Ferrocenyl-based electron-rich phosphines and their complexes

Abstract

Provided are ferrocenyl-based phosphine compounds containing either (i) a di(adamantyl)phosphine group on a first cyclopentadienide ring and a pentaaryl substitution on a second cyclopentadienide ring, or (ii) the respective di(adamantyl)phosphine groups on the first and second cyclopentadienide rings. Also provided are expandable processes for synthesizing the ferrocenyl-based phosphine compounds starting from readily available starting materials in a simple operation, as well as various pre-catalysts containing the ferrocenyl-based phosphine compounds as transition metals and ligands.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 494,077, filed on April 4, 2023, the entirety of which is incorporated herein by reference.

[0002] The offered products are novel ferrocenyl-based electron-rich phosphine compounds containing either (i) a di(adamantyl)phosphine group on a first cyclopentadienide ring and a pentaaryl substitution on a second cyclopentadienide ring (AdQPhos type), or (ii) the respective di(adamantyl)phosphine groups on the first and second cyclopentadienide rings (AdMPhos type).

[0003] Furthermore, the provided method is an expandable process for synthesizing the novel ferrocenyl-based electron-rich phosphine compounds, starting from readily available starting materials with minimal effort.

[0004] Furthermore, various precatalysts are provided, each containing a transition metal and the novel ferrocenyl-based electron-rich phosphine compound as a ligand. Such precatalysts include, for example, as shown in Figure 1, (a) Ar-X or XX transition metal complexes of type LMArX (formula VI) and LMX2 (formula VII) that are useful for catalysis, (b) R-allyl transition metal complexes of type LM(R-allyl)X (formula VIII) and LM(R-allyl) (formula IX), and (c) type LM(biphenyl-NR)X (formula X) and LM(biphenyl-NR) + It includes the N-biphenyl transition metal complex of formula XI.

[0005] All compounds and complexes prepared herein were meticulously characterized by various analytical techniques, including NMR, elemental analysis, and single-crystal X-ray diffraction. For example, (1)C(sp 2 )-C(sp 2 ) Coupling reaction, (2) C(sp 2 )-C(sp3 ) Coupling reaction, (3) C(sp 2 )-N coupling reaction, (4) C(sp 2 )-O coupling reaction, (5) C(sp 2 )-S coupling reaction, (6) C(sp 2 )-P coupling reaction or (7) α-arylation of amides, esters, nitriles, nitroalkanes, ketones, etc. The excellent catalytic activity in many types of cross-coupling reactions, such as the above, has been demonstrated in comparison with QPhos and other ligands known in the art.

[0006] Therefore, a method for carrying out a transition metal-catalyzed coupling reaction between a first substrate and a second substrate is further provided, wherein the transition metal-catalyzed coupling reaction is a C(sp 2 )-C(sp 2 )-C(sp 3 ) coupling reaction, C(sp 2 )-C(sp 3 ) coupling reaction, C(sp 2 )-N coupling reaction, C(sp 2 )-O coupling reaction, C(sp 2 )-S coupling reaction, C(sp 2 )-P coupling reaction or α-arylation of amides, esters, nitriles, nitroalkanes or ketones. Figure 2 shows non-limiting examples of the reactions noted.

Background Art

[0007] The rise of palladium as the metal of the 21st century is due to its application in catalysis where the role of phosphine ligands is of utmost importance. These ligands define the overall effectiveness and efficiency in catalysis by electronic, steric, and other kinetic / thermodynamic factors. Ferrocene-based bisphosphines constitute an important class of modern ligands and are widely used in various cross-coupling reactions such as dtbpf, dppf, dippf, MPhos, etc. (2) ​​

[0008] The study of the synthesis and applications of ferrocenyl monophosphines has been limited by various challenges related to their synthesis, purification, and scale-up. Sollot et al. reported the first monosubstituted ferrocenyl phosphine in 1962 via the Friedel-Craft route (suffering from low yields and selectivity); (3) After that, Knox & Pauson, (4) Juge&Genet, (5) Jamison (6) Their pioneering work revealed general strategies for incorporating dialkyl / arylphosphine motifs into ferrocene rings.

[0009] Despite these advances, the direct application of these ligands in cross-coupling reactions remained limited until the early 2000s. In 2002, Hartwig et al. reported the synthesis of pentaphenylferrocenylphosphine (also known as QPhos) and its derivatives. (7) QPhos is relatively stable compared to other non-arylated species and exhibits unconventional catalytic activity for various CC, CO, and CN cross-coupling reactions; however, scaling up this ligand has been considerably difficult due to the involvement of chromatography. Compared to the corresponding bisphosphinylferrocene, the challenge of the exceptionally good scalability of this ligand limits its industrial application. (8) Precatalysts derived from these novel ligands exhibit superior activity compared to other commercially available ligands containing QPhos. (9)

[0010] Despite these advances, there is still a need for new ligands that (1) can address some of the existing challenges in cross-coupling and (2) have a synthesis suitable for scale-up in manufacturing sufficient to prepare sufficient quantities with purity acceptable for industrial applications.

[0011] With this in mind, the present invention addresses two major advances in this field: (1) the development of a new class of electron-rich polyarylated ferrocenyl monophosphines and their transition metal complexes, and (2) the development / optimization of processes for scalable synthesis for use in commercial applications. This process does not rely on comprehensive purification techniques such as chromatography.

[0012] In summary, the present invention relates to the synthesis and catalytic application of a new class of air-stable polyarylated ferrocenyl monophosphines and their transition metal complexes, as well as a green route for their scalable synthesis. [Overview of the project]

[0013] The offered products are novel ferrocenyl-based electron-rich phosphine compounds containing either (i) a di(adamantyl)phosphine group on a first cyclopentadienide ring and a pentaaryl substitution on a second cyclopentadienide ring (AdQPhos type), or (ii) the respective di(adamantyl)phosphine groups on the first and second cyclopentadienide rings (AdMPhos type).

[0014] Therefore, in a first embodiment of the present invention, a compound of formula I is provided: [ka] Equation I During the ceremony: Cp 1 This is expressed by equation II or equation III. [ka] Formula II [ka] Formula III R 1 Each instance of C6-C is independently of the others and can be arbitrarily substituted. 10Selected from aryl or C3-C9 heteroaryl; Ad is adamantyl, preferably 1-adamantyl; and, If present, each optional substituent is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, preferably methyl, trifluoromethyl, and methoxy.

[0015] In a second aspect of the present invention, a process for synthesizing the compound described in formula IV is provided, wherein the process comprises the following steps: (a) Lithiation of the compound described in formula A, and Ad2PY 2 The step of reacting with to obtain the compound described in formula B; and, (b) The compound described in formula B is prepared in the presence of a base and a catalytic amount of Pd(OAc)2 in R 1 Y 3 The step includes reacting with to obtain the compound described in formula IV, [ka] During the ceremony: Y 1 This is selected from a halogen atom or a hydrogen atom; Y 2 , Y 3 These are selected independently from halogen atoms; R 1 Each instance of C6-C is independently of the others and can be arbitrarily substituted. 10 Selected from aryl or C3-C9 heteroaryl; Ad is adamantyl, preferably 1-adamantyl; and, If present, each optional substituent is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, preferably methyl, trifluoromethyl, and methoxy.

[0016] In a third aspect of the present invention, a process for synthesizing the compound described in formula IV is provided, wherein the process comprises the following steps: (a') Lithiation of the compound described in formula C, and its Ad2PY 2 The step includes reacting with to obtain the compound described in formula V, [ka] During the ceremony: Y 1 This is selected from a halogen atom or a hydrogen atom; Y 2 These are selected independently from halogen atoms; and, Ad is adamantyl, preferably 1-adamantyl.

