Complexes for transition metal-catalyzed N-heterocyclic carbenes

Abstract

This paper describes a new class of highly active Pd(II)-NHC complexes bearing anilines as disposable ligands. These catalysts are well-defined, stable to air and moisture, and can be easily purified by chromatographic techniques. The high activity and versatility are illustrated by C-N, C-O, and C-Cl cleavage in the Suzuki-Miyaura cross-coupling. The facile synthesis of these catalysts is also described.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application Serial No. 62 / 958,583, filed on January 8, 2020, entitled "COMPLEXES OF N - HETEROCYCLIC CARBENES FOR TRANSITION METAL CATALYSIS", the disclosure of which is incorporated herein by reference in its entirety.

[0003] Statement Regarding Federally Sponsored Research

[0004] This invention was made with government support under CHE1650766 awarded by the National Science Foundation and GM133326 awarded by the National Institutes of Health. The government has certain rights in this invention. Background of the Invention

[0005] Palladium - catalyzed cross - coupling reactions have revolutionized the synthesis of small molecules and are one of the most important methods for constructing a variety of chemicals. In particular, in recent years, well - defined Pd(II) precatalysts have emerged, allowing the use of an optimal 1:1 Pd - to - ligand ratio in operationally convenient protocols. Many of these precatalysts, including Nolan's [Pd(NHC)(allyl)Cl] and [Pd(NHC)(cin)Cl] complexes, Organ's Pd - PEPPSI system, Hazari's [Pd(NHC)(ind)Cl] catalyst, or Buchwald's G1 - G4 palladacycles, are now commercially available, enabling end - users to directly perform applications and reaction optimizations.

[0006] NHC (NHC = N - heterocyclic carbene) was initially designed as a complement to phosphines and has shown significant advantages as an ancillary ligand in Pd - catalysis, including strong σ - donation and steric modulation around the metal center. The stabilizing effect of the amine - type nitrogen on palladium is a key feature of Nolan's and Buchwald's palladacycles. As an ideal catalyst design criterion, a throw - away ligand should be easily removed in the activation step to generate an active monocoordinated Pd(0) complex, while its re - association can stabilize the active metal species, thereby extending the catalyst lifetime.

[0007] Accordingly, there is a need in the art for novel complexes that can be used as catalysts in cross - coupling reactions. The present invention addresses this need. Summary of the Invention

[0008] In various embodiments, the present disclosure provides a compound of Formula I or a salt or solvate thereof:

[0009]

[0010] Wherein:

[0011] is a single bond or a double bond;

[0012] R 1 and R 2 are each independently C 3-10 cycloalkyl, aryl or heteroaryl, each of which is optionally substituted by at least one group selected from the following: halogen, OR, SiR 3 、OSiR 3 、OSiR 3 、OSi(OR) 3 、BR 3 、BR 2 、B(OR) 3 、B(OR) 2 、CN, CF 3 、OCF 3 、SO 2 R, SO 2 N(R) 2 、SO 3 R, C(O)R, NR 2 、N(R)SO 2 R, N(R)SO 2 N(R) 2 、(CH 2 ) 0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 、N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, O C 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl;

[0013] R 3 and R 4 are each independently hydrogen, optionally substituted C 3-10 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, C 1-12 alkyl or O C 1-12 alkyl, wherein the optional substitution includes at least one group selected from the following: halogen, OR, SiR 3 、OSiR 3 、OSiR 3 、OSi(OR) 3 、BR 3 、BR 2 、B(OR)3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 , (CH 2 ) 0-2 N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, O 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl; or

[0014] R 3 and R 4 together with the ring to which they are attached are used to form a C 4-20 cycloalkyl, C 6-20 aryl or C 6-20 heteroaryl, each of which is optionally substituted by at least one group selected from the following: halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 , N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 , (CH 2 ) 0-2 N(R)N(R) 2, N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl;

[0015] R 5 is H or optionally substituted C 1-3 alkyl;

[0016] M is a transition metal;

[0017] X is a counteranion;

[0018] A is aryl or heteroaryl, optionally substituted by at least one group selected from the following: halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 , N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 , N(R)C(O)R, (CH 2 ) 0-2 , N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl;

[0019] R is independently hydrogen or C 1-10 alkyl at each occurrence;

[0020] m is 1, 2 or 3; and

[0021] n is 1, 2, 3 or 4.

[0022] In various embodiments, there is provided a method for preparing a compound of formula I or a salt, solvate, geometric isomer or stereoisomer thereof. The method comprises contacting a compound of the following structure or a salt, solvate, geometric isomer or stereoisomer thereof with a compound having the structure or a salt, solvate, geometric isomer or stereoisomer thereof in a solvent to form a compound of formula I or a salt, solvate, geometric isomer or stereoisomer thereof,

[0023]

[0024] where each R 9 is independently selected from hydrogen, halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 , N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, O C 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl, and where p is 0, 1, 2, 3, 4 or 5.

[0025] Another method for preparing a compound of formula I or a salt, solvate, geometric isomer or stereoisomer thereof comprises, in some embodiments, contacting a compound of formula I-SM or a salt, solvate, geometric isomer or stereoisomer thereof with MX 2 (A—N(H)(R 5 )) 2The compounds are contacted in a solvent to form a compound of formula I or a salt, solvate, geometric isomer or stereoisomer thereof,

[0026]

[0027] In some embodiments, the reaction is carried out in the presence of a base. The compound of formula I-SM can be a stable salt of any of the NHC moieties described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The drawings generally illustrate, by way of example and not limitation, various embodiments of the present application.

[0029] Figure 1 Shows the structures of well-defined Pd(II) precatalysts with different monodentate ligands.

[0030] Figure 2 Shows the X-ray crystal structures of complexes 6a (a) and 7a (b). Two views: front view (top); side view (bottom). For clarity, hydrogen atoms other than those of the NHC backbone and the ArNH 2 portion are omitted. Selected bond lengths and bond angles [°] (6a): Pd1–C1, 1.970(3); Pd1–N3, 2.109(2); Pd1–Cl1, 2.2997(9); Pd1–Cl2, 2.2990(9); C1–N1, 1.354(3); C1–N2, 1.358(3); C1–Pd1–N3, 175.5(1); N3–Pd1–Cl1, 87.59(6); N3–Pd1–Cl2, 90.51(6); C1–Pd1–Cl2, 90.54(8); N1–C1–N2, 105.3(2); N1–C1–Pd1, 124.2(2); N2–C1–Pd1, 130.4(2). Selected bond lengths and bond angles [°] for (7a).

[0031] Figure 3 Shows the topological stereograms of [(IPr)PdCl 2 (AN)] (6a) and [(SIPr)PdCl 2 (AN)] (7a), showing the %V of each quadrant bur .

[0032] Figures 4A - 4B Shows IPr # –PEPPSI, [Pd(IPr # )(3-Cl-py)Cl 2Front view (Figure 4A) and side view (Figure 4B) of the X-ray crystal structure of Detailed Description of the Invention

[0033] The synthesis, characterization, and reactivity of [(NHC)PdCl 2 (aniline)] complexes that meet the criteria of an ideal catalyst are described herein. In certain non-limiting embodiments, unexpected features of the catalysts herein include well-defined stability that is stable to air and moisture, as well as high activity in the Suzuki-Miyaura cross-coupling of amides via N-C(O) activation and high activity in the Suzuki-Miyaura cross-coupling of esters and aryl chlorides and Buchwald-Hartwig amination. The compounds herein use widely available anilines as disposable ligands for well-defined Pd(II)-NHC catalysis. The availability of various aniline scaffolds, including structural and electronic diversity, provides advantages for the design and fine-tuning of challenging cross-coupling reactions.

[0034] Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. Although the disclosed subject matter will be described in conjunction with the recited claims, it should be understood that the illustrated subject matter is not intended to limit the claims to the disclosed subject matter.

[0035] Throughout this document, values expressed in range format should be interpreted in a flexible manner, including not only the explicitly recited values that define the range limits, but also all individual values or sub-ranges subsumed within that range as if each value and sub-range were explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also individual values within the specified range (e.g., 1%, 2%, 3%, and 4%) and sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). Unless otherwise stated, the statement "about X to Y" has the same meaning as "about X to about Y". Similarly, unless otherwise stated, the statement "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z".

