RU2777977C2 - Cross-combination methods - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method for the production of substituted bicyclo[1,1,1]pentane of the formula (I). The method includes: bringing into contact of a compound of the formula (A) with a compound of the formula (B) in the presence of the first catalyst based on transition metal, optionally the second catalyst based on transition metal, and optionally a base, under conditions selected for the formation of a compound of the formula (I); wherein the compound of the formula (A) has a structure, as is shown further where R¹ is selected from a group consisting of C_6-10 aryl substituted with unsubstituted C_1-4 alkyl, benzoxazole substituted with unsubstituted C_1-4 alkyl, C-carboxy substituted with unsubstituted C_1-4 alkyl,

, and the first boron-containing fragment, wherein the first boron-containing fragment is bound by means of boron; wherein the first boron-containing fragment is selected from a group consisting of

and

; where X¹ is selected from a group consisting of -C(=O)Y,

and the second boron-containing fragment; wherein the second boron-containing fragment is selected from a group consisting of

,

and

, wherein the compound of the formula (B) has a structure R²-X²; where R² is selected from a group consisting of C_6-10 aryl substituted with unsubstituted C_1-4 alkyl or C_1-4 alkoxy, pyridine substituted with C_1-6 halogenalkyl, pyrimidine, and quinoline; where X² is selected from a group consisting of chloride, bromide, iodide, and pseudo-halogenide, where pseudo-halogenide is sulfonate, phosphate, cyanide, azide, isocyanate, thioisocyanate, or quaternary nitrogen fragment; wherein the first catalyst based on transition metal is selected from a group consisting of Pd catalyst and Ni catalyst, where Pd catalyst is selected from a group consisting of Pd(PPh₃)₄ and PdCl₂(dppf); and where Ni catalyst is NiCl₂·dimethoxyethane; wherein the second catalyst based on transition metal is Ir catalyst, where Ir is Ir[dF(CF₃)ppy]₂(dtbpy)PF₆; wherein the compound of the formula (I) has a structure as is shown further: wherein a bond between R² and bicyclo[1,1,1]pentane in the compound of the formula (I) is a carbon-carbon bond; wherein Y is selected from a group consisting of OR⁶ and OM; wherein R⁶ is hydrogen; and where M is monovalent cation; provided that at least one of X¹ and X² is not a boron-containing fragment; and provided that if the second catalyst based on transition metal is present, then either X¹ or X² is -C(=O)Y.

EFFECT: use of the proposed method allows for obtaining a wide range of substituted bicyclo[1,1,1]pentanes.

14 cl, 10 ex, 2 tbl, 1 dwg

Description

INCLUSION IN THIS DOCUMENT BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] Without exception, all applications for which foreign or national priority is determined in the list of application data that are filed with this application are incorporated herein by reference under Article 37 CFR, paragraph 1.57.

Technical field

[0002] This application relates to methods for carrying out coupling reactions of substituted bicyclo[1,1,1]pentanes catalyzed by transition metals to obtain functionalized organic molecules, the conditions for performing such coupling reactions, and the products obtained therefrom.

Description

[0003] A number of conditions have been demonstrated for transition metal-catalyzed cross-coupling reactions of organic moieties. These reactions fall into the broad categories of cross-coupling and homocoupling reactions. In a cross-coupling reaction, both partners in a coupling reaction are different from each other, while in a homocoupling reaction they are the same. The cross-coupling reaction is of particular interest because the variety of possible reaction products is greater than in the homocoupling reaction. Organic moieties that react with each other are often components of two separate molecules, but intramolecular reactions are also known, that is, those in which two moieties are present in the same molecule.

[0004] Coupling reactions are generally believed to proceed by breaking the carbon-heteroatom bond to form an organometallic moiety containing a transition metal; transmetalization of the organometallic moiety to form a second transitional organometallic moiety; and forming a final carbon-carbon bond along with isolating the ligand-bound metal. These coupling reactions are generally classified in terms of the identity of the originally formed organometallic moiety, which includes a bond between a carbon atom and a metal or semimetal atom. For example, when the originally formed organometallic moiety includes boron, the coupling reaction is generally classified as a Suzuki coupling reaction (see Miyaura et al., Chem. Rev. (1995) vol. 95, 2457-2483; Han, Chem. Soc. Rev. (2013) Vol.42, 5270-5298). When the originally formed organometallic moiety includes zinc, the coupling reaction is generally classified as a Negishi coupling reaction (see Negishi et al., Aldrichim. Acta, (2005) Vol. 38 (3), 71-87). Other types of cross-coupling reactions are known, including the Stille reaction (organotin compound), Kumada (organomagnesium halide), and Khiyama (organosilicon compound).

[0005] Recently, coupling reactions have been demonstrated in which an organometallic group of a transition metal is combined with a carbon atom bearing a redox labile (“redox”) group, (see Prier et al., Chem. Rev., (2013) Vol.113, 5322-5363). This type of combination has not been shown to be applicable to a wide range of substrates. In addition, where this coupling reaction has been demonstrated to bond to the sp ³ carbon atom, the presence of an adjacent heteroatom has been required (see Zuo et al., Science (2014) Vol. 345, Issue 6195, 437-440). In addition, tertiary alkyl carboxylic acids have not been considered suitable coupling partners (see Noble et al., J. Am. Chem. Soc. (2015), Vol. 137(2), 624-627). Compounds having redox labile moieties have been coupled with arylorganic zinc compounds and arylorganic magnesium compounds using a catalyst containing iron (see Toriyama F. et al., Toriyama, F., et al., Redox-Active Esters in Fe-catalyzed CC Coupling, J. Am. Chem. Soc, Publication Date (Web): 22 Aug 2016).

[0006] Each of these coupling methods is essentially limited to the formation of bonds between two sp ² carbon atoms. Although some coupling reactions have been demonstrated in which a bond to the sp ³ carbon atom is formed, such reactions have a limited scope. In addition, cross-coupling reactions have not been used to successfully prepare a wide range of substituted bicyclo[1,1,1]pentanes.

SHORT DESCRIPTION

[0007] Various embodiments provide methods for preparing a substituted bicyclo[1,1,1]pentane of formula (I) comprising contacting a compound of formula (A) with a compound of formula (B) in the presence of a first transition metal catalyst as illustrated in FIG. Fig. 1 and beyond.

[0008] In one embodiment, the bond between R ² and bicyclo[1,1,1]pentane in the compound of formula (I) is a carbon-carbon bond. In one embodiment, at least one of X ¹ and X ² is not a boron moiety.

[0009] One embodiment provides a process for preparing a substituted bicyclo[1,1,1]pentane of formula (I), which may include: contacting a compound of formula (A) with a compound of formula (B) in the presence of a first catalyst based on a transition metal, optionally a second transition metal catalyst, and optionally a base, under the conditions chosen to form the compound of formula (I).

[0010] In one embodiment, R ¹ in formula (A) and formula (I) can be selected from hydrogen, optionally substituted C _1-30 alkyl, optionally substituted C _2-30 alkenyl, optionally substituted C _3-10 monocyclic cycloalkyl , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, halogen, optionally substituted C-carboxy, amino, monosubstituted amino, disubstituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted C _1-30 alkoxy, hydroxy , optionally substituted C _1-30 haloalkyl, cyano, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted O-carboxy, optionally substituted C _2-30 alkynyl, optionally substituted C _3-10 cycloalkenyl, optionally substituted aryl(alkyl ), optionally substituted heteroaryl(alkyl), optionally substituted heterocyclyl(alkyl), optionally s substituted acyl, optionally substituted thiocarbonyl, optionally substituted O-carbamyl, optionally substituted N-carbamyl, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted C-thioamido, optionally substituted N-thioamido, optionally substituted sulfenyl, optionally substituted sulfinyl , an optionally substituted sulfonyl, an optionally substituted haloalkoxy, and a first boron moiety, the first boron moiety being linked via a boron atom; In one embodiment, the first boron moiety can be selected from organoborane, boronic acid ester, boronic acid, trifluoroborate, N-coordinated boronate, boronate, and boronamide.

[0011] In one embodiment, X ¹ in formula (A) can be selected from halide, pseudohalide, -C(=O)Y, and a second boron moiety. In one embodiment, the second boron moiety can be selected from organoborane, boronic acid ester, boronic acid, trifluoroborate, N-coordinated boronate, boronate, and boronamide, with the second boron moiety linked via a boron atom.

[0012] In one embodiment, the compound of formula (B) may have the structure R ² -X ² . In one embodiment, R ² in formula (B) and formula (I) may be selected from optionally substituted C _1-30 alkyl, optionally substituted C _2-30 alkenyl, optionally substituted C _3-10 cycloalkyl, optionally substituted C _{3- 10} cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl. In one embodiment, X ² in formula (B) may be selected from halide, pseudohalide, -C(=O)Y, zinc halide, pseudozinc halide, and a third boron moiety selected from organoborane, boronic acid ester, boronic acid, trifluoroborate, N-coordinated boronate, boronate and boronamide.

[0013] In one embodiment, contacting a compound of formula (A) with a compound of formula (B) can be carried out in the presence of a first transition metal catalyst. In one embodiment, the first transition metal catalyst may be selected from a Pd catalyst and a Ni catalyst.

[0014] In one embodiment, contacting a compound of formula (A) with a compound of formula (B) can be carried out in the presence of a first transition metal catalyst and optionally a second transition metal catalyst. In one embodiment, the second transition metal catalyst may be selected from an Ir catalyst, a Cu catalyst, and a Ru catalyst. In one embodiment, when a second transition metal catalyst is present, either X ¹ in formula (A) or X ² in formula (B) can be -C(=O)Y.

[0015] In one embodiment, in which X ¹ in formula (A) and/or X ² in formula (B) may be -C(=O)Y, each Y may be independently selected from halide, optionally substituted heterocyclyl , optionally substituted heteroaryl, SR ⁶ , OR ⁶ , SM and OM. In one embodiment, each R ⁶ can be independently selected from hydrogen, optionally substituted C _1-30 alkyl, optionally substituted C _2-30 alkenyl, optionally substituted C _3-30 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl. In one embodiment, each M can be independently selected from a monovalent cation and a divalent cation.

[0016] These and other embodiments are described in more detail below.

GRAPHIC MATERIALS

[0017] In FIG. 1 shows the general scheme 1 for the preparation of compounds of formula (I).

DETAILED DESCRIPTION

Definitions

[0018] Unless otherwise defined, all technical and scientific terms used herein have the common meaning understood by a person skilled in the art. Unless otherwise noted, all patents, applications, published applications, and other publications referenced herein are incorporated herein by reference in their entirety. Unless otherwise noted, where there are multiple definitions for a term provided in this document, the definitions provided in this section shall prevail.

[0019] If a group is indicated to be "optionally substituted", said group may be unsubstituted or may be substituted with one or more of the indicated substituents. Similarly, if a group is said to be "unsubstituted or substituted" if it is substituted, the substituent(s) may be selected from one or more of the substituents indicated. If substituents are not indicated, this means that the specified "optionally substituted" or "substituted" group may be substituted by one or more group(s), individually and independently selected from D (deuterium), halogen, hydroxy, C _1-4 alkoxy, C _1-4 alkyl, C _3-10 cycloalkyl, aryl, heteroaryl, C _1-6 haloalkyl, cyano, alkenyl, alkynyl, C _3-10 cycloalkenyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl) , acyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-thioamido, N-thioamido, S-sulfonamido, N-sulfonamido, C-carboxy, O -carboxy, sulfenyl, sulfinyl, sulfonyl, haloalkoxy, amino, monosubstituted amino group and disubstituted amino group.

[0020] As used herein, the terms "C _a -C _b ", in which "a" and "b" are equal to integers, mean the number of carbon atoms in the group. The specified group may contain from "a" to "b" carbon atoms, inclusive. Thus, for example, the group "C ₁ -C ₄ alkyl" refers to all alkyl groups having from 1 to 4 carbon atoms, i.e. CH ₃ - CH ₃ CH ₂ -, CH ₃ CH ₂ CH ₂ -, (CH ₃ ) ₂ CH-, CH ₃ CH ₂ CH ₂ CH ₂ -, CH ₃ CH ₂ CH (CH ₃ ) - and (CH ₃ ) ₃ C-. If the designations "a" and "b" are absent, the widest range described in these definitions is assumed.