[0017] In a fourth aspect of the present invention, a pre-catalyst of formula VI or formula VII is provided: [ka] Equation VI [ka] Formula VII During the ceremony: R 1 Each instance of C6-C is independently of the others and can be arbitrarily substituted. 10 Selected from aryl or C3-C9 heteroaryl; Ad is adamantyl, preferably 1-adamantyl; M is a transition metal selected from Group 9, Group 10, or Group 11; X is a halide, triflate (TfO - ), tetrafluoroborate (BF4 - ), hexafluorophosphate (PF6 - ), Mesylate (MsO - ), Tosilato (TsO - ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate(B[(CF3)2C6H3]4 - ), hexafluoroantimonate (SbF6 - ) and selected from the group consisting of combinations thereof; Ar is optionally substituted with C6-C 10 It is aryl; and, If present, each optional substituent is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, preferably methyl, trifluoromethyl, and methoxy.

[0018] In a fifth aspect of the present invention, a pre-catalyst of formula VIII or formula IX is provided. [ka] Formula VIII [ka] Formula IX During the ceremony: R 1 Each instance of C6-C is independently of the others and can be arbitrarily substituted. 10 Selected from aryl or C3-C9 heteroaryl; Ad is adamantyl, preferably 1-adamantyl; M is a transition metal selected from Group 9, Group 10, or Group 11; X is a halide, triflate (TfO - ), tetrafluoroborate (BF4 - ), hexafluorophosphate (PF6 - ), Mesylate (MsO - ), Tosilato (TsO - ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate(B[(CF3)2C6H3]4 - ), hexafluoroantimonate (SbF6 - ) and selected from the group consisting of combinations thereof; R 2 H, C1-C4 alkyl and C6-C 10 Selected from the group consisting of aryls, preferably selected from the group consisting of H, Me, and Ph; and, If present, each optional substituent is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, preferably methyl, trifluoromethyl, and methoxy.

[0019] In a sixth aspect of the present invention, a pre-catalyst of formula X or formula XI is provided: [ka] formula [ka] Formula XI During the ceremony: R 1 Each instance of C6-C is independently of the others and can be arbitrarily substituted. 10 Selected from aryl or C3-C9 heteroaryl; Ad is adamantyl, preferably 1-adamantyl; M is a transition metal selected from Group 9, Group 10, or Group 11; X is a halide, triflate (TfO - ), tetrafluoroborate (BF4 - ), hexafluorophosphate (PF6 - ), Mesylate (MsO - ), Tosilato (TsO - ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate(B[(CF3)2C6H3]4 - ), hexafluoroantimonate (SbF6 - ) and selected from the group consisting of combinations thereof; R 3 is selected from the group consisting of H, Me, NHMe, Ph, and NPHh; and, If present, each optional substituent is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, preferably methyl, trifluoromethyl, and methoxy.

[0020] A seventh aspect of the present invention provides a method for carrying out a transition metal-catalyzed coupling reaction between a first substrate and a second substrate, wherein the method comprises the following steps: (a) (i) providing a compound and transition metal source according to the first aspect of the present invention, or (ii) a pre-catalyst according to any one of the fourth, fifth, or sixth aspects of the present invention, into a reaction vessel; (b) Adding the first substrate and the second substrate to the reaction vessel; and, (c) The step of reacting the first substrate and the second substrate at a temperature and time sufficient to carry out a transition metal-catalyzed coupling reaction. [Brief explanation of the drawing]

[0021] [Figure 1] Figure 1 shows various precatalysts: (a) Ar-X or XX transition metal complexes of type LMArX (formula VI) and LMX2 (formula VII), (b) R-allyl transition metal complexes of type LM(R-allyl)X (formula VIII) and LM(R-allyl) (formula IX), and (c) N-biphenyl transition metal complexes of type LM(biphenyl-NR)X (formula X) and LM(biphenyl-NR)+ (formula XI).

[0022] [Figure 2] Figure 2 shows examples of the following transition metal-catalyzed coupling reactions: a) C(sp2)-C(sp2) coupling reaction, b) C(sp2)-C(sp3) coupling reaction, c) C(sp2)-N coupling reaction, d) C(sp2)-O coupling reaction, e) C(sp2)-S coupling reaction, f) α-arylation of ketones, g) α-arylation of nitriles, h) α-arylation of esters, i) α-arylation of nitroalkanes, j) α-arylation of amides, and k) C(sp2)-P coupling reaction, where R represents hydrogen or a substituent when R is attached to a heteroatom (e.g., N, P, etc.), and where R represents hydrogen or one or more substituents when R is attached to an aromatic ring system. [Modes for carrying out the invention]

[0023] As shown in Figure 1, the novel compounds and precatalysts described herein overcome the problems associated with conventional catalysts, provide a robust new route to cross-coupling reactions that were previously difficult to achieve, and are scalable to be obtained and supplied in quantities and purity sufficient for industrial applications.

[0024] These novel compounds and precatalysts are based on a ferrocenyl backbone and contain either (i) a di(adamantyl)phosphino group on the first cyclopentadienide ring and a pentaaryl substitution on the second cyclopentadienide ring, or (ii) the respective di(adamantyl)phosphino groups on the first and second cyclopentadienide rings. As described herein, they offer significant advantages over existing ligands and precatalysts.

[0025] Conventional processes for synthesizing ferrocenyl-based phosphine compounds are not suitable for incorporating two Ad2P moieties into a ferrocenyl compound to prepare Fc(Ad2P)(Ad2P) type compounds.

[0026] The novel ferrocenyl-based phosphine compounds described herein contain either (i) a di(adamantyl)phosphine group on a first cyclopentadienide ring and a pentaaryl substitution on a second cyclopentadienide ring (AdQPhos type), or (ii) the respective di(adamantyl)phosphine groups on the first and second cyclopentadienide rings (AdMPhos type).

[0027] Furthermore, what is provided is an expandable synthesis of the novel ferrocenyl-based electron-rich phosphine compound, starting from readily available starting materials in a simple operation.

[0028] Furthermore, provided is a pre-catalyst containing the novel ferrocenyl-based electron-rich phosphine compound as a transition metal and ligand, which is useful for catalytic activity, as shown in Figure 1.

[0029] Furthermore, what is provided is a method for carrying out a transition metal-catalyzed coupling reaction between a first substrate and a second substrate, where the transition metal-catalyzed coupling reaction is C(sp 2 )-C(sp 2 )-C(sp 3 ) Coupling reaction, C(sp 2 )-C(sp 3 ) Coupling reaction, C(sp 2 )-N coupling reaction, C(sp 2 )-O coupling reaction, C(sp 2 )-S coupling reaction, C(sp 2 This includes )-P coupling reactions or α-arylation of amides, esters, nitriles, nitroalkanes, or ketones. See Figure 2 for non-limiting examples of the reactions mentioned.

[0030] In a first embodiment of the present invention, a compound of formula I is provided: [ka] Equation I During the ceremony: Cp 1 This is expressed by equation II or equation III, [ka] Formula II [ka] Formula III R 1 Each instance of C6-C is independently of the others and can be arbitrarily substituted. 10 Selected from aryl or C3-C9 heteroaryl; Ad is adamantyl, preferably 1-adamantyl; and, If present, each optional substituent is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, preferably methyl, trifluoromethyl, and methoxy.

[0031] In a preferred embodiment of the present invention, the compound of formula I is represented by formula IV: [ka] Formula IV During the ceremony: R 1 Each instance of C6-C is independently of the others and can be arbitrarily substituted. 10 Selected from aryl or C3-C9 heteroaryl; and, Ad is adamantyl, preferably 1-adamantyl.

[0032] Preferably, in formulas II and / or IV of the present invention, R1 is selected independently of each other for each occurrence from an optionally substituted C6 aryl; and, if present, each optional substituent is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, preferably methyl, trifluoromethyl, and methoxy. More preferably, in formulas II and / or IV of the present invention, R 1 Each instance is independently selected from the group consisting of phenyl, tolyl, and (trifluoromethyl)phenyl. Most preferably, in formula II and / or formula IV of the present invention, R 1 Each instance is independently selected from the group consisting of phenyl, p-tolyl, and p-(trifluoromethyl)phenyl.

[0033] In a preferred embodiment of the present invention, the compound of formula I is represented by formula V: [ka] Formula V In the formula, Ad is adamantyl, preferably 1-adamantyl.