[0036] In this document, unless the context clearly dictates otherwise, the terms "a", "an", or "the" are used to include one or more. Unless otherwise stated, the term "or" is used to refer to a non-exclusive "or". The statements "at least one of A and B" or "at least one of A or B" have the same meaning as "A, B, or A and B". Additionally, it should be understood that, unless otherwise defined, the phrases or terms used herein are for descriptive purposes only and not for purposes of limitation. The use of any section headings is for the purpose of assisting in the reading of the document and should not be construed as limiting; information related to a section heading may appear within or outside of that particular section. All publications, patents, and patent documents mentioned in this document are hereby incorporated by reference in their entirety as if individually incorporated by reference.

[0037] In the methods described herein, the acts may be performed in any order, unless a time or order of operation is explicitly recited. Additionally, the recited acts may be performed concurrently unless explicit statement language indicates that they are to be performed separately. For example, the claimed act of doing X and the claimed act of doing Y may be performed concurrently in a single operation, and the resulting process will fall within the literal scope of the claimed method.

[0038] Definitions

[0039] As used herein, the term "about" may allow for a degree of variability in a value or range, e.g., within 10%, within 5%, or within 1% of the stated value or the bounds of the stated range, and includes the exact stated value or range.

[0040] As used herein, the term "substantially" means mostly or mainly, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99% or at least about 99.999% or more or 100%. As used herein, the term "substantially free of" may mean none or having a negligible amount such that the amount of the material present does not affect the material properties of the composition including the material, such that the composition contains from about 0 wt% to about 5 wt% of the material or from about 0 wt% to about 1 wt% or 5 wt% or less or less than, equal to, or more than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01 or about 0.001 wt% or less. The term "substantially free of" may mean having a negligible amount such that the composition contains from about 0 wt% to about 5 wt% of the material or from about 0 wt% to about 1 wt% or 5 wt% or less or less than, equal to, or more than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01 or about 0.001 wt% or less or about 0 wt%.

[0041] As used herein, the term "organic group" refers to any carbon-containing functional group. Examples can include oxygen-containing groups such as alkoxy, aryloxy, aralkyloxy, oxo (carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylates, and carboxylic esters; sulfur-containing groups such as alkyl, aryl thioether groups, etc.; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R) 2 、CN、CF 3 、OCF 3 、R、C(O)、 methylenedioxy, ethylenedioxy, N(R) 2 ,SR、SOR、SO 2 R、SO 2 N(R) 2 、SO 3 R、C(O)R、C(O)C(O)R、C(O)CH 2 C(O)R、C(S)R、C(O)OR、OC(O)R、C(O)N(R) 2 、OC(O)N(R) 2 ,C(S)N(R) 2 、(CH 2 ) 0-2N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R) 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R) 2 , N(R)C(S)N(R) 2 , N(COR)COR, N(OR)R, C(=NH)N(R) 2 , C(O)N(OR)R, C(=NOR)R and substituted or unsubstituted (C 1 -C 100 ) hydrocarbyl groups, where R can be hydrogen (in instances that include other carbon atoms) or a carbon-based moiety, and where the carbon-based moiety can be substituted or unsubstituted.

[0042] As used herein, the term "substituted" when used in connection with a molecule or organic group refers to a state in which one or more of the hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. As used herein, the term "functional group" or "substituent" refers to a group that can or has been substituted onto a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); atoms in groups such as hydroxy, alkoxy, aryloxy, aralkyloxy, oxo (carbonyl) groups, including oxygen atoms in carboxyl groups such as carboxylic acids, carboxylates, and carboxylic esters; atoms in groups such as mercapto, alkyl and aryl sulfide groups, sulfinyl, sulfonyl, sulfamoyl, and sulfonamide groups; atoms in groups such as amines, hydroxylamines, nitriles, nitro, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R) 2 , CN, NO, NO 2 , ONO 2 , azide, CF 3 , OCF 3 , R, O (oxo), S (thiocarbonyl), C(O), S(O), methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR, SO 2 R, SO 2 N(R)2 and SO 3 R, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R) 2 and OC(O)N(R) 2 , C(S)N(R) 2 and (CH 2 ) 0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 and N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R) 2 and N(R)SO 2 R, N(R)SO 2 N(R) 2 and N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R) 2 and N(R)C(S)N(R) 2 and N(COR)COR, N(OR)R, C(=NH)N(R) 2 and C(O)N(OR)R and C(=NOR)R, where R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (C 1 -C 100 ) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclic, heteroaryl or heteroaralkyl; or two R groups bonded to a nitrogen atom or adjacent nitrogen atoms can together with one or more nitrogen atoms form a heterocyclic group.

[0043] As used herein, the term "alkyl" refers to straight-chain and branched-chain alkyls and cycloalkyls having from 1 to 40 carbon atoms, from 1 to about 20 carbon atoms, from 1 to 12 carbons or in some embodiments from 1 to 8 carbon atoms. Examples of straight-chain alkyls include those having from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl. Examples of branched-chain alkyls include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl and 2,2-dimethylpropyl. As used herein, the term "alkyl" includes n-alkyl, isoalkyl and anti-isoalkyl and other branched forms of alkyl. Representative substituted alkyls can be substituted one or more times with any of the groups listed herein such as amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy and halogen groups.

[0044] As used herein, the term "alkenyl" refers to straight-chain, branched-chain, and cyclic alkyl groups as defined herein, except that there is at least one double bond between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or from 2 to about 20 carbon atoms, or from 2 to 12 carbon atoms, or in some embodiments from 2 to 8 carbon atoms. Examples include, but are not limited to, vinyl, -CH=C=CCH 2 、-CH=CH(CH 3 )、-CH=C(CH 3 ) 2 、-C(CH 3 )=CH 2 、-C(CH 3 )=CH(CH 3 )、-C(CH 2 CH 3 )=CH 2 , cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, and the like.

[0045] As used herein, the term "alkynyl" refers to straight-chain and branched-chain alkyl groups, except that there is at least one triple bond between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, from 2 to about 20 carbon atoms, or from 2 to 12 carbon atoms, or in some embodiments from 2 to 8 carbon atoms. Examples include, but are not limited to, –C≡CH, -C≡C(CH 3 ), -C≡C(CH 2 CH 3 ), -CH 2 C≡CH, -CH 2 C≡C(CH 3 ), and -CH 2 C≡C(CH 2 CH 3 ), and the like.

[0046] As used herein, the term "acyl" refers to a group containing a carbonyl moiety, wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen atom to form a "formyl" group or to another carbon atom, which can be part of an alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, heterocyclicalkyl, heteroaryl, heteroarylalkyl, etc. The acyl group can include from 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. The acyl group can include double or triple bonds as defined herein. Acryloyl is an example of an acyl group. The acyl group can also include heteroatoms as defined herein. Nicotinoyl (pyridinyl-3-carbonyl) is an example of an acyl group as defined herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridinylacetyl, cinnamoyl, acryloyl, etc. When a group containing a carbon atom bonded to the carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl group". An example is trifluoroacetyl.

[0047] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group, such as but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group can have from 3 to about 8 - 12 ring members, while in other embodiments, the number of ring carbon atoms is 3 to 4, 5, 6, or 7. The cycloalkyl group further includes polycyclic cycloalkyl groups, such as but not limited to norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, as well as fused rings, such as but not limited to decahydronaphthyl, etc. The cycloalkyl group also includes rings substituted with straight-chain or branched-chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as but not limited to 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl or mono-, di-, or tri-substituted norbornyl or cycloheptyl, which can be substituted with, for example, amino, hydroxy, cyano, carboxyl, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl", used alone or in combination, denotes a cyclic alkenyl group.

[0048] As used herein, the term "aryl" refers to a cyclic aromatic hydrocarbon group that does not contain heteroatoms in the ring. Thus, aryl includes but is not limited to phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, tetracenyl, Groups include, but are not limited to, phenyl, biphenylyl, anthryl, and naphthyl. In some embodiments, the aryl contains from about 6 to about 14 carbons in the ring portion of the group. As defined herein, the aryl may be unsubstituted or substituted. Representative substituted aryls may be mono-substituted or substituted more than once, such as but not limited to phenyl substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the benzene ring or naphthyl substituted at any one or more of its 2-8-positions.

[0049] As used herein, the term "aralkyl" refers to an alkyl group as defined herein, wherein a hydrogen bond or carbon bond of the alkyl is replaced by a bond attached to an aryl group as defined herein. Representative aralkyls include benzyl and phenethyl, as well as fused (cycloalkylaryl)alkyls, such as 4-ethyl-indanyl. An aralkenyl is an alkenyl group as defined herein, wherein a hydrogen bond or carbon bond of the alkyl is replaced by a bond attached to an aryl group as defined herein.

[0050] As used herein, the term "heterocyclyl" refers to aromatic and non-aromatic cyclic compounds containing three or more ring members, one or more of which are heteroatoms, such as but not limited to N, O, and S. Thus, heterocyclyl may be cycloheteroalkyl or heteroaryl, or any combination thereof if polycyclic. In some embodiments, heterocyclyl includes from 3 to about 20 ring members, while other such groups have from 3 to about 15 ring members. A heterocyclyl designated C 2 -heterocyclyl may be a 5-ring having two carbon atoms and three heteroatoms, a 6-ring having two carbon atoms and four heteroatoms, etc. Similarly, C 4- A heterocyclyl group can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, etc. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. The heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused-ring species, which includes those containing fused aromatic and non-aromatic groups. For example, dioxolane and benzodioxolane ring systems (methylenedioxyphenyl ring systems) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic systems containing heteroatoms, such as but not limited to quinuclidinyl. A heterocyclyl group can be unsubstituted or can be substituted as discussed herein. Heterocyclyl groups include but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, phenylthio, benzophenylthio, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as but not limited to piperidinyl or quinolinyl, which are substituted 2-, 3-, 4-, 5-, or 6-fold or disubstituted with those groups listed herein.

[0051] As used herein, the term "heteroaryl" refers to an aromatic ring compound containing 5 or more ring members, one or more of which are heteroatoms, such as but not limited to N, O, and S; for example, a heteroaryl ring can have 5 to about 8 - 12 ring members. A heteroaryl is a type of heterocyclyl group having an aromatic electronic structure. A heteroaryl named C 2 - heteroaryl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms, etc. Similarly, C 4- A heteroaryl group can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, etc. The sum of the number of carbon atoms and the number of heteroatoms is equal to the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, phenylthio, benzophenylthio, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thionaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolyl, isoquinolyl, tetrahydroquinolyl, quinoxalinyl, and quinazolinyl. The heteroaryl group can be unsubstituted or can be substituted by the groups discussed herein. Representative substituted heteroaryl groups can be substituted one or more times by groups such as those enumerated herein.

[0052] Additional examples of aryl and heteroaryl include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthryl (1-anthryl, 2-anthryl, 3-anthryl), phenylthio (2-phenylthio, 3-phenylthio), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isochromanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolinyl (2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl), isoquinolinyl (1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl, 8-isoquinolinyl), benz[b]furyl (2-benz[b]furyl, 3-benz[b]furyl, 4-benz[b]furyl, 5-benz[b]furyl, 6-benz[b]furyl, 7-benz[b]furyl), 2,3-dihydro-benz[b]furyl (2-(2,3-dihydro-benz[b]furyl), 3-(2,3-dihydro-benz[b]furyl), 4-(2,3-dihydro-benz[b]furyl), 5-(2,3-dihydro-benz[b]furyl), 6-(2,3-dihydro-benz[b]furyl), 7-(2,3-dihydro-benz[b]furyl), benz[b]phenylthio (2-benz[b]phenylthio, 3-benz[b]phenylthio, 4-benz[b]phenylthio, 5-benz[b]phenylthio, 6-benz[b]phenylthio, 7-benz[b]phenylthio), 2,3-dihydro-benz[b]phenylthio, (2-(2,3-dihydro-benz[b]phenylthio), 3-(2,3-dihydro-benz[b]phenylthio), 4-(2,3-dihydro-benz[b]phenylthio), 5-(2,3-dihydro-benz[b]phenylthio), 6-(2,3-dihydro-benz[b]phenylthio), 7-(2,3-dihydro-benzo[b]benzothioyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazolyl (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo[b,f]azepine, (5H-dibenzo[b,f]azepine -1-yl, 5H-dibenzo[b,f]azepine -2-yl, 5H-dibenzo[b,f]azepine -3-yl, 5H-dibenzo[b,f]azepine -4-yl, 5H-dibenzo[b,f]azepine -5-yl), 10,11-dihydro-5H-dibenzo[b,f]azepine (10,11-dihydro-5H-dibenzo[b,f]azepine -1-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine -2-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine -3-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine -4-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine -5-yl), etc.

[0053] As used herein, the term "heterocyclylalkyl" refers to an alkyl as defined herein, wherein a hydrogen or carbon bond of the alkyl as defined herein is replaced by a bond connected to a heterocyclyl as defined herein. Representative heterocyclylalkyls include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0054] As used herein, the term "heteroarylalkyl" refers to an alkyl as defined herein, wherein a hydrogen bond or carbon bond of the alkyl is replaced by a bond connected to a heteroaryl as defined herein.

[0055] As used herein, the term "alkoxy" refers to an oxygen atom attached to an alkyl group (including cycloalkyl groups) as defined herein. Examples of straight-chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched-chain alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group may contain from about 1 to about 12, from about 1 to about 20, or from about 1 to about 40 carbon atoms bonded to the oxygen atom, and may further include double or triple bonds, and may also include heteroatoms. For example, allyloxy or methoxyethoxy are also alkoxy groups within the meaning herein, such as methylenedioxy in the context of being substituted for two adjacent atoms of a structure. Text

[0056] As used herein, the term "amine" refers to primary, secondary, and tertiary amines having, for example, the formula N(group) 3 where each group can independently be H or non-H, such as an alkyl group, an aryl group, and the like. Amines include, but are not limited to, R-NH 2 , such as alkylamines, arylamines, alkylarylamines; R 2 NH, where each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclic amines, and the like; and R 3 N, where each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.

[0057] As used herein, the term "amino group" refers to substituents of the form -NH 2 , -NHR, -NR 2 , -NR 3 + , where each R is independently selected, and their respective protonated forms, except for -NR 3 + , which cannot be protonated. Thus, any compound substituted with an amino group can be considered an amine. An "amino group" within the meaning herein can be primary, secondary, tertiary, or quaternary. "Alkylamino" includes monoalkylamino, dialkylamino, and trialkylamino.

[0058] As used herein, unless otherwise specified, the term "halo", "halogen", or "halide" group, either alone or as part of another substituent, refers to a fluorine, chlorine, bromine, or iodine atom. ​

[0059] As used herein, the term "haloalkyl" group includes monohaloalkyl, polyhaloalkyl (wherein all halogen atoms may be the same or different), and perhaloalkyl (wherein all hydrogen atoms are replaced by halogen atoms such as fluorine). Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[0060] As used herein, the term "monovalent" refers to a substituent that is attached to the substituted molecule via a single bond. When the substituent is monovalent, such as F or Cl, it is bonded to the atom it replaces by a single bond.

[0061] As used herein, the term "hydrocarbon" or "hydrocarbyl" refers to a molecule or functional group that includes carbon and hydrogen atoms. The term may also refer to a molecule or functional group that typically includes carbon atoms and hydrogen atoms but in which all hydrogen atoms are replaced by other functional groups.

[0062] As used herein, the term "hydrocarbyl" refers to a functional group derived from a straight-chain, branched-chain, or cyclic hydrocarbon and may be an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. A hydrocarbyl may be represented as (C a -C b ) hydrocarbyl, where a and b are integers and mean any of the carbon atoms having from a to b carbon atoms. For example, (C 1 -C 4 ) hydrocarbyl means that the hydrocarbyl may be methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ), or butyl (C 4 ), and (C 0 -C b ) hydrocarbyl means that in some embodiments there is no hydrocarbyl. In some embodiments, the hydrocarbyl is an optionally substituted C 1-12 alkyl. In some embodiments, the hydrocarbyl is an optionally substituted C 2-12 alkenyl. In some embodiments, the hydrocarbyl is an optionally substituted C 2-12 alkynyl. In some embodiments, the hydrocarbyl is an optionally substituted C 3-12 cycloalkyl. In some embodiments, the hydrocarbyl is an optionally substituted C 1-12 heteroalkyl. In some embodiments, the hydrocarbyl is an optionally substituted C 1-12 alkoxy. In some embodiments, the hydrocarbyl is an optionally substituted C 6-14 aryl and / or an optionally substituted C 6-12Aryl and / or optionally substituted C 6-10 aryl. In certain embodiments, the hydrocarbyl group is optionally substituted C 2 -C 12 heterocyclic group. In certain embodiments, the hydrocarbyl group is optionally substituted C 4 -C 12 heteroaryl. In certain embodiments, the hydrocarbyl group is optionally substituted C 1-12 acyl group.

[0063] As used herein, the term "solvent" refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0064] As used herein, the term "independently selected from" means that the groups mentioned are the same, different, or a mixture thereof, unless the context clearly dictates otherwise. Thus, under this definition, the phrase "X 1 , X 2 and X 3 are independently selected from noble gases" will include cases where, for example, X 1 , X 2 and X 3 are all the same, where X 1 , X 2 and X 3 are all different, where X 1 and X 2 are the same but X 3 is different, and other similar arrangements.

[0065] As used herein, the term "room temperature" refers to a temperature of about 15 °C to 28 °C.

[0066] As used herein, the term "standard temperature and pressure" refers to 20 °C and 101 kPa.

[0067] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates the administration of the compound to a patient or subject. There are various techniques for administering compounds in the art, including but not limited to intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0068] As used herein, the abbreviation "Np" refers to naphthyl. Thus, 1-Np is 1-naphthyl, and 2-Np is 2-naphthyl.

[0069] Preparation of Compounds

[0070] The compounds of Formula I or other compounds described herein can be prepared by the general schemes described herein using synthetic methods known to those skilled in the art. The following examples illustrate non-limiting embodiments of the compounds (one or more) described herein and their preparation.

[0071] In various embodiments, the present disclosure provides a compound of Formula I, or a salt, solvate, geometric isomer or stereoisomer thereof:

[0072]

[0073]

[0074] Wherein:

[0075] is a single bond or a double bond;

[0076] R 1 and R 2 are each independently C 3-10 cycloalkyl, aryl or heteroaryl, each of which is optionally substituted with at least one group selected from the following: halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 , N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 , N(R)C(O)R, (CH 2 ) 0-2 , N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl;

[0077] R 3 and R 4 are each independently hydrogen, optionally substituted C 3-10 cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, C 1-12 alkyl or OC 1-12 alkyl, wherein the optional substitution includes at least one group selected from the following: halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl; or

[0078] R 3 and R 4 together with the ring to which they are attached are used to form C 4-20 cycloalkyl, C 6-20 aryl or C 6-20 heteroaryl, each of which is optionally substituted with at least one group selected from the following: halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3, BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 , (CH 2 ) 0-2 N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl;

[0079] R 5 is H or optionally substituted C 1-3 alkyl;

[0080] M is a transition metal;

[0081] X is a counteranion;

[0082] A is aryl or heteroaryl, optionally substituted by at least one group selected from: halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0-2N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl;

[0083] R is independently hydrogen or optionally substituted C 1-10 alkyl each time it appears;

[0084] m is 1, 2 or 3; and

[0085] n is 1, 2, 3 or 4.

[0086] The nature of the variable A in the compounds of formula I is not particularly limited, provided that a stable complex with a transition metal can be formed with the ligands described herein and the resulting transition metal complex has catalytic activity. Other suitable A moieties include anthracene (e.g., 1-aminoanthracene, 2-aminoanthracene, 9-aminoanthracene); aminobiphenyl (e.g., 4-aminobiphenyl); aminophenanthrene (e.g., 1-aminophenanthrene, 2-aminophenanthrene, 9-aminophenanthrene); aminopyrene (e.g., 1-aminopyrene, 2-aminopyrene); amino (e.g., 1-amino 2-amino 6-amino ); aminofluorene (e.g., 1-aminofluorene, 2-aminofluorene); naphthalene (e.g., 1-aminonaphthalene, 2-aminonaphthalene); acridine (e.g., 9-aminoacridine, 2-aminoacridine); quinoline (e.g., 8-aminoquinoline, 2-aminoquinoline, 5-aminoquinoline); and so on. Any arylamine or heteroarylamine described herein can be a primary or secondary amine.

[0087] In some embodiments, the compound has the structure of formula Ia, or a salt, solvate, geometric isomer or stereoisomer thereof:

[0088]

[0089] In some embodiments, the compound has the structure of formula Ib, formula Ic, formula Id, formula Ie or formula If, or a salt, solvate, geometric isomer or stereoisomer thereof:

[0090]

[0091] In some embodiments, R 1 and R 2 are both aryl. In various embodiments, the aryl has the following structure:

[0092]

[0093] or a salt, solvate, geometric isomer or stereoisomer thereof, wherein:

[0094] R 6 and R 7 are each independently C 1-12 alkyl or C 1-12 alkyl substituted with at least one aryl group; and

[0095] R 8 is hydrogen or C 1-12 alkyl or C 1-12 alkyl substituted with at least one aryl group.

[0096] In some embodiments, R 8 is hydrogen. In various embodiments, R 6 and R 7 are each C 1-6 alkyl. In some embodiments, R 6 and R 7 are each C(H)(CH 3 ) 2 . In various embodiments, M is selected from Fe, Co, Ni, Cu, Ru, Rh, Pd, Ag, Re, Os, Ir, Pt and Au. In some embodiments, M is Pd. In various embodiments, X is selected from F, Cl, Br, I, OSO 2 R, OSO 3 R and OC(=O)R. In some embodiments, X is Cl. In various embodiments, m is 1. In various embodiments, n is 2.

[0097] In some embodiments, A is and

[0098] each occurrence of R 9 is independently selected from OCH 3 , CF 3 , 2,6-dimethyl, 2,6-diisopropyl and hydrogen, and p is 0, 1, 2, 3, 4 or 5. In some embodiments, R 5 is hydrogen or methyl.

[0099] The compound of formula I has the following three parts:

[0100]

[0101] In various embodiments, the NHC moiety in the compound of formula I is selected from:

[0102]

[0103] wherein R 1 is selected from tert-butyl, 1-adamantyl, cyclohexyl, isopropyl, methyl, ethyl, n-propyl, butyl, pentyl, and

[0104] R 6 is CH(phenyl) 2 , CH(Me) 2 , CH(2-Np) 2 or CH(Et); 2 ;

[0105] R 6 ' is CH(phenyl) 2 , CH(Me) 2 or CH(Et); and

[0106] R 8 is CH(phenyl) 2 , Me, OMe or H.

[0107] In various embodiments, the NHC moiety in the compound of formula I is selected from:

[0108]

[0109]

[0110] In various embodiments, a method for preparing a compound of formula I or a salt, solvate, geometric isomer or stereoisomer thereof is provided. The method comprises contacting a compound having the following structure or a salt, solvate, geometric isomer or stereoisomer thereof with a compound having the structure of in a solvent to form a compound of formula I,

[0111]

[0112] wherein each R 9 is independently selected from hydrogen, halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R)2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl, and wherein p is 0, 1, 2, 3, 4 or 5.

[0113] In various embodiments, the solvent is a non-polar aprotic solvent. Suitable non-polar aprotic solvents include, but are not limited to, chloroform, diethyl ether, deuterated chloroform, pentane, hexane, benzene, toluene, dichloromethane, or mixtures thereof. In some embodiments, the contacting is carried out at room temperature.

[0114] Another method for preparing a compound of formula I or a salt, solvate, geometric isomer or stereoisomer thereof comprises, in some embodiments, contacting a compound of formula I-SM or a salt, solvate, geometric isomer or stereoisomer thereof with a compound of formula MX 2 (A—N(H)(R 5 )) 2 or a salt, solvate, geometric isomer or stereoisomer thereof in a solvent to form a compound of formula I or a salt, solvate, geometric isomer or stereoisomer thereof,

[0115]

[0116] In some embodiments, the reaction is carried out in the presence of a base. The compound of formula I-SM can be a stable salt of any of the NHC moieties described herein.

[0117] Suitable bases include, but are not limited to, NaOC 1-4 alkyl, KOC 1-4 alkyl, lithium diisopropylamide, sodium hexamethyldisilazide, LiC 1-4 alkyl or combinations thereof, etc. In some embodiments, the reaction with the base occurs in a polar aprotic solvent. Suitable polar aprotic solvents include, but are not limited to, tetrahydrofuran, 2-N-methylpyrrolidone, dimethylformamide, acetonitrile, or mixtures thereof, etc.

[0118] In various embodiments, the compound is a compound of Formula II, or a salt, solvate, geometric isomer or stereoisomer thereof,

[0119]

[0120] In the compound of Formula II, X and 'n' are as defined herein.

[0121] R A 、R 6 and R 7 Each occurrence of is independently selected from optionally substituted C 1-12 alkyl, optionally substituted C 1-12 heteroalkyl, optionally substituted OC 1-12 alkyl, optionally substituted C 3-12 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 6-10 heteroaryl, A, R 1 or R 2 . R 6 and R 7 The optional substitution in is at least one group selected from the following: halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 , N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl.

[0122] In various embodiments, the compound is a compound of Formula III, or a salt, solvate, geometric isomer or stereoisomer thereof:

[0123]

[0124] In the compound of Formula III, X, n, R 6 and R 7 are as defined herein. The definition of variable R 8 is the same as that of R 6 . Variable Y is N or C, Z is N or C, provided that Y and Z cannot both be C. G is absent or is defined the same as R 6 . The compound of Formula III is a mesoionic carbene complex.

[0125] The compound of Formula III can be formed by, for example, the following reaction:

[0126]

[0127] In various embodiments, the compound is a mesoionic carbene complex selected from the following:

[0128]

[0129] The compounds described herein can have one or more stereocenters, and each stereocenter can exist independently in the (R) or (S) configuration. In certain embodiments, the compounds described herein exist in enantiomeric or racemic form. It should be understood that the compounds described herein include racemic, enantiomeric, regioisomeric and stereoisomeric forms or combinations thereof having the therapeutically useful properties described herein. The preparation of enantiomeric forms is achieved in any suitable manner, including, by way of non-limiting example, resolution of the racemic form by recrystallization techniques, synthesis from enantiomerically pure starting materials, chiral synthesis or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomers is used as the therapeutic compound described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of enantiomers and / or mixtures of diastereomers. The resolution of the compounds and their isomers can be achieved by any means, including but not limited to chemical processes, enzymatic processes, fractional crystallization, distillation and chromatography.

[0130] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any of the compounds (one or more) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates, etc. In certain embodiments, the compounds described herein exist in a solvated form with pharmaceutically acceptable solvents such as water and ethanol. In other embodiments, the compounds described herein exist in a non-solvated form.

[0131] In certain embodiments, the compound(s) described herein may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0132] In certain embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted in vivo to the parent drug. In certain embodiments, after administration in vivo, the prodrug is chemically converted to the biological, pharmaceutical, or therapeutic active form of the compound. In other embodiments, the prodrug is enzymatically metabolized to the biological, pharmaceutical, or therapeutic active form of the compound through one or more steps or processes.

[0133] In certain embodiments, for example, sites on the aromatic ring moiety of the compounds described herein are susceptible to various metabolic reactions. The addition of appropriate substituents on the aromatic ring structure can reduce, minimize, or eliminate such metabolic pathways. In certain embodiments, by way of example only, suitable substituents that reduce or eliminate the sensitivity of the aromatic ring to metabolic reactions are deuterium, halogen, or alkyl.

[0134] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include, but are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P and 35S. In some embodiments, isotopically labeled compounds can be used in drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium provides higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirements). In yet other embodiments, substitution with positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N is useful in positron emission topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or by a process of using a suitable isotopically labeled reagent in place of an unlabeled reagent otherwise used.

[0135] In some embodiments, the compounds described herein are labeled otherwise, including but not limited to using chromophores or fluorescent moieties, bioluminescent labels or chemiluminescent labels.

[0136] The compounds described herein and other related compounds with different substituents are synthesized using the techniques and materials described in Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1 - 17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1 - 5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1 - 40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry, 4th Edition, (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry, 4th Edition, Volumes A and B (Plenum 2000, 2001) and Green & Wuts, Protective Groups in Organic Synthesis, 3rd Edition, (Wiley 1999) (all of which are incorporated herein by reference). General methods for preparing the compounds described herein are modified using suitable reagents and conditions to introduce the various moieties present in the formulas provided herein.

[0137] The compounds described herein are synthesized starting from compounds available from commercial sources using any suitable procedure or prepared using the procedures described herein.

[0138] In certain embodiments, reactive functional groups such as hydroxyl, amino, imino, thio or carboxyl groups are protected to avoid their undesired participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent these groups from participating in chemical reactions until the protecting group is removed. In other embodiments, each protecting group can be removed by a different means. Protecting groups that cleave under completely different reaction conditions meet the requirements for differential removal.

[0139] In certain embodiments, the protecting groups are removed by acids, bases, reducing conditions (such as hydrogenolysis) and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid-labile and are used to protect carboxyl and hydroxyl reactive moieties in the presence of an amino group protected by a Cbz group removable by hydrogenolysis and a base-labile Fmoc group. In the presence of an amine blocked by an acid-labile group (such as tert-butyl carbamate) or a carbamate that is stable to acids and bases but removable by hydrolysis, the carboxylic acid and hydroxyl reactive moieties are blocked by base-labile groups (such as but not limited to methyl, ethyl and acetyl).

[0140] In certain embodiments, the carboxylic acid and hydroxyl reactive moieties are blocked by a hydrolyzable protecting group such as benzyl, while amine groups capable of forming hydrogen bonds with acids are blocked by base-labile groups such as Fmoc. The carboxylic acid reactive moiety is protected by conversion to a simple ester compound exemplified herein, including conversion to an alkyl ester or blocking with an oxidizable protecting group such as 2,4-dimethoxybenzyl, while co-existing amino groups are blocked with a fluoride-labile silyl carbamate.

[0141] Allyl blocking groups are useful in the presence of acid and base protecting groups because the former is stable and subsequently removed by a metal or π-acid catalyst. For example, in the presence of an acid-labile tert-butyl carbamate or a base-labile acetamide protecting group, palladium-catalyzed reaction is used to deprotect allyl-blocked carboxylic acids. Another form of protecting group is a resin attached to the compound or intermediate. As long as the residue is attached to the resin, the functional group is blocked and no reaction occurs. Once released from the resin, the functional group can react.

[0142] Typical blocking / protecting groups can be selected from:

[0143]

[0144] Other protecting groups, and a detailed description of the techniques suitable for the generation and removal of protecting groups, are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, the disclosures of which are hereby incorporated herein by reference.

[0145] Examples

[0146] The various embodiments of the present application can be better understood by reference to the examples provided below. The scope of the present application is not limited to the examples given herein.

[0147] In recent years, many well-defined stable precatalysts ( Figure 1 , 1 -5) have emerged. The stabilizing effect of amine-type nitrogen on palladium is a key feature of the Nolan and Buchwald palladacycles ( Figure 1 , 4-5). The synthesis of compounds of formula I, such as [(NHC)PdCl 2 (aniline)] complexes, is illustrated in Scheme 1. IPr was chosen as the model NHC ancillary ligand because it is a privileged motif in Pd-NHC catalysis (6). In addition, a representative imidazolinyl complex, Pd-SIPr (7), was synthesized. The synthesis of [(NHC)PdCl 2 (aniline)] complexes was readily achieved by the reaction of aniline with [{Pd(NHC)(Cl)(μ-Cl)} 2 dimers in CH 2 Cl 2 at room temperature in excellent yield. The [(NHC)PdCl 2 (aniline)] complexes were isolated after trituration with cold pentane. All complexes were found to be stable to air and moisture. Note that, if desired, [(NHC)PdCl 2 (aniline)] complexes are also suitable for chromatographic purification, which will facilitate their use. Complexes 6a and 7a were fully characterized by X-ray crystallography ( Figure 2 , see below). Considering the utility of the PdCl 2 (aniline) 2 precursor in the rapid screening of various NHCs, the direct synthesis of [(IPr)PdCl 2 (AN)] (AN = aniline) was developed (Scheme 2). In some embodiments, IPrHCl (1.5 equiv) was reacted with Pd(PhNH2 ) 2 Cl 2 (1.0 equiv) and KOt-Bu (1.5 equiv) react in THF at 80 °C to give a well-defined [(IPr)PdCl 2 (AN)] complex in 70% yield.

[0148] As Figure 2 shown in A-2B, complexes 6a and 7a adopt a slightly distorted square-planar geometry (6a: C–Pd–N, 175.5°; 7a: C–Pd–N, 175.3°). The C-Pd and Pd-N bond lengths in 6a are and and in 7a are and The Cl 1 –Pd and Cl 2 –Pd bond lengths in 6a are and (Cl 1 –Pd–Cl 2 , 175.8°), and in 7a are and (Cl 1 –Pd–Cl 2 , 174.7°). These bond lengths are in the range comparable to those of Pd(NHC)(heterocycle)Cl 2 complexes. It is thus inferred that the availability of aniline provides a direct way to modulate the steric and electronic effects of the metal center in [(NHC)PdCl 2 (aniline)] complexes.

[0149] To evaluate the steric effects in [(NHC)PdCl 2 (aniline)] complexes, the percentage of buried volume (%V bur ) and the steric maps ( Figure 3 ) were calculated for 6a and 7a. The (%V bur ) values for 6a and 7a are 36.1% and 39.7%, representing bulky [Pd-NHC] complexes. These values can be compared with those of [Pd(IPr)(3-Cl-py)Cl 2 and [Pd(SIPr)(3-Cl-py)Cl 2 complexes, which are 34.8% and 39.2% for (%V bur) were compared. As expected, the asymmetric aniline-based monodentate ligands led to uneven quadrant distribution, with 30.7%, 41.0%, 36.9%, 35.9% (6a) and 35.4%, 44.5%, 37.3%, 41.6% (7a) in each quadrant. Different spatial environments around the metal may affect the substrate approach and catalyst activation in [(NHC)PdCl 2 (aniline)] complexes.

[0150] Scheme 1. Synthesis of (NHC)PdCl 2 (aniline) complexes a

[0151]

[0152] a Conditions: [{Pd(NHC)(Cl)(μ-Cl)} 2 (1.0 equiv), aniline (2.0 equiv), CH 2 Cl 2 23 °C.

[0153] Scheme 2. Direct synthesis of (IPr)PdCl 2 (AN) a

[0154]

[0155] a Conditions: IPrHCl (1.5 equiv), PdCl 2 (AN) 2 (1.0 equiv), KOt-Bu (1.5 equiv), THF, 80 °C. AN = PhNH 2 .

[0156] By directly obtaining (NHC)PdCl 2 (aniline) complexes, the reactivity of these new Pd(II)-NHC precatalysts was then explored. For the initial screening, the Suzuki-Miyaura cross-coupling of amides via N-C(O) activation was chosen (Table 1). At 1.0 mol% (IPr)PdCl 2 (aniline) (K 2 CO 3 , H 2The reactions carried out with a series of electronically and sterically differentiated precatalysts 6a - h in O, THF, 16 h exhibited high reactivity at mild room temperature (Table 1, column A). Thus, the electronically neutral aniline ligand (6a), the electron - donating 4 - anisidine (6b), the electron - withdrawing 4 - trifluoromethylaniline (6c), and the moderately sterically hindered 2,6 - dimethylaniline (6d) all provided cross - coupling products in quantitative yields under these conditions. Using the more sterically demanding 2,6 - diisopropylaniline (6e) led to a decrease in cross - coupling efficiency. The electron - withdrawing trifluoromethyl group in the meta - position (6f), as well as the use of N - Me - aniline (6g - h) and the NHC (7a) with a saturated backbone (SIPr)PdCl 2 (AN) provided cross - coupling products with excellent efficiency.

[0157] Table 1. Activity of (NHC)PdCl 2 (aniline) complexes in the Suzuki - Miyaura cross - coupling of amides

[0158]

[0159]

[0160]

[0161] a [Pd](1.0 mol%), amide (1.0 equiv), Ar - B(OH) 2 (2.0 equiv), K 2 CO 3 (3.0 equiv), H 2 O(5.0 equiv), THF (0.25 M), 23 °C, 16 h. b [Pd](0.25 mol%). c [Pd](1.0 mol%), 3 h.

[0162] Next, the cross - coupling was carried out at a 0.25 mol% loading of (IPr)PdCl 2 (aniline) to distinguish the activity of these new precatalysts (Table 1, column B). In this more discerning screening, the electronically neutral (6a) and electron - withdrawing (6c) substituents were superior to the electron - donating substituents (6b), while steric hindrance on the aniline ring (6d - e) led to lower cross - coupling efficiency. The trifluoromethyl group in the meta - position (6f) and N - Me - aniline (6g - h) performed well in this screening, while the saturated (SIPr)PdCl 2(AN)(7a) was shown to be less efficient. To gain insight into the activation of these new precatalysts, the reaction was carried out with 1.0 mol% of (IPr)PdCl 2 (aniline) for a shorter reaction time (Table 1, column C, RT, 3 h). As shown, electron-neutral (6a), electron-withdrawing (6b), and N-Me substitution (6g) led to high reaction efficiency. Thus, this study found that 3-trifluoromethylaniline (6f) was the optimal ligand, while neutral aniline (6a) was a cheap, bulky variant.

[0163] The generality of Suzuki-Miyaura cross-coupling using (IPr)PdCl 2 (AN) is shown in Table 2. As shown, the reaction has good tolerance for functional groups and substituents on the boronic acid and amide cross-coupling partners. Electron-donating, electron-withdrawing, and sterically hindered substituents are well tolerated on both coupling partners, providing cross-coupling products in excellent yields.

[0164] Table 2. [(IPr)PdCl 2 (AN)]-Catalyzed Suzuki-Miyaura Cross-Coupling of Amides via C–N Cleavage a

[0165]

[0166]

[0167] a Conditions: [Pd] (1.0 mol%), amide (1.0 equiv), Ar-B(OH) 2 (2.0 equiv), K 2 CO 3 (3.0 equiv), H 2 O (5.0 equiv), THF (0.25 M), 23 °C, 16 h.

[0168] Using this new catalyst system, Suzuki-Miyaura cross-coupling of esters via C-O activation is also feasible (Scheme 3). In some embodiments, in this more challenging C-O cross-coupling, the Pd-NHC catalyst with 3-trifluoromethylaniline (6f) is more effective than the neutral aniline (6a) ligand, reflecting the reactivity trend observed in amide C-N bond activation. To expand the utility of the (NHC)PdCl 2 (aniline) complex, (IPr)PdCl 2(AN) Reactivity in the Suzuki-Miyaura cross-coupling of aryl chlorides (Scheme 4 and Table 3). As shown, the reaction shows excellent tolerance. Aryl chlorides substituted with electron-donating, electron-withdrawing, and sterically hindered functional groups, as well as boronic acids bearing electron-donating, electron-withdrawing, and sterically hindered substituents, afford the cross-coupling products in excellent yields.

[0169] Scheme 3. [(IPr)PdCl-catalyzed Suzuki-Miyaura cross-coupling of esters by C–O cleavage 2 (aniline)]

[0170]

[0171] Scheme 4. [(IPr)PdCl-catalyzed Suzuki-Miyaura cross-coupling of aryl chlorides 2 (aniline)]

[0172]

[0173] Table 3. [(IPr)PdCl-catalyzed Suzuki-Miyaura cross-coupling of aryl chlorides 2 (AN)] a

[0174]

[0175]

[0176] a Conditions: [Pd] (1.0 mol%), aryl chloride (1.0 equiv), Ar-B(OH) 2 (2.0 equiv), NaOH (2.0 equiv), EtOH (0.25 M), 23 °C, 16 h.

[0177] The utility of the (NHC)PdCl(aniline) complex was evaluated in the Buchwald-Hartwig cross-coupling of aryl chlorides (Scheme 5). Thus, the Pd-NHC catalysts bearing neutral aniline (6a) and 3-trifluoromethylaniline (6f) promoted the cross-coupling in excellent yields. 2

[0178] Scheme 5. [(IPr)PdCl-catalyzed Buchwald-Hartwig cross-coupling of aryl chlorides 2 (aniline)]

[0179]

[0180] To gain insight into these novel (NHC)PdCl2 The properties of the (aniline) complex were determined at the B3LYP 6-311++g(d,p) theoretical level for the representative (IPr)PdCl 2 (AN) (6a) for the HOMO and LUMO energy levels (Figure 4). The computational evaluation of the ground state properties based on the solid state structure determined by X-ray provides a powerful method for predicting the reactivity of metal-NHC complexes. The determination of the HOMO (-6.08 eV) and LUMO (-1.76 eV) of (6a) indicates that the HOMO is located on palladium, while the LUMO is located on the carbene ligand, chloride, and ancillary ligand. This can be compared with similar Pd-PEPPSI systems (-6.06 eV; -1.88 eV) and imidazolinyl systems (7a) (-6.07 eV; -1.75 eV). To further understand the nature of the Pd–C(carbene) bond in the (NHC)PdCl 2 (aniline) complex, we performed NBO analysis. The Wiberg bond orders of the Pd-C(carbene) and Pd-N bonds in (6a) are 0.6776 and 0.3142 (Pd–C 1 , 0.6299; Pd–Cl 2 , 0.6305), which can be compared with a similar [Pd(IPr)(3-Cl-py)Cl 2 system (Pd–C, 0.6871; Pd–N, 0.6302; Pd–Cl 1 , 0.6302; Pd–Cl 2 , 0.6278) and imidazolinyl system (7a) (Pd–C, 0.6745; Pd–N, 0.3024). Computational studies indicate that the aniline ligand is well-suited for altering the electron density along the metal-NHC axis.

[0181] Scheme 6. Synthesis of IPr # -PEPPSI, [Pd(IPr # )(3-Cl-py)Cl 2 general procedure

[0182]

[0183] Charge a dried flask equipped with a stir bar with IPr # HCl (552 mg, 0.44 mmol, 1.1 equiv), PdCl 2 (71 mg, 0.4 mmol, 1.0 equiv) and K 2 CO 3(276 mg, 2.0 mmol, 5.0 equiv) was placed under a positive pressure of argon and subjected to three evacuation / backfill cycles under high vacuum. 3-Chloropyridine (2.0 mL) was added and the reaction mixture was stirred at 80 °C for 24 h. After the specified time, the reaction was cooled to room temperature, diluted with CH 2 Cl 2 and filtered. The solution was collected and concentrated. The product was obtained as a white solid by trituration from CH 2 Cl 2 / hexanes. Yield 82% (494 mg). 1 H NMR (500 MHz, CDCl 3 ) δ 8.97 (s, 1H), 8.81 (d, J = 5.5 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.27 (m, 8H), 7.15 (m, 12H), 7.10 - 7.05 (m, 16H), 7.00 (dd, J = 19.7, 7.4 Hz, 16H), 6.78 (s, 4H), 6.69 (d, J = 7.5 Hz, 8H), 6.32 (s, 4H), 5.38 (s, 2H), 4.98 (s, 2H). 13 C NMR (125 MHz, CDCl 3 ) δ 150.85, 149.93, 144.16, 144.04, 143.61, 141.79, 138.01, 135.88, 132.61, 131.42, 130.27, 129.47, 129.36, 128.27, 127.83, 126.23, 126.14, 126.06, 124.81, 124.14, 56.30, 51.09. C 98 H 76 N 3 Cl 2 Pd(M + -Cl) HRMS calcd for 1472.4452, found 1472.4450. The structure was confirmed by X-ray crystallography.

[0184] Table 4: Activity of IPr # -PEPPSI, [Pd(IPr # )(3-Cl-py)Cl 2 in cross-coupling reactions

[0185]

[0186] The terms and expressions used herein are used as descriptive terms and not of a limiting nature, and in using these terms and expressions there is no intention to exclude any equivalents of the features shown and described or parts thereof, but it should be recognized that various modifications are possible within the scope of the embodiments of the present application. Accordingly, it is to be understood that although the present application describes specific embodiments and optional features, those of ordinary skill in the art may make modifications and variations to the compositions, methods and concepts disclosed herein, and such modifications and variations are considered to be within the scope of the embodiments of the present application.

[0187] Enumerated embodiments

[0188] The following exemplary embodiments are provided, the numbers of which should not be construed as designating a degree of importance:

[0189] Embodiment 1 provides a compound of formula I, or a salt, solvate, geometric isomer or stereoisomer thereof:

[0190]

[0191] Wherein: is a single bond or a double bond; R 1 and R 2 are each independently C 3-10 cycloalkyl, aryl or heteroaryl, each of which is optionally substituted with at least one group selected from the following: halogen, OR, SiR 3 、OSiR 3 、OSiR 3 、OSi(OR) 3 、BR 3 、BR 2 、B(OR) 3 、B(OR) 2 、CN, CF 3 、OCF 3 、SO 2 R、SO 2 N(R) 2 、SO 3 R、C(O)R、NR 2 、N(R)SO 2 R、N(R)SO 2 N(R) 2 、(CH 2 ) 0-2 N(R)C(O)R、(CH 2 ) 0-2 N(R)N(R) 2 、N(R)C(O)OR、C 1-12 alkyl, C 1-12 heteroalkyl, O C 1-12 alkyl, C3-12 Naphthenyl, C 6-10 aryl and C 6-10 heteroaryl; R 3 and R 4 are each independently hydrogen, optionally substituted C 3-10 naphthenyl, optionally substituted aryl, optionally substituted heteroaryl, C 1-12 alkyl or OC 1-12 alkyl, where optionally substituted includes at least one group selected from the following: halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 , N(R)C(O)R, (CH 2 ) 0-2 , N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 naphthenyl, C 6-10 aryl and C 6-10 heteroaryl; or R 3 and R 4 together with the ring to which they are attached are used to form C 4-20 naphthenyl, C 6-20 aryl or C 6-20 heteroaryl, each of which is optionally substituted by at least one group selected from the following: halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl; R 5 is H or C 1-3 alkyl; M is a transition metal; X is a counteranion; A is C 6-18 aryl or C 6-18 heteroaryl, which is optionally substituted by at least one group selected from the following: halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 cycloalkyl, C6-10 Aryl and C 6-10 heteroaryl; R is independently hydrogen or optionally substituted C 1-10 alkyl each time it appears; m is 1, 2 or 3; and n is 1, 2, 3 or 4.

[0192] Embodiment 2 provides a compound according to Embodiment 1, which has the structure: Formula Ia, or a salt, solvate, geometric isomer or stereoisomer thereof.

[0193] Embodiment 3 provides a compound according to any one of Embodiments 1-2, wherein R 1 and R 2 are both aryl.

[0194] Embodiment 4 provides a compound according to any one of Embodiments 1-3, wherein the aryl is: wherein: R 6 and R 7 are each independently C 1-12 alkyl or C alkyl substituted with at least one aryl 1-12 alkyl; and R 8 is hydrogen or C 1-12 alkyl or C alkyl substituted with at least one aryl 1-12 alkyl.

[0195] Embodiment 5 provides a compound according to any one of Embodiments 1-4, wherein R 8 is hydrogen.

[0196] Embodiment 6 provides a compound according to any one of Embodiments 1-5, wherein R 6 and R 7 are each C 1-6 alkyl.

[0197] Embodiment 7 provides a compound according to any one of Embodiments 1-6, wherein R 6 and R 7 are each C(H)(CH 3 ) 2 .

[0198] Embodiment 8 provides a compound according to any one of Embodiments 1-7, wherein M is selected from Fe, Co, Ni, Cu, Ru, Rh, Pd, Ag, Re, Os, Ir, Pt and Au.

[0199] Embodiment 9 provides a compound according to any one of Embodiments 1-8, wherein M is Pd.

[0200] Embodiment 10 provides a compound according to any one of Embodiments 1-9, wherein X is selected from F, Cl, Br, I, OSO2 R, OSO 3 R and OC(=O)R.

[0201] Embodiment 11 provides a compound according to any one of Embodiments 1-10, wherein the N-heterocyclic carbene (NHC) moiety of the compound of Formula I is selected from:

[0202]

[0203] wherein

[0204] R 1 is independently selected from tert-butyl, 1-adamantyl, cyclohexyl, isopropyl, methyl, ethyl, n-propyl, butyl, pentyl and

[0205] R 6 is CH(phenyl) 2 、CH(Me) 2 、CH(2-Np) 2 or CH(Et) 2 ;

[0206] R 6 ' is CH(phenyl) 2 、CH(Me) 2 or CH(Et); and

[0207] R 8 is CH(phenyl) 2 、Me、OMe or H.

[0208] Embodiment 12 provides a compound according to any one of Embodiments 1-11, wherein the NHC moiety of the compound of Formula I is selected from:

[0209]

[0210]

[0211] Embodiment 13 provides a compound according to any one of Embodiments 1-12, wherein n is 2.

[0212] Embodiment 14 provides a compound according to any one of Embodiments 1-13, wherein A is and wherein each occurrence of R 9 is independently selected from OCH 3 、CF 3 、2,6-dimethyl, 2,6-diisopropyl and hydrogen, and wherein p is 0, 1, 2, 3, 4 or 5.

[0213] Embodiment 15 provides a compound according to any one of Embodiments 1-14, wherein R5 is hydrogen or methyl.

[0214] Embodiment 16 provides a method for preparing a compound according to any one of Embodiments 1-15, the method comprising: contacting a compound having the structure or a salt, solvate, geometric isomer or stereoisomer thereof with a compound having the structure or a salt, solvate, geometric isomer or stereoisomer thereof in a solvent to form a compound of Formula I, wherein each occurrence of R 9 is independently selected from hydrogen, halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl.

[0215] Embodiment 17 provides the method according to Embodiment 16, wherein the solvent is a nonpolar aprotic solvent.

[0216] Embodiment 18 provides the method according to any one of Embodiments 16-17, wherein the solvent comprises chloroform, diethyl ether, deuterated chloroform, pentane, hexane, benzene, toluene, dichloromethane or a mixture thereof.

[0217] Embodiment 19 provides the method according to any one of Embodiments 16-18, wherein the contacting is carried out at room temperature.

[0218] Embodiment 20 provides a method for preparing the compound according to any one of Embodiments 1-15, the method comprising: reacting a compound having the structure or a salt, solvate, geometric isomer or stereoisomer thereof with a compound of formula MX 2 (A—N(H)(R 5 )) 2 or a salt, solvate, geometric isomer or stereoisomer thereof in a solvent to form a compound of formula I or a salt, solvate, geometric isomer or stereoisomer thereof.

[0219] Embodiment 21 provides the method according to Embodiment 20, wherein the contacting is carried out in the presence of a base.

[0220] Embodiment 22 provides the method according to any one of Embodiments 20-21, wherein the base comprises NaOC 1-4 alkyl, KOC 1-4 alkyl, lithium diisopropylamide, sodium hexamethyldisilazide, LiC 1-4 alkyl or a combination thereof.

[0221] Embodiment 23 provides the method according to any one of Embodiments 20-22, wherein the solvent comprises a polar aprotic solvent.

[0222] Embodiment 24 provides the method according to any one of Embodiments 20-23, wherein the solvent comprises tetrahydrofuran, 2-N-methylpyrrolidone, dimethylformamide, acetonitrile and combinations thereof.

[0223] Embodiment 25 provides a compound of formula II, or a salt, solvate, geometric isomer or stereoisomer thereof: Formula II, wherein: R 5 is H or C 1-3 alkyl; R A , R 6 and R 7 are independently selected from optionally substituted C 1-12 alkyl, optionally substituted C 1-12 heteroalkyl, optionally substituted OC 1-12 alkyl, optionally substituted C 3-12 cycloalkyl, optionally substituted C 6-18 aryl, optionally substituted C 6-18 heteroaryl and C 1-3 alkyl substituted with at least one aryl or heteroaryl, wherein the optional substitution is by at least one group selected from: halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3, BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 , (CH 2 ) 0-2 , N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl; M is a transition metal; X is a counteranion; n is an integer from 1 to 4; and R is independently hydrogen or optionally substituted C 1-10 alkyl.

[0224] Embodiment 26 provides a compound of formula III, or a salt, solvate, geometric isomer or stereoisomer thereof: Formula III, wherein: R 5 is H or optionally substituted C 1-3 alkyl; R 6 , R 7 and R 8 are independently selected from optionally substituted C 1-12 alkyl, optionally substituted C 1-12 heteroalkyl, optionally substituted OC 1-12 alkyl, optionally substituted C 3-12 cycloalkyl, optionally substituted C 6-18 aryl, optionally substituted C 6-18 heteroaryl or C 1-3 alkyl substituted with at least one aryl or heteroaryl, wherein the optional substitution is by at least one group selected from: halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 ) 0-2 , (CH 2 ) 0-2 , N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl; G is absent, optionally substituted C 1-12 alkyl, optionally substituted C 1-12 heteroalkyl, optionally substituted OC 1-12 alkyl, optionally substituted C 3-12 cycloalkyl, optionally substituted C 6-18 aryl, optionally substituted C 6-18 heteroaryl or C substituted by at least one aryl or heteroaryl 1-3 alkyl, where the optional substitution is by at least one group selected from: halogen, OR, SiR 3 , OSiR 3 , OSiR 3 , OSi(OR) 3 , BR 3 , BR 2 , B(OR) 3 , B(OR) 2 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , (CH 2 )0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 1-12 heteroalkyl, OC 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl; M is a transition metal; X is a counteranion; Y is N or C; Z is N or C; n is an integer from 1 to 4; and R is independently hydrogen or optionally substituted C 1-10 alkyl, provided that Y and Z are not both C.

Claims

1. A compound of formula I, or a salt thereof: Wherein: is a single bond or a double bond; R 1 and R 2 each independently is R 3 and R 4 each independently is hydrogen or C 1-12 alkyl; or R 3 and R 4 together with the rings to which they are attached are used to form C 6-20 aryl or C 6-20 heteroaryl, each of which is optionally substituted with at least one group selected from the following: halogen, OR, SiR 3 , OSiR 3 , OSi(OR) 3 , CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , N(R)C(O)OR, C 1-12 alkyl, C 3-12 cycloalkyl, C 6-10 aryl and C 6-10 heteroaryl; R 5 is H or C 1-3 alkyl; R 6 and R 7 each independently is C 1-12 alkyl or C alkyl substituted by at least one phenyl; 1-12 alkyl; R 8 is hydrogen or C 1-3 alkyl or C alkyl substituted by at least one phenyl 1-12 alkyl; M is Pd; X is a counteranion; A is phenyl, which is optionally substituted by at least one group selected from the following: halogen, OR, CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 , N(R)SO 2 N(R) 2 and N(R)C(O)OR; R is independently hydrogen or C 1-10 alkyl; m is 1; and n is 2.

2. The compound according to claim 1, having the following structure, or a salt thereof:

3. The compound according to claim 1, wherein R 8 is hydrogen.

4. The compound according to claim 3, wherein R 6 and R 7 are each C 1-6 alkyl.

5. The compound according to claim 3, wherein R 6 and R 7 are each C(H)(CH 3 ) 2 .

6. The compound according to claim 1, wherein X is selected from F, Cl, Br, I, OSO 2 R, OSO 3 R and OC(=O)R.

7. The compound according to claim 1, wherein the N - heterocyclic carbene (NHC) moiety of the compound of formula I is selected from: Where R 6 and R 7 is CH(phenyl) 2 、CH(Me) 2 or CH(Et) 2 ; R 8 is CH(phenyl) 2 , Me or H.

8. The compound according to claim 1, wherein the NHC moiety of the compound of formula I is selected from:

9. The compound according to claim 1, wherein A is and wherein R 9 each occurrence of which is independently selected from OCH 3 and CF 3 , and p is 1, 2, 3, 4 or 5.

10. The compound according to claim 1, wherein R 5 is hydrogen or methyl.

11. A method for preparing the compound according to claim 1, the method comprising: Contact a compound having the following structure or a salt thereof with a compound having the structure or a salt thereof in a solvent to form a compound of formula I or a salt thereof, wherein R 9 each occurrence of which is independently selected from hydrogen, halogen, OR, CN, CF 3 , OCF 3 , SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, NR 2 , N(R)SO 2 , N(R)SO 2 N(R) 2 and N(R)C(O)OR, and p is 1, 2, 3, 4 or 5.

12. The method according to claim 11, wherein the solvent is a non - polar aprotic solvent.

13. The method according to claim 12, wherein the solvent comprises chloroform, diethyl ether, deuterated chloroform, pentane, hexane, benzene, toluene, dichloromethane, or a mixture thereof.

14. The method according to claim 11, wherein the contacting is carried out at room temperature.

15. A method for preparing the compound according to claim 1, the method comprising: Contact a compound having the following structure or a salt thereof with a compound of the formula MX 2 (A—N(H)(R 5 )) 2 or a salt thereof in a solvent to form a compound of formula I 16. The method according to claim 15, wherein the contacting is carried out in the presence of a base.

17. The method according to claim 16, wherein the base comprises NaOC 1-4 alkyl, KOC 1-4 alkyl, lithium diisopropylamide, sodium hexamethyldisilazide, LiC 1-4 alkyl or a combination thereof.

18. The method according to claim 15, wherein the solvent comprises a polar aprotic solvent.

19. The method according to claim 18, wherein the solvent comprises tetrahydrofuran, 2 - N - methylpyrrolidone, dimethylformamide, acetonitrile, and combinations thereof.

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