[0021] If two "R" groups are described as being "taken together", the R groups with the atoms to which they are attached can form cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycle. For example, without limitation, if it is indicated that R ^a and R ^b from the group NR ^a R ^b are "taken together", this means that they are covalently bonded either indirectly through intermediate atoms or directly to each other to form a ring, for example:

[0022] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, without limitation, isopropyl, sec-butyl, t-butyl, and the like. Examples of straight chain alkyl groups include, without limitation, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. The alkyl group may have from 1 to 30 carbon atoms (When referred to herein, a numerical range such as "1 to 30" refers to each integer in the given range; for example, "1 to 30 carbon atoms" means that an alkyl group may consist of 1 carbon, 2 carbons, 3 carbons, etc., up to and including 30 carbons, although the present definition also covers the reference to the term "alkyl" in which no numerical range is specified). The alkyl group may also be a medium sized alkyl having 1 to 12 carbon atoms. The alkyl group may also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group may be substituted or unsubstituted.

[0023] As used herein, the term "alkenyl" refers to a monovalent straight or branched chain hydrocarbon group containing one or more carbon-carbon double bonds. The alkenyl group may contain 2 to 30 carbon atoms, 2 to 12 carbon atoms, or 2 to 6 carbon atoms. Examples of alkenyl include, without limitation, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. The alkenyl group may be substituted or unsubstituted.

[0024] As used herein, the term "alkynyl" refers to a monovalent straight or branched chain hydrocarbon group containing one or more carbon-carbon triple bonds. The alkynyl group may contain 2 to 30 carbon atoms, 2 to 12 carbon atoms, or 2 to 6 carbon atoms. Examples of alkynyl include, without limitation, 1-propynyl, 1-butynyl, 2-butynyl, and the like. The alkynyl group may be substituted or unsubstituted.

[0025] As used herein, the term "cycloalkyl" refers to a fully saturated (no double or triple bonds) mono- or multicyclic hydrocarbon ring system. If the rings are composed of two or more rings, they may be joined together by condensation, bridge, or spiro coupling. Cycloalkyl groups may contain 3 to 30 ring(s), 3 to 20 ring(s), 3 to 10 ring(s), 3 to 8 ring(s) ) or 3 to 6 atoms in the ring(s). The cycloalkyl group may be substituted or unsubstituted.

. Примеры структур с конденсированными кольцами включают в себя, без ограничений, декагидронафталин, 1H-индол, хинолон, хроман, бицикло[2.1.0]пентан и 6,7,8,9-тетрагидро-5H-бензо[7]аннулен.[0026] As used herein, the term "fused" means a method of connection between two rings, in which two neighboring atoms and at least one bond (saturated or unsaturated) are common to the rings. For example, in the following structure, rings A and B are fused

. Examples of fused ring structures include, without limitation, decahydronaphthalene, 1H-indole, quinolone, chroman, bicyclo[2.1.0]pentane, and 6,7,8,9-tetrahydro-5H-benzo[7]annulene.

[0027] As used herein, the term "bridged" means a connection method in which three or more atoms are shared by two rings. The following structures: and are examples of "bridged" rings, since these atoms are common to at least two rings.

[0028] Examples of bridged ring structures include, without limitation, bicyclo[1.1.1]pentane, 2-oxabicyclo[1.1.1]pentane, 5-azabicyclo[2.1.1]hexane, 6-azabicyclo[ 3.1.1] heptane, adamantane and norbornane.

кольца С и D имеют спиросоединение. Примеры кольцевых структур со спиросоединением включают в себя, без ограничений, спиро[3.3]гептан, 2,6-диазаспиро[3.3]гептан, 2-окса-6-азаспиро[3.3]гептан, спиро[4.5]декан и 2,6-диоксаспиро[3.3]гептан.[0029] As used herein, the term "spiro" means a method of connection between two rings, in which the rings have only one common atom. For example, in the structure

rings C and D have a spiro compound. Examples of spiro ring structures include, without limitation, spiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, spiro[4.5]decane, and 2,6- dioxaspiro[3.3]heptane.

[0030] As used herein, the term "cycloalkenyl" refers to a mono- or multicyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; however, if there is more than one double bond, the double bonds cannot form a completely delocalized pi-electron system across all rings (otherwise the group will be "aryl" as defined herein). Cycloalkenyl groups may contain 3 to 30 ring(s), 3 to 20 ring(s), 3 to 10 ring(s), 3 to 8 ring(s) ) or 3 to 6 atoms in the ring(s). If the rings are composed of two or more rings, they may be joined together by condensation, bridge or spiro coupling. The cycloalkenyl group may be substituted or unsubstituted.

[0031] As used herein, the term "cycloalkynyl" refers to a mono- or multicyclic hydrocarbon ring system that contains one or more triple bonds in at least one ring, if more than one triple bond is present, the triple bonds cannot form a completely delocalized all rings a pi-electron system. Cycloalkynyl groups may have 8 to 30 ring(s), 8 to 20 ring(s) or 8 to 10 ring(s). If the rings are composed of two or more rings, they may be joined together by condensation, bridge, or spiro coupling. The cycloalkynyl group may be substituted or unsubstituted.

[0032] As used herein, the term "aryl" refers to a carbocyclic (containing only carbons) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a completely delocalized pi across all rings. - electronic system. The number of carbon atoms in the aryl group may vary. For example, the aryl group may be a C ₆ -C ₁₄ aryl group, a C ₆ -C ₁₀ aryl group, or a C ₆ aryl group. Examples of aryl groups include, without limitation, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0033] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, and tricyclic aromatic ring system (a ring system with a fully delocalized pi electron system) that contains one or more hetero atoms (e.g., 1, 2, 3, 4 or 5 hetero atoms), that is, elements other than carbon, including, without limitation, nitrogen, oxygen, and sulfur. The heteroaryl may be connected to the rest of the molecule and/or substituted through a carbon atom or a heteroatom such as a nitrogen atom. The number of atoms in the ring(s) with a heteroaryl group may vary. For example, a heteroaryl group may have 4 to 14 ring(s), 5 to 10 ring(s), or 5 to 6 ring(s). Moreover, the term "heteroaryl" includes fused ring systems. Examples of heteroaryl rings include, without limitation, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3- thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. The heteroaryl group may be substituted or unsubstituted.

[0034] As used herein, the terms “heterocyclyl” or “heteroalicyclyl” refer to three-, four-, five-, six-, seven-, eight-, nine-, ten- and up to 18-membered monocyclic, bicyclic and tricyclic ring systems in which carbon atoms together with 1-5 heteroatoms constitute said ring system. The heterocycle may optionally contain one or more unsaturated bonds, which, however, are arranged in such a way that a completely delocalized pi-electron system does not extend to all rings. A heteroatom(s) is(are) an element(s) other than carbon, including, without limitation, oxygen, sulfur, and nitrogen. The heterocyclyl may be linked to the rest of the molecule and/or substituted via a carbon atom or a heteroatom such as a nitrogen atom. The heterocycle may further contain one or more carbonyl or thiocarbonyl functional groups, so that the definition includes oxo systems and thio systems such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. If the rings are composed of two or more rings, they may be joined together by condensation, bridge, or spiro coupling. In addition, any nitrogen atoms in the heteroalicyclyl may be quaternized. Heterocyclyl or heteroalicyclic groups may be substituted or unsubstituted. Examples of such "heterocyclyl" or "heteroalicyclyl" groups include, without limitation, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4 -dioxolane, 1,3-oxatian, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxatian, tetrahydro-1,4-thiazine, 2H-1 ,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxpiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine , morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfonated and their condensed benzenes analogues (eg benzimidazolidinone, tetrahydroquinoline and/or 3,4-methylenedioxyphenyl). Examples of bridged heterocyclic compounds include, without limitation, 1,4-diazabicyclo[2.2.2]octane and 1,4-diazabicyclo[3.1.1]heptane. Examples of heterocyclic compounds with a spiro compound include, without limitation, 2-azaspiro[3,3]heptane, 2,6-diazaspiro[3,3]heptane, and 2-oxa-6-azaspiro[3,3]heptane.

[0035] As used herein, the terms "aralkyl" and "aryl(alkyl)" refer to an aryl group attached as a substituent via a lower alkylene group. The lower alkylene and aryl group of the aralkyl may be substituted or unsubstituted. Examples include, without limitation, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0036] As used herein, the terms "heteroaralkyl" and "heteroaryl(alkyl)" refer to a heteroaryl group attached as a substituent via a lower alkylene group. The lower alkylene and heteroaryl group of the heteroalkyl may be substituted or unsubstituted. Examples include, without limitation, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and their benzofused analogs.

[0037] The terms "heteroalicyclyl(alkyl)" and "heterocyclyl(alkyl)" refer to a heterocyclic or heteroalicyclic group attached as a substituent via a lower alkylene group. The lower alkylene group and heterocyclyl (heteroalicyclyl) alkyl may be substituted or unsubstituted. Examples include, without limitation, tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl ) and 1,3-thiazinan-4-yl(methyl).

).[0038] The term "lower alkylene groups" refers to linear -CH ₂ - connecting groups that form bonds to attach molecular fragments via their terminal carbon atoms. Examples include, without limitation, methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -) and butylene (-CH ₂ CH ₂ CH ₂ CH ₂ - ). The lower alkylene group may be substituted by replacing one or more hydrogen atoms of the lower alkylene group and/or replacing both hydrogen atoms on one carbon atom with a cycloalkyl group (e.g.,

).

[0039] As used herein, the term "hydroxy" refers to the -OH group.

[0040] As used herein, the term "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl( alkyl) or heterocyclyl (alkyl) as defined herein. The non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, t-butoxy, phenoxy and benzoxy. Alkoxy may be substituted or unsubstituted.

[0041] As used herein, the term "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), and heterocyclyl(alkyl) substituted via a carbonyl group. . Examples include formyl, acetyl, propanoyl, benzoyl, and acrylic. The acyl may be substituted or unsubstituted.

[0042] The term "cyano" group refers to the -CN group.

[0043] As used herein, the term "halogen atom" or "halogen" means any of the radiostable atoms of Group 7 of the Periodic Table of the Elements, such as fluorine, chlorine, bromine, and iodine.

[0044] The term "thiocarbonyl" group refers to a -C(=S)R group in which R may be the same as defined with respect to O-carboxy. The thiocarbonyl may be substituted or unsubstituted.

[0045] The term "O-carbamyl" group refers to the group "-OC(=O)N(R _A R _B )", in which R _A and R _B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). O-carbamyl may be substituted or unsubstituted.

[0046] The term "N-carbamyl" group refers to the group "ROC(=O)N(R _A )-", in which R and R _A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl , heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The N-carbamyl may be substituted or unsubstituted.

[0047] The term "O-thiocarbamyl" group refers to the group "-OC(=S)-N(R _A R _B )", in which R _A and R _B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl , cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-thiocarbamyl may be substituted or unsubstituted.

[0048] The term "N-thiocarbamyl" group refers to the group "ROC(=S)N(R _A )-", in which R and R _A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl , heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The N-thiocarbamyl may be substituted or unsubstituted.

[0049] The term "C-amido" group refers to the group "-C(=O)N(R _A R _B )", in which R _A and R _B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). C-amido may be substituted or unsubstituted.

[0050] The term "N-amido" group refers to the group "RC(=O)N(R _A )-", in which R and R _A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl , heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The N-amido may be substituted or unsubstituted.

[0051] The term "C-thioamido" group refers to the group "-C(=O)N(R _A R _B )", in which R _A and R _B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). C-thioamido may be substituted or unsubstituted.

[0052] The term "N-thioamido" group refers to the group "RC(=S)N(R _A )-", in which R and R _A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl , heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The N-thioamido may be substituted or unsubstituted.

[0053] The term "S-sulfonamido" group refers to the group "-SO ₂ N(R _A R _B )", in which R _A and R _B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl , heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The S-sulfonamido may be substituted or unsubstituted.

[0054] The term "N-sulfonamido" group refers to the group "RSO ₂ N(R _A )-" in which R and R _A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The N-sulfonamido may be substituted or unsubstituted.

[0055] The term "O-carboxy" group refers to the group "RC(=O)O-" in which R can be hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. O-carboxy may be substituted or unsubstituted.

