, the method comprising the following steps: A process (or step) of contacting a pre-catalyst having formula II described in any one of the above items {9} to {15} with a first substrate (or base or substrate) and a second substrate (or base or substrate) in a reaction vessel in the presence of a solvent, The first substrate has the formula: Ar-X', Ar is optionally substituted aryl or optionally substituted heteroaryl; X' is chloro, bromo or iodo; The second substrate has the formula: R'{M}, R' is C1-C 10 Alkyl, C1-C 10 Fluoroalkyl and C3-C 10 cycloalkyl; {M} is selected from the group consisting of Li, MgX', ZnX', and B(OH)2 and related boron reagents; X' is selected from the group consisting of chloro, bromo and iodo; Process (or step) and, if necessary, heating the reaction vessel; and C sp2 -C sp3 reacting the first substrate and the second substrate in the presence of a pre-catalyst for a period of time sufficient to effect cross-coupling of Includes.

[0105] {33} The method according to item {32} above, wherein the first substrate is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl, and optionally substituted furyl.

[0106] {34} The method according to item {32} or {33} above, wherein {M} is Li, the solvent is toluene, and the reaction vessel is not heated.

[0107] {35} The method according to the above item {32} or {33}, wherein {M} is selected from MgX' and ZnX', the solvent is tetrahydrofuran, and the reaction vessel is heated to 50°C.

[0108] {36} The method according to item {32} or {33} above, wherein {M} is B(OH)2, the solvent is toluene, and the reaction vessel is heated to 100°C. EXAMPLES

[0109] (Example)

[0110] Synthesis of Ligands Having Formula I

[0111] Example 1 Synthesis of (1-diisopropylphosphino)-(1'-diadamantylphosphino)ferrocene (Ic)

[0112] [ka]

[0113] Under nitrogen, 1,1'-dibromoferrocene (5 g, 0.015 mol) was placed in a 250 mL Schlenk flask and dissolved in 50 mL of anhydrous THF. The solution was then cooled to -78°C using a dry ice / acetone bath. n-BuLi (2.5 M in hexane, 6 mL, 0.015 mol) was slowly added dropwise to the reaction solution at -78°C. The resulting orange reaction solution was stirred at -78°C for approximately 1 hour. Chlorodiisopropylphosphine (ClP iPr2, 2.5 mL, 0.016 mol) was slowly added dropwise via syringe at -78 °C. The reaction mixture was allowed to slowly warm to room temperature and stirred at room temperature for about 3 h. Methanol (2 mL) was added to the reaction mixture to quench the reaction. The solvent was removed on a rotary evaporator, and the residue was dissolved in 20 mL of hexane and filtered through a plug of silica. The plug was washed with hexane until the first light orange band (impurity band) was completely eluted. The subsequent dark orange band (product band) was then collected with TBME (until no more colored filtrate was eluted). The dark orange filtrate was first concentrated on a rotary evaporator (until most of the solvent was evaporated) and then concentrated under high vacuum to give an orange oil (5 g). The oil was then eluted with 100 mL of hexane (1.0 mL). 31 The product was confirmed by P-NMR (purity >95%, 0.37 ppm). The material at this stage was used as is in the next step.

[0114] Pd(OAc)2 (100 mg, 0.4 mmol), D i PPF (1,1'-bis(diisopropylphosphino)ferrocene (180 mg, 0.4 mmol), (1-diisopropylphosphino)-1'-bromoferrocene (5.0 g, 0.013 mol), diadamantylphosphine (Ad2PH, 4.20 g, 0.014 mol) and NaO t Bu (1.4 g, 0.015 mol) was placed in a 250 mL Schlenk flask, followed by 100 mL of anhydrous toluene. The reaction mixture was stirred at room temperature for 10 min. It was then heated to reflux for 20 h. At this point, the reaction was deemed complete (the HCl content obtained from the removed aliquot was 1.0 g). 31Based on P NMR data. The reaction mixture was then cooled and passed through a plug of silica, which was then washed with CH2Cl2 until all of the orange solution was collected. The combined eluents were collected and the solvent removed under reduced pressure to give an orange solid. The solid was washed as a slurry with 50 mL of Et2O to give an orange solid. The solid was filtered, washed with Et2O (2 x 10 mL) and dried under reduced pressure to give 6.3 g (80% yield) of an orange solid. 1 H NMR (CD2Cl2): δ = 4.35 (m, 2H; Fc-H), 4.32 (m, 2H; Fc-H), 4.23 (m, 2H; Fc-H), 4.15 (m, 2H; Fc-H), 2.09 (m, 6H), 1.96 - 1.85 (m, 14H; 1-Ad), 1.72 (s, 12H; 1-Ad), 1.12 - 1.07 (m, 12H, CH3); 31 P{ 1 H} NMR (CD2Cl2): δ = 25.39 ( P Ad2), -0.03 ( P i Pr2).

[0115] In a similar manner, the other ligands described in this disclosure were synthesized.

[0116] Example 2 (1-Diphenylphosphino)-(1'-diadamantylphosphino)ferrocene (Ia) The general procedure for compound Ic was used, except that chlorodiphenylphosphine (3.53 g, 0.016 mol) was used instead of chlorodiisopropylphosphine. The compound obtained was an orange solid. 1H NMR (CD2Cl2): δ = 7.50 - 7.33 (m, 10H, Ar-H), 4.42 (m, 2H; Fc-H), 4.29 (m, 2H; Fc-H), 4.15 (m, 2H; Fc-H), 4.08 (m, 2H; Fc-H), 2.01 - 1.97 (m, 6H, 1-Ad), 1.91 - 1.87 (m, 6H; 1-Ad), 1.84 - 1.80 (m, 6H; 1-Ad), 1.68 (s, 12 H, 1-Ad); 31 P{ 1 H} NMR (CD2Cl2): δ = 25.66 ( P Ad2), 17.05 ( P Ph2).

[0117] Example 3 (1-Dicyclohexylphosphino)-(1'-diadamantylphosphino)ferrocene (1-b) The general procedure for compound Ic was used, except that chlorodicyclohexylphosphine (3.72 g, 0.016 mol) was used instead of chlorodiisopropylphosphine. The compound obtained was an orange solid. 1 H NMR (CD2Cl2): δ = 4.33 (m, 2H; Fc-H), 4.30 (m, 2H; Fc-H), 4.21 (m, 2H; Fc-H), 4.13 (m, 2H; Fc-H), 2.10 - 2.06 (m, 6H), 1.95 - 1.70 (m, 37H), 1.35 - 1.20 (m, 9H); 31 P{ 1 H} NMR (CD2Cl2): δ = 25.18 ( P Ad2), -8.15 ( P Cy2).

[0118] Example 4 (1-Di-t-butylphosphino)-(1'-diadamantylphosphino)ferrocene (Id) The general procedure for compound Ic was used, except that chlorodi-t-butylphosphine (2.89 g, 0.016 mol) was used instead of chlorodiisopropylphosphine. The resulting compound was an orange solid. 1 H NMR (CD2Cl2): δ = 4.38 - 4.35 (m, 4H; Fc-H), 4.20 - 4.18 (m, 4H; Fc-H), 2.09 - 2.05 (m, 6H, 1-Ad), 1.95 - 1.84 (m, 12H; 1-Ad), 1.70 (s, 12H; 1-Ad), 1.18 (d, 18H, t Bu-H); 31 P{ 1 H} NMR (CD2Cl2): δ = 27.07 ( P t Bu2), 25.31 ( P Ad2).

[0119] Example 5 (1-Diisopropylphosphino)-(1'-di-t-butylphosphino)ferrocene (Ie) Under nitrogen, 1,1'-dibromoferrocene (5 g, 0.013 mol) was placed in a 250 mL Schlenk flask and dissolved in 50 mL of anhydrous THF. The solution was then cooled to -78°C using a dry ice / acetone bath. n-BuLi (2.5 M in hexane, 6 mL, 0.015 mol) was slowly added dropwise to the reaction solution at -78°C. The resulting orange reaction solution was stirred at -78°C for approximately 1 hour. Chlorodiisopropylphosphine (ClP iPr2, 2.5 mL, 0.016 mol) was slowly added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred at room temperature for about 3 hours. Methanol (2 mL) was added to the reaction mixture to quench the reaction. The solvent was removed on a rotary evaporator, and the residue was dissolved in 20 mL of hexane and filtered through a plug of silica. The plug was washed with hexane until the first light orange band (impurity band) was completely eluted. The subsequent dark orange band (product band) was then collected with TBME (until no more colored filtrate was eluted). The dark orange filtrate was first concentrated on a rotary evaporator (until most of the solvent was evaporated). Then, under high vacuum, an orange oil (5 g) was obtained. The oil was 31 The product was confirmed by P-NMR (purity >95%, 0.37 ppm). The material at this stage was used as is in the next step.

[0120] Under nitrogen, (1-diisopropylphosphino)-1'-bromoferrocene (5 g, 0.013 mol) was placed in a 250 mL Schlenk flask and dissolved in 50 mL of anhydrous THF. The solution was then cooled to -78°C using a dry ice / acetone bath. n-BuLi (2.5 M in hexane, 6 mL, 0.015 mol) was slowly added dropwise to the reaction solution at -78°C. The resulting orange reaction solution was stirred at -78°C for approximately 1 hour. Chlorodi-t-butylphosphine (ClP tBu2, 2.89 g, 0.016 mol) was slowly added dropwise. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for about 3 h. Methanol (2 mL) was added to the reaction mixture to quench the reaction. The solvent was removed on a rotary evaporator, and the residue was dissolved in 20 mL of dichloromethane and filtered through a plug of silica. The plug was then washed with dichloromethane (until the orange band was completely eluted and collected). The filtrate was concentrated using a rotary evaporator. The residue was dissolved in 20 mL of hexane. The deep orange solution was cooled to -20°C in a freezer overnight to give a solid precipitate. The solid was collected and washed with cold hexane (5 mL x 2) to give an orange solid (4.4 g, 75%). 1 H NMR (CD2Cl2): δ = 4.35 (m, 2H; Fc-H), 4.32 (m, 2H; Fc-H), 4.27 (m, 2H; Fc-H), 4.19 (m, 2H; Fc-H), 2.00 - 1.92 (m, 2H, CH (CH3)2), 1.22 (d, 18H; t Bu), 1.15 - 1.05 (m, 12H; CH(C H 3)2); 31 P{ 1 H} NMR (CD2Cl2): δ = 27.06 ( P t Bu2), -0.22 ( P i Pr2).

[0121] Synthesis of precatalyst having formula II

[0122] Example 6 Synthesis of [(1-diisopropylphosphino)(1'-diadamantylphosphino)ferrocene]dichloropalladium(II-c)

[0123] [ka]

[0124] Under nitrogen, (1-diisopropylphosphino)-(1'-diadamantylphosphino)ferrocene (603 mg, 1.0 mmol) and Pd(CH3CN)2Cl2 (259 mg, 1.0 mmol) were dissolved in 50 mL of anhydrous dichloromethane in a 100 mL Schlenk flask. The reaction mixture was stirred at room temperature for 2 h. The solvent was then removed to give a brown solid. The solid was slurried with 50 mL of hexane for 30 min to give a red-brown solid. The solid was filtered and dried under vacuum to give the pure product (750 mg, 96%). Single crystals suitable for X-ray diffraction studies were obtained by slow diffusion of pentane into a solution of the product in dichloromethane. 1 H NMR (CD2Cl2): δ = 4.77 (m, 2H; Fc-H), 4.59 (s, 2H; Fc-H), 4.52 (s, 2H; Fc-H), 4.50 (m, 2H; Fc-H), 3.31 - 3.23 (m, 2H; CH(CH3)2), 2.75 (br, 6H), 2.38 (br, 6H), 2.06 (s, br, 6H), 1.84 - 1.60 (m, 18H), 1.35 - 1.22 (m, 6H); 31 P{ 1 H} NMR (CD2Cl2): δ = 68.50 (d), 58.10 (d).

[0125] In a similar manner, the other metal complexes described in this disclosure were synthesized.

[0126] Example 7 [(1-diphenylphosphino)(1'-diadamantylphosphino)ferrocene]dichloropalladium(II-a) The general procedure for compound II-c was used, except that (1-diphenylphosphino)-(1'-diadamantylphosphino)ferrocene (671 mg, 1.0 mmol) was used instead of (1-diisopropylphosphino)-(1'-diadamantylphosphino)ferrocene. The product obtained was a brown solid. 1 H NMR (CD2Cl2): δ = 8.10 (br, 4H, Ph-H), 7.60 - 7.50 (m, 6H, Ph-H), 4.96 (m, 2H, Fc-H), 4.57 (m, 2H, Fc-H), 4.33 (m, 2H, Fc-H), 3.91 (m, 2H, Fc-H), 3.20 - 2.05 (br, 12H, Ad-H), 2.02 (m, 6H, Ad-H), 1.90 - 1.75 (m, 12H, Ad-H); 31 P{ 1 H} NMR (CD2Cl2): δ = 75.10 (d), 38.25 (d).

[0127] Example 8 [(1-Dicyclohexylphosphino)(1'-diadamantylphosphino)ferrocene]dichloropalladium(II-b) The general procedure for compound II-c was used, except that (1-dicyclohexylphosphino)-(1'-diadamantylphosphino)ferrocene (683 mg, 1.0 mmol) was used instead of (1-diisopropylphosphino)-(1'-diadamantylphosphino)ferrocene. The product obtained was a brown solid. 1 H NMR (CD2Cl2): δ = 4.72 (m, 2H, Fc-H), 4.57 (m, 2H, Fc-H), 4.55 - 4.45 (m, 4H, Fc-H), 3.10 - 2.20 (br, 18H), 2.20 - 1.60 (m, 18H), 1.55 - 1.20 (m, 16H); 31 P{ 1H} NMR (CD2Cl2): δ = 75.10 (d), 38.25 (d).

[0128] Example 9 [(1-di-t-butylphosphino)(1'-diadamantylphosphino)ferrocene]dichloropalladium(II-d) The general procedure for compound II-c was used, except that (1-di-t-butylphosphino)-(1'-diadamantylphosphino)ferrocene (631 mg, 1.0 mmol) was used instead of (1-diisopropylphosphino)-(1'-diadamantylphosphino)ferrocene. The product obtained was a brown solid. 31 P{ 1 H} NMR (CD2Cl2): δ = 66.66 (d), 60.00 (d).

[0129] Example 10 [(1-Diisopropylphosphino)(1'-di-t-butylphosphino)ferrocene]dichloropalladium(II-e) The general procedure for compound II-c was used, except that (1-diisopropylphosphino)-(1'-di-t-butylphosphino)ferrocene (446 mg, 1.0 mmol) was used instead of (1-diisopropylphosphino)-(1'-diadamantylphosphino)ferrocene. The product obtained was a brown solid. 31 P{ 1 H} NMR (CD2Cl2): δ = 74.37 (d), 58.80 (d).

[0130] Synthesis of a precatalyst having formula III Example 11 Synthesis of [(1-diisopropylphosphino)(1'-diadamantylphosphino)ferrocene][2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (III-c) Under nitrogen, (1-diisopropylphosphino)-(1'-diadamantylphosphino)ferrocene (603 mg, 1.0 mmol) and di-μ-mesylbis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II) (370 mg, 0.5 mmol) were placed in a 100 mL Schlenk flask and dissolved in 50 mL of anhydrous dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. The solvent was then removed to give a brown solid. The solid was slurried with 50 mL of hexane for 30 minutes to give a red-brown solid. The solid was filtered and dried under reduced pressure to give the pure product (875 mg, 90%). 1 H NMR (CD2Cl2): δ = 7.65 - 7.55 (m, 2H, Ar-H), 7.35 - 7.25 (m, 6H, Ar-H), 4.65 - 4.55 (m, 3H, Fc-H), 4.51 (m, 1H, Fc-H), 4.48 (m, 1H, Fc-H), 4.39 (m, 1H, Fc-H), 4.37 (m, 1H, Fc-H), 4.34 (m, 1H, Fc-H) 2.97 (br, 3H), 2.77 (br, 3H), 2.40 (br, 2H), 2.25 (s, 3H), 2.20 - 1.70 (m, 26H), 1.35 - 1.20 (m, 6H), 0.65 - 0.50 (m, 6H); 31 P{ 1 H} NMR (CD2Cl2): δ = 38.94 (d), 38.65 (d).

[0131] In a similar manner, other metal complexes III described in this disclosure were synthesized.

[0132] Example 12 [(1-diphenylphosphino)(1'-diadamantylphosphino)ferrocene][2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate(III-a)(brown solid) The general procedure for compound II-c was used, except that (1-diphenylphosphino)-(1′-diadamantylphosphino)ferrocene (671 mg, 1.0 mmol) was used instead of (1-diisopropylphosphino)-(1′-diadamantylphosphino)ferrocene. 1 H NMR (CD2Cl2): δ = 7.80 - 7.65 (m, 3H, Ar-H), 7.48 - 7.40 (m, 2H, Ar-H), 7.38 - 7.30 (m, 3H, Ar-H), 7.25 - 7.00 (m, 4H, Ar-H), 6.90 - 6.75 (m, 3H, Ar-H), 6.60 - 6.50 (m, 1H, Ar-H), 6.45 - 6.30 (m, 2H, Ar-H), 6.20 (d, 2H), 4.85 (m, 1H, Fc-H), 4.77 (m, 1H, Fc-H), 4.59 (m, 1H, Fc-H), 4.48 (m, 1H, Fc-H), 4.42 (m, 1H, Fc-H), 4.23 (m, 1H, Fc-H), 4.19 (m, 1H, Fc-H), 3.89 (m, 1H, Fc-H), 2.79 (s, 3H), 2.38 (s, 3H), 2.25 (m, 2H), 2.20 - 1.55 (m, 25H); 31 P{ 1 H} NMR (CD2Cl2): δ = 34.89 (d), 25.78 (d).

[0133] [(1-dicyclohexylphosphino)(1'-diadamantylphosphino)ferrocene][2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (III-b) The general procedure for compound II-c was used, except that (1-dicyclohexylphosphino)-(1'-diadamantylphosphino)ferrocene (683 mg, 1.0 mmol) was used instead of (1-diisopropylphosphino)-(1'-diadamantylphosphino)ferrocene. The product obtained was a brown solid. 1H NMR (CD2Cl2): δ = 7.70 - 7.65 (m, 1H, Ar-H), 7.60 - 7.50 (m, 1H, Ar-H), 7.45 - 7.40 (m, 1H, Ar-H), 7.38 - 7.30 (m, 3H, Ar-H), 7.30 - 7.25 (m, 2H, Ar-H), 4.62 (m, 2H, Fc-H), 4.58 (m, 1H, Fc-H), 4.50 (m, 2H, Fc-H), 4.36 (m, 2H, Fc-H), 4.28 (m, 1H, Fc-H), 2.95 (br, 3H), 2.78 (br, 3H), 2.36 (s, 3H), 2.25 (s, 2H), 2.20 - 0.75 (m, 46H); 31 P{ 1 H} NMR (CD2Cl2): δ = 38.93 (d), 25.97 (d).

[0134] Example 13 [(1-diisopropylphosphino)(1'-di-t-butylphosphino)ferrocene][2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (III-e) The general procedure for compound II-c was used, except that (1-diisopropylphosphino)-(1'-di-t-butylphosphino)ferrocene (446 mg, 1.0 mmol) was used instead of (1-diisopropylphosphino)-(1'-diadamantylphosphino)ferrocene. The product obtained was a brown solid. 1H NMR (CD2Cl2): δ = 7.65 - 7.60 (m, 1H, Ar-H), 7.58 - 7.50 (m, 1H, Ar-H), 7.40 - 7.25 (m, 6H, Ar-H), 4.59 (m, 2H, Fc-H), 4.55 (m, 2H, Fc-H), 4.51 (m, 1H, Fc-H), 4.38 (m, 3H, Fc-H), 2.35 (s, 3H), 2.25 - 2.15 (br, 3H,), 1.94 (d, 9H), 1.40 - 1.22 (m, 16H), 0.70 - 0.50 (m, 6H); 31 P{ 1 H} NMR (CD2Cl2): δ = 47.08 (d), 39.07 (d).

[0135] Synthesis of a precatalyst having formula IV

[0136] Example 14 Synthesis of Pd(crotyl)[Fc(PAd2)(PPh2)]Cl(IV-c) Under nitrogen, (1-diphenylphosphino)-(1'-diadamantylphosphino)ferrocene (671 mg, 1.0 mmol) and (2-butenyl)chloropalladium dimer (or dimer) (197 mg, 0.5 mmol) were placed in a 100 mL Schlenk flask and dissolved in 50 mL of anhydrous THF. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was removed to give a brown solid. The solid was slurried with 50 mL of hexane for 30 minutes to give a red-brown solid. The solid was filtered and dried under reduced pressure to give the pure product (747 mg, 86%). 31 P{ 1 H} NMR (CD2Cl2): δ = 75.70 (d), 38.90 (d).

[0137] In a similar manner, other metal complexes IV described in this disclosure were synthesized.

[0138] Application study Two difficult and underestimated classes of reactions, namely, C sp2 -C sp3 The ligands and crystals described in this disclosure were used in coupling and PC coupling. Not only was the concept proof demonstrated, but also the further synthesis of some ligands (e.g., adamantyl-based phosphines (e.g., S-Phos, Ru-Phos, X-Phos, Amphos, etc.)) was demonstrated without the selection of PC coupling.

[0139] Example 15 C sp2 -C sp3 Cross coupling of

[0140] In organic synthesis, cross-coupling chemistry, which involves sp2-sp3 coupling, is one of the most challenging reactions (19). Over the past 30 years, transition metal catalyzed cross-coupling reactions, which involve the reaction of sp2-hybridized carbon nucleophiles with aryl or vinyl halides, have been intensively studied (18). Meanwhile, C sp2 -C sp3The chemical studies on the coupling of aryl groups are very limited (19). Among them, palladium- and nickel-catalyzed cross-coupling reactions are two of the most intensively studied catalytic systems. Several have been reported occasionally in the literature using model substrates. However, major challenges remain unsolved, especially regarding the scope of reactions for various named reactions of cross-coupling, and especially regarding the use of more complex drug-like molecules (19)-(23). Late-stage functionalization of complex molecules remains one of the hot research areas to make such technologies viable for real-world applications.

[0141] Such studies began by evaluating a series of ferrocenyl-based precatalysts using bromobenzene (PhBr), methylmagnesium bromide (MeMgBr), and a catalyst loading of 1 mol % in THF at ambient temperature (Table 3). sp2 -C sp3 (3), which has been reported to be a very powerful catalyst for the coupling of aryl groups, gave very low conversions with methylmagnesium bromide. Other commercially available next-generation precatalysts of ferrocenyl-based bidentate ligands (i.e., Pd(dcypf)Cl, Pd(d i ppf)Cl2,Pd(d t Further screening of bpf)Cl2) did not result in any satisfactory conversion (or rate of conversion or conversion). However, Pd(d tbpf)Cl2 gave moderate conversion (66%). In contrast, by incorporating (or introducing) an Ad2P site into the ferrocenyl ligand, i.e., Pd(L1-4)Cl2, sp2 -C sp3 The coupling of Pd(L4)Cl2 (Pd4-a) gave almost quantitative conversion (room temperature, 2 h). Interestingly, the ligand of Stepnicka et al., [Fc(P t Neither Ad2P nor Ad2(PPh2)]PdCl2 gave satisfactory conversion (8%, entry 10), suggesting the importance of the Ad2P site. As a baseline comparison, the reaction did not proceed at all without the addition of catalyst (entry 1, Table 3).

[0142] [ka]

[0143] [Table 3]

[0144] With the preferred catalyst in hand, cross-coupling reactions were tested between methylmagnesium bromide and various (hetero)aryl halides. With relatively low catalyst loading (1 mol% Pd(L4)Cl2) (Pd4-a), very good yields were obtained for many substrates (Table 3). Both electron-donating and electron-withdrawing aryl bromides showed no significant difference in terms of conversion / yield (conversion >95%). Reactions of sterically bulky aryl bromides (1e and 1f) required slightly higher temperatures (~50 °C). Isolated yields of >85% were obtained. Substrates with nitrogen-containing heterocycles (i.e. pyridines (1g and 1h) and pyrimidines (1i)) also gave very good results. Finally, Ar-Cl coupling was also successful. At this time, the temperature was increased slightly (1b, 75% GC conversion, 50° C.).

[0145] To further explore the generality of this technique, various alkyl Grignard reagents were investigated (Table 5). Reagents lacking a β-hydrogen (e.g., CD3-, TMSCH2-, p-TolCH2-) all worked well and gave good to excellent isolated yields (1l–1p). Cyclic alkyl reagents (e.g., cyclopropyl, cyclobutyl, cyclopentyl) also worked effectively (2a–2s). However, reagents containing an easily accessible β-hydrogen (e.g., Et-, i Pr-, n Bu-, s Bu-, etc.) did not work well enough under these conditions using Pd(L4)Cl2 (Pd4-a). A significant amount of dehalogenated by-products was observed, which resulted in rather low yields (e.g., 30% GC conversion, 3a). To solve this problem, 4-bromoanisole and nIn the reaction of BuMgCl (Table 4), catalysts were screened. The catalysts were [Fc(Ad2P)(R2P)]PdCl2 (R = Ph(Pd1-a), Cy(Pd2-a), i Pr(Pd3-a) and t Bu(Pd4-a) and (dppf)PdCl2 were used. Pd4-a gave only 30% GC yield. All other catalysts tested gave good conversions. Surprisingly, despite the above yields, almost no isomerization product (i.e., 4-sec-butylanisole) was produced in all catalysts. Reactions with Pd4-a and (dppf)PdCl2 were slower than the other reactions with Pd2-a and Pd3-a. Even after 20 h at room temperature, both reactions gave significant amounts of unreacted starting material, 4-bromoanisole.

[0146] [Table 4]

[0147] For the purpose of simplifying the synthesis, sp2 -C sp3 (L1)PdCl2 (Pd1-a) was selected as a model catalyst to study the application in the coupling of various alkyl Grignard reagents with easily accessible β-hydrogens (Table 5). i BuMgBr) and a second alkyl Grignard reagent (or secondary alkyl Grignard reagent) (e.g., s BuMgBr, i Both PrMgBr worked well, giving moderate to good yields, and N-containing heteroaryl substrates also worked well.

[0148] [Table 5]

[0149] (a) Conditions: Ar-X (0.8 mmol), RMgX (2.0 equiv.), catalyst (1 mol%), THF, room temperature or 50°C (b) Reaction temperature: 50℃ (c) Isolated as the HCl salt (d) Conversion of GC from the reaction using (L4)PdCl2 as catalyst Under the conditions of Negishi (Zn) or Suzuki-Miyaura (B), products 2j, 2k, 2q and 2s showed higher yields (see Table 5).

[0150] In addition, one of the more difficult classes of nucleophiles (or nucleophiles or nucleophiles) (i.e., Grignard reagents (Kumada-Corriu coupling)) can be used to form C sp2 -C sp3 To successfully demonstrate the coupling of sp3The generality of coupling reactions using hybridized organometallic reagents (nucleophiles) such as alkyllithiums (Murahashi-Feringa), alkylzincs (Negishi) and alkylboronic acids (Suzuki-Miyaura) was examined in randomly selected examples (see Table 6). Using a similar strategy employed in alkyl-Grignard reactions (i.e., balancing the steric and electronic properties of the ligand with the steric and electronic properties of the substrate), good to excellent yields were obtained in all the name reactions examined in this disclosure (see examples in Table 6). Due to the lower nucleophilicity of the alkylzinc / boron reagents, C sp2 -C sp3 Couplings of alkyl Grignard reagents typically yielded better results than those of alkyl Grignard reagents. For example, product 2j was isolated in significantly higher yields from reactions involving cyclopropylzinc bromide or cyclopropylboronic acid (95%(B), 95%(Zn), 42%(Mg) compared to the corresponding cyclopropylmagnesium bromide). A similar trend was observed for product 2k (95%(B), 86%(Zn), 53%(Mg)).

[0151] The same methodology has also been applied to organozinc reagents bearing various functional groups with great success. Functional groups such as terminal alkenes (4b, 94%; 4c, 83%; 4d, 81%; and 4e, 79%), esters (4g, 89% and 4h, 75%), and cyanos (4f, 86% and 4i, 80%) were all well tolerated. Interestingly, reactions with organozinc reagents containing strong electron-withdrawing groups close to the nucleophilic carbon center did not require harsher reaction conditions. For example, reactions with EtOC(=O)CH2CH2ZnBr required higher reaction temperatures (e.g., 50 °C) versus room temperature reactions (GC conversion <10%) along with longer reaction times (>20 h). The electronic influence on organozinc reagents appears to decrease with increasing chain length from the nucleophilic carbon center. This is because the products 4f and 4l were isolated in excellent yields even at room temperature.

[0152] C with Li and Mg-based nucleophiles (or nucleophiles or nucleophiles) sp2 -C sp3 In addition to the reported isomerization and dehalogenation side reactions, couplings of alkylboronic acids under Suzuki-Miyaura conditions have also been reported, which undergo protodeboration from the corresponding alkylboronic acids, especially at elevated temperatures. To minimize the protodeboration side reactions, Molander, Hazari, and Burk have used the boronates BF3K and MIDA (23). C sp2 -C sp3 The direct use (or method of use) of alkylboronic acids in the coupling of has only recently been demonstrated, with a few examples, in the literature by Goosen et al. (23a).

[0153] C under the conditions of Kumada-Corriu (Mg), Negishi (Zn), and Suzuki-Miyaura (B) sp2 -C sp3 The success of the coupling of C was ultimately due to at least some of the pioneering coupling reactions (i.e., the Murahashi-Feringa (Li) coupling, especially the C sp3One of the studies on Li nucleophiles based on Pd(L1-4)Cl2 (where severe competing reactions of halogen exchange as well as side reactions originating from isomerization have been reported) was studied. Due to such shortcomings, the Murahashi-Feringa coupling has generally been fairly neglected for the past 30-40 years since its first discovery in the 1970s. Until recently, Feringa's group and Gessner's group independently reported some notable developments in the Murahashi-Feringa coupling. The substrate scope, functional group tolerance, and reaction conditions have been significantly improved. However, the catalyst system described in this disclosure (i.e., Pd(L1-4)Cl2 for the Murahashi-Feringa coupling (Table 6)) was very effective at low catalyst loadings compared to the reported methods. This employs up to 5% Pd loading with O2 to activate the catalyst. Some of these recent ligands cannot be scaled beyond R&D for practical application. Simple aromatic substrates (3f and 3g) and nitrogen-containing heterocycles (3i) were both obtained in good to excellent yields with alkyllithiums. Interestingly, the reaction with MeLi did not require slow addition or dilution. This is probably due to the slow kinetics of Li / halogen exchange under these conditions, related to its stability in ethereal solvents (1i, 73%).

[0154] As mentioned above, for Ar-Cl, the Kumada-Corriu and Negishi reactions required heating (about 50° C.), whereas those for Ar-Br typically proceeded at room temperature. This is due to the continuous C-catalysis of a substrate containing both Cl and Br groups. sp2 -C sp3 The desired products have been isolated with excellent selectivity and yield (e.g., 3p, 87%, and 3p' (from 3p), 91%). n The mono-coupled product 3p was isolated in high yield by coupling with BuZnBr, while keeping the chloro intact. Subsequent coupling of 3p(Ar-Cl) with cyclopropylboronic acid under Suzuki-Miyaura conditions at 100 °C gave the product 3p' in 91% isolated yield.

[0155] [Table 6]

[0156] (a) Negishi's condition (Zn): Ar-X (0.8 mmol), RZnX (2.0 equiv.), catalyst (1 mol%), THF, room temperature or 50°C Suzuki-Miyaura conditions (B): Ar-X (0.8 mmol), RB(OH) (2.0 equiv), catalyst (1 mol%), KPO (3 equiv), toluene / HO (10 / 1), 100°C Murahashi-Feringa conditions (Li): Ar-X (0.8 mmol), RLi (1.2 equiv., diluted with toluene to 0.2 M), catalyst (1 mol%), toluene, room temperature Add slowly using a syringe pump over a period of 2 hours. (b) Reaction temperature: 50℃

[0157] Deuterium-labeled drugs (Table 7.1) (24), especially CD3-based molecules, are prominent due to the “magic methyl effect” (the introduction of a methyl group into a drug can positively affect biological activity). This is due to the remarkable improvement to drug candidates in terms of absorption, distribution, and metabolism in the organism when replacing H atom(s) with deuterium (D). Furthermore, deuterium atoms can be used as tracer atoms, thereby clarifying metabolic pathways in medicinal chemistry. The cyclopropane motif is also highly prominent in drug synthesis, since it is the 10th most frequently found ring system in small molecular drugs (Table 7.1) (25). With regard to the success of model substrates, the grafting of various “alkyl fragments” onto “drug-like” molecules (i.e., mimicking “late stage functionalization”), especially in conjunction with various cross-coupling chemistries, has been attempted using the “Chemistry Informer Libraries” (26) developed at Merck & Co. Good isolated yields have been obtained in nine cases (Table 7.2). Compounds X3a, X4a, X6b and X14a represent drug-like molecules incorporating a cyclopropane ring. Also, the subsequent Negishi and Suzuki C sp2 -C sp3 The coupling strategy was successfully achieved (X6a, 79% yield, and X6b, 90% yield). Surprisingly, nReaction of the same “informer” substrate (or base or substrate or substrate) (or informer-substrate) with BuB(OH)2 at elevated temperature (100 °C) afforded the double coupling product X6c in excellent yield (88%). Finally, the CD3 group was successfully incorporated into one of the “informer” molecules (X15a) in moderate yield (43%). The lower yield of X15a is likely due to the strong nucleophilicity of the Grignard reagent towards the functional group. However, it is predicted that various nucleophiles (or nucleophiles or nucleophiles) of Negishi or Suzuki-Miyaura may give better results in a manner similar (or analogy) to the results on the model substrates (currently such reagents are not commercially available).

[0158] [Table 7]

[0159] (a) Kumada-Corriu conditions (Mg): Ar-X (100 mg), RMgX (2.0 equiv.), catalyst (2 mol%), THF, room temperature or 50°C Negishi's conditions (Zn): Ar-X (100 mg), RZnX (2.0 equiv.), catalyst (2 mol%), THF, room temperature or 50°C Suzuki-Miyaura conditions (B): Ar-X (100 mg), RB(OH) (2.0 equivalents), catalyst (2 mol%), KPO (3 equivalents), toluene / HO (10 / 1), 100°C

[0160] Example 16 Coupling of PC to produce new ligands

[0161] To further understand the utility of the ligand / catalyst system described in this disclosure in other cross-coupling chemistries, the coupling of PC was investigated with a view to synthesizing several new ligands as well as to demonstrating the practicality of coupling PC. Following similar protocols reported by the groups of Buchwald (27) and Stradiotto (12), a screen of reactions was tested with the ligands described in this disclosure and a variety of commercially available monodentate and bidentate ligands (Table 8). All monodentate ligands screened in this work showed less than 5% 1 H NMR conversion. On the other hand, bidentate (or bidentate) ligands 1 H NMR conversions performed better, most of which exceeded 20%. 1 H NMR conversion was shown, except for the following, which showed less than 10% 1 H NMR conversion was shown for dppe (<5%, entry 5) and Fc(PAd2)(PPh2) (8%, entry 9). Surprisingly, Fc(P) has been reported as a ligand that can tolerate PC coupling. i Pr2)(P i Pr2)(dippf) did not work very well in the model reaction, giving only a 24% yield (entry 7). More electron-rich and bulky Fc(P t Bu2)(P t Bu2)(dtbpf) did not show good conversion (yield 21%, entry 8). When the ligands were exchanged for the PAd2-based ligands (L1-4) described in this disclosure, the yields improved significantly. All showed good yields, except for Fc(PAd2)(PPh2)(L1, 8%). On the other hand, Fc(PAd2)(PPh2)(Pi Pr2) (L3) gave the highest yield (87%). Also of note, XantPhos is an acceptable 1 H NMR showed conversion (45%, entry 6). The reaction without the phosphine ligand did not proceed at all (entry 1).

[0162] [Table 8]

[0163] Such techniques were further applied (or adapted) to synthesize a variety of phosphine ligands using optimized reaction conditions and phosphine ligands at hand. Some examples are given below: Notably, several bulky Buchwald ligands have also been synthesized (using this PC coupling) in good to excellent isolated yields. Conventionally, it is difficult to produce (or prepare) such bulky (or bulky) Buchwald ligands, particularly on an industrial large scale (or large scale).

[0164] [Table 9]

[0165] The examples provided in this disclosure are not meant to limit the scope of the invention, as set forth in the claims.

[0166] literature

[0167] (1) (a) Colacot, TJ A Concise Update on the Applications of Chiral Ferrocenyl Phosphines in Homogeneous Catalysis Leading to Organic Synthesis Chem. Rev. 2003, 103(8), 3101. (b) Stepnicka, P. (eds.), Ferrocenes: Ligands, Materials and Biomolecules. Wiley, 2008; (c) Ferrocenes. Homogeneous Catalysis, Organic Synthesis and Materials Science; Togni, A., Hayashi, T., eds.; VCH: Weinheim, Germany,1995 (and references therein). (d) Atkinson, RCJ; Gibson, VC; Long, NJ The syntheses and catalytic applications of unsymmetrical ferrocene ligands. Chem. Soc. Rev. 2004, 33, 313.

[0168] (2) (a) Sollot, G. P.; Snead, J. L.; Portnoy, S.; Peterson, W. R., Jr.;Mertway, H. E. Chem. Abstr. 1965, 63, 18147b. (b) Bishop, J. J.;Davison, A.; Katcher, M. L.; Lichtenberg, D. W.; Merril, R. E.; Smart,J. C. Symmetrically disubstituted ferrocenes : I. The synthesis of potential bidentate ligands J. Organomet. Chem. 1971, 27, 241. (c) Marr, G.; Hunt, T. Unsymmetrically Disubstituted Ferrocenes. Part Vlll. Synthesis and Reactivity of Some 2-Substituted Ferrocenyl phosphines J. Chem. Soc. C 1969, 1070.

[0169] (3) Hayashi, T.; Konishi, M.; Kumada, M. Dichloro[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II): an effective catalyst for cross-coupling reaction of a secondary alkyl Grignard reagent with organic halides. Tetrahedron Lett. 1979, 20, 1871.

[0170] (4) Review: Li, H.; Seechurn, C.C.C.J.; Colacot, T. Development of Preformed Pd Catalysts for Cross-Coupling Reactions, Beyond the 2010 Nobel Prize. ACS Catal. 2012, 2, 1147.

[0171] (5) (a) Colacot, T.J.; Shea, H. A. Cp2Fe(PR2)2PdCl2(R = i-Pr, t-Bu) Complexes as Air-Stable Catalysts for Challenging Suzuki Coupling Reactions. Org. Lett. 2004, 6, 3731. (b) Grasa, G.A.; Colacot, T.J. α-Arylation of Ketones Using Highly Active, Air-Stable (DtBPF)PdX2(X = Cl, Br) Catalysts. Org. Lett. 2007, 9, 5489; c) New Trends in Cross Coupling: Theory and Applications, T. Colacot (編), 2015, RSC.

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[0184] (18) For recent reviews see: (a) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., eds., Wiley-VCH: New York, 2004. (b) Tamao, K.; Miyaura, N. Top. Curr. Chem. 2002, 219, 1. (c) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.

[0185] (19) C sp2 -C sp3For recent publications on coupling, see: (a) Hazra, S.; Jo-hansson Seechurn, CCC; Handa, S.; Colacot, TJ The Resurrection of Murahashi Coupling after Four Decades. ACS Catalysis, 2021, 11, 13188; (b) Janwa, EM; Tharwat Mohy, ED; Lu, CS; Iyad, K.; Ali, K.; Kyriaki, P.; Janah, S. Recent Advances in Metal-Catalyzed Alkyl-Boron (C(sp3)-C(sp2)) Suzuki-Miyaura Cross-Couplings. Catalysts, 2020, 10, 296; (c) Campeau, L.; Hazari, N. Cross-Coupling and Related Reactions: Connecting Past Success to the Development of New Reactions for the Future. Organometallics, 2019, 38, 3; (d) Wang, C.; Derosa, J.; Biscoe, MR Configurationally stable, enantioenriched organometallic nucleophiles in stereo-specific Pd-catalyzed cross-coupling reactions: an alternative ap-proach to asymmetric synthesis. Chem. Sci., 2015, 6, 5105; (e) Jana, R.; Pathak, TP; Sigman, MS Advances in Transition Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-organometallics as Reaction Partners. Chem.Rev., 2011, 111, 1417; (f) Kambe, N.; Iwasaki, T.; Terao, J. Pd-catalyzed cross-coupling reactions of alkyl halides. Chem. Soc. Rev., 2011, 40, 4937.

[0186] (20) For the Murahashi-Feringa coupling (Li), see the following: (a) Helbert, H.; An-tunes, I. F.; Luurtsema, G.; Szymanski, W.; Feringa, B. L.; Elsinga, P. H. Cross-coupling of [11C]methyllithium for 11C-labelled PET trac-er synthesis. Chem. Commun., 2021, 57, 203; (b) Zhao, Q.; Meng, G.; Li, G.; Flach, C.; Mendelsohn, R.; Lalancette, R.; Szostak, R.; Szostak, M. IPr# - highly hindered, broadly applicable N-heterocyclic carbenes Chem. Sci., 2021, 12, 10583; (c) Freure, G. P. R.; Skrotzki, E. A.; Lavertu, J. E.; Newman, S. G. Palladium-Catalyzed Cross-Coupling of Superbase-Generated C(sp3) Nucleophiles. ACS Catal., 2021, 11, 12258; (d) Scherpf, T.; Steinert, H.; Groβjohann, A.; Dilchert, K.; Tappen, J.; Rodstein, I.; Gessner, V. H. Efficient Pd-Catalyzed Direct Coupling of Aryl Chlorides with Alkyllithium Reagents. Angew. Chem. Int. Ed., 2020, 59, 20596; (e) Heijnen, D.; Hornillos, V.; Corbet, B. P.; Giannerini, M.; Feringa, B. L.Palladium-Catalyzed C(sp3)-C(sp2) Cross-Coupling of (Trimethylsilyl)methyllithium with (Hetero)Aryl Halides. Org. Lett., 2015, 17, 2262; (f) Vila, C.; Hornillos, V.; Giannerini, M.; Fananas-Mastral, M.; Feringa, B. L. Palladium-Catalysed Direct Cross-Coupling of Organolithium Reagents with Aryl and Vinyl Triflates. Chem. Eur. J., 2014, 20, 13078; (g) Vila, C.; Giannerini, M.; Hornil-los, V.; Fana'as-Mastral, M.; Feringa, B. L. Palladium-catalysed direct cross-coupling of secondary alkyllithium reagents. Chem. Sci., 2014, 5, 1361; (h) Giannerini, M.; Fananas-Mastral, M.; Feringa, B. L. Direct catalytic cross-coupling of organolithium compounds. Nat. Chem. 2013, 5, 667; (i) Murahashi, S.; Yamamura, M.; Yanagisawa, K.; Mita, N.; Kondo, K. Stereoselective synthesis of alkenes and alkenyl sulfides from alkenyl halides using palladium and ruthenium catalysts. J. Org. Chem., 1979, 44, 2408; (j) Yamamura, M.; Moritani, I.; Murahashi, S.The reaction of σ-vinylpalladium complexes with alkyllithiums. Stereospecific syntheses of olefins from vinyl halides and alkyllithiums. J. Organomet. Chem., 1975, 91, C39.

[0187] (21) Kumada-Corriu glycoprotein (Mg) and: (a) Limmert, ME; Roy , AH ; Hartwig, JF Kumada Coupling of Aryl and Vinyl Tosylates under Mild Conditions. J. Org. Chem. Rev. 2005 , 70 , 9364; (b) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi , T. ; Hirotsu, K. Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II): an effective catalyst for cross-coupling of secondary and primary alkyl Grignard and alkylzinc reagents with organic halides. J. Am. Chem. Soc. 1984 , 106 , 158 ; (c) Tamao, K.; Kiso, Y.; Sumitani, K.; Kumada, M. Alkyl Group Isomerization in the Cross-Coupling Re-action of Secondary Alkyl Grignard Reagents with Organic Halides in the Presence of Nickel-Phosphine Complexes as Catalysts. J. Am. Chem. Soc. Rev. 1972 , 94 ,

[0188] (22) For Negishi coupling (Zn), see the following: (a) Dilauro, G.; Azzollini, C. S.; Vitale, P.; Salomone, A.; Perna, F. M.; Capriati, V. Scalable Negishi Coupling between Organozinc Compounds and (Hetero)Aryl Bro-mides under Aerobic Conditions when using Bulk Water or Deep Eutectic Solvents with no Additional Ligands. Angew. Chem. 2021, 133, 10726; (b) Bhonde, V. R.; O'Neill, B. T.; Buchwald, S. L. An Improved System for the Aqueous Lipshutz-Negishi Cross-Coupling of Alkyl Halides with Aryl Electrophiles. Angew. Chem. Int. Ed. 2016, 55, 1849; (c) Atwater, B.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Pompeo, M.; Froese, R. D. J.; Organ, M. G. The Selective Cross-Coupling of Secondary Alkyl Zinc Reagents to Five-Membered-Ring Heterocycles Using Pd-PEPPSI-IHeptCl. Angew. Chem. Int. Ed. 2015, 54, 9502; (d) Alonso, N.; Miller, L. Z.; Munoz, J. de M.; Alcazar, J.; McQuade, D. T. Continuous Synthesis of Organozinc Halides Coupled to Negishi Reactions. Adv. Synth. Catal. 2014, 356, 3737; (e) Pompeo, M.; Froese, R. D. J.; Hadei, N.; Organ, M. G. Pd-PEPPSI-IPentCl: A Highly Effective Catalyst for the Selective Cross-Coupling of Secondary Organozinc Reagents. Angew. Chem. Int. Ed. 2012, 51, 11354; (f) Duplais, C.; Krasovskiy, A.; Lipshutz, B. H. Organozinc Chemistry Enabled by Micellar Catalysis. Palladium-Catalyzed Cross-Couplings between Alkyl and Aryl Bromides in Water at Room Temperature. Organometallics 2011, 30, 6090; (g) Krasovskiy, A.; Thome', I.; Graff, J.; Kra-sovskaya, V.; Konopelski, P.; Duplais, C.; Lipshutz, B. H. Cross-couplings of alkyl halides with heteroaromatic halides, in water at room temperature. Tetrahedron Letters 2011, 52, 2203; (h) Valente, C.; Belowich, M. E.; Hadei, N.; Organ, M. G. Pd-PEPPSI Complexes and the Negishi Reaction. Eur. J. Org. Chem. 2010, 4343; (i) Duplais, C.; Krasovskiy, A.; Wattenberg, A.; Lipshutz, B. H. Cross-couplings between benzylic and aryl halides "on water": synthesis of diarylmethanes. Chem. Commun., 2010, 46, 562; (j) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. Zn-Mediated, Pd-Catalyzed Cross-Couplings in Water at Room Temperature Without Prior Formation of Organozinc Reagents. J. Am. Chem. Soc. 2009, 131, 15592; (k) Han, C.; Buchwald, S. L. Negishi Coupling of Secondary Alkylzinc Halides with Aryl Bromides and Chlorides. J. Am. Chem. Soc. 2009, 131, 7532; (l) Luo, X.; Zhang, H.; Duan, H.; Liu, Q.; Zhu, L.; Zhang, T.; Lei, A. Superior Effect of a π-Acceptor Ligand (Phosphine-Electron-Deficient Olefin Ligand) in the Negishi Coupling Involving Alkylzinc Reagents. Org. Lett. 2007, 9, 4571; (m) Melzig, L.; Gavryushin, A.; Knochel, P. Direct Aminoalkylation of Arenes and Hetarenes via Ni-Catalyzed Negishi Cross-Coupling Reactions. Org. Lett. 2007, 9, 5529; (n) Kondolff, I.; Doucet, H.; Santelli, M. Palladium-Tetraphosphine as Catalyst Precursor for High-Turnover-Number Negishi Cross-Coupling of Alkyl- or Phenylzinc Derivatives with Aryl Bromides. Organometallics 2006, 25, 5219; (o) Corley, E. G.; Conrad, K.; Murry, J.A.; Savarin, C.; Holko, J.; Boice, G. Direct Synthesis of 4-Arylpiperidines via Palladi-um / Copper(I)-Cocatalyzed Negishi Coupling of a 4-Piperidylzinc Iodide with Aromatic Halides and Triflates. J. Org. Chem. 2004, 69, 5120; (p) Dai, C.; Fu, G. C. The First General Method for Palladium-Catalyzed Negishi Cross-Coupling of Aryl and Vinyl Chlorides: Use of Commercially Available Pd(P(t-Bu)3)2as a Catalyst. J. Am. Chem. Soc. 2001, 123, 2719; (q) Boudier, A.; Knochel, P. Palladium catalyzed stereoselective cross-couplings and acylations of chiral secondary diorganozincs. Tetrahedron Lett. 1999, 40, 687.

[0189] (23) The Suzuki-Miyaura scaffold (B) is one of: (a) Sivendran, N.; Pirk, N.; Hu, Z.; Doppiu, A.; Gooβen, LJ Halogen-Bridged Methylnaphthyl Palladium Dimers as Versatile Catalyst Precursors in Coupling Reactions. Angew. Chem. Int. Ed. 2021, 60, 25151. (b) Spinosa, MR; Doppiu, A.; Hazari, N. Differences in the Performance of Allyl Based Palladium Precatalysts for Suzuki-Miyaura Reactions. Adv. Synth. Catalog. 2020 , 362 , 5062 ; (c) Chen, L.; Ren, P.; Carrow, BP Tri(1-adamantyl)phosphine: Expanding the Boundary of Electron-Releasing Character Available to Organophosphorus Compounds. J. Am. Chem. Soc. Rev. 2016 , 138 , 6392 ; (d) Li, L.; Zhao, S.; Joshi-Pangu, A.; Diane, M.; Biscoe, MR Stereospecific Pd-Catalyzed Cross-Coupling Reactions of Secondary Alkylboron Nucleophiles and Aryl Chlorides. J. Am. Chem. Soc. Rev. 2014 , 136 , 14027 ; (e) Sandrock, DL; Jean-Gerard, L.; Chen , C. ; Dreher , SD ; Molander, GA Stereospecific Cross-Coupling of Secondary Alkyl β-Trifluoroborathoamides. J. Am. Chem. Soc.2010, 132, 17108; (f) Molander, G. A.; Canturk, B. Organotrifluoroborates and Monocoordinated Palladium Complexes as Catalysts-A Perfect Combina-tion for Suzuki-Miyaura Coupling. Angew. Chem. Int. Ed. 2009, 48, 9240; (g) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. Efficient Cross-Coupling of Secondary Alkyltrifluoroborates with Aryl Chlorides-Reaction Discovery Using Parallel Microscale Experimentation. J. Am. Chem. Soc. 2008, 130, 9257; (h) Molander, G. A.; Gormisky, P. E. Cross-Coupling of Cyclopropyl- and Cyclobutyltrifluoroborates with Aryl and Heteroaryl Chlorides. J. Org. Chem. 2008, 73, 7481; (i) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. Efficient Cross-Coupling of Secondary Alkyltrifluoroborates with Aryl Chlorides-Reaction Discovery Using Parallel Microscale Experimentation. J. Am. Chem. Soc. 2008, 130, 9257; (j) Knapp, D. M.; Gillis, E. P.; Burke, M. D.A General Solution for Unstable Boronic Acids: Slow-Release Cross-Coupling from Air-Stable MIDA Boronates. J. Am. Chem. Soc. 2009, 131, 6961.

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Claims

1. Formula I 【Chemistry 1】 I [In the formula, R １ and R ２ is independently １ -C １２ Alkyl, C ３ -C １２ Cycloalkyl, C １ -C １２ Alkoxy, -NR ４ R ５ and optionally substituted phenyl; R ４ and R ５ are H and C, respectively. １ -C １２ alkyl; or R ４ and R ５ can be taken together to form a saturated or unsaturated 5- or 6-membered ring, said ring optionally containing one or more additional heteroatoms selected from O, S and N, and one or more optional substituents; Each optional substituent, when present, is １ -C ４ Alkyl, C １ -C ４ Haloalkyl and C １ -C ４ alkoxy] A compound having the formula:

2. R １ and R ２ The compound of claim 1, wherein is independently selected from the group consisting of phenyl, optionally substituted phenyl, cyclohexyl, isopropyl, and tert-butyl.

3. R １ and R ２ The compound of claim 1 or 2, wherein each is a substituted phenyl.

4. -PR １ R ２ は、 【Chemistry 2】 3. The compound according to claim 1 or 2, selected from the group consisting of:

5. Formula I 【Chemistry 3】 I [In the formula, R １ and R ２ is independently １ -C １２ Alkyl, C ３ -C １２ Cycloalkyl, C １ -C １２ Alkoxy, -NR ４ R ５ and optionally substituted phenyl; R ４ and R ５ are H and C, respectively. １ -C １２ alkyl; or R ４ and R ５ can be taken together to form a saturated or unsaturated 5- or 6-membered ring, said ring optionally containing one or more additional heteroatoms selected from O, S and N, and one or more optional substituents; Each optional substituent, when present, is １ -C ４ Alkyl, C １ -C ４ Haloalkyl and C １ -C ４ alkoxy] A ligand having the formula:

6. R １ and R ２ The ligand of claim 5, wherein is independently selected from the group consisting of phenyl, optionally substituted phenyl, cyclohexyl, isopropyl and tert-butyl.

7. R １ and R ２ The ligand of claim 5 or 6, wherein each is a substituted phenyl.

8. The ligand is 【Chemistry 4】 The ligand according to claim 5 or 6, selected from the group consisting of:

9. Formula II below 【Chemistry 5】 II [In the formula, R １ and R ２ is independently １ -C １２ Alkyl, C ３ -C １２ Cycloalkyl, C １ -C １２ Alkoxy, -NR ４ R ５ and optionally substituted phenyl; R ４ and R ５ are H and C, respectively. １ -C １２ alkyl; or R ４ and R ５ can be taken together to form a saturated or unsaturated 5- or 6-membered ring, said ring optionally containing one or more additional heteroatoms selected from O, S and N, and one or more optional substituents; Each optional substituent, when present, is １ -C ４ Alkyl, C １ -C ４ Haloalkyl and C １ -C ４ alkoxy; M is a transition metal selected from Group 9 or 10; Y is halo. A pre-catalyst having

10. R １ and R ２ The pre-catalyst of claim 9, wherein is independently selected from the group consisting of phenyl, optionally substituted phenyl, cyclohexyl, isopropyl, and tert-butyl.

11. R １ and R ２ The pre-catalyst of claim 9 or 10, wherein each is a substituted phenyl.

12. A pre-catalyst according to any one of claims 9 to 11, wherein M is selected from the group consisting of Pd, Ni, Rh, Co, Ir and Pt.

13. The pre-catalyst according to any one of claims 9 to 12, wherein M is Pd.

14. A pre-catalyst according to any one of claims 9 to 13, wherein Y is selected from chloro, bromo and iodo.

15. below 【Chemistry 6】 The pre-catalyst according to any one of claims 9, 10 or 12 to 14, selected from the group consisting of:

16. The following formula III 【Chemistry 7】 III [In the formula, R １ and R ２ is independently １ -C １２ Alkyl, C ３ -C １２ Cycloalkyl, C １ -C １２ Alkoxy, -NR ４ R ５ and optionally substituted phenyl; R ４ and R ５ are H and C, respectively. １ -C １２ alkyl; or R ４ and R ５ can be taken together to form a saturated or unsaturated 5- or 6-membered ring, said ring optionally containing one or more additional heteroatoms selected from O, S and N, and one or more optional substituents; Each optional substituent, when present, is １ -C ４ Alkyl, C １ -C ４ Haloalkyl and C １ -C ４ alkoxy; M is a transition metal selected from Group 9 or 10; X is H, C １ -C ４ selected from the group consisting of alkyl and phenyl; Y － is a halide, triflate ( － OTf), tetrafluoroborate ( － BF ４ ), hexafluorophosphate ( － P.F. ６ ), mesylate ( － OMs), tosylate ( － OTs), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate ( － BArF), hexafluoroantimonate ( － SbF 6 ) and combinations thereof. A pre-catalyst having

17. R １ and R ２ is independently selected from the group consisting of phenyl, cyclohexyl, isopropyl and tert-butyl.

18. 18. A pre-catalyst according to claim 16 or 17, wherein M is selected from the group consisting of Pd, Ni, Rh, Co, Ir and Pt.

19. The pre-catalyst according to any one of claims 16 to 18, wherein M is Pd.

20. The pre-catalyst according to any one of claims 16 to 19, wherein X is selected from the group consisting of H, methyl and phenyl.

21. Y － , Cl － , B － , I － , － O.T.F., － BF ４ , － O.M.S., － O.T.s., － P.F. ６ , － BArF and － SbF ６ The pre-catalyst according to any one of claims 16 to 20, selected from the group consisting of:

22. below 【Chemistry 8】 The pre-catalyst according to any one of claims 16 to 21, selected from the group consisting of:

23. The following formula IV 【Chemistry 9】 IV [In the formula, R １ and R ２ is independently １ -C １２ Alkyl, C ３ -C １２ Cycloalkyl, C １ -C １２ Alkoxy, -NR ４ R ５ and optionally substituted phenyl; R ４ and R ５ are H and C, respectively. １ -C １２ alkyl; or R ４ and R ５ can be taken together to form a saturated or unsaturated 5- or 6-membered ring, said ring optionally containing one or more additional heteroatoms selected from O, S and N, and one or more optional substituents; Each optional substituent, when present, is １ -C ４ Alkyl, C １ -C ４ Haloalkyl and C １ -C ４ alkoxy; M is a transition metal selected from Group 9 or 10; X is H, C １ -C ４ selected from the group consisting of alkyl and phenyl; Y － is a halide, triflate ( － OTf), tetrafluoroborate ( － BF ４ ), hexafluorophosphate ( － P.F. ６ ), mesylate ( － OMs), tosylate ( － OTs), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate ( － BArF), hexafluoroantimonate ( － SbF ６ ) and combinations thereof. A pre-catalyst having

24. R １ and R ２ is independently selected from the group consisting of phenyl, cyclohexyl, isopropyl, and tert-butyl.

25. 25. A pre-catalyst according to claim 23 or 24, wherein M is selected from the group consisting of Pd, Ni, Rh, Co, Ir and Pt.

26. The pre-catalyst according to any one of claims 23 to 25, wherein M is Pd.

27. The pre-catalyst of any one of claims 23 to 26, wherein X is selected from the group consisting of H, methyl and phenyl.

28. Y － , Cl － , B － , I － , － O.T.F., － BF ４ , － O.M.S., － O.T.s., － P.F. ６ , － BArF and － SbF ６ The pre-catalyst according to any one of claims 23 to 27, selected from the group consisting of:

29. below 【Chemistry 10】 The pre-catalyst according to any one of claims 23 to 28, selected from the group consisting of:

30. 1. A method for conducting a metal catalyzed P-C cross-coupling reaction, the method comprising the steps of: contacting a ligand according to any one of claims 5 to 8 with a metal catalyst in the presence of an aromatic solvent and a base in a reaction vessel; adding a first substrate and a second substrate to the reaction vessel, said first substrate has the formula: Ar-X', where Ar is aryl and X' is halo; The second substrate has the formula: R' ２ PH, where R′ is C １ -C １０ Alkyl and C ３ -C １０ cycloalkyl, The process and heating the reaction vessel to a temperature in the range of 100° C. to 200° C. for a period of time sufficient to form carbon-phosphorus bonds; A method comprising:

31. 31. The method of claim 30, wherein the ligand is a ligand according to claim 8 and the metal catalyst is a Pd catalyst.

32. Metal-catalyzed C ｓｐ２ -C ｓｐ３ The method comprises the steps of: Contacting a pre-catalyst of formula II according to any one of claims 9 to 15 with a first substrate and a second substrate in a reaction vessel in the presence of a solvent. Including, The first substrate has the formula: Ar-X'; Ar is optionally substituted aryl or optionally substituted heteroaryl; X' is chloro, bromo or iodo; The second substrate has the formula: R'[M], R' is C １ -C １０ Alkyl, C １ -C １０ Fluoroalkyl and C ３ -C １０ cycloalkyl; [M] is Li, MgX', ZnX' and B(OH) ２ and related boron reagents, X' is selected from the group consisting of chloro, bromo and iodo; The method comprises: Optionally, heating the reaction vessel; C ｓｐ２ -C ｓｐ３ reacting the first substrate and the second substrate in the presence of said pre-catalyst for a period of time sufficient for cross-coupling of A method comprising:

33. 33. The method of claim 32, wherein the first substrate is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl, and optionally substituted furyl.

34. 34. The method of claim 32 or 33, wherein [M] is Li, the solvent is toluene, and the reaction vessel is not heated.

35. 34. The method of claim 32 or 33, wherein [M] is selected from MgX' and ZnX', the solvent is tetrahydrofuran, and the reaction vessel is heated to 50°C.

36. [M] is B(OH) ２ 34. The method of claim 32 or 33, wherein the solvent is toluene and the reaction vessel is heated to 100°C.

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