WO2024011559A1

WO2024011559A1 - Fused aromatic amine preparing from isocyanide and cyclopropene

Info

Publication number: WO2024011559A1
Application number: PCT/CN2022/105897
Authority: WO
Inventors: Chun-Yu HO; Jianqiang Huang
Original assignee: Southern University of Science and Technology
Current assignee: Southern University of Science and Technology
Priority date: 2022-07-15
Filing date: 2022-07-15
Publication date: 2024-01-18
Anticipated expiration: 2025-01-15
Also published as: CN119948008A

Abstract

Disclosed is a process for preparing fused aromatic amine from isocyanide and cyclopropene.

Description

FUSED AROMATIC AMINE PREPARING FROM ISOCYANIDE AND CYCLOPROPENE

TECHNICAL FIELD

The present application is directed to organic synthesis chemistry, in particular to a process for preparing fused aromatic amines from cyclopropenes and isocyanides.

BACKGROUND

Synthesis of fused aromatic amines is one of the most important aspects in organic synthesis chemistry, they are the core structures of many important functional materials and bioactive molecules. Fused aromatic compounds may serve as primary starting point for preparations of various materials via subsequent transformations, such as electrophilic and nucleophilic aromatic substitution, aromatic CH activations, and dearomatization.

Today’s major obstacle to reveal the full potential of these indispensible transformations may probably come from the cost of starting materials and their preparation. Most of the fused aromatic amines employed in above systems are obtained from the natural resources, such as coal tar or oil, which have very limited structural variations.

Synthesis of fused aromatic amines is still based on intramolecular reactions, such as cycloisomerization, in which has significantly affected the medicinal and combinatorial chemistry development as well as functional materials optimization. As a result, there are huge demands to develop intermolecular methodologies that lead to higher functionalized aromatic amines in high efficiency, preferable from easily accessible starting materials.

SUMMARY

In one aspect, the present application is directed to a process for preparing a compound of formula (III) with a compound of formula (I) and a compound of formula (II) in the presence of a carbene and a transition metal catalyst or a precursor thereof,

wherein,

Ar ¹ is optionally substituted aryl, heteroaryl, and alkenyl,

R ¹, R ² and R ³ is independently selected from the group consisting of H, halide or optionally substituted alkyl, aryl, heteroaryl, alkenyl, alkynyl or metalloid,

Substituents on a compound of formula (I) is optionally being connected by alkylene chains.

R ⁴ is optionally substituted alkyl, aryl, heteroaryl, alkenyl, alkynyl or metalloid, and is optionally being connected with the substituents on a compound of formula (I) .

Ar ² is optionally substituted aryl, heteroaryl came from the substituted aryl and heteroaryl of Ar ¹, or is optionally substituted aliphatic structures came from the substituent alkenyl of Ar ¹.

Transition metal catalyst is selected from Groups 3 to 12.

Carbene is selected from any member of a class of molecules containing divalent carbon atom.

DETAILED DESCRIPTION

Definitions

In the following description, certain specific details are included to facilitate a thorough understanding of various disclosed embodiments. One skilled in the relevant art, however, will recognize that embodiments may be practiced without one or more of these specific details, or with other methods, components, materials, etc.

Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, which is as “including, but not limited to” .

Reference throughout this specification to “one embodiment” , or “an embodiment” , or “in another embodiment” , or “some embodiments” , or “in some embodiments” means that a particular referent feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearance of the phrases “in one embodiment” , or “in an embodiment” , or “in another embodiment” , or “in some embodiments” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

It should be noted that, as used in this specification and the appended claims, the singular forms “a” , “an” , and “the” include plural referents unless the content clearly dictates otherwise. In the present application, the use of “or” means “and/or” unless stated otherwise.

Certain chemical groups named herein are preceded by a shorthand notation indicating the total number of carbon atoms that are to be found in the indicated chemical group. For example, C ₇-C ₁₂ alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms, and C ₄-C ₁₂ cycloalkyl describes a cycloalkyl group, as defined below, having a total of 4 to 12 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.