[0056] The terms "ester" and "C-carboxy" refer to the group "-C(=O)OR" in which R may be the same as defined with respect to O-carboxy. The ester and C-carboxy may be substituted or unsubstituted.

[0057] The term "oxo" group refers to the group "=O".

[0058] The term "sulfenyl" group refers to the group "-SR" in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The sulfenyl may be substituted or unsubstituted.

[0059] The term "sulfinyl" group refers to the group "-S(=O)-R" in which R may be the same as defined with respect to sulfenyl. The sulfinyl may be substituted or unsubstituted.

[0060] The term "sulfonyl" group refers to the group "SO ₂ R", in which R may be the same as defined with respect to sulfenyl. The sulfonyl may be substituted or unsubstituted.

[0061] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by a halogen (eg, monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, without limitation, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. The haloalkyl may be substituted or unsubstituted.

[0062] As used herein, the term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms have been replaced by a halogen (eg, monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, without limitation, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. The haloalkoxy may be substituted or unsubstituted.

[0063] As used herein, the term "amino" refers to a -NH ₂ group.

[0064] The term "mono-substituted amino group" refers to the group "-NHR", in which R can be alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) as defined herein. The monosubstituted amino group may be substituted or unsubstituted. Examples of monosubstituted amino groups include, without limitation, -NH(methyl), -NH(phenyl) and the like.

[0065] The term "disubstituted amino group" refers to the group "-NR _A R _B ", in which R _A and R _B can independently represent alkyl, alkenyl, alkynyl, haloalkyl cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl ), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. The disubstituted amino group may be substituted or unsubstituted. Examples of disubstituted amino groups include, without limitation, -NH(methyl) ₂ , -N(phenyl)(methyl), -N(ethyl)(methyl), and the like.

[0066] As used herein, the term "contacting" is a broad term that refers to the act of causing a chemical reaction by which the molecular and/or ionic structure of a substance and/or substances is rearranged. The term "contacting" includes placing a molecule in an environment that results in a chemical transformation and/or changing the environment around the compound so as to result in a chemical transformation. Such contacting actions involve bringing together two or more compounds that react chemically with each other, either directly or through intermediate compounds. The term "contacting" can also refer to the occurrence of chemical transformations of intermediates arising from molecules that have been placed in a certain environment.

[0067] As used herein, the term "ligand" is a broad term that refers to a compound that is bonded or capable of bonding to a metal or semimetal atom. A ligand can bond to a metal or semimetal atom via bonding or nonbonding electrons. The ligand molecule may include one or more atoms. A ligand-bound metal or semi-metal is a metal that is coordinated by a ligand. Examples of ligands can be found in "Organotransition Metal Chemistry - From Bonding to Catalysis" by John Hartwig (University Science Books, 2010).

[0068] As used herein, the term "pseudohalide" is a broad term that refers to a moiety capable of undergoing a reaction characteristic of a halide. For example, the pseudohalide may be a sulfonate, phosphate, cyanide, azide, isocyanate, thioisocyanate, or a quaternary nitrogen moiety. When the pseudohalide is a sulfonate, it may be, for example, triflate, mesylate, tosylate, nitrophenylsulfonate, bromophenylsulfonate or benzenesulfonate.

[0069] When the number of substituents is not specified (eg, in haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C ₁ -C ₃ alkoxyphenyl" may include one or more of the same or different alkoxy groups containing one, two or three atoms.

[0070] As used herein, the term "free radical" refers to a particle containing an unpaired electron, or to an unpaired electron in such a particle.

[0071] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation in the organism into which it is administered and does not interfere with the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by contacting the compound with inorganic acids such as hydrohalic acids (eg hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by contacting the compound with an organic acid, such as aliphatic or aromatic carboxylic or sulfonic acids, for example, formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, trifluoroacetic, benzoic, salicylic, 2-oxo-pentanedioic or naphthalenesulfonic acid. Pharmaceutical salts can also be prepared by contacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt, an alkaline earth metal salt such as a calcium or magnesium salt, a carbonate salt, a bicarbonate salt, salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C ₁ -C ₇ alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and amino acid salts such as arginine and lysine. With respect to compounds of formula (I), those skilled in the art will appreciate that when a salt is formed by protonation of a nitrogen-containing group (eg, NH ₂ ), the nitrogen-containing group may be associated with a positive charge (eg, NH ₂ may become NHH ₃ ⁺ ), and the positive charge can be balanced by a negatively charged counterion (such as Cl ^- ).

[0072] It should be understood that in any compound described herein having one or more chiral centers, each center may independently have an R-configuration, or an S-configuration, or a mixture thereof, unless the absolute stoichiometry is explicitly stated. Therefore, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, may be a racemic mixture, may be diastereomeric pure, diastereomeric enriched, or may be a mixture of stereoisomers. In addition, it should be understood that in any compound described herein having one or more double bonds, creating geometric isomers that can be denoted as E or Z, each double bond can independently be E or Z, or a mixture thereof.

[0073] It should be understood that any compound described is also intended to include all tautomeric forms. For example, the following structures are tautomers:

[0074] It should be understood that where compounds disclosed herein have unfilled valences, said valences should be filled with hydrogen atoms or isotopes thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0075] It should be understood that the compounds described herein may be isotopically labeled compounds. Substitution with isotopes such as deuterium may provide some treatment advantages due to greater metabolic stability, such as, for example, a longer in vivo half-life or a reduced required dose. Each chemical element present in the structure of a compound can include any isotope of the specified element. For example, a hydrogen atom may be explicitly disclosed in a compound structure, or its presence in a compound structure may be implied. At any position on the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, reference herein to a compound includes all potential isotopic forms unless the context clearly dictates otherwise.

[0076] It should be understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystalline ways of packing the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and may be formed by crystallization with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein may exist in unsolvated and solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present compounds and methods.

[0077] If a range of values is proposed, it should be understood that the upper and lower limits, as well as any intermediate value between the upper and lower limits, are included in the embodiments.

[0078] The terms and phrases used in this application, as well as their variations, in particular in the attached claims, unless expressly stated otherwise, should be considered non-limiting and not having a restrictive nature. As examples of the foregoing, the term "including" should be read as "including without limitation", "including but not limited to", or the like; as used herein, the term "comprising" is synonymous with the terms "including", "comprising" or "characterized" and is inclusive or non-limiting, and does not exclude additional unspecified elements or method steps; the term "having" should be interpreted as "having at least"; the term "comprises" should be interpreted as "includes, without limitation"; the term "example" is used to provide examples of implementation of an element in the description, but is not exhaustive or limiting their list; and the use of terms such as "preferred", "preferred", "desired" or "desired" or similar words should not be understood as suggesting that certain features are critical, essential, or even important to structure or function. , but are intended to highlight alternative or additional features that may or may not be used in a particular embodiment. In addition, the term "comprising" should be interpreted as synonymous with the phrases "having at least" or "comprising at least". In the context of the method, the term "comprising" means that the method includes at least these steps, but may include additional steps. In the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the indicated features or components, but may include additional features or components. Similarly, a group of elements connected by the conjunction "and" should not be interpreted as requiring the mandatory presence of all and each of the elements in the group, but should be interpreted as "and/or", unless otherwise indicated in the context. Likewise, a group of elements linked by "or" should not be interpreted as requiring mutual exclusivity of the elements in the group, but should be interpreted as "and/or" unless otherwise indicated in the context.

[0079] With respect to the use of essentially any plural and/or singular variants for terms herein, those skilled in the art may change plural to singular and/or singular to plural as required by the context and/or scope. In this document, the various permutations of the singular/plural may be stated explicitly for the sake of clarity. The use of the singular does not exclude plurality. One processor or other block can perform the functions of several elements specified in the claims. The mere fact that certain indicators are indicated in mutually different dependent claims does not indicate that a combination of these indicators cannot be used if necessary. Any reference designations in the claims should not be considered as limiting the scope.

[0080] As presented herein, the term "coupling" is the formation of a sigma bond between two atoms, for example, between two carbon atoms. Each bonded atom is necessarily a component of a fragment, and each fragment is necessarily a component of a molecule. Linked fragments can be constituents of one molecule or two different molecules.

[0081] As provided herein, a cross-coupling reaction catalyst is a transition metal complex (comprising one or more ligands) that can, under appropriate conditions, cause a coupling reaction between two different moieties.

[0082] As provided herein, a photochemical redox catalyst is a transition metal complex (comprising one or more ligands) that can, upon irradiation and other suitable conditions, form a free radical by oxidizing or reducing a moiety.

Processes

[0083] Various embodiments provide a process for preparing a substituted bicyclo[1,1,1]pentane of formula (I) having the following structure:

[0084] In one embodiment, the bond between R ² and bicyclo[1,1,1]pentane in the compound of formula (I) is a carbon-carbon bond.

[0085] In one embodiment, a method for preparing a compound of formula (I) comprises contacting a compound of formula (A) with a compound of formula (B), as illustrated in FIG. 1. In one embodiment, contacting a compound of formula (A) with a compound of formula (B) is carried out in the presence of a first transition metal catalyst, optionally a second transition metal catalyst, and optionally a base under the conditions chosen to form the compound of formula (I) . In one embodiment, the compound of formula (B) may be R ² -X ² . In one embodiment, the compound of formula (A) has the structure:

[0086] In various embodiments, the variable R ¹ in compounds of formula (I) and/or formula (A) may be hydrogen, optionally substituted C _1-30 alkyl, optionally substituted C _2-30 alkenyl, optionally substituted C _{3- 10} monocyclic cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, halogen, optionally substituted C-carboxy, amino, monosubstituted amino, disubstituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted C _1-30 alkoxy, hydroxy, optionally substituted C _1-30 haloalkyl, cyano, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted O-carboxy, optionally substituted C _2-30 alkynyl, optionally substituted C _3-10 cycloalkenyl, optionally substituted aryl(alkyl), optionally substituted heteroaryl(alkyl), optionally substituted heterocyclyl(alkyl), optionally substituted further acyl, optionally substituted thiocarbonyl, optionally substituted O-carbamyl, optionally substituted N-carbamyl, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted C-thioamido, optionally substituted N-thioamido, optionally substituted sulfenyl, optionally substituted sulfinyl , an optionally substituted sulfonyl, an optionally substituted haloalkoxy, or a first boron moiety, the first boron moiety being linked via a boron atom. In some embodiments, the variable R ¹ in compounds of formula (I) and/or formula (A) may be hydrogen, optionally substituted C _1-30 alkyl, optionally substituted C _2-30 alkenyl, optionally substituted C _3-10 monocyclic cycloalkyl , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, halogen, amino, monosubstituted amino, disubstituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted C _1-30 alkoxy, hydroxy, optionally substituted C _{1- 30} haloalkyl, cyano, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted O-carboxy, optionally substituted _C2-30 alkynyl, optionally substituted _C3-10 cycloalkenyl, optionally substituted aryl(alkyl), optionally substituted heteroaryl( alkyl), optionally substituted heterocyclyl (alkyl), optionally substituted acyl, optionally substituted ti ocarbonyl, optionally substituted O-carbamyl, optionally substituted N-carbamyl, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted C-thioamido, optionally substituted N-thioamido, optionally substituted sulfenyl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted haloalkoxy or a first boron moiety, wherein the first boron moiety is bonded via a boron atom; For example, in one embodiment, the first boron moiety can be an organoborane, boronic acid ester, boronic acid, trifluoroborate, N-coordinated boronate, boronate, or boronamide.