[0034] In a more preferred embodiment of the present invention, the compound of formula I is selected from the group consisting of:

Chemical formula

[0035] In a second embodiment of the present invention, a process for synthesizing the compound described in formula IV is provided, wherein the process comprises the following steps: (a) lithiation of the compound described in formula A and reacting it with Ad2PY 2 to obtain the compound described in formula B; and, (b) reacting the compound described in formula B with R 1 Y 3 in the presence of a base and a catalytic amount of Pd(OAc)₂ to obtain the compound described in formula IV,

Chemical formula

[0036] Preferably, Y 1 is selected from the group consisting of Cl, Br, I, and H, and Y 2 and Y 3 are independently selected from the group consisting of Cl, Br, and I. More preferably, Y1 is Br or H; Y 2 is Cl; Y 3 It is Cl.

[0037] R in the second aspect 1 The preferred, more preferred, and most preferred embodiments are the same as those described above for the first embodiment.

[0038] Preferably, the lithiation in step (a) is carried out by reacting the compound described in formula A with an organolithium reagent. More preferably, the lithiation in step (a) is carried out by reacting the compound described in formula A with an organolithium reagent selected from the group consisting of nBuLi, sBuLi, and tBuLi. Most preferably, the lithiation in step (a) is carried out by reacting the compound described in formula A with nBuLi.

[0039] Preferably, step (a) is carried out in an ether solvent. More preferably, step (a) is carried out in a tetrahydrofuran.

[0040] Preferably, the lithiation in step (a) is carried out at a temperature of about -78°C. More preferably, the lithiation in step (a) is carried out at a temperature of about -78°C, and the Ad2PY in step (a) 2 This reaction takes place over a temperature gradient from approximately -78°C to room temperature.

[0041] Preferably, the base in step (b) is an alkali metal alkoxide or an alkaline earth metal alkoxide. More preferably, the base in step (b) is sodium alkoxide. Most preferably, the base in step (b) is NaOtBu.

[0042] Preferably, step (b) is carried out at a temperature in the range of about 80°C to about 130°C. More preferably, step (b) is carried out at a temperature in the range of about 100°C to about 120°C. Most preferably, step (b) is carried out at a temperature of about 110°C.

[0043] In a third aspect of the present invention, a process for synthesizing the compound described in formula IV is provided, wherein the process comprises the following steps: (a') Lithiation of the compound described in formula C, and its Ad2PY 2 The step includes reacting with to obtain the compound described in formula V, [ka] During the ceremony: Y 1 This is selected from a halogen atom or a hydrogen atom; Y 2 is selected from halogen atoms; and, Ad is adamantyl, preferably 1-adamantyl.

[0044] Preferably, Y 1 It is selected from the group consisting of Cl, Br, I, and H, and Y 2 is selected from the group consisting of Cl, Br, and I. More preferably, Y 1 is Br or H; Y 2 It is Cl.

[0045] Preferably, the lithiation in step (a) is carried out by reacting the compound described in formula C with an organolithium reagent. More preferably, the lithiation in step (a') is carried out by reacting the compound described in formula C with an organolithium reagent selected from the group consisting of nBuLi, sBuLi, and tBuLi. Most preferably, the lithiation in step (a') is carried out by reacting the compound described in formula C with nBuLi.

[0046] Preferably, step (a') is carried out in an ether solvent. More preferably, step (a') is carried out in tetrahydrofuran.

[0047] Preferably, the lithiation in step (a') is carried out at a temperature of about -78°C. More preferably, the lithiation in step (a') is carried out at a temperature of about -78°C, and the Ad2PY in step (a') 2 This reaction takes place over a temperature gradient from approximately -78°C to room temperature.

[0048] In a fourth aspect of the present invention, a pre-catalyst of formula VI or formula VII is provided: [ka] Equation VI [ka] Formula VII During the ceremony: R 1 Each instance of C6-C is independently of the others and can be arbitrarily substituted. 10 Selected from aryl or C3-C9 heteroaryl; Ad is adamantyl, preferably 1-adamantyl; M is a transition metal selected from Group 9, Group 10, or Group 11; X is a halide, triflate (TfO - ), tetrafluoroborate (BF4 - ), hexafluorophosphate (PF6 - ), Mesylate (MsO - ), Tosilato (TsO - ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate(B[(CF3)2C6H3]4 - ), hexafluoroantimonate (SbF6 - ) and selected from the group consisting of combinations thereof; Ar is optionally substituted with C6-C 10 It is aryl; and, If present, each optional substituent is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, preferably methyl, trifluoromethyl, and methoxy.

[0049] Preferably, in formula VI of the present invention, R 1 Each occurrence is independently selected from any optionally substituted C6 aryls; and, if present, each optional substituent is selected from the group consisting of C1-C4 alkyls, C1-C4 haloalkyls, and C1-C4 alkoxys, preferably methyl, trifluoromethyl, and methoxy. More preferably, in formula VI of the present invention, R 1 Each instance is independently selected from the group consisting of phenyl, tolyl, and (trifluoromethyl)phenyl. Most preferably, in formula VI of the present invention, R 1 Each instance is independently selected from the group consisting of phenyl, p-tolyl, and p-(trifluoromethyl)phenyl.

[0050] Preferably, in formula VI and / or formula VII of the present invention, M is selected from the group consisting of Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, and Au. More preferably, in formula VI and / or formula VII of the present invention, M is selected from the group consisting of Ni, Pd, and Pt. Most preferably, in formula VI and / or formula VII of the present invention, M is Pd.

[0051] Preferably, in formula VI and / or formula VII of the present invention, X is a chloride (Cl - ), bromide (Br - ), iodide (I - ), triflate (TfO - ), Mesylate (MsO - ), Tosilato (TsO - ) and combinations thereof are selected from the group.

[0052] Preferably, in formula VI of the present invention, Ar is an optionally substituted C6 aryl. More preferably, in formula VI of the present invention, Ar is selected from the group consisting of Ph, tolyl, and (trifluoromethyl)phenyl. Most preferably, in formula VI of the present invention, Ar is selected from the group consisting of p-tolyl and p-(trifluoromethyl)phenyl.

[0053] In a preferred embodiment of the present invention, a precatalyst of formula VI or formula VII is selected from the group consisting of the following: [ka] During the ceremony: Ad is 1-adamantyl; Ar is Ph or p-(trifluoromethyl)phenyl; and, X is chloride (Cl - ), bromide (Br - ), triflate (TfO - ), and mesylate (MsO - Selected from the group consisting of ).

[0054] In a fifth aspect of the present invention, a pre-catalyst of formula VIII or formula IX is provided. [ka] Formula VIII [ka] Formula IX During the ceremony: R 1 Each instance of C6-C is independently of the others and can be arbitrarily substituted. 10 Selected from aryl or C3-C9 heteroaryl; Ad is adamantyl, preferably 1-adamantyl; M is a transition metal selected from Group 9, Group 10, or Group 11; X is a halide, triflate (TfO - ), tetrafluoroborate (BF4- ), hexafluorophosphate (PF6 - ), Mesylate (MsO - ), Tosilato (TsO - ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate(B[(CF3)2C6H3]4 - ), hexafluoroantimonate (SbF6 - ) and selected from the group consisting of combinations thereof; R 2 H, C1-C4 alkyl and C6-C 10 Selected from the group consisting of aryls, preferably selected from the group consisting of H, Me, and Ph; and, If present, each optional substituent is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, preferably methyl, trifluoromethyl, and methoxy.

[0055] Preferably, in formula VIII of the present invention, R 1 Each occurrence is independently selected from any optionally substituted C6 aryls; and, if present, each optional substituent is selected from the group consisting of C1-C4 alkyls, C1-C4 haloalkyls, and C1-C4 alkoxys, preferably methyl, trifluoromethyl, and methoxy. More preferably, in formula VIII of the present invention, R 1 Each instance is independently selected from the group consisting of phenyl, tolyl, and (trifluoromethyl)phenyl. Most preferably, in formula VIII of the present invention, R 1 Each instance is independently selected from the group consisting of phenyl, p-tolyl, and p-(trifluoromethyl)phenyl.

[0056] Preferably, in formula VIII and / or formula IX of the present invention, M is selected from the group consisting of Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, and Au. More preferably, in formula VIII and / or formula IX of the present invention, M is selected from the group consisting of Ni, Pd, and Pt. Most preferably, in formula VIII and / or formula IX of the present invention, M is Pd.

[0057] Preferably, in formulas VIII and / or IX of the present invention, X is a chloride (Cl - ), bromide (Br - ), iodide (I - ), triflate (TfO - ), tetrafluoroborate (BF4 - ), hexafluorophosphate (PF6 - ), Mesylate (MsO - ), Tosilato (TsO - ) and combinations thereof are selected from the group.

[0058] Preferably, in formula VIII and / or formula IX of the present invention, R 2 This is selected from the group consisting of H, Me, and Ph.

[0059] In a preferred embodiment of the present invention, a precatalyst of formula VIII or formula IX is selected from the group consisting of the following: [ka] During the ceremony: Ad is 1-adamantyl; R 2 is selected from the group consisting of H, Me, and Ph; and, X is chloride (Cl - ), bromide (Br - ), iodide (I - ), triflate (TfO - ), tetrafluoroborate (BF4 - ), and hexafluorophosphate (PF6 - Selected from the group consisting of ).

[0060] In a sixth aspect of the present invention, a pre-catalyst of formula X or formula XI is provided: [ka] formula [ka] Formula XI During the ceremony: R 1 Each instance of C6-C is independently of the others and can be arbitrarily substituted. 10 Selected from aryl or C3-C9 heteroaryl; Ad is adamantyl, preferably 1-adamantyl; M is a transition metal selected from Group 9, Group 10, or Group 11; X is a halide, triflate (TfO - ), tetrafluoroborate (BF4 - ), hexafluorophosphate (PF6 - ), Mesylate (MsO - ), Tosilato (TsO - ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate(B[(CF3)2C6H3]4 - ), hexafluoroantimonate (SbF6 - ) and selected from the group consisting of combinations thereof; R 3 is selected from the group consisting of H, Me, NHMe, Ph, and NPHh; and, If present, each optional substituent is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy, preferably methyl, trifluoromethyl, and methoxy.

[0061] Preferably, in formula X of the present invention, R 1Each occurrence is independently selected from any optionally substituted C6 aryls; and, if present, each optional substituent is selected from the group consisting of C1-C4 alkyls, C1-C4 haloalkyls, and C1-C4 alkoxys, preferably methyl, trifluoromethyl, and methoxy. More preferably, in formula X of the present invention, R 1 Each instance is independently selected from the group consisting of phenyl, tolyl, and (trifluoromethyl)phenyl. Most preferably, in formula X of the present invention, R 1 Each instance is independently selected from the group consisting of phenyl, p-tolyl, and p-(trifluoromethyl)phenyl.

[0062] Preferably, in formula X and / or formula XI of the present invention, M is selected from the group consisting of Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, and Au. More preferably, in formula X and / or formula XI of the present invention, M is selected from the group consisting of Ni, Pd, and Pt. Most preferably, in formula X and / or formula XI of the present invention, M is Pd.

[0063] Preferably, in formula X and / or formula XI of the present invention, X is a chloride (Cl - ), bromide (Br - ), iodide (I - ), triflate (TfO - ), tetrafluoroborate (BF4 - ), hexafluorophosphate (PF6 - ), Mesylate (MsO - ), Tosilato (TsO - ) and combinations thereof are selected from the group.

[0064] Preferably, in formula X and / or formula XI of the present invention, R 3 The element is selected from the group consisting of H, Me, and NHMe.

[0065] In a preferred embodiment of the present invention, a pre-catalyst of formula X or formula XI is selected from the group consisting of the following: [ka] [ka] During the ceremony: Ad is 1-adamantyl; and X is mesylate (MsO - )

[0066] In a seventh aspect of the present invention, a method is provided for carrying out a transition metal-catalyzed coupling reaction between a first substrate and a second substrate, wherein the method comprises the following steps: (a) (i) providing a compound and transition metal source according to the first aspect of the present invention, or (ii) a pre-catalyst according to any one of the fourth, fifth, or sixth aspects of the present invention, into a reaction vessel; (b) Adding the first substrate and the second substrate to the reaction vessel; and, (c) The step of reacting the first substrate and the second substrate at a temperature and time sufficient to carry out a transition metal-catalyzed coupling reaction.

[0067] In a preferred embodiment of the present invention, the transition metal source in the seventh aspect is a Pd metal source, and the precatalyst is a Pd precatalyst.

[0068] In a more preferred embodiment of the present invention, the transition metal source in the seventh aspect is Pd(cod)X2, [Pd(allyl)X]2, [Pd(clotyl)X]2, [Pd(cinnamyl)X]2, [Pd(cinnamyl)X]2, [(2-biphenyl-NHR)Pd(OMs)]2, (cod)Pd(CH2CMe2C6H4), (cod)Pd(CH2TMS)2, Pd(dba)2, Pd2(dba)3, and PdX2(CH3CN)2; where cod=1,5-cyclooctadiene; X=Cl or Br; R=H, Me or Ph; Ms=methylsulfonyl; TMS=trimethylsilyl; dba=dibenzylideneacetone.

[0069] In the most preferred embodiment of the present invention, the transition metal source in the seventh aspect is Pd(cod)Cl2, [Pd(allyl)Cl]2, [Pd(clotyl)Cl]2, [Pd(cinnamyl)Cl]2, [Pd(cinnamyl)Cl]2, [(2-biphenyl-NHR)Pd(OMs)]2, (cod)Pd(CH2CMe2C6H4), (cod)Pd(CH2TMS)2, Pd(dba)2, Pd2(dba)3, and PdCl2(CH3CN)2; where cod = 1,5-cyclooctadiene; R = H, Me or Ph; Ms = methylsulfonyl; TMS = trimethylsilyl; dba = dibenzylideneacetone.

[0070] In a preferred embodiment of the present invention, the transition metal-catalyzed coupling reaction in the seventh aspect is C(sp 2 )-C(sp 2 ) Coupling reaction, C(sp 2 )-C(sp 3 ) Coupling reaction, C(sp 2 )-N coupling reaction, C(sp 2 )-O coupling reaction, C(sp 2 )-S coupling reaction, C(sp 2 The reaction is selected from a )-P coupling reaction or α-arylation of an amide, ester, nitrile, nitroalkane, or ketone.

[0071] Preferably, the temperature in step (c) of the method for carrying out a transition metal-catalyzed coupling reaction according to the present invention is in the range of room temperature to 130°C, more preferably in the range of room temperature to 100°C, and most preferably in the range of room temperature to 70°C.

[0072] In a preferred embodiment of the present invention, the compound provided in step (a) of a method for carrying out a transition metal-catalyzed coupling reaction according to the present invention is selected from the following group: [ka]

[0073] In a preferred embodiment of the present invention, the pre-catalyst provided in step (a) of a method for carrying out a transition metal-catalyzed coupling reaction according to the present invention is selected from the following group: [ka]

[0074] In a preferred embodiment of the present invention, the first substrate provided in step (b) of a method for carrying out a transition metal-catalyzed coupling reaction according to the present invention is selected from aromatic compounds substituted with halogens, preferably Br or Cl, and optionally contains one or more substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, halogen, hydroxy, nitro, and nitrile.

[0075] In a more preferred embodiment of the present invention, the first substrate provided in step (b) of a method for carrying out a transition metal-catalyzed coupling reaction according to the present invention is a C6-C substituted with a halogen, preferably Br or Cl. 18 Selected from aromatic compounds, C1-C 10 Alkyl, C1-C 10 Alkoxy, C6-C 10 Ariel, C6-C 10 It optionally contains one or more substituents selected from the group consisting of aryloxy, C3-C9 heteroaryl, heteroaryloxy, F, Br, Cl, I, hydroxy, nitro, and nitrile.

[0076] In the most preferred embodiment of the present invention, the first substrate provided in step (b) of a method for carrying out a transition metal-catalyzed coupling reaction according to the present invention is selected from C6 aromatic compounds substituted with Br or Cl and optionally contains one or more substituents selected from the group consisting of C1-C5 alkyl, C1-C5 alkoxy, C6 aryl, C6 aryloxy, F, Br, Cl, I, hydroxy, nitro, and nitrile.

[0077] In a preferred embodiment of the present invention, the second substrate provided in step (b) of a method for carrying out a transition metal-catalyzed coupling reaction according to the present invention is selected from the group consisting of alkyl metal halides, alkoxides, boronic acids, thiols, ketones, amides, nitroalkanes, nitriles, esters, and phosphines.

[0078] In a more preferred embodiment of the present invention, the second substrate provided in step (b) of a method for carrying out a transition metal-catalyzed coupling reaction according to the present invention is selected from the group consisting of alkylmagnesium halides containing 1 to 20 carbon atoms, alkylzinc halides containing 1 to 20 carbon atoms, alkoxides containing 1 to 20 carbon atoms, boronic acids containing 1 to 20 carbon atoms, alkylthiols containing 1 to 20 carbon atoms, ketones containing 2 to 20 carbon atoms, amides containing 2 to 20 carbon atoms, nitroalkanes containing 1 to 20 carbon atoms, nitriles containing 1 to 20 carbon atoms, esters containing 2 to 20 carbon atoms, and phosphines containing 1 to 20 carbon atoms, which are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, phenyl, methoxy, ethoxy, propoxy, and phenoxy. definition

[0079] The precatalytic complexes described herein have at least one metallic center containing a transition metal ("M"). Examples of transition metals include, but are not limited to, the transition metals of Groups 9, 10, and 11 of the periodic table. The metals of Group 9 include Co, Rh, and Ir. The elements of Group 10 include Ni, Pd, and Pt. The elements of Group 11 include Cu, Ag, and Au.

[0080] As used herein, the terms “about” or “approximately,” when used in relation to a measurable numerical variable, refer to the indicated value of the variable and all values ​​of the variable that are within the experimental error of the indicated value (e.g., within the 95% confidence interval of the mean) or within ±10%, preferably ±5%, of the indicated value, whichever is greater.

[0081] As used herein, the term "Ad" refers to the adamantyl group, i.e., the group of formula (-C 10 H 15 This refers to tricyclo-bridged hydrocarbons. 1-Adamantyl may also be written as (-C(CH)3(CH2)6), and 2-Adamantyl may also be written as (-CH(CH)4(CH2)5).

[0082] As used herein, the term "tBu" refers to a tert-butyl group, i.e., a branched alkyl group of formula (-C4H9), which may also be written as (-C(CH3)3).

[0083] As used herein, the term "iPr" refers to an isopropyl group, i.e., a branched alkyl group of formula (-C3H7), which may be written as (-CH(CH3)2).

[0084] As used herein, the term “alkyl” refers to, but is not limited to, saturated hydrocarbon chains such as methyl, ethyl, propyl, and butyl. Alkyl chains can be linear or branched. For example, as used herein, propyl encompasses both n-propyl and iso-propyl; butyl encompasses n-butyl, sec-butyl, iso-butyl, and tert-butyl, etc.

[0085] As used herein, the term "cycloalkyl" refers to, but is not limited to, saturated hydrocarbon cyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl (Cy). It also includes, but is not limited to, crosslinked saturated hydrocarbon (poly)cyclic groups such as adamantyl.

[0086] As used herein, the term "aryl" refers to an aromatic hydrocarbon group. Examples of aryls include phenyl, biphenyl, naphthyl, anthracenyl, and their respective substituted forms.

[0087] As used herein, the term “heteroaryl” refers to an aromatic group containing one or more heteroatoms. Preferably, the heteroatoms are selected from O, N, and / or S. Heteroaryls include, as examples, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzoxazolyl, isoquinolyl, quinolyl, quinazolinyl, quinoxalinyl, benzoxazinyl, purinyl, pteridinyl, and the like, as well as their respective substituted forms.

[0088] As used herein, “substitution” means that one or more hydrogen atoms of a described compound or functional group are substituted for another functional group or substituent. For example, a substituted phenyl may contain one or more substituents in place of any hydrogen atom on the phenyl ring. In one embodiment, one substituent may be present at the ortho, meta, or para position. In another embodiment, substituents may be present at both ortho positions or both para positions. In yet another embodiment, an optionally substituted phenyl may contain substituents at both ortho and para positions, or at both meta and para positions, for example. In some embodiments with multiple substituents, the substituents are all identical, while in other embodiments with multiple substituents, the substituents are distinct from one another. Typical substituents include, but are not limited to, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups. When a functional group is described as “optionally substituted,” that functional group may have one or more substituents or may not have substituents.

[0089] Examples Synthesis of phosphine compounds and related palladium precatalysts Example 1: Synthesis of AdQPhos(1) and its derivatives (2) and (3) [ka]

[0090] Step 1: Synthesis of di-1-adamantylphosphinoferrocene (1b)

[0091] A 50 mL Schlenk flask containing a PTFE-coated stirring bar was filled with 1-bromoferrocene (1a, 4.0 g, 15.1 mmol). The container was closed with a rubber septum, evacuated, and filled with nitrogen. This cycle was repeated two more times. Then, 40 mL of dry THF was added, and the mixture was stirred for 5 minutes. The solution was cooled to -78°C, and nBuLi (2.6 M in hexane, 5.7 mL, 15.1 mmol) was added over 15 minutes using an additional flask. After stirring the mixture for 1 hour, a significant precipitate was observed (indicating lithiation). Di(1-adamantyl)chlorophosphine in THF (0.75 M, 15.1 mmol) was then added dropwise. The solution was warmed to room temperature and stirred overnight (18 hours). After 18 hours, a considerable precipitate was observed, and aliquots of the reaction mixture were obtained. 31 3P NMR analysis showed complete consumption of the starting material. The solution was cooled to 0–5°C using an ice bath. The pure product was ground and filtered under nitrogen. The resulting solid was washed with ether and pentane to obtain pure product 1b (yellow solid, 5.6 g, 76.6%).

[0092] Step 2: Synthesis of AdQPhos(1) [ka]

[0093] A 50 mL three-necked round-bottom flask containing a PTFE-coated stirring bar was packed with 1b (0.972 g, 2 mmol), tert-butoxide sodium (1.9 g, 20 mmol), and palladium acetate (22.4 mg, 0.1 mmol). The container was evacuated and filled with nitrogen. This cycle was repeated two additional times. Then, chlorobenzene (20 mL, 197.2 mmol) was added to solubilize the reaction products. The mixture was stirred at rt for 15 minutes. The mixture was then refluxed at 110–120°C for 18 hours. 31Reaction aliquot analysis using 3P NMR showed complete consumption of 1b. The mixture was then cooled to rt, diluted with DCM (20 mL), and filtered through a Celite plug. The Celite plug was washed with DCM, and the remaining product was eluted. The solvent was removed under reduced pressure. The resulting dark reddish solid was washed with acetone to obtain final product 1 (1.2 g, 71%). 1 H NMR(500MHz,CD2Cl2) δ7.33-7.31(m,10H), 7.14-7.07(m,15H), 4.68(d,J= 5Hz,2H), 4.47(d,J=5Hz,2H), 1.92-1.89(m,6H), 1.58-1.57(m,6H),1.58-1.57(m,12H), 1.50-1.47(m,6H); 31 P NMR (202 MHz) 18.4 ppm.

[0094] The products (p-tolyl)AdQPhos(2) and (p-CF3-C6H4)AdQPhos(3) were synthesized similarly, except that chlorobenzene was replaced with a suitable chloroarene. [ka]

[0095] (p-trill)AdQPhos(2): 1 H NMR(500MHz,CD2Cl2) δ7.15(d,J=10Hz,10H), 6.87(d,J=10Hz,10H), 4.56(d,J=5Hz,2H), 4.34(d,J=5Hz,2H), 2.25(s,15H), 1.86-1.84(m,6H), 1.64-1.61(m,6H), 1.54-1.53(m,12H),1.44-1.42(m,6H); 31 P NMR (202 MHz) 18.9 ppm.

[0096] (p-CF3-C6H4)AdQPhos(3): 1H NMR(500MHz,CD2Cl2) δ7.43-7.39(m,20H), 4.69(d,J= 5Hz,2H), 4.4(d,J=5Hz,2H), 4.88(s,4H), 1.85-1.82(m,6H), 1.64-1.52(m,18H), 1.44-1.41(m,6H); 31 P NMR (202 MHz) 16.5 ppm.

[0097] Example 2: Palladium pre-catalyst (Pd-1.2) (allyl / clotyl / cinnamyl type) [ka]

[0098] A 20 mL Schlenk flask containing a PTFE-coated stirring bar was filled with AdQPhos (1,346.4 mg, 0.4 mmol) and palladium precursor (80 mg, 0.2 mmol). The vessel was closed with a rubber septum, evacuated, and filled with nitrogen. This cycle was repeated two more times. Then, dry THF (5 mL) was added and the mixture was stirred for 2 hours. After that, reaction aliquots were prepared. 31 3P NMR analysis showed complete consumption of ligand 1. After removing the solvent and washing the resulting solid with pentane, the final product Pd-1.2 was obtained (412 mg, 96%).

[0099] (AdQPhos)Pd(clotyl)Cl(Pd-1.2): 1 H NMR(500MHz,CD2Cl2) δ7.26-7.23(m,9H), 7.19-7.12(m,6H), 7.10-7.03(m,10H), 5.14(bs,1H), 4.81-4.73(m,2H), 4.63(bs,2H), 4.2-4.15(m,1H), 3.70-3.67(m,1H), 2.20-2.04(m,10H), 1.86-1.77(m,9H), 1.62-1.52(m,15H); 31 P NMR (202 MHz): 61.0 ppm.

[0100] Example 3: Synthesis of palladium pre-catalyst (Pd-1.4) (Palladacycle G3 type) [ka]

[0101] A 20 mL Schlenk flask containing a PTFE-coated stirring bar was filled with AdQphos (1,346.4 mg, 0.4 mmol) and palladium precursor (148 mg, 0.2 mmol). The vessel was closed with a rubber septum, evacuated, and filled with nitrogen. This cycle was repeated two more times. Then, 5 mL of dry DCM was added, and the mixture was stirred for 2 hours. After that, the reaction aliquots were prepared. 31 3P NMR analysis showed complete consumption of ligand 1. After removing the solvent and washing the resulting solid with pentane, the final product Pd-1.4 was obtained (349 mg, 94%).

[0102] (AdQPhos)PdG3(Pd-1.4): 1 H NMR(500MHz,CD2Cl2) δ7.48-7.43(m,1H), 7.40-7.35(m,1H), 7.30-7.25(m,2H), 7.21-7.06(m,27H), 6.98-6.93(m,1H), 6.62-6.59(m,1H), 4.89(bs,1H), 4.42(bs,1H), 4.15(bs,1H), 3.99(bs 1H), 2.52(bs 3H), 2.04(bs,6H), 1.83-1.78(m,9H), 1.60-1.57(m,12H), 1.42-1.40(m,3H); 31 3P NMR (202MHz) 58.3 ppm (bs).

[0103] Example 4: Synthesis of palladium pre-catalyst (Pd-1.7) (Palladacycle G6 type). [ka]

[0104] A 20 mL Schlenk flask containing a PTFE-coated stirring bar was filled with AdQphos (1,182 mg, 0.21 mmol), bromoalene (67 mg, 0.3 mmol), and palladium precursor (78.1 mg, 0.2 mmol). The vessel was closed with a rubber septum, evacuated, and filled with nitrogen. This cycle was repeated two more times. Then, dry THF (5 mL) was added, and the mixture was stirred for 16 hours. Subsequently, reaction aliquots were prepared. 31 3P NMR analysis showed complete consumption of AdQPhos. After removing the solvent and washing the resulting solid with pentane, the final product Pd-1.7 was obtained (133 mg, 53%).

[0105] (AdQPhos)PdG6(Pd-1.7): 1 H NMR(500MHz,CD2Cl2) δ7.42-7.07(m,34H), 4.80(d,J= 10Hz,2H), 4.61(d,J=5Hz,2H), 1.93-1.87(m,6H), 1.78-1.74(m,9H), 1.60-1.54(m,15H); 31 P NMR (202 MHz): 41.2 ppm (s).

[0106] Example 5: Synthesis of AdMPhos(4) and its precatalyst (Pd-4.1) [ka] [ka]

[0107] A 50 mL Schlenk flask containing a PTFE-coated stirring bar was filled with 1-bromoferrocene (4a, 1.0 g, 3.77 mmol). The vessel was closed with a rubber septum, evacuated, and filled with nitrogen. This cycle was repeated two more times. Furthermore, 20 mL of dry THF was added, and the mixture was stirred for 5 minutes. The solution was cooled to -78°C, and nBuLi (2.6 M in hexane, 2.9 mL, 7.72 mmol) was added over 15 minutes using an additional flask. After stirring the mixture for 2 hours, a significant precipitate was observed (indicating lithiation). Then, di(1-adamantyl)chlorophosphine in THF (0.75 M, 8.0 mmol) was added dropwise. The solution was warmed to room temperature and stirred overnight (18 hours). After 18 hours, a considerable precipitate was observed, and aliquots of the reaction mixture were formed. 31 3P NMR analysis showed a considerable consumption of the starting material. The solution was cooled to 0–5°C using an ice bath. The pure product was ground and filtered under nitrogen. The resulting solid was washed with ether and pentane to obtain pure product 4 (yellow solid, 0.72 g, 62%).

[0108] A 20 mL Schlenk flask containing a PTFE-coated stirring bar was filled with AdMPhos (4 mg, 100.0 mg, 0.13 mmol) and palladium precursor (36.3 mg, 0.13 mmol). The vessel was closed with a rubber septum, evacuated, and filled with nitrogen. This cycle was repeated two more times. Then, 5 mL of dry DCM was added, and the mixture was stirred for 5 hours. Subsequently, reaction aliquots were prepared. 31 3P NMR analysis showed complete consumption of ligand 4. After removing the solvent and washing the resulting solid with pentane, the final product Pd-4.1 was obtained (113 mg, 90%).

[0109] (AdMPhos)PdCl2(Pd-4.1): 1 H NMR(500MHz,CD2Cl2) δ4.71-4.28(m,8H), 2.44-1.44(m,60H); 31 P NMR (202 MHz): 59.6 ppm. Application of palladium precatalysts in palladium-catalyzed organic conversion

[0110] Example 6: Palladium-catalyzed sp2-sp3 coupling reaction [ka]

[0111] A 20 mL vial was packed with various pre-catalysts (1.0 mol%), 2-bromoviphenyl (0.17 mL, 1.0 mmol, 1.0 equiv.), and a stirring bar. The mixture was dissolved in THF (5 mL). Then, isopropyl-Nu solution (iPrZnBr: 4.0 mL, 0.5 M, 2.0 mmol, 2.0 equiv.) was added dropwise, and the mixture was stirred at rt for 6 hours. The reaction yield was determined by GC. For the reaction with isopropyllithium, Ferringa's procedure was used. The individual reactions are shown in Table 1 below.

[0112] Table 1: Reactions to Example 6 [Table 1] (*)GC yield: The ratio refers to 2-isopropylbiphenyl:2-(n-propyl)biphenyl.

[0113] 2-Isopropylbiphenyl: 1 H NMR(500MHz,CDCl3) δ7.48-7.43(m,3H), 7.41(d,J=10Hz,2H), 7.36-7.33(m,2H), 7.28-7.22(m,2H), 3.18-3.15(m,1H), 1.21(d,J=10Hz,6H) ppm.

[0114] 2-Isopropylnaphthalene: 1 H NMR(500MHz,CDCl3) δ7.82-7.78(m,3H), 7.65(s,1H), 7.5-7.39(m,3H), 3.08-3.15(m,1H), 1.35(d,J=10Hz,6H) ppm.

[0115] Example 7 Palladium-Catalyzed C-O Coupling Reaction

Chem.

[0116] A 20 mL vial was charged with various precatalysts (1.0 mol%), 4-nitro-bromobenzene (0.17 mL, 1.0 mmol, 1.0 equiv.), sodium tert-butoxide (60 mg, 0.62 mmol, 1.25 equiv.), and a stir bar. The mixture was dissolved in toluene (2 mL). The mixture was then stirred at 50 °C. The reaction yield was determined by GC. The individual reactions are shown in Table 2 below.

[0117] Table 2: Reactions of Example 7

Table 2

[0118] 4-tert-butoxy-nitrobenzene: 1 H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 10 Hz, 2H), 7.04 (d, J = 5 Hz, 2H), 1.46 (s, 9H) ppm.

[0119] Example 8 Palladium-Catalyzed C-S Coupling Reaction

Chem.

[0120] A 4 mL vial was charged with various precatalysts (2.0 mol%), 4-bromoanisole (0.063 mL, 0.5 mmol, 2.0 equiv.), sodium tert-butoxide (72 mg, 0.75 mmol, 3.0 equiv.), and a stir bar. The mixture was dissolved in toluene (2 mL). Then, hexanethiol (0.035 mL, 0.25 mmol, 1.0 equiv.) was added and the mixture was then stirred at 70 °C. The reaction yield was determined by GC. The individual reactions are shown in Table 3 below.

[0121] Table 3: Reactions to Example 8 [Table 3]

[0122] 1-(hexylthio)-4-methoxybenzene: 1 H NMR(500MHz,CDCl3) δ7.33 (d,J=10Hz,2H), 6.84(d,J=10Hz,2H), 3.85(s,3H), 2.81(t,J=10Hz,2H), 1.60-1.55(m,2H), 1.46-1.55(m,2H), 1.30-1.26(m,4H), 0.88(t,J=10 Hz,3H) ppm.

[0123] Example 9: Palladium-catalyzed α-arylation of ketones [ka]

[0124] 20 mL vials were packed with various pre-catalysts (1.0 mol%), 4-fluorobromobenzene (0.26 mL, 2.0 mmol, 2.1 equiv.), ethyl phenyl ketone (0.14 mL, 1.0 mmol, 1.0 equiv.), tert-butoxide sodium (153 mg, 1.5 mmol, 1.5 equiv.), and a stirring bar. The mixtures were dissolved in THF (5 mL). The mixtures were then stirred at 50°C. The reaction yields were determined by GC. The individual reactions are shown in Table 4 below.

[0125] Table 4: Reactions to Example 9 [Table 4]

[0126] Product: [ka] 11H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 10 Hz, 2H), 7.42 (d, J = 10 Hz, 2H), 7.29 - 7.26 (m, 2H), 7.02 - 6.99 (m, 2H), 4.71 (q, J = 10 Hz, 1H) 1.54 (d, J = 5 Hz, 3H) ppm.

[0127] Example 10: Palladium-Catalyzed α-Arylation of Amides

Chemical Structure

[0128] A 20 mL vial was charged with the amide (73.59 mg, 0.50 mmol, 1.00 eq.), precatalyst (2 mol%), and a stir bar. The mixture was dissolved in THF. Then bromobenzene (0.06 mL, 0.55 mmol, 1.10 eq.) was added and stirred for 5 minutes. Then, a 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (0.55 mL, 0.55 mmol, 1.10 eq.) was added dropwise, and the mixture was stirred at 70 °C for 20 hours. Conversion was measured using GC. The individual reactions are shown in Table 5 below.

[0129] Table 5: Reactions of Example 10

Table 5

[0130] Product:

Chemical Structure

[0131] Example 11: Palladium-Catalyzed α-Arylation of Nitroalkanes [ka]

[0132] A 20 mL vial was packed with a pre-catalyst (2 mol%), nitropropane (0.45 mL, 5.0 mmol, 10 eq.), 4-bromoanisole (0.06 mL, 0.5 mmol, 1.0 equiv.), K3PO4 (127.2 mg, 0.75 mmol, 1.5 equiv.), and a stirring bar. The mixture was dissolved in 1,4-dioxane. The mixture was then stirred at 60°C for 20 hours. The conversion was measured using GC. The individual reactions are shown in Table 6 below.

[0133] Table 6: Reactions in Example 11 [Table 6]

[0134] Example 12: Palladium-catalyzed α-arylation of nitriles [ka]

[0135] A 20 mL vial was packed with a pre-catalyst (2 mol%), nitrile (0.07 mL, 0.5 mmol, 1.0 eq.), 4-bromoanisole (0.06 mL, 0.5 mmol, 1.0 equiv.), K3PO4 (318 mg, 1.5 mmol, 3.0 equiv.), and a stirring bar. The mixture was dissolved in 1,4-dioxane. The mixture was then stirred at 60°C for 20 hours. The conversion was measured using GC. The individual reactions are shown in Table 7 below.

[0136] Table 7: Reactions in Example 12 [Table 7]

[0137] Example 13: Palladium-catalyzed α-arylation of esters [ka]

[0138] A 20 mL vial was packed with a pre-catalyst (3 mol%), ester (200 mg, 1.22 mmol, 2.4 equiv.), and a PTFE-coated stirring bar. Then, 5 mL of dry toluene was added, and the mixture was stirred for 2 minutes. LiHMDS (1.25 mmol) was added to the solution at 0°C. The mixture was stirred for 10 minutes. Then, a 4-bromoanisole solution in 0.5 mL of toluene was added dropwise. The mixture was then stirred at 70°C for 20 hours. The conversion was measured using GC. The individual reactions are shown in Table 8 below.

[0139] Table 8: Reactions in Example 13 [Table 8]

[0140] Example 14: Palladium-catalyzed PC coupling reaction [ka]

[0141] A 4 mL vial was packed with various pre-catalysts (5.0 mol%), 4-bromoanisole (0.032 mL, 0.25 mmol, 1.0 equiv.), tert-butoxide sodium (72 mg, 0.75 mmol, 3.0 equiv.), and a stirring bar. The mixture was dissolved in toluene (2 mL). Then, Ad2PH (83 mg, 0.25 mmol, 1.1 equiv.) was added, and the mixture was then stirred at 70°C. The reaction yield was: 31 The reaction was determined by 1P NMR. The individual reactions are shown in Table 9 below.

[0142] Table 9: Reactions to Example 14 [Table 9]

[0143] The examples provided herein are not intended in any way to limit the scope of the invention as described in the claims. reference

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[0152] (9) CCC Johansson Seechurn, SL Parisel, TJ Colacot, J. Org. Chem. 2011, 76, 7918-7932.

Claims

1. A compound of formula I: 【Chemistry 1】 Equation I During the ceremony: Cp 1 This is expressed by equation II or equation III, 【Chemistry 2】 Formula II 【Transformation 3】 Formula III R 1 Each instance is an arbitrary substitution of C, independently of each other. 6 -C 10 Aryl or C 3 -C 9 Selected from heteroaryls; Ad is adamantyl; and, When present, each optional substituent is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 the compound selected from the group consisting of alkoxy.

2. The compound is represented by formula IV, 【Chemistry 4】 Formula IV In the formula, R 1 and Ad are defined as in claim 1, the compound according to claim 1.

3. A compound according to claim 1 or 2, wherein R 1 However, each instance of C is independently substituted for the others. 6 Selected from aryls; and, if present, each arbitrary substituent is C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl and C 1 -C 4 The compound selected from the group consisting of alkoxys.

4. The compound is represented by formula V: 【Transformation 5】 Formula V In the formula, Ad is defined as in claim 1, the compound according to claim 1.

5. A compound according to claim 1, selected from the group consisting of the following: 【Transformation 6】

6. A process for synthesizing the compound described in claim 2, comprising the following steps: (a) Lithiation of the compound described in formula A, and Ad 2 PY 2 The step of reacting with to obtain the compound described in formula B; and, (b) The compound described in formula B is given a base and a catalytic amount of Pd(OAc) 2 In the presence of R 1 Y 3 The step of reacting with to obtain the compound described in formula IV; 【Transformation 7】 During the ceremony: Y 1 This is selected from a halogen atom or a hydrogen atom; Y 2 , Y 3 These are selected independently from halogen atoms; R 1 Each instance is an arbitrary substitution of C, independently of each other. 6 -C 10 Aryl or C 3 -C 9 Selected from heteroaryls; Ad is adamantyl; and, If present, each arbitrary substituent is C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl and C 1 -C 4 The process is selected from the group consisting of alkoxys.

7. The process according to claim 6, wherein the lithiation in step (a) is carried out by reacting the compound described in formula A with an organolithium reagent.

8. The process according to claim 6 or 7, wherein the base in step (b) is an alkali metal alkoxide or an alkaline earth metal alkoxide.

9. A process for synthesizing the compound described in claim 4, comprising the following steps: (a') Lithiation of the compound described in formula C, and Ad 2 PY 2 The step includes reacting with to obtain the compound described in formula V, 【Transformation 8】 During the ceremony: Y 1 This is selected from a halogen atom or a hydrogen atom; Y 2 is selected from halogen atoms; and, Ad is adamantyl in the process described above.

10. The process according to claim 9, wherein the lithiation in step (a') is carried out by reacting the compound described in formula C with an organolithium reagent.

11. A pre-catalyst of formula VI or formula VII: 【Chemistry 9】 Equation VI 【Chemistry 10】 Formula VII During the ceremony: R 1 Each instance is an arbitrary substitution of C, independently of each other. 6 -C 10 Aryl or C 3 -C 9 Selected from heteroaryls; Ad is adamantyl; M is a transition metal selected from Group 9, Group 10, or Group 11; X is a halide, triflate (TfO - ), tetrafluoroborate (BF 4 - ), hexafluorophosphate (PF 6 - ), Mesylate (MsO - ), Tosilato (TsO - ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate(B[(CF 3 ) 2 C 6 H 3 ] 4 - ), hexafluoroantimonate (SbF 6 - ) and selected from the group consisting of combinations thereof; Ar is an arbitrarily substituted C 6 -C 10 It is aryl; and, If present, each arbitrary substituent is C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl and C 1 -C 4 The pre-catalyst is selected from the group consisting of alkoxys.

12. The pre-catalyst according to claim 11, wherein R 1 However, each instance of C is independently substituted for the others. 6 Selected from aryls; and, if present, each arbitrary substituent is C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl and C 1 -C 4 The pre-catalyst is selected from the group consisting of alkoxys.

13. The pre-catalyst according to claim 11 or 12, wherein M is selected from the group consisting of Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, and Au, preferably Ni, Pd, and Pt, and more preferably M is Pd.

14. Ar is arbitrarily substituted with C 6 A pre-catalyst according to one or more of claims 11 to 13, wherein the pre-catalyst is an aryl compound.

15. A pre-catalyst according to one or more of claims 11 to 14, wherein the pre-catalyst is selected from the group consisting of the following: 【Chemistry 11】 During the ceremony: Ad is 1-adamantil; Ar is Ph or p-(trifluoromethyl)phenyl; and, X is chloride (Cl - ), bromide (Br - ), triflate (TfO - ), and mesylate (MsO - The pre-catalyst selected from the group consisting of ).

16. A pre-catalyst of formula VIII or formula IX: 【Chemistry 12】 Formula VIII 【Chemistry 13】 Formula IX During the ceremony: R 1 is, for each occurrence, independently of one another, optionally substituted C 6 -C 10 -aryl or C 3 -C 9 -heteroaryl selected from; Ad is adamantyl; M is a transition metal selected from Group 9, Group 10, or Group 11; X is selected from the group consisting of halides, triflates (TfO - ), tetrafluoroborates (BF 4 - ), hexafluorophosphates (PF 6 - ), mesylates (MsO - ), tosylates (TsO - ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (B[(CF 3 ) 2 C 6 H 3 ) 4 - ), hexafluoroantimonates (SbF 6 - ) and combinations thereof; R 2 H, C 1 -C 4 Alkyl and C 6 -C 10 Selected from the group consisting of aryls; and, If present, each arbitrary substituent is C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl and C 1 -C 4 The pre-catalyst is selected from the group consisting of alkoxys.

17. The pre-catalyst according to claim 16, wherein R 1 However, each instance of C is independently substituted for the others. 6 Selected from aryls; and, if present, each arbitrary substituent is C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl and C 1 -C 4 The pre-catalyst is selected from the group consisting of alkoxys.

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

19. A pre-catalyst according to one or more of claims 16 to 18, wherein the pre-catalyst is selected from the group consisting of the following: 【Chemistry 14】 During the ceremony: Ad is 1-adamantil; R 2 is selected from the group consisting of H, Me, and Ph; and, X is chloride (Cl - ), bromide (Br - ), iodide (I - ), triflate (TfO - ), tetrafluoroborate (BF 4 - ), and hexafluorophosphate (PF 6 - The pre-catalyst selected from the group consisting of ).

20. A pre-catalyst of formula X or formula XI: 【Chemistry 15】 formula 【Chemistry 16】 Formula XI During the ceremony: R 1 Each instance is an arbitrary substitution of C, independently of each other. 6 -C 10 Aryl or C 3 -C 9 Selected from heteroaryls; Ad is adamantyl; M is a transition metal selected from Group 9, Group 10, or Group 11; X is a halide, triflate (TfO - ), tetrafluoroborate (BF 4 - ), hexafluorophosphate (PF 6 - ), Mesylate (MsO - ), Tosilato (TsO - ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate(B[(CF 3 ) 2 C 6 H 3 ] 4 - ), hexafluoroantimonate (SbF 6 - ) and selected from the group consisting of combinations thereof; R 3 is selected from the group consisting of H, Me, NHMe, Ph, and NPHh; and, If present, each arbitrary substituent is C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl and C 1 -C 4 The pre-catalyst is selected from the group consisting of alkoxys.

21. The pre-catalyst according to claim 20, wherein R 1 However, each instance of C is independently substituted for the others. 6 Selected from aryls; and, if present, each arbitrary substituent is C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl and C 1 -C 4 The pre-catalyst is selected from the group consisting of alkoxys.

22. The pre-catalyst according to claim 20 or 21, wherein M is selected from the group consisting of Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, and Au, preferably Ni, Pd, and Pt, and more preferably M is Pd.

23. A pre-catalyst according to one or more of claims 20 to 22, wherein the pre-catalyst is selected from the group consisting of the following: 【Chemistry 17】 During the ceremony: Ad is 1-adamantyl; and X is mesylate (MsO - The pre-catalyst is the aforementioned pre-catalyst.

24. A method for carrying out a transition metal-catalyzed coupling reaction between a first substrate and a second substrate, comprising the following steps: (a) (i) providing a compound and a transition metal source according to one or more of claims 1 to 5, or (ii) a pre-catalyst according to one or more of claims 11 to 23, to a reaction vessel; (b) Adding the first substrate and the second substrate to the reaction vessel; and, (c) The method comprising the step of reacting a first substrate and a second substrate at a temperature and time sufficient to carry out a transition metal-catalyzed coupling reaction.

25. The method according to claim 24, wherein the transition metal source is a Pd metal source and the precatalyst is a Pd precatalyst.

26. The method according to claim 24 or 25, wherein the transition metal-catalyzed coupling reaction is C(sp 2 )-C(sp 2 ) Coupling reaction, C(sp 2 )-C(sp 3 ) Coupling reaction, C(sp 2 )-N coupling reaction, C(sp 2 )-O coupling reaction, C(sp 2 )-S coupling reaction, C(sp 2 The method, selected from a )-P coupling reaction or α-arylation of an amide, ester, nitrile, nitroalkane, or ketone.

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