As used herein, “C _m to C _n” or “C _m _to _n” in which “m” and “n” are integers refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group or the number of carbon atoms in the ring of a cycloalkyl or cycloalkenyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl or ring of the cycloalkenyl can contain from “m” to “n” , inclusive, carbon atoms. Thus, for example, a “C ₁ to C ₄ alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH ₃-, CH ₃CH ₂-, CH ₃CH ₂CH ₂-, (CH ₃) ₂CH-, CH ₃CH ₂CH ₂CH ₂-, CH ₃CH ₂CH (CH ₃) -and (CH ₃) ₃C-. If no “m” and “n” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group, the broadest range described in these definitions is to be assumed.

Accordingly, as used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:

The term “alkyl” as used herein alone or as part of a group means any unbranched or branched, substituted or unsubstituted, saturated hydrocarbon group. The alkyl moiety, may be branched or straight chain. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated) . The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 5 carbon atoms. The alkyl group may be designated as “C ₁-C ₄ alkyl” or similar designations. By way of example only, “C ₁-C ₄ alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

The alkyl group may be substituted or unsubstituted. When substituted, the substituent group (s) is (are) one or more group (s) individually and independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cylcloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy, heterocyclyl, heterocyclooxy, heteroalicyclyl, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, acyl, thiol, substituted or unsubstituted thioalkoxy, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, acylalkyl, acylamino, acyloxy, aminoacyl, aminoacyloxy, oxyacylamino, keto, thioketo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and substituted or unsubstituted amino, including mono-and di-substituted amino groups, and the protected derivatives thereof, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO ₂-alkyl, -SO ₂-substituted alkyl, -SO ₂-aryl and -SO ₂-heteroaryl.

Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like. Wherever a substituent is described as being “optionally substituted” , that substitutent may be substituted with one or more of the above substituents.

The term “alkenyl” as used herein alone or as part of a group refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, preferably two to eight carbon atoms and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, propenyl, butenyl, pentenyl, penta-1, 4-dienyl, cyclohexenyl, and the like.

The term “alkynyl” as used herein alone or as part of a group refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to twelve carbon atoms, preferably two to eight carbon atoms and which is attached to the rest of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

The term “aryl” as used herein alone or as part of a group is intended to mean a carbocyclic aromatic ring or ring system. A aryl group may be unsubstituted or substituted. Moreover, the term “aryl” includes fused ring systems wherein at least two aryl rings, or at least one aryl and at least one C _3-8-cycloalkyl share at least one chemical bond. Some examples of “aryl” rings include optionally substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.

The term “aryl” relates to aromatic, including, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from heterocyclyl, heteroaryl, halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C _1-6-alkoxy, C _1-6-alkyl, C _1-6-hydroxyalkyl, C _1-6-aminoalkyl, C _1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. The aryl group can be substituted optionally at the para, ortho and/or meta positions.

The term “heteroaryl” as used herein alone or as part of a group is intended to mean a heterocyclic aromatic group where one or more carbon atoms in an aromatic ring have been replaced with one or more heteroatoms selected from the group comprising nitrogen, sulfur, and oxygen.

Furthermore, in the present context, the term “heteroaryl” comprises fused ring systems wherein at least one aryl ring and at least one heteroaryl ring, at least two heteroaryl rings, at least one heteroaryl ring and at least one heterocyclyl ring, or at least one heteroaryl ring and at least one cycloalkyl ring share at least one chemical bond.

The term “heteroaryl” is understood to relate to aromatic, C _3-8 cyclic groups further containing one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom with up to two nitrogen atoms, and their substituted as well as benzo-and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms. Heteroaryl groups can carry one or more substituents, selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C _1-6-alkoxy, C _1-6-alkyl, C _1-6-hydroxyalkyl, C _1-6-aminoalkyl, C _1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. In some embodiments, heteroaryl groups can be five-and six-membered aromatic heterocyclic systems carrying 0, 1, or 2 substituents, which can be the same as or different from one another, selected from the list above.

Representative examples of heteroaryl groups include, but are not limited to, unsubstituted and mono-or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quionoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1, 2, 3-oxadiazole, 1, 2, 3-thiadiazole, 1, 2, 4-thiadiazole, borazine, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O-C _1-6-alkyl, C _1-6-alkyl, hydroxy-C _1-6-alkyl, and amino-C _1-6-alkyl.

The term “optional” or “optionally” as used herein means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.

Unless otherwise indicated, when a substituent is deemed to be “optionally substituted” , it is meant that the substituent is a group that may be substituted with one or more group (s) individually and independently selected from morpholinoalkanoate, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono-and di-substituted amino groups, and the protected derivatives thereof.

For example, “optionally substituted aryl” means that the aryl may or may not be substituted and that the description includes both substituted aryl and aryl having no substitution.

The term “transition metal” as used herein refers to any element in the d-block of the periodic table of the elements. This corresponds to groups 3 (IIIB) to 12 (IIB) on the periodic table.

The term “ligand” in chemistry generally refers to an atom, ion, or molecule that bonds to a central metal, generally involving formal donation of one or more of its electrons. The metal-ligand bonding ranges from covalent to more ionic.

The term “carbene (s) ” as used herein refers to an organic molecule containing a carbon atom with six valence electrons and having the general formula RR’C: .

The term “alkylene” or “alkylene chain” as used herein alone or as part of a group refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.

The term “alkenylene” or “alkenylene chain” as used herein alone or as part of a group refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, e.g., ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.

The term “alkynylene” or “alkynylene chain” as used herein alone or as part of a group refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one triple bond and having from two to twelve carbon atoms, e.g., propynylene, n-butynylene, and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.

The term “amine” as used herein refers to a compound that comprises an amino group. The term “amino” as used herein alone or as part of a group refers to the substituted N-groups.

Metalloid, or semi metal, is a term used in chemistry when classifying the chemical elements. On the basis of their general physical and chemical properties, nearly every element in the periodic table can be termed either a metal or a nonmetal. However, a few elements are referred to as metalloids. There is no rigorous definition of the term, but the following properties are usually considered characteristic of metalloids: (1) metalloids often form amphoteric oxides; and (2) metalloids often behave as semiconductors (B, Si, Ge) .

The following elements are generally considered metalloids: Boron (B) , Silicon (Si) , Germanium (Ge) , Arsenic (As) , Antimony (Sb) , Tellurium (Te) , and Polonium (Po) .

In one aspect, the present application is directed to a process for preparing a compound of formula (III) with a compound of formula (I) and a compound of formula (II) in the presence of a N-heterocyclic carbene and transition metal catalyst or a precursor thereof,

wherein,

Ar ¹ is optionally substituted aryl, heteroaryl, and alkenyl,

Transition metal catalyst is selected from Groups 3 to 12.

Carbene is optionally substituted with one or more than one heteroatom. When cyclic carbene is used, the ring size is optionally ranged from 4 to 12.

In some embodiments of the present application, Ar ¹ is optionally substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, alkenyl, indenyl, or indanyl.

In some embodiments of the present application, the compound of formula (I) is selected from the group consisting of cyclopropene and substituted derivatives.

In some embodiments of the present application, R ¹, R ², and R ³ is independently selected from the group consisting of H, halide or optionally substituted alkyl, aryl, heteroaryl, alkenyl, alkynyl or metalloid.

In some embodiments of the present application, substituents on a compound of formula (I) is optionally being connected by alkylene chains.

In some embodiments of the present application, R ⁴ is optionally substituted alkyl, aryl, heteroaryl, alkenyl, alkynyl or metalloid.

In some embodiments of the present application, the compound of formula (II) is selected from the group consisting of isocyanides, such as phenyl isocyanide, furanyl isocyanide, tertiary butyl isocyanide and their substituted derivatives.

The transition metal catalyst of the present invention may include any catalytic transition metal and/or catalyst precursor as it is introduced into the reaction vessel and which may be, if needed, converted in situ into active form, as well as the active form of the catalyst which participates in the reaction. In some embodiments of the present application, the transition metal is selected from Groups 3 to 12.

Exemplary transition metal that can be used in the present application includes, but is not limited to, Scandium (Sc) , Titanium (Ti) , Vanadium (V) , Chromium (Cr) , Manganese (Mn) , Iron (Fe) , Cobalt (Co) , Nickel (Ni) , Copper (Cu) , Zinc (Zn) , Yttrium (Y) , Zirconium (Zr) , Niobium (Nb) , Molybdenum (Mo) , Technetium (Tc) , Ruthenium (Ru) , Rhodium (Rh) , Palladium (Pd) , Silver (Ag) , Cadmium (Cd) , Hafnium (Hf) , Tantalum (Ta) , Tungsten (W) , Rhenium (Re) , Osmium (Os) , Iridium (Ir) , Platinum (Pt) , Gold (Au) , Mercury (Hg) , Rutherfordium (Rf) , Dubnium (Db) , Seaborgium (Sg) , Bohrium (Bh) , Hassium (Hs) , Meitnerium (Mt) , Darmstadtium (Ds) , Roentgenium (Rg) , and Ununbium (Uub) .

In some embodiments of the present application, the transition metal is selected from Group 10.

In some embodiments of the present application, the transition metal is selected from the group consisting of Nickel (Ni) , Palladium (Pd) and Platinum (Pt) . In some embodiments of the present application, the transition metal is Nickel (Ni) .

In some embodiments of the present application, a ligand on the transition metal catalyst is selected from the group consisting of carbenes, heterocyclic carbenes (NHCs) , biscarbenes, bisheterocyclic carbenes, phosphines, amines, imines, arsines, and their hybrids, combinations, and derivatives.

In some embodiments of the present application, the ligand or metal bears a weakly or non-nucleophilic stabilizing ion, including but not limited to halogen, boronates, sulfonates, and phosphonates.

The ligand can be added to the reaction mixture in the form of a metal complex, or added as separate reagent relative to the addition of the metal. The ligand, if chiral, can be provided as a racemic mixture or a purified stereoisomer.

In some embodiments of the present application, the carbene is IPr (IPr = 1, 3-bis (2, 6-di-isopropylphenyl) imidazol-2-ylidene; CAS: 244187-81-3) .

In some embodiments of the present application, the transition metal catalyst is NiCl ₂DME, or its dimer, trimer or higher order oligomers, optionally used with NaBArF together, where NaBArF is employed in stoichiometric or catalytic amount.

In some embodiments of the present application, the transition metal catalyst and the carbene are used as an isolated complex [ (carbene) NiX ₂] L, optionally used with NaBArF together, where L is a solvent molecule or an isocyanide of formula (II) , carbene is IPr (IPr = 1, 3-bis (2, 6-di-isopropylphenyl) imidazol-2-ylidene; CAS: 244187-81-3) , X is a halide or other group alike.

In some embodiments of the present application, the transition metal catalyst is provided in the reaction in a catalytic amount. In certain embodiments, that amount is in the range of < 10 mol%, with respect to the limiting reagent, which may be either the compound of formula (I) or the compound of formula (II) , depending upon which reagent is in stoichiometric excess.

In some embodiments of the present application, the reaction can be carried out optionally with a solvent. The solvent is selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halohydrocarbons, alcohols, ethers, esters, ketones, nitriles and diol derivatives.

Exemplary aromatic hydrocarbons that can be used in the present application include, but are not limited to, benzene, toluene, xylene, and the like. Exemplary aliphatic hydrocarbons that can be used in the present application include, but are not limited to, pentane, hexane, heptane, octane, and the like. Exemplary alicyclic hydrocarbons that can be used in the present application include, but are not limited to, cyclohexane, cyclohexanone, methylcyclohexanone, and the like. Exemplary alcohols that can be used in the present application include, but are not limited to, methanol, ethanol, isopropanol, and the like. Exemplary ethers that can be used in the present application include, but are not limited to, diethyl ether, methyl ethyl ether, propyl ether, propylene oxide, and the like. Exemplary esters that can be used in the present application include, but are not limited to, methyl formate, ethyl formate, butyl formate, pentyl formate, methyl acetate, ethyl acetate, propyl acetate, benzyl phenylacetate, and the like. Exemplary ketones that can be used in the present application include, but are not limited to, acetone, methylbutanone, methyl isobutyl ketone, and the like. Exemplary nitriles that can be used in the present application include, but are not limited to, acetonitrile, propionitrile, acrylonitrile, and the like. Exemplary diol derivatives that can be used in the present application include, but are not limited to, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, and the like.

In some embodiments of the present application, the solvent is an aromatic hydrocarbon. In some embodiments of the present application, the solvent is selected from the group consisting of benzene, toluene and xylene.

Alternatively, the reaction can be carried out in neat condition. Ionic liquid, such as imidazolium salts, can be also used as reaction medium.

In some embodiments of the present application, the process may be carried out optionally in a buffer to minimize the problems related to isomerization, oligomerization and polymerization. Examples of the buffer which can be used in the present application include but not limited to ammonium salt, phosphorous buffer, carbonates.

EXAMPLES

The reaction is oxygen and moisture sensitive, the substrates shall be dried and degassed before use (normally over CaH ₂, or over powdered CaCl ₂ overnight) . Unless otherwise indicated, all reactions were performed under an oxygen-free atmosphere of nitrogen or argon with rigid exclusion of moisture from reagents and glassware. NiBr ₂DME was purchased from ACROS or IL, stored under nitrogen atmosphere and used without further purification. IPr and NaBARF were purchased from Aldrich or Strem. Isocyanide or isonitrile were filtered through a short plug of silica gel and dried before use to remove possible stabilizer. Substituted cyclopropenes were prepared according to common procedure. Toluene was distilled over sodium before use.

Analytical thin layer chromatography (TLC) was performed using EM Science silica gel 60 F254 plates. The developed chromatogram was analyzed by UV lamp (254 nm) , ethanolic phosphomolybdic acid (PMA) or potassium permanganate (KMnO ₄) . Liquid chromatography was performed using a forced flow (flash chromatography) of the indicated solvent system on Silica Gel (230–400 mesh) . ¹H and ¹³C NMR spectra were recorded on Bruker 400 MHz or 300 MHz spectrometers in CDCl ₃. Chemical shifts in ¹H NMR spectra are reported in ppm on the δ scale from an internal standard of residual chloroform (7.27 ppm) . Data are reported as follows: chemical shift, multiplicity (s= singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad) , coupling constant in hertz (Hz) , and integration. Chemical shifts of ¹³C NMR spectra are reported in ppm from the central peak of CDCl ₃ (77.16 ppm) on the δ scale.

The catalyst with a general formula of [ (NHC) NiX ₂] (NaBArF) _n, [ (IPr) NiBr ₂] / (NaBArF) ₂ as an example in this case, can be generated according to but not limited to the following method: IPr, NiBr ₂DME and NaBArF in 1: 1: 2 ratio was stirred in toluene for 3-5 mins at 80℃.

The [ (NHC) NiBr ₂] / (NaBARF) ₂ catalyst can be also generated by other methods, include but not limited to mixing a Ni source with 1) an imidazolium salt or an ionic liquid in general with or without a base; or 2) alkyl, aryl, benzyl, vinyl, alkenyl or alkynyl X; or 3) a hydride or hydrogen source in general, optionally with the use of activators and buffers, this include but not limited to Lewis acidic additives, protic acid and or nucleophiles; or 4) other common organometallic transformations and manipulations techniques, such as hydride addition or elimination steps as well as substitutions and alike.

Experimental results suggested that the coupling reactions are sensitive to the carbene catalyst structures, the counter ion used and possibly generation methods.

General Procedure for catalyst generation: NHC (0.05 mmol, 10 mol%) , NiBr ₂DME (0.05 mmol, 10 mol%) and NaBARF (0.10 mmol, 20 mol%) were added to an oven-dried test tube equipped with a stir bar in glove box. The catalyst mixture was dissolved in degassed toluene (1 mL) under nitrogen and stirred at 80℃ for 3-5 mins.

General Procedure for the Fused Aromatic Amine Synthesis: The compound of formula (I) and (II) (0.5 mmol, 100 mol%and 1 mmol, 200 mol%, respectively) in 1 mL toluene were added to the [NHC-NiBr ₂] (NaBARF) ₂ catalyst mixture together at 80℃, and the mixture was stirred overnight (～ 12 hrs) . Then the mixture was cooled down, diluted with n-hexane/ethyl acetate (6 mL, 10: 1) and was allowed to stir 30 mins in open air at room temperature. The mixture was then filtered through a short plug of silica gel and rinsed with 20%ethyl acetate/hexane (50 mL) . The solvent was removed under reduced pressure, and purification via flash chromatography on silica gel and afforded the product.

Following the above general procedures, the following compounds are synthesized from the corresponding starting materials and the characterization data thereof are provided.

Example 1

89%yield, purified by 5%EA/Hex

¹H NMR (400 MHz, CDCl ₃) δ: 8.17-8.10 (m, 1H) , 8.05-7.98 (m, 1H) , 7.63-7.52 (m, 2H) , 7.35-7.28 (m, 1H) , 7.24-7.21 (m, 2H) , 7.03 (dd, J = 0.8, 6.8 Hz, 1H) , 6.10 (d, J = 7.6 Hz, 1H) , 5.61 (br, 1H) , 3.14 (hept, J = 6.8 Hz, 2H) , 2.58 (s, 3H) , 1.18 (d, J = 6.8 Hz, 6H) , 1.09 (d, J = 6.8 Hz, 6H) ; ¹³C NMR (100 MHz, CDCl ₃) δ: 146.9, 142.0, 136.1, 133.4, 127.2, 126.9, 125.8, 125.2, 124.8, 124.1, 124.0, 120.8, 107.2, 28.3, 24.9, 23.3, 19.1.

HRMS (EI-MS) : calculated C ₂₃H ₂₈N: 318.2216 (M+H) , found: 318.2216

Example 2

81%yield, purified by 10%EA/Hex

¹H NMR (400 MHz, CDCl ₃) δ: 7.95 (d, J = 8.0 Hz, 1H) , 7.63 (d, J = 8.0 Hz, 1H) , 7.44 (dt, J = 1.2, 8.0 Hz, 1H) , 7.37 (dt, J = 1.2, 7.2 Hz, 1H) , 7.35-7.30 (m, 1H) , 7.29-7.22 (m, 2H) , 6.97 (d, J = 8.0 Hz, 1H) , 6.04 (dd, J = 1.2, 8.0 Hz, 1H) , 5.70-5.60 (br, 1H) , 3.23 (hept, J = 6.8 Hz, 2H) , 2.48 (s, 3H) , 1.20 (d, J = 6.8 Hz, 6H) , 1.13 (d, J = 6.8 Hz, 6H) ; ¹³C NMR (100 MHz, CDCl ₃) δ: 156.0, 155.6, 147.0, 142.5, 135.3, 129.1, 127.4, 125.6, 124.7, 124.1, 122.7, 120.5, 111.6, 111.3, 110.3, 106.1, 28.5, 24.8, 23.3, 14.7.

HRMS (EI-MS) : calculated C ₂₅H ₂₈NO: 358.2165 (M+H) , found: 358.2158.

Example 3

95%yield, purified by 5%EA/Hex

¹H NMR (400 MHz, CDCl ₃) δ: 8.14 (dd, J = 1.2, 8.4 Hz, 1H) , 8.00 (dd, J = 1.2, 8.4 Hz, 1H) , 7.59-7.53 (m, 1H) , 7.50-7.40 (m, 5H) , 7.38-7.31 (m, 2H) , 7.30-7.24 (m, 2H) , 7.16-7.12 (m, 1H) , 6.24 (d, J = 7.6 Hz, 1H) , 5.77 (br, 1H) , 3.19 (hept, J = 6.8 Hz, 2H) , 1.21 (d, J = 6.8 Hz, 6H) , 1.13 (d, J = 6.8 Hz, 6H) ; ¹³C NMR (100 MHz, CDCl ₃) δ: 147.1, 143.0, 141.5, 135.6, 132.5, 130.6, 130.5, 128.3, 127.9, 127.3, 127.1, 126.7, 126.1, 125.0, 124.2, 123.4, 120.4, 106.9, 28.4, 25.0, 23.4.

HRMS (EI-MS) : calculated C ₂₈H ₃₀N: 380.2373 (M+H) , found: 380.2376.

Example 4

60%yield, purified by 5%EA/Hex

¹H NMR (400 MHz, CDCl ₃) δ: 8.05 (dd, J = 1.6, 8.4 Hz, 1H) , 7.97 (dd, J = 1.2, 8.0 Hz, 1H) , 7.54-7.41 (m, 7H) , 7.41-7.35 (m, 1H) , 7.27 (d, J = 8.0 Hz, 1H) , 7.22-7.12 (m, 2H) , 7.08-7.02 (m, 1H) , 7.00 (d, J = 7.6 Hz, 1H) , 6.06 (br, 1H) , 1.52 (s, 9H) ; ¹³C NMR (100 MHz, CDCl ₃) δ: 142.2, 141.7, 141.2, 140.9, 133.0, 132.7, 130.4, 128.4, 127.6, 127.2, 127.1, 127.0, 126.9, 126.3, 126.2, 125.5, 124.7, 123.2, 121.3, 112.1, 35.0, 30.8.

HRMS (EI-MS) : calculated C ₂₆H ₂₆N: 352.2060 (M+H) , found: 352.2058.

Example 5

28%yield, purified by 5%EA/Hex

¹H NMR (400 MHz, CDCl ₃) δ: 7. xx-7. x (m, xH) , . ¹H NMR (500 MHz, CDCl ₃) δ: 7.93-7.85 (m, 2H) , 7.50-7.40 (m, 5H) , 7.41-7.35 (m, 2H) , 7.30-7.25 (m, 1H) , 7.02-6.95 (m, 1H) , 1.51 (s, 9H) ; ¹³C NMR (125 MHz, CDCl ₃) δ: 141.5, 141.2, 132.7, 130.5, 130.1, 128.3, 127.4, 126.9, 126.6, 125.7, 125.4, 124.7, 120.7, 109.4, 51.9, 30.1;

HRMS (EI-MS) : calculated C ₂₀H ₂₂N: 276.1747 (M+H) , found: 276.1740.

Example 6

81%yield, purified by 5%EA/Hex

¹H NMR (500 MHz, CDCl ₃) δ: 8.20-8.10 (m, 2H) , 7.67-7.52 (m, 2H) , 7.42-7.36 (m, 1H) , 7.35-7.30 (m, 2H) , 6.15-6.08 (m, 1H) , 5.98-5.82 (m, 1H) , 5.72-5.66 (m, 1H) , 5.02-4.94 (m, 1H) , 4.94-4.84 (m, 1H) , 3.45-3.40 (m, 2H) , 3.29-3.18 (m, 2H) , 2.60-2.55 (m, 3H) , 1.25 (d, J = 6.8 Hz, 6H) , 1.16 (d, J = 6.8 Hz, 6H) ; ¹³C NMR (125 MHz, CDCl ₃) δ: 146.9, 141.5, 136.9, 135.9, 135.5, 134.0, 126.9, 126.0, 125.0, 124.2, 124.0, 122.9, 121.4, 120.5, 115.1, 110.1, 39.0, 28.3, 24.9, 23.4, 13.9.

HRMS (EI-MS) : calculated C ₂₆H ₃₂N: 358.2529 (M+H) , found: 358.2521.

Example 7

62%yield, purified by 5%EA/Hex

¹H NMR (500 MHz, CDCl ₃) δ: 7.93 (dd, J = 1.0, 8.5 Hz, 1H) , 7.44 (dd, J = 7.0, 8.5 Hz, 1H) , 7.35-7.27 (m, 2H) , 7.27-7.23 (m, 2H) , 6.94 (d, J = 8.0 Hz, 1H) , 6.12 (d, J = 7.5 Hz, 1H) , 5.57 (br, 1H) , 3.20-3.08 (m, 4H) , 3.00 (t, J = 6.5 Hz, 2H) , 2.05 (hept, J = 6.8 Hz, 2H) , 1.18 (d, J = 6.8 Hz, 6H) , 1.09 (d, J = 6.8 Hz, 6H) ; ¹³C NMR (125 MHz, CDCl ₃) δ: 130.8, 126.9, 126.2, 124.7, 124.4, 124.3, 124.0, 123.7, 118.2, 107.2, 31.9, 31.0, 28.3, 24.9, 23.5, 23.3.

HRMS (EI-MS) : calculated C ₂₅H ₃₀N: 344.2373 (M+H) , found: 344.2368.

Example 8

65%yield, purified by 5%EA/Hex

HRMS (EI-MS) : calculated C ₂₅H ₃₀N: 344.2373 (M+H) , found: 344.2368.

¹H NMR (400 MHz, CDCl ₃) δ: 7.30-7.16 (m, 3H) , 6.73 (d, J = 8.0 Hz, 1H) , 5.92 (d, J = 8.4 Hz, 1H) , 4.81 (br, 1H) , 3.07 (hept, J = 6.8 Hz, 2H) , 2.65 (t, J = 6.4 Hz, 4H) , 2.13 (s, 3H) , 1.98-1.80 (m, 4H) , 1.14 (t, J = 6.8 Hz, 6H) , 1.13 (t, J = 6.8 Hz, 6H) ; ¹³C NMR (100 MHz, CDCl ₃) δ: 147.1, 143.8, 136.4, 136.0, 127.2, 126.8, 125.5, 123.8, 121.2, 108.7, 28.3, 27.6, 25.0, 24.8, 23.1, 22.91, 22.87, 19.1.

HRMS (EI-MS) : calculated C ₂₃H ₃₂N: 322.2529 (M+H) , found: 322.2520.

All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety.

From the foregoing it will be appreciated that, although specific embodiments of the application have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the application. Accordingly, the application is not limited except as by the appended claims.

Claims

A process for preparing a compound of formula (III) with a compound of formula (I) and a compound of formula (II) in the presence of a transition metal catalyst thereof,

wherein,

Ar ¹ is optionally substituted aryl, heteroaryl, and alkenyl,

R ¹, R ² and R ³ is independently selected from the group consisting of H, halide or optionally substituted alkyl, aryl, heteroaryl, alkenyl, alkynyl or metalloid,

Substituents on a compound of formula (I) is optionally being connected by alkylene chains.

R ⁴ is optionally substituted alkyl, aryl, heteroaryl, alkenyl, alkynyl or metalloid, and is optionally being connected with the substituents on a compound of formula (I) .

Ar ² is optionally substituted aryl, heteroaryl came from the substituted aryl and heteroaryl of Ar ¹, or is optionally substituted aliphatic structures came from the substituent alkenyl of Ar ¹.

Transition metal catalyst is selected from Groups 3 to 12.

Carbene is selected from any member of a class of molecules containing divalent carbon atom.
A process of claim 1, wherein the compound of formula (I) is selected from the group consisting of substituted cyclopropene, such as 3-methyl-3-phenylcyclopropene, and their substituted derivatives.
A process of claim 1, wherein the compound of formula (II) is selected from the group consisting of isocyanide or isonitrile, such as tertiary butyl isonitrile, and their substituted derivatives.
A process of claim 1, wherein a ligand on the transition metal catalyst is selected from the group consisting of carbenes, heterocyclic carbenes, biscarbenes, bisheterocyclic carbenes, phosphines, amines, imines, arsines and derivatives thereof.
A process of claim 1, wherein the catalyst bears a weakly or non-nucleophilic stabilizing ion.
A process of claim 1, wherein the transition metal catalyst is or generated from [ (NHC) NiBr ₂] L/ (NaBARF) ₂ and alike, where L is a solvent molecule like toluene, THF, DME, or isocyanide with a formula (II) .
A process of claim 1, wherein the process is carried out in a solvent and the solvent is selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halohydrocarbons, alcohols, ethers, esters, ketones, nitriles and diol derivatives, and ionic liquids such as imidazolium salts.
A process of claim 1, wherein the process is carried out in a buffer.