В различных вариантах осуществления X¹ может представлять собой сульфонат или галогенид, выбранный из хлорида, бромида или йодида. В различных вариантах осуществления, переменная X¹ в соединениях формулы (А) может представлять собой второй борсодержащий фрагмент, такой как таковые, которые описаны в настоящем документе. Преимущество способов, описанных в настоящем документе, состоит в том, что X¹ не нужно превращать в активированный сложный эфир (например, -С(=O)O (алкил)) для проведения реакции и обеспечения хороших выходов продукта, такого как соединение формулы (I). Например, когда второй катализатор на основе переходного металла представляет собой фотохимический окислительно-восстановительный катализатор, X¹ может представлять собой карбоновую кислоту (-С(=O)ОН) и подвергаться реакции и обеспечивать хорошие выходы продукта, такого как соединение формулы (I).[0087] In various embodiments, the variable X ¹ in the compounds of formula (A) may be a halide, pseudohalide, -C(=O)Y, or a second boron moiety. In some embodiments, the second boron moiety may be an organoborane, boronic acid ester, boronic acid, trifluoroborate, N-coordinated boronate, boronate, or boronamide. In some embodiments, each Y can independently be a halide, optionally substituted heterocyclyl, optionally substituted heteroaryl, SR ⁶ , OR ⁶ , SM, or OM. In one embodiment, each R ⁶ may independently be hydrogen, optionally substituted C _1-30 alkyl, optionally substituted C _2-30 alkenyl, optionally substituted C _3-30 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl. In one embodiment, each M can independently be a monovalent cation (eg Li ⁺ , Na ⁺ , K ⁺ or NH ₄ ⁺ ) or a divalent cation (eg Mg ²⁺ or Ca ²⁺ ). In some embodiments, the variable X ¹ in the compounds of formula (A) may be -C(=O)OR ⁶ . In some embodiments, Y may be OR ⁶ and R ⁶ may be hydrogen. In other embodiments, Y may be OR ⁶ and R ⁶ may be unsubstituted C _1-30 alkyl. In other embodiments, Y may be OR ⁶ and R ⁶ may be unsubstituted C _1-4 alkyl. In other embodiments, Y may be OR ⁶ and R ⁶ may be an optionally substituted heterocyclyl. In variants of these embodiments, the heterocyclyl may have the structure

In various embodiments, X ¹ may be a sulfonate or a halide selected from chloride, bromide, or iodide. In various embodiments, the variable X ¹ in the compounds of formula (A) may be a second boron moiety, such as those described herein. The advantage of the methods described herein is that X ¹ does not need to be converted to an activated ester (e.g. -C(=O)O(alkyl)) in order to carry out the reaction and provide good yields of the product, such as the compound of formula ( I). For example, when the second transition metal catalyst is a photochemical redox catalyst, X ¹ may be a carboxylic acid (-C(=O)OH) and react and provide good product yields such as a compound of formula (I).

[0088] In some embodiments, X ¹ cannot be a halide or pseudohalide. In some other embodiments, X ¹ may not be a boron moiety. In other embodiments, X ¹ cannot be -C(=O) Y. In other embodiments, X ¹ cannot be -C(=O)O (unsubstituted C _1-4 alkyl), such as -C(= O) DOS ₃ .

[0089] In some embodiments, R ² may be optionally substituted C _1-30 alkyl, optionally substituted C _2-30 alkenyl, optionally substituted C _3-10 cycloalkyl, optionally substituted C _3-10 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl; or optionally substituted heterocyclyl. In some embodiments, R ² may be an optionally substituted C _2-30 alkenyl, an optionally substituted C _3-10 cycloalkenyl, or an optionally substituted aryl. In various embodiments, aryl may be monosubstituted phenyl, disubstituted phenyl, trisubstituted phenyl, ortho-substituted phenyl, meta-substituted phenyl, or para-substituted phenyl. In other embodiments, R ² may be an optionally substituted heteroaryl, such as an optionally substituted 5- or 6-membered monocyclic heteroaryl, an optionally substituted 9- or 10-membered bicyclic heteroaryl. When substituted, heteroaryl R ² may be substituted with one substituent. Heteroaryl R ² may also be substituted with multiple substituents. Possible substituents that may be present on the substituted R ² group are referred to herein as "optionally substituted". In some embodiments, R ² may be substituted when the substituent may be selected from halogen, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 haloalkyl, unsubstituted C _1-4 haloalkoxy, unsubstituted mono- substituted amino, unsubstituted disubstituted amino, cyano, nitro, optionally substituted sulfenyl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl. In other embodiments, R ² may be an optionally substituted (E)-C _2-30 alkenyl or an optionally substituted (Z)-C _2-30 alkenyl. In still other embodiments, R ² cannot contain a heteroatom in the alpha (α) position. The R ² substitution described in this paragraph is independent of the X ² substitution.

[0090] In some embodiments, X ² may be a halide, pseudohalide, -C(=O)Y, zinc halide, pseudozinc halide, or a third boron moiety. In one embodiment, the third boron moiety can be an organoborane, boronic acid ester, boronic acid, trifluoroborate, N-coordinated boronate, boronate, or boronamide. In some embodiments, when R ² is alkyl, X ² cannot be halide or pseudohalide. In some other embodiments, at least one of X ¹ and X ² cannot be a halide or pseudohalide. In various embodiments, the bond between R ² and X ² may be an sp ² carbon-heteroatom bond.

[0091] In some embodiments, the first transition metal catalyst may be a Pd catalyst or a Ni catalyst. In some embodiments, when the first transition metal catalyst is a Pd catalyst, there is no second transition metal catalyst.

[0092] In some embodiments, the second transition metal catalyst may be an Ir catalyst, a Cu catalyst, or a Ru catalyst. In some embodiments, when a second transition metal catalyst is present, the second transition metal catalyst may be an Ir catalyst, the first transition metal catalyst may be a Ni catalyst, X ¹ may be -C(=O)Y, and X ² may be a halide or a pseudohalide.

[0093] In some embodiments, at least one of X ¹ and X ² cannot be a boron moiety.

[0094] In some embodiments, provided that a second transition metal catalyst is present, then either X ¹ or X ² is -C(=O)Y.

[0095] In some embodiments, the first transition metal catalyst may be a cross-coupling reaction catalyst. In various embodiments, the cross-coupling catalyst may be a Suzuki coupling catalyst or a Negishi coupling catalyst. In some embodiments, the first transition metal catalyst is selected to undergo oxidative addition to a compound of formula (A) and/or a compound of formula (B). In one embodiment, the first transition metal catalyst is not an iron (Fe) catalyst that contains an Fe atom.

[0096] In some embodiments, the first transition metal catalyst may be a Pd catalyst that contains a Pd atom. In embodiments of these embodiments, the Pd atom may be bonded to the ligand with one or more halides, sulfonates, carboxylates, phosphines, imines, aromatic N (eg, pyridine), alkenes, amines, nitriles, carbanions, or carbenes. In further embodiments, the Pd catalyst may include a Pd(0) atom. In further embodiments, the Pd catalyst may include a Pd(II) atom. In some embodiments, the implementation of the Pd atom may be associated with the ligand bidentate fragment. In some additional embodiments, the implementation of the Pd atom may be associated with the ligand tridentate fragment.

[0097] In some embodiments, the Pd catalyst may be a catalyst as described elsewhere in this document. In some embodiments, the Pd catalyst may be Pd(PPh ₃ ) ₄ .

[0098] In some embodiments, the first transition metal catalyst may be a Ni catalyst containing a Ni atom. In embodiments of these embodiments, the Ni atom may be bonded to one or more of halides, sulfonates, carboxylates, phosphines, N-aromatized imines, alkenes, amines, nitriles, carbanions, or carbenes. In additional embodiments, the implementation of the Ni catalyst may contain a Ni atom (0). In further embodiments, the Ni catalyst may contain a Ni(II) atom. In some embodiments, the Ni atom may be a ligand-bound bidentate moiety. In some additional embodiments, the Ni atom may be a ligand-bound tridentate moiety.

[0099] In some embodiments, the Ni catalyst may be a catalyst as described elsewhere in this document. In some embodiments, the Ni catalyst may be NiCl ₂ ·dimethoxyethane.

[0100] In some embodiments, the second transition metal catalyst may be a photochemical redox catalyst. In one embodiment, the second transition metal catalyst is not an iron (Fe) containing catalyst that contains an Fe atom.

[0101] In some embodiments, the second transition metal catalyst may be a Ru catalyst containing a Ru atom. In embodiments of these embodiments, the Ru atom may be ligand-bound one or more of halides, sulfonates, carboxylates, phosphines, imines, aromatic N (eg, pyridine), alkenes, amines, nitriles, carbanions, or carbenes. In other embodiments, the Ru atom may be a ligand-bound bidentate moiety, such as bipyridine (bpy) or a derivative thereof. In some embodiments, the implementation of the Ru catalyst may be a catalyst, as described in another paragraph of this document.

[0102] In some embodiments, the second transition metal catalyst may be an Ir catalyst containing an Ir atom. In embodiments of these embodiments, the Ir atom may be ligand-linked one or more of halides, sulfonates, carboxylates, phosphines, imines, aromatic N (eg, pyridine), alkenes, amines, nitriles, carbanions, or carbenes. In other embodiments, the Ir atom may be a ligand-bound bidentate moiety, such as bipyridine (bpy) or a derivative thereof. In some embodiments, the Ir catalyst may be a catalyst as described in another paragraph herein. In some embodiments, the Ir catalyst may be [Ir{dF(CF ₃ )ppy} ₂ (dtbpy)]PF ₆ .

[0103] In some embodiments, the second transition metal catalyst may be a Cu catalyst containing a Cu atom.

[0104] In some embodiments, the compound of formula (A) may have the structure:

или 8-членный гетероциклил, такой как

В некоторых вариантах осуществления каждый R^1A и R^1B могут представлять собой водород. В некоторых вариантах осуществления каждый R^1C может независимо представлять собой водород, необязательно замещенный C_1-30 алкил или необязательно замещенный С_3-10 циклоалкил.[0105] In some embodiments, R ^1A and R ^1B can independently be hydrogen, optionally substituted C _1-30 alkyl, or optionally substituted C _3-10 cycloalkyl. In other embodiments, OR ^1A , OR ^1B and the boron atom to which they are attached can be taken together to form an optionally substituted heterocyclyl. For example, OR ^1A , OR ^1B and a boron atom can form an optionally substituted 5-membered heterocyclyl such as

or an 8-membered heterocyclyl such as

In some embodiments, each R ^1A and R ^1B may be hydrogen. In some embodiments, each R ^1C may independently be hydrogen, optionally substituted C _1-30 alkyl, or optionally substituted C _3-10 cycloalkyl.

[0106] In some embodiments, R ^2A and R ^2B can independently be hydrogen or optionally substituted C _1-30 alkyl. In other embodiments, OR ^2A , OR ^2B and the boron atom to which they are attached can be taken together to form an optionally substituted heterocyclyl. For example, OR ^2A , OR ^2B and a boron atom can form an optionally substituted 5-membered heterocyclyl such as

[0107] In some embodiments, R ^3A and R ^3B may independently be optionally substituted C _1-30 alkyl, optionally substituted C _3-10 cycloalkyl, amine, arylamine, or alkylamine. In other embodiments, R ^3A , R ^3B and the boron atom to which they are attached can be taken together to form an optionally substituted heterocyclyl.

[0108] In some embodiments, R ^4A and R ^4B can independently be optionally substituted C _1-30 alkyl, optionally substituted C _3-10 cycloalkyl, amine, arylamine, or alkylamine. In other embodiments, R ^4A , R ^4B and the boron atom to which they are attached can be taken together to form an optionally substituted heterocyclyl.

[0109] In some embodiments, R ^5A and R ^5B may independently be optionally substituted C _1-30 alkyl, optionally substituted C _3-10 cycloalkyl, amine, arylamine, or alkylamine. In other embodiments, R ^5A , R ^5B and the boron atom to which they are attached can be taken together to form an optionally substituted heterocyclyl.

[0110] In some embodiments, X ¹ may be a halide, such as chloride, bromide, or iodide.

[0111] In some embodiments, X ¹ may be a pseudohalide, such as a sulfonate, phosphate, cyanide, azide, isocyanate, thioisocyanate, or a quaternary nitrogen moiety. In embodiments of these embodiments, X ¹ may be a sulfonate, such as triflate, mesylate, tosylate, nitrophenylsulfonate, bromophenylsulfonate, or benzenesulfonate.

[0112] In some embodiments, X ² may be a halide, such as chloride, bromide, or iodide.

[0113] In some embodiments, X ² may be zinc halide or zinc pseudohalide, such as zinc chloride or zinc bromide. In some embodiments, when X ² is a zinc halide or pseudo zinc halide, the first transition metal catalyst may be a Negishi coupling catalyst. In other embodiments, X ² may be magnesium halide or magnesium pseudohalide, such as magnesium chloride or magnesium bromide.

[0114] In some embodiments, R ¹ may be hydrogen. In other embodiments, X ¹ may be an optionally substituted aryl, such as unsubstituted or substituted phenyl. In some embodiments, X ¹ may be a monosubstituted phenyl. Possible substituents that may be present on a monosubstituted phenyl are referred to herein as "optionally substituted". In some embodiments, R ¹ may be monosubstituted phenyl, wherein the substitution may be selected from halo, hydroxy, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 haloalkyl, unsubstituted C _1-4 haloalkoxy , unsubstituted monosubstituted amino, unsubstituted disubstituted amino, cyano, nitro, optionally substituted sulfenyl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl. In other embodiments, R ¹ may be an optionally substituted heteroaryl. For example, R ¹ may be unsubstituted or substituted monocyclic heteroaryl or unsubstituted or substituted bicyclic heteroaryl. In some embodiments, R ¹ may be an optionally substituted 5- or 6-membered monocyclic heteroaryl. In other embodiments, R ¹ may be an optionally substituted 9- or 10-membered bicyclic heteroaryl. When substituting heteroaryl R ¹ may be monosubstituted. Heteroaryl R ¹ may also be substituted with multiple substituents. Possible substituents that may be present in the substituted heteroaryl R ¹ are presented herein as "optionally substituted". In some embodiments, R ¹ may be monosubstituted heteroaryl, wherein the substitution may be selected from halo, hydroxy, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 haloalkyl, unsubstituted C _1-4 haloalkoxy , unsubstituted monosubstituted amino, unsubstituted disubstituted amino, cyano, nitro, optionally substituted sulfenyl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl. In yet other embodiments, R ¹ may be a first boron moiety, wherein the first boron moiety is linked via boron. Examples of the first boron-containing fragments are described in more detail herein. In some embodiments, R ¹ may be an optionally substituted C-carboxy, such as an optionally substituted -C(=O)-O- (optionally substituted heteroaryl). In other embodiments, R ¹ may be an optionally substituted N-carbamyl. For example, R ¹ may be -NH(C=O))O- (C _1-4 alkyl).

[0115] In some embodiments, R ¹ may be a first boron moiety, wherein the first boron moiety is linked via boron; and X ¹ may be a second boron moiety, such as described herein. In other embodiments, R ¹ may be an optionally substituted aryl or an optionally substituted heteroaryl; and X ¹ may be -C(=O)Y such as -C(=O)OR ⁶ (eg -C(=O)OH). In other embodiments, R ¹ may be an optionally substituted aryl or an optionally substituted heteroaryl; and X ¹ may be a second boron moiety. In other embodiments, R ¹ may be an optionally substituted C-carboxy; and X ¹ may be -C(=O)Y such as -C(=O)OR ⁶ (eg -C(=O)OH). As described herein, X ¹ may be -C(=O)OH or -C(=O)O (unsubstituted C _1-4 alkyl).

[0116] In some embodiments, contacting a compound of formula (A) with a compound of formula (B) to form a compound of formula (I) may occur in the presence of a ligand. In embodiments of these embodiments, the ligand may be A-caPhos, a-taPhos, Binap, BIPHEP, BippyPhos, Ad-BrettPhos, ditBuBrettPhos, BrettPhos, CataCXcium POMeCy, CataCXcium PtB, CataCXium PiCy, CataCXium FBn, CataCXium PCy, CataCXium PInCy . DCyPF, DiPPF, di-tBu-neopentylphosphonium HBF ₄ , DPEPhos, DPPBz, DPPE, DPPF, DtBPF, DTP-DPEPhos, JackiePhos, JohnPhos, Me4XPhos, Me4t-BuXPhos, MeDalPhos, MePhos, MorDalPhos, N-dicyclohexylphosphino-2-(2 '-methylphenyl)-1H-indole, XantPhos, PCy ₃ HBF ₄ , P(o-OMePh) ₃ , PPh ₃ , PtBu ₃ HBF ₄ , PXy ₃ , QPhos, PhDavePhos, RockPhos, RuPhos, SL-J003-1, SL -J009-1, SPhos, SPhos-SO ₃ Na, SymPhos, tBuBiNap, tBuDavePhos, tBuMePhos, tBuXantPhos, tBuXPhos, TrixiePhos, XantPhos, XPhos, XPhos-SO ₃ Na, Me ₃ P HBF ₄ , Et ₃ P HBF ₄ , xylBinap, Cy-cBRIDP, AmindolePhos, NPCy o-Andole-Phos, NPCy Phendole-Phos, cBRIDP, vBRIDP, CyvBRIDP, CM-Phos, KitPhos, 4,4'-di-tert-butyl-2,2 '-dipyridyl (bbbpy), 2,2'-bipyridyl, 4,4'-dimethoxy-2,2'-bipyridyl, 2,2'-biquinoline, bathophenanthroline, s-BuPyBox, neocuproin, trans-2-aminocyclohexanol and their combinations. In some embodiments, the ligand may be bbbpy.

[0117] In some embodiments, contacting a compound of formula (A) with a compound of formula (B) to form a compound of formula (I) may occur in the presence of a precatalyst. In embodiments of these embodiments, the precatalyst can be 3rd generation XantPhos, 3rd generation tBuXPhos, 3rd generation CPhos, 3rd generation APhos, 3rd generation phosphadamantane, 3rd generation XPhos, 3rd generation RuPhos , JackiePhos 3rd gen, BrettPhos 1st gen, ditBuXPhos 1st gen, RuPhos 1st gen, SPhos 1st gen, XPhos 1st gen, RuPhos 2nd gen, SPhos 2nd gen, XPhos 2nd generation, OMs Pd dimer, or combinations thereof.

[0118] In some embodiments, contacting a compound of formula (A) with a compound of formula (B) to form a compound of formula (I) may occur in the presence of a base. In some embodiments, the base may be a metal hydroxide base, a metal carbonate base, a metal bicarbonate base, an amine base, a metal fluoride base, a metal alkoxide base, a metal carbonate base, or a metal phosphate base. In variants of these embodiments, the base may be a base as described in another paragraph herein.

[0119] In some embodiments, the variable M in describing Y and X ¹ may be a monovalent cation, such as Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ , or a quaternary nitrogen atom. In other embodiments, M may be a divalent cation, such as Mg ⁺² , Ca ⁺² , Sr ⁺² , or Ba ⁺² .

[0120] In some embodiments, each R ⁶ may independently be hydrogen or C _1-4 alkyl. In some embodiments, R ⁶ may be hydrogen

[0121] In some embodiments, contacting a compound of formula (A) with a compound of formula (B) to form a compound of formula (I) may occur in the presence of visible light. In additional embodiments, when the second transition metal catalyst is present as a photochemical redox catalyst, such contacting may occur in the presence of visible light.

[0122] In some embodiments, the compound of formula (I) can be obtained as a salt.

[0123] In some embodiments, the molar ratio of the compound of formula (A) to the compound of formula (B) may be from about 0.1:1 to about 10:1, the base may be a metal alkoxide base, the first transition metal catalyst may be a Pd catalyst. In some embodiments of the reaction, X ¹ may be a second boron moiety selected from organoborane, boronic acid ester, boronic acid, trifluoroborate, N-coordinated boronate, boronate, or boronamide. In some embodiments of the reaction, X ¹ may be a halide selected from chloride, bromide, and iodide.

[0124] In some embodiments, the molar ratio of a compound of formula (A) to a compound of formula (B) when brought into contact to form a compound of formula (I) may range from about 0.1:1 to about 10:1, base may be a metal carbonate base, the first transition metal catalyst may be a Ni catalyst, X ¹ may be -C(=O)Y, Y may be OR ⁶ , and X ¹ may be a halide selected from chloride , bromide and iodide.

[0125] A person skilled in the art, guided by the detailed instructions given herein, can select a suitable cross-coupling reaction catalyst as the first transition metal catalyst. The catalyst for the cross-coupling reaction is usually chosen to perform at least two functions: oxidative addition and reductive elimination. In oxidative addition, a metal (eg, a transition metal) donates an electron pair to an organic halide or organic pseudohalide to form a first organometallic intermediate. Typically, electron-enriched or low-valent types of transition metals will undergo oxidative addition. In reductive elimination, the metal in the carbon-metal bond in the second organometallic intermediate undergoes a two-electron reduction, leaving a new bond between the two ligands of the organic molecules. Typically, electron-depleted or high-valent types of transition metals will undergo reductive elimination. Thus, selection of the first transition metal catalyst may include identifying a cross-coupling catalyst that can circulate between the two types of compounds. When there is no photochemical redox catalyst in the reaction mixture, the cross-coupling reaction catalyst can also be selected for the transmetalation reaction. In a transmetalation, the first metal or non-metal bound to the organic moiety is replaced by a second metal to form a second organometallic intermediate, where the first metal or semimetal may be, for example, the boron atom of the boron moiety or the zinc atom of the zinc moiety, and the second metal may be a transition metal. a cross-coupling reaction catalyst metal, for example, included in the first intermediate organometallic types of compounds. The cross-coupling reaction catalyst, especially in combination in the reaction mixture with a photochemical redox catalyst, can also be selected to perform the function of one-electron oxidation by a free radical (wherein the free radical is reduced). In such a function, a metal, for example, a transition metal of a cross-coupling reaction catalyst, included in the first intermediate organometallic type of compound, donates an electron to a free radical to form a new carbon-metal bond. The various functions of the cross-coupling catalyst may occur separately or simultaneously, and typically each is accompanied by a cycling of the oxidation state of the transition metal in the catalyst.

[0126] The cross-coupling reaction catalyst may perform the functions described herein in the form in which it is added to the reaction mixture, or may be active in another form, for example, in the form that is formed in situ in the reaction mixture, for example, through ligand exchange. The cross-coupling reaction catalyst may be charged or uncharged, and may cycle between uncharged and charged in the reaction mixture. The transition metal atom in the cross-coupling reaction catalyst can typically be any suitable transition metal atom to effect oxidative addition, transmetalation, one electron free radical oxidation, and/or reductive elimination. Such atoms are known to include Ni atoms and Pd atoms, although in some cases other transition metals may be effective in inducing the coupling reaction. The cross-coupling reaction catalyst may include one or more transition metal atoms. In some embodiments, the cross-coupling reaction catalyst may be a Ni catalyst comprising a Ni atom. In other embodiments, the cross-coupling reaction catalyst may be a Pd catalyst comprising a Pd atom. The transition metal in the cross-coupling catalyst will bind to one or more ligands. A person skilled in the art can select the appropriate catalyst and ligands based on the knowledge available to such person, guided by the details provided herein. For a discussion of cross-coupling reaction catalysts, see Meijere et al., Eds., Metal-Catalyzed Cross coupling Reactions and More (2014, Wiley-VCH); Phan et al., On the Nature of the Active Species in Palladium Catalyzed Mizoroki-Heck and Suzuki-Miyaura Couplings -Homogeneous or Heterogeneous Catalysis, A Critical Review, Advanced Synthesis & Catalysis (2006) Vol. 348, Issue 6, pages 609-679; "Organotransition Metal Chemistry - From Bonding to Catalysis" John Hartwig (University Science Books, 2010). The amount of catalyst must be chosen to provide the desired yield. In some embodiments, the cross-coupling catalyst may be added in an amount of about 0.1 mole %, about 1 mole %, about 5 mole %. or about 10 mol%. based on the compound of formula (A).

[0127] The Suzuki coupling reaction catalyst is a cross-coupling reaction catalyst that can, under appropriate conditions, result in coupling between an organic halide or pseudohalide and a boron-containing organic moiety. One skilled in the art, guided by the teachings herein, can select a suitable Suzuki coupling catalyst and determine an effective amount for a particular reaction. See Miyaura et al., Chem. Rev. (1995) vol. 95, 2457-2483; Han, Chem. soc. Rev. (2013) Vol. 42, 5270-5298. The Negishi coupling reaction catalyst is a cross-coupling reaction catalyst that can, under appropriate conditions, lead to coupling between an organic halide or pseudohalide and a zinc-containing organic moiety. One skilled in the art, guided by the teachings herein, can select an appropriate Negishi coupling catalyst for a particular reaction. See Negishi et al., Aldrichim. Acta, (2005) Vol. 38(3), 71-87.

и NiCl₂⋅глима.[0128] Various Ni catalysts are cross-coupling reaction catalysts that can lead to a coupling reaction. One skilled in the art, guided by the teachings herein, can select an appropriate Ni catalyst and determine an effective amount for a particular coupling reaction. The Ni catalyst may include ligands that dissociate under certain conditions, with their replacement, for example, by a solvent molecule or another ligand. The Ni catalyst may be active in a form that is added to the reaction mixture or may be active in another form that is formed in situ. In some embodiments, the Ni catalyst may be selected to undergo oxidative addition to a carbon-halogen or carbon-pseudo-halogen bond. In further embodiments, the Ni catalyst may be selected to undergo oxidative addition to a compound of formula (A) or a compound of formula (B). In other embodiments, the Ni catalyst may contain a Ni atom in a specific oxidation state, such as a Ni(0) atom or a Ni(II) atom. In some embodiments, the Ni catalyst may be selected from NiCl ₂ (dtbpy), chloro(2-methylphenyl)bis(triphenylphosphine)nickel(II), [1,2-bis(diphenylphosphino)ethane]dichloronickel(II), Ni( acac) ₂ , NCl ₂ (PCy ₃ ) ₂ , Ni(1,5-COD) ₂ , NiCl ₂ ⋅ dimethoxyethane, NiCl ₂ -glyme, NiCl ₂ , NiCl ₂ (dppf), NiCl ₂ (dppe), bis (cyclopentadienyl )nickel(II), 2,3-bis(2,6-diisopropylphenylimino)butane nickel(II) dibromide, bis[(2-dimethylamino)phenyl]amine nickel(II) chloride, bis(isopropylcyclopentadienyl)nickel, bis(methylcyclopentadienyl )nickel(II), N,N'-bis(salicylidene)ethylenediaminonickel(II), bis(triphenylphosphine)nickel(II) dichloride, chlorine(cyclopentadienyl)(triphenylphosphine)nickel(II), chlorine(ethylcyclopentadienyl)(triphenylphosphinenickel(II ), chloro(2-methylphenyl)bis(triphenylphosphine)nickel(II), chlor(1-naphthyl)bis(triphenylphosphine)nickel(II), dibrombis(tributylphosphine)nickel(II), dibrombis(triphenylphosphine)nickel(II), dichlorobis(tributylphosphine)nickel(II), dichlorobis(trimethylphosphine)nickel(II), metallylnickel chloride dimer, hexa amine nickel(II) bromide, nickel(II) acetate, nickel(II) acetylacetonate, nickel(II) bis(trifluoromethanesulfonimide), nickel(II) bromide, nickel(II) hexafluoroacetylacetonate, nickel(II) trifluoromethanesulfonate, tetrakis(triphenylphosphite)nickel (0), Trovic's Ni precatalyst, and NiCl ₂ (dppp). See Adhikary, A. et al., Pincer and Pincer-Type Complexes (2014), 117-147; Takahashi, T. et al., Modern Organonickel Chemistry (2005), 41-55. In some embodiments, when a photochemical redox catalyst is present, the Ni catalyst may be selected from

and NiCl ₂ ⋅ glyma.

(см., Aldrich ChemFiles (2007) 7.5, 6), клешневидного Pd комплекса (см., Selander et al., Chem. Rev. (2011) Vol. 111, 2048-2076; Albrecht et al., Angew. Chem. Int Ed. (2001) Vol. 40, 3750-3781 и приведенные в них ссылки) и Pd катализатора из наночастиц.[0129] Various Pd catalysts are cross-coupling reaction catalysts that can induce a coupling reaction. One skilled in the art, guided by the guidance provided herein, can select the appropriate Pd catalyst and determine the effective amount for a particular coupling reaction. The Pd catalyst may include ligands which, under certain conditions, will dissociate to be replaced by, for example, a solvent molecule or another ligand. The Pd catalyst may be active in the form in which it is added to the reaction mixture or may be active in another form which is formed in situ. In some embodiments, the Pd catalyst is selected for oxidative attachment to a carbon halide or carbon pseudo halide bond. In further embodiments, the Pd catalyst is selected for oxidative addition to a compound of Formula (A) or a compound of Formula (B). In other embodiments, the implementation of the Pd catalyst may contain a Pd atom in a specific oxidation state, for example, a Pd(0) atom or a Pd(II) atom. In some embodiments, the Pd catalyst may be selected from PdCl ₂ , Pd(ACN) ₂ Cl ₂ , Pd(benzonitrile) ₂ Cl ₂ , Pd(1,5-COD)Cl ₂ , allylpalladium chloride dimer, Pd(dba) ₂ , Pd ₂ (dba) ₃ , Pd(OAc) ₂ , Pd(AmPhos) ₂ , Pd(P(tBu) ₃ ) ₂ , Pd(AmPhos) ₂ Cl ₂ , Pd(P(o-tolyl) ₃ ) ₂ , Pd(PPh ₃ ) ₄ , Pd(QPhos) ₂ , PdCl ₂ (dtbpf), Pd(PCy ₃ ) ₂ , bis(di-tert-butyl-phenylphosphine)Pd(Cl) ₂ , PdCl ₂ (PPh ₃ ) ₄ , PdCl ₂ (dppf), chloro{2-[1-(N-methoxy)iminoethyl]phenyl}{[1,3-bis(2,6-di-iso-propylphenyl]imidazol-2-ylidene}palladium (II) , chloro{2-[(1-(N-phenyl)iminoethyl]phenyl}{[1,3-bis(2,6-di-iso-propylphenyl]imidazol-2-ylidene}palladium (II), methanesulfonate(1 ,1-bis(di-tert-butylphosphino)ferrocene)(2'-amino-1,1'-biphenyl-2-yl)palladium (II), methanesulfonate(2-di-tert-butylphosphino-3,4,5 ,6-tetramethyl-2',4',6'-tri-iso-propylbiphenyl)(2''-amino-1,1'-biphenyl-2-yl)palladium (II), allyl(cyclopentadienyl)palladium (II ), methanesulfonate (2-di-tert-butylphosphino-1,1'-binaphthyl) (2'-amino-1,1'-biphenyl-2-yl)palladium (II), di-MU-iodine is(tri-tert-butylphosphino)dipalladium (I), methanesulfonate[2-diethylphosphino-2',6'-bis(dimethylamino)-1,1-biphenyl](2'-amino-1,1'-biphenyl-2 -yl)palladium II), acetateto(2'-di-tert-butylphosphino-1,1'-biphenyl-2-yl)palladium(II), acetateto(2,9-dimethyl-1,10-phenanthroline)palladium dimer (II) bis(trifluoromethanesulfonate), allylchloro[1,3-bis(2,6-di-isopropylphenyl)-4,5-dihydroimidazol-2-ylidene]palladium(II), allylchloro[1,3-bis( 2,6-di-iso-propylphenyl)imidazol-2-ylidene]palladium(II), allylchloro[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]palladium(II), trans- bis(dicyclohexylamine)bis(acetato)palladium(II), bis{[4-(N,N-dimethylamino)phenyl]di-tert-butnlphosphino}palladium(0), N,N'-[bis(2,6- dimethylphenyl)-1,3-dimethyl-1,3-propanediylidene](methyl)(triethylphosphine)palladium(II), [1,3-bis(2,6-di-iso-propylphenyl)-4,5-dihydroimidazole- 2-ylidene]{2-[(dimethylamino-kK)methyl]phenyl-kC}(pyridine)palladium(II) tetrafluoroborate, 1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidene( 1,4-naphthoquinone)palladium(0), [P,P'-1,3-bis(di-iso-propylphosphino)propane][P -1,3-bis(di-isopropylphosphino)propane]palladium(0), 1,2-bis(phenylsulfinyl)ethanepalladium(II) acetate, bis(tri-tert-butylphosphine)palladium(0), [1, 3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene]{2-[(dimethylamino-kN)methyl]phenyl-kC}(pyridine)palladium (II) tetrafluoroborate, dimer 1, palladium(0), bis(tri-o-tolylphosphine)palladium(0), chloro(1-tert-butylindenyl) [1,3-bis(2,6-di-iso-propylphenyl)imidazol-2-yl]palladium(II), chloro(1-tert-butylindenyl)[2-(dicyclohexylphosphino)-2',6'-dimethoxy -1,1'-biphenyl]palladium(II), chloro(1-tert-butylindenyl)[2-(dicyclohexylphosphino)-2',6'-di-iso-propoxy-1,1'-biphenyl]palladium(II ), chloro(1-tert-butylindenyl)[2-(dicyclohexylphosphino)-2',4',6'-tri-iso-propyl-1,1'-biphenyl]palladium(II), chloro(1-tert -butylindenyl)palladium(II), chloro(2-di-tert-butylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II), chlorine(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2- yl)palladium(II), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), chloro(2-dicyclohexylphosphino-3, 6-dimethoxy-2',4',6'-tri-iso-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), chloro[ 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-tri-iso-propyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II), chlorine [2-(dicyclohexylphosphino)-2'-(N,N-dimethylamino)-1,1'-biphenyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II), chlorine(2 -dicyclohexylphosphino-2',6'-di-iso-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), chloro(2-dicyclohexylphosphino- 2',6'-di-iso-propoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), chloro(2-dicyclohexylphosphino-2',4',6'-tri- iso-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), chloro(2-dicyclohexylphosphino-2',4',6'-tri- iso-propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II), chloro{[4-(N,N-dimethylamino)phenyl]di-tert-butylphosphino}(2'- amino-1,1'-biphenyl-2-yl)palladium(II), chloro[9,9-dimethyl-4,5-bis(diphenylphosphine but)xanthene][2'-amino-1,1'-biphenyl]palladium(II), chloro(di-2-norbornylphosphino)(2'-dimethylamino-1,1'-biphenyl-2-yl)palladium(II ), chloro(di-2-norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladium(II), chloro[(1,2,3-η))-1-phenyl-2-propen-1-yl]- {[1,3-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]-2H-imidazol-2-ylidene}palladium(II), chloro[(1,2,3-η)-3-phenyl -2-propenyl][1,3-bis(2,6-di-iso-propylphenyl)-4,5-dihydroimidazol-2-ylidene]palladium(II), chloro[(1,2,3-η)- 3-phenyl-2-propenyl][1,3-bis(2,6-di-iso-propylphenyl)imidazol-2-ylidene]palladium(II), chloro(tri-tert-butylphosphine)(2'-amino- 1,1'-biphenyl-2-yl)palladium(II), diacetate[1,3-bis(diphenylphosphino)propane]palladium(II), trans-di((μ-acetato)bis[o-(di-o -tolylphosphino)benzyl]dipalladium(II), di-(μ-brombis(tri-tert-butylphosphino)dipalladium(I), dichlorobis(acetonitrile)palladium(II), dichlorobis(benzonitrile)palladium(II), dichlorobis(di- tert-butylphenylphosphino)palladium(II), dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]palladium(II), dichloro[(R)-(+)-2,2'-bis(di-2-furanylphosphino) -6.6'-dimethoxy-1,1'-biphenyl]palladium(II), dichlorobis{[4-(N,N-dimethylamino)phenyl]di-tert-butylphosphino}palladium(II), dichloro[(R)-(+)- 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II), dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]palladium (II), dichloro[1,4-bis(diphenylphosphino)butane]palladium(II), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II), dichloro{bis[2-(diphenylphosphino)phenyl] ether} of palladium(II), dichloro[1,1'-bis(di-iso-propylphosphino)ferrocene]palladium(II), trans-dichlorobis(triphenylphosphine)palladium(II), dichloro(di-μ-chloro)bis[ 1,3-bis(2,6-di-iso-propylphenyl)imidazol-2-ylidene]dipalladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II), dichloro(norbornadiene)palladium(II), [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, methanesulfonate[1,1'-bis(diphenylphosphino)ferrocene)](2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate[4,6-bis(diphenylphosphino)phenoxazine](2 '-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate[2-bis(3,5-di( trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',4',6'-tri-iso-propyl-1,1'-biphenyl](2'-amino-1,1'-biphenyl-2-yl) palladium(II), methanesulfonate (diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate [2-(di-1-adamantylphosphino)-3.6 -dimethoxy-2',4',6'-tri-iso-propyl-1,1'-biphenyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate[di -tert-butyl(n-butyl)phosphine](2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate(di-tert-butylneopentylphosphine)(2'-amino-1,1 '-biphenyl-2-yl)palladium(II), methanesulfonate[2-(di-tert-butylphosphino)-2'-(N,N-dimethylamino)-1,1'-biphenyl](2'-amino-1 ,1'-biphenyl-2-yl)palladium(II), methanesulfonate (2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-tri-iso-propyl-1, 1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate(2-(di-tert-butylphosphino)-3-methoxy-6-methyl-2', 4',6'-tri-iso-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate(2-di-tert-butylphosphino -2',4',6'-tri-iso-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II), (2-di-tert-butylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl- 2-yl)palladium(II), (2-dicyclohexylphosphino-2',6'-bis(dimethylamino)-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) methanesulfonate palladium(II), methanesulfonate(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate( 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate(2-dicyclohexylphosphino-3,6 -dimethoxy-2',4',6'-tri-iso-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate(2 -dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-iso-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium( II), [2-(dicyclohexylphosphino)-2'-(N,N-dimethylamino)-1,1'-biphenyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate , methanesulfonate(2-dicyclohexylphosphino-2',6'-di-iso-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate( 2-dicyclolog exylphosphino-2',6'-di-iso-propoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate {(R)-( -)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine}(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate(2-dicyclohexylphosphino -2',4',6'-tri-iso-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate(2-dicyclohexylphosphino -2',4',6'-tri-iso-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate{[4- N,N-dimethylamino)phenyl]di-tert-butylphosphino}(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate[9,9-dimethyl-4,5-bis( diphenylphosphino)xanthene][2'-amino-1,1'-biphenyl]palladium(II), methanesulfonate[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2'-methylamino-1,1' -biphenyl-2-yl)palladium(II), methanesulfonate(tri-tert-butylphosphino)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate(tri-tert-butylphosphino) (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonate(tricyclohexylphosphine)(2'-amino-1,1'-biphenyl-2-yl)pal ladium(II), methanesulfonate(tricyclohexylphosphino)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II), dimer(2'-methylamino-1,1'-biphenyl-2-yl)methanesulfonatepalladium (II), tris{tris[3,5-bis(trifluoromethyl)phenyl]phosphine}palladium(0), chloro(η ² -P,C-tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine )palladium(II), 2-(2'-di-tert-butylphosphine)biphenylpalladium(II) acetate, di-(μ-chlorobis[5-chloro-2-[(4-chlorophenyl)(hydroxyimino-κN)methyl) dimer ]phenyl-κC]palladium, di-(μ-chlorobis[5-hydroxy-2-[1-(hydroxyimino-κN)ethyl]phenyl-κC]palladium(II) dimer, dicyclohexyl[9-(3-phenylpropyl)- 9-fluorenyl]phosphonium tetrafluoroborate, dicyclohexyl-{2-sulfo-9-[3-(4-sulfo-phenyl)propyl]-9-fluorenyl}phosphonium hydrogen sulfate, 2'-(dimethylamino)-2-biphenylylpalladium(II) dinorbornylphosphine complex chloride, 2-(dimethylaminomethyl)ferrocen-1-yl-palladium(II) dinorbornylphosphine chloride, Buchwald catalyst, e.g. (2013) 4: 916-920; Bruno et al., The Strem Chemiker Vol. XXVII No. 1, January, 2014 and references therein), palladacyclic 2-aminobiphenyl mesylate, Bedford catalyst (see, Sommer, W., Aldrich ChemFiles (2007) 7.10, 17), catalyst

(see, Aldrich ChemFiles (2007) 7.5, 6), a pincer Pd complex (see, Selander et al., Chem. Rev. (2011) Vol. 111, 2048-2076; Albrecht et al., Angew. Chem. Int Ed (2001) Vol 40, 3750-3781 and references cited therein) and Pd nanoparticle catalyst.

[0130] A person skilled in the art, guided by the detailed instructions given herein, can select a suitable photochemical redox catalyst as the second transition metal catalyst. The catalyst for a photochemical redox reaction will typically be selected to perform at least two functions: excitation upon irradiation and one-electron oxidation and/or reduction of the organic molecule. The photochemical redox reaction catalyst may be selected to excite the bound electron upon irradiation, especially upon irradiation with visible light. In a one-electron oxidation, a metal (for example, a transition metal) in an excited catalyst donates one electron to an organic molecule. If an organic molecule initially contains only paired electrons, the result of oxidation or reduction will be a free radical. Such a free radical can form a carbon-metal bond with a cross-coupling reaction catalyst as described above. Thus, selection of a second transition metal catalyst may include identifying a photochemical redox catalyst that can be excited by irradiation, especially visible light, and that can undergo one-electron oxidation and/or reduction of a moiety in an organic molecule. The light source can be any source that emits a suitable wavelength to interact with the selected photochemical redox catalyst, as follows from the ideas herein and the knowledge of a person skilled in the art, and can be, for example, a household light source, for example, incandescent or fluorescent lamp, LED and the like. The excited photochemical redox catalyst may accept an electron from or donate an electron to a moiety of an organic molecule, the moiety being, for example, a carboxylate or a thiohydroxamate ester (eg, a Barton ester). In some embodiments, the photochemical redox catalyst may oxidize the carboxylate anion. The photochemical redox reaction catalyst may perform the functions described herein in the form in which it is added to the reaction mixture, or may be active in another form, for example, in a form that is formed in situ in the reaction mixture, for example, through a ligand exchange. The photochemical redox reaction catalyst may be charged or uncharged, and may cycle between uncharged and charged states in the reaction mixture. For examples of photochemical redox catalysts, see Zuo et al., Merging photoredox with nickel catalysis: Coupling of a-carboxyl sp ³ -carbons with aryl halides, Science (2014) Vol. 345, Issue 6195, 437-440; Prier et al, Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis, Chem. Rev., (2013) Vol. 113, 5322-5363. The amount of catalyst must be chosen to provide the desired yield. In some embodiments, the photochemical redox catalyst may be present in an amount of about 0.1 mole %, about 1 mole %, about 5 mole %, about 10 mole %. or about 20 mol%. based on the compound of formula (A), and preferred is 1 mol%.

[0131] The transition metal atom in the photochemical redox catalyst can generally be any suitable transition metal atom that is excited by irradiation to form particles capable of accepting an electron from an organic molecule. Such atoms are known to include Ir atoms, Ru atoms, and Cu atoms, although other transition metals may be suitable in some cases for inducing a photochemical redox reaction. The photochemical redox reaction catalyst may contain one or more transition metal atoms. The transition metal atom in the photochemical redox catalyst is preferably bonded to one or more bpy ligand, bpm ligand, bpz ligand, bipy ligand, phen ligand, dap ligand and ppy ligand, where ppy ligand is particularly preferred.

[0132] In some embodiments, the photochemical redox catalyst may be a Ru catalyst. A person skilled in the art, guided by the guidance provided herein, can select the appropriate Ru catalyst and determine the effective amount for a particular coupling reaction. The Ru catalyst may include ligands which, under certain conditions, dissociate in order to be replaced by, for example, a solvent molecule or another ligand. The Ru catalyst may be active in the form in which it is added to the reaction mixture or may be active in another form which is formed in situ. In some embodiments, the Ru catalyst may be selected from Ru(bpy) ₃ Cl ₂ , Ru(bpm) ₃ (PF ₆ ) ₂ , Ru(bpz) ₃ (PF ₆ ) ₂ , Ru(bpy) ₃ (PF ₆ ) ₂ Ru(menbpy) ₃ (PF ₆ ) ₂ Ru(bpm) ₃ (PF ₆ ) ₂ and Ru(phen) ₃ (PF ₆ ) ₂ .

[0133] In other embodiments, the photochemical redox catalyst may be an Ir catalyst. One skilled in the art, guided by the guidance provided herein, can select the appropriate Ir catalyst and determine the effective amount for a particular coupling reaction. The Ir catalyst may include ligands which, under certain conditions, dissociate in order to be replaced by, for example, a solvent molecule or another ligand. The Ir catalyst may be active in the form in which it is added to the reaction mixture or may be active in another form which is formed in situ. In some embodiments, the Ir catalyst may be selected from Ir[dF(CF ₃ )ppy] ₂ (bpy)PF ₆ , Ir[dF(Me)ppy] ₂ (dtbpy)PF ₆ , Ir[dF(CF ₃ )ppy ] ₂ (dtbpy)PF ₆ , Ir(ppy) ₂ (dtbpy)PF ₆ , Ir(ppy) ₃ , Ir[pF(t-Bu)ppy] ₃ , Ir(dFppy) ₃ and Ir(Fppy) ₃ .

[0134] In some embodiments, the photochemical redox catalyst may be an Ir complex or a Ru complex having the structure:

where M ^T may be Ir or Ru, each L ¹ and L ² may independently be C or N, m is 3, each R ^L1 may independently be F, CF ₃ or C _1-4 alkyl, and each p may independently be from 0 to 3, and wherein the complex may be positively charged or uncharged and, if positively charged, may be associated with one or more counterions selected from perchlorate (ClO ₄ ^- ), acetate (CH ₃ CO ₂ ^- ), chloride (Cl ^- ), cyanide (CN ^- ), tetrafluoroborate (BF ₄ ^- ) and hexafluorophosphate (PF ₆ ^- ).

[0135] The term "base" as used herein has its usual meaning to those skilled in the art (and should not be limited to a particular or individual meaning) and refers, without limitation, to a compound that can bond a proton. The base may optionally perform other functions, for example, the base may be a ligand and/or activate a boron-containing moiety. The base may be charged or uncharged, and may cycle between charged and uncharged states, and between different charge states when bound to a proton. A proton bonded to a base may be bonded at any suitable position or positions of the base, typically the lone pair of electrons of the base atom. In some embodiments, the base may be included in an amount of about 1 mole %, about 5 mole %, about 10 mole %, about 100 mole %, about 200 mole %, about 300 mole %. or in excess, based on the compound of formula (A). The base must be included in the molar amount chosen to contact each mole of protons produced by the reaction as provided herein, and is preferably included in an amount of about 100 mole %. based on the compound of formula (A). In some embodiments, the base may be Et ₃ N, Hunig's base, pyridine, piperidine, morpholine, Proton Sponge™, DBU, Na ₂ CO ₃ , K ₂ CO ₃ , Li ₂ CO ₃ , Cs ₂ CO ₃ , KOtBu, K ₂ HPO ₄ , Na ₂ HPO ₄ , Na ₃ PO ₄ , K ₃ PO ₄ , NaOH, KOH, CsOH, LiOH, KF, CsF, NaOAc, KOAc, CsOAc, LiOAc, LiOtBu, NaOtBu, NaHCO ₃ , KHCO ₃ , CsHCO ₃ or LiHCO ₃ .

[0136] In some embodiments, a compound of formula (A) may be represented by formula (A1), formula (A2), formula (A3), formula (A4), formula (A5), formula (A6), or formula (A7) having structures:

[0137] In various embodiments of such compounds of formula (A), the variables R ¹ , R ^1A , R ^1B , R ^1C , R ^3A , R ^3B , R ⁶ and X ¹ may be as described in any other paragraph of this document. Each R ¹¹ and each R ¹² in such compounds of formula (A) may independently represent D (deuterium), halogen, hydroxy, C _1-4 alkoxy, C _1-4 alkyl, C _3-10 cycloalkyl, optionally substituted with C _{3- 10} cycloalkenyl, aryl, heteroaryl, C _1-6 haloalkyl, cyano, alkenyl, alkynyl, cycloalkenyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), acyl, thiocarbonyl, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-thioamido, N-thioamido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, sulfenyl, sulfinyl, sulfonyl, haloalkoxy, amino, monosubstituted amino group or a disubstituted amino group.

-О- и -S-. В одном варианте осуществления каждый R^2B может независимо представлять собой D (дейтерий), гидрокси, C_1-4 алкокси, C_1-4 алкил, С_3-10 циклоалкил, арил, гетероарил, C_1-6 галогеналкил, алкенил, алкинил, циклоалкенил, арил(алкил), гетероарил(алкил), гетероциклил(алкил), ацил, сульфенил, сульфинил, сульфонил, амино, монозамещенную аминогруппу или дизамещенную аминогруппу.[0138] In one embodiment, the variable n in such compounds of formula (A) is an integer from 0 to 4. In one embodiment, the variable Q ₁ is an optionally substituted monocyclic or bicyclic heteroaryl or an optionally substituted monocyclic or bicyclic heterocyclyl comprising 0 -4 heteroatomic moieties selected from -N=, -N(R ^2B )-,

-O- and -S-. In one embodiment, each R ^2B may independently be D (deuterium), hydroxy, C _1-4 alkoxy, C _1-4 alkyl, C _3-10 cycloalkyl, aryl, heteroaryl, C _1-6 haloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), acyl, sulfenyl, sulfinyl, sulfonyl, amino, monosubstituted amino or disubstituted amino.

[0139] In certain embodiments, a process for preparing a substituted bicyclo[1,1,1]pentane of formula (I) comprises contacting a compound of formula (A1), formula (A2), formula (A3), or formula (A4) with a compound of formula (B). In additional embodiments, a method for preparing a substituted bicyclo[1,1,1]pentane of formula (I) comprises contacting a compound of formula (A5), formula (A6), or formula (A7) with a compound of formula (B).

[0140] In various embodiments, the compound of formula (A1) may be a compound of formula (A1a), formula (A1b), formula (A1c), or formula (A1d):

[0141] In some embodiments, R ^{1 of} formula (A1a), formula (A1b), formula (A1c), and/or formula (A1d) may be selected from optionally substituted C _1-30 alkyl, optionally substituted C _2-30 alkenyl , optionally substituted C _3-10 monocyclic cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, halogen, optionally substituted C-carboxy, amino, monosubstituted amino, disubstituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted C _1-30 alkoxy, hydroxy, optionally substituted C _1-30 haloalkyl, cyano, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted O-carboxy, optionally substituted C _2-30 alkynyl, optionally substituted C _{3 -10} cycloalkenyl, optionally substituted aryl(alkyl), optionally substituted heteroaryl(alkyl), optionally substituted hetero ocyclyl(alkyl), optionally substituted acyl, optionally substituted thiocarbonyl, optionally substituted O-carbamyl, optionally substituted N-carbamyl, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted C-thioamido, optionally substituted N-thioamido, optionally substituted sulfenyl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted haloalkoxy, and a first boron moiety, the first boron moiety being bonded via boron.

[0142] In some embodiments, R ^{1 of} formula (A1a), formula (A1b), formula (A1c), and/or formula (A1d) may be an optionally substituted N-carbamyl, e.g., -NH(C=O)) O-(C _1-4 alkyl). In other embodiments, R ^{1 of} formula (A1a), formula (A1b), formula (A1c), and/or formula (A1d) may be an optionally substituted aryl such as substituted or unsubstituted phenyl. In other embodiments, R ^{1 of} formula (A1a), formula (A1b), formula (A1c), and/or formula (A1d) may be an optionally substituted monocyclic heteroaryl, such as a substituted or unsubstituted 5- or 6-membered heteroaryl. In still other embodiments, R ^{1 of} formula (A1a), formula (A1b), formula (A1c), and/or formula (A1d) may be an optionally substituted bicyclic heteroaryl, such as a substituted or unsubstituted 9- or 10-membered heteroaryl. In some embodiments, R ^{1 of} formula (A1a), formula (A1b), formula (A1c), and/or formula (A1d) may be the first boron moiety. Examples of the first boron moiety for R ¹ include, but are not limited to,

[0143] In some embodiments, a compound selected from formula (A1a), formula (A1b), formula (A1c), and formula (A1d), wherein the compound may be selected from:

или фармацевтически приемлемой соли любого из вышеупомянутых соединений.

or a pharmaceutically acceptable salt of any of the above compounds.

[0144] In some embodiments, contacting a compound of formula (A) with a compound of Formula (B) to form a compound of formula (I) when the compound of formula (A) is a compound of formula (A1), formula (A2), formula (A3) or formula (A4), the first transition metal catalyst may be a Suzuki coupling catalyst, the second transition metal catalyst is absent, and X ² may be a halide or pseudohalide. In some embodiments, when the compound of formula (A) is a compound of formula (A5), the first transition metal catalyst may be a Ni catalyst, the second transition metal catalyst may be present, the second transition metal catalyst may be a Ni catalyst. photochemical redox reaction, and X ² may be a halide or pseudohalide.

[0145] In some embodiments, a compound of formula (B) may be represented by formula (B1) or formula (B2) having the structure:

-О- и -S-. В различных вариантах осуществления каждый R^2B может независимо представлять собой D (дейтерий), гидрокси, C_1-4 алкокси, C_1-4 алкил, С_3-10 циклоалкил, арил, гетероарил, C_1-6 галогеналкил, алкенил, алкинил, циклоалкенил, арил(алкил), гетероарил(алкил), гетероциклил(алкил), ацил, сульфенил, сульфинил, сульфонил, амино, монозамещенную аминогруппу или дизамещенную аминогруппу.[0146] In various embodiments of such compounds of formula (B), the variable X ² may be as described in another paragraph of this document. Each R ²¹ in such compounds of formula (B) may independently represent D (deuterium), halogen, hydroxy, C _1-4 alkoxy, C _1-4 alkyl, C _3-10 cycloalkyl, optionally substituted C _3-10 cycloalkenyl, aryl , heteroaryl, C _1-6 haloalkyl, cyano, alkenyl, alkynyl, cycloalkenyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), acyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, C-thioamido, N-thioamido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, sulfenyl, sulfinyl, sulfonyl, haloalkoxy, amino, monosubstituted amino group or disubstituted amino group. In various embodiments, n is an integer from 0 to 4. In various embodiments, the variable Q ₂ is an optionally substituted monocyclic or bicyclic heteroaryl or an optionally substituted monocyclic or bicyclic heterocyclyl comprising 0-4 heteroatomic moieties selected from -N=, -N( ^R2B )-,

-O- and -S-. In various embodiments, each R ^2B may independently be D (deuterium), hydroxy, C _1-4 alkoxy, C _1-4 alkyl, C _3-10 cycloalkyl, aryl, heteroaryl, C _1-6 haloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), acyl, sulfenyl, sulfinyl, sulfonyl, amino, monosubstituted amino or disubstituted amino.

[0147] In some embodiments, the compound of formula (A), R ¹ cannot be hydrogen. In additional embodiments, R ¹ cannot be unsubstituted phenyl. In other embodiments, R ¹ cannot be monosubstituted phenyl. In other embodiments, R ¹ cannot be disubstituted phenyl. In various embodiments, R ¹ cannot be substituted or unsubstituted alkyl. In additional embodiments, R ¹ cannot be substituted or unsubstituted alkenyl. In various embodiments, R ¹ cannot be a substituted or unsubstituted heterocyclyl. In additional embodiments, R ¹ cannot be substituted or unsubstituted heteroaryl. In some embodiments, R ¹ cannot be substituted or unsubstituted C _1-4 alkyl. In some embodiments, R ¹ may not be an optionally substituted C-carboxy, eg, -C(=O)O(unsubstituted C _1-4 alkyl). In some embodiments, R ¹ may not be an optionally substituted C-carboxy, eg, -C(=O)OCH ₃ .

[0148] Starting materials, including compounds of formula (A) and compounds of formula (B), can be obtained by any suitable method. One of skill in the art, informed by the guidance provided herein, has the knowledge and skill to prepare such compounds in the various ways available. For compounds of formula (A), see, for example, WO 2015/089170; WO2015/134710; US patent No. 5405550; Levin et al., Chem. Rev. (2000), Vol. 100, 169-234; Bunker et al., Org. Lett. (2011), Vol. 13(17), 4746-4748; Atack, T.C., et al., J. Am. Chem. soc. (2014), Vol. 136(27), 9521-9523; and Atack, T.C., et al, J. Am. Chem. soc. (2016), Vol. 138(19), 6139-6142. Any preliminary reaction steps used to obtain the starting compounds of formula (A) can be easily carried out by those skilled in the art. Methods and procedures useful in preparing compounds of formula (B) are also well known to those skilled in the art (see, for example, March, J., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th Ed., Wiley, John & Sons, Inc., Jan. 2007) Larock, R.C., Comprehensive Organic Transformations, A Guide to Functional Group Preparations (Wiley 1999, 2nd Ed.)).

[0149] In certain embodiments, the compound of formula (A) or the compound of formula (B) may be present as a salt.

[0150] In some embodiments, a compound described herein may be selected from:

или фармацевтически приемлемой соли любого из вышеупомянутых соединений.

or a pharmaceutically acceptable salt of any of the above compounds.

[0151] The methods provided herein can be performed in various ways by those skilled in the art in accordance with the detailed instructions provided herein. Generally, unless otherwise indicated, components, for example, a compound of formula (A), a compound of formula (B), a first transition metal catalyst, optionally a second transition metal catalyst, and optionally a base, may be combined in the reaction mixture with one or more solvents, and the reaction mixture could be subjected to temperature and pressure, guided by the instructions given in this document. Physical stirring is preferred, such as stirring the reaction mixture. The components of the reaction mixture are usually in solution, but may be suspended in a solvent, or may be partially dissolved and partially suspended. In particular, the compound of formula (A), the compound of formula (B), the first transition metal catalyst, and optionally the second transition metal catalyst should preferably be dissolved. A component, such as a catalyst, may be bonded to a polymer or adsorbed to a solid substrate such as silica, alumina, charcoal, and the like.

[0152] Routine experimentation based on the guidelines provided herein can be used to select the mixing sequence of the components and apply the conditions to obtain the desired coupling reaction. Generally, the order in which the various components are added to the reaction mixture is not critical to achieve the coupling reaction, however, typically the cross-coupling reaction will occur when the compound of formula (A), the compound of formula (B), the first transition metal catalyst, and optionally the second transition metal catalyst is combined in the reaction mixture. The compound of formula (A) or formula (B), the first transition metal catalyst, the second transition metal catalyst, and the base may be added to the reaction mixture as a solid, oil, solution, or any suitable method. The component is usually added all at once, but may also be added in batches during contact.

[0153] The reactions described herein can be carried out at various temperatures. In some embodiments, the method provided herein is carried out at room temperature, about 0°C, about 20°C, about 40°C, about 60°C, about 80°C, about 100°C, about 120°C , about 140°C, about 160°C, about 180°C, about 200°C, or values in between. Preferred temperatures typically range from room temperature to about 80°C. This temperature is measured at the source of heating or cooling. Typically, the temperature will vary during the course of the reaction, but the highest temperature achievable will be the reaction temperature.

[0154] The reaction described herein should generally be carried out for the period of time necessary to provide the required amount of reaction product. The formation of the desired product, such as a compound of formula (I), may be monitored by any suitable analytical method. As a rule, the reaction time will be from several minutes to several days.

[0155] A person skilled in the art, guided by the guidelines given herein, can choose the molar ratios of the various components of the reaction in the practice of the methods described herein. In some embodiments, one or more of the compounds of formula (A) and the compounds of formula (B) may be present in a molar ratio of about 1.1:1, about 1.5:1, about 2:1, about 3:1, about 0, 9:1, about 0.7:1, about 0.5:1, about 0.3:1, about 0.1:1 or values in between relative to each other. In additional embodiments, the compound of formula (A) and the compound of formula (B) may be included in a molar ratio of about 1:1.

[0156] As a rule, bringing into contact is carried out in an inert atmosphere, such as an atmosphere of nitrogen or argon. In some embodiments, contacting occurs in an environment substantially free of oxygen, where substantially free is defined as that which is necessary to ensure the stability of the included catalyst or other component.

[0157] A person skilled in the art can select an appropriate solvent based on available knowledge and detailed guidance herein. Generally, an aprotic solvent is preferred. In some embodiments, the solvent may include an ether such as tetrahydrofuran, a sulfoxide such as dimethyl sulfoxide, an amide such as dimethylformamide or N-methylpyrrolidinone, an alkyl halide such as dichloromethane, an optionally substituted benzene such as toluene, a nitrile such as acetonitrile , an ester such as ethyl acetate, an optionally substituted alkane such as heptane, an alcohol such as ethanol, or a combination thereof. In some embodiments, the solvent may be selected from dimethylformamide, acetonitrile, or tetrahydrofuran.

[0158] In some embodiments, an oxidizing agent or reducing agent may be included in the reaction mixture. An oxidizing agent or reducing agent, if included, may, for example, reduce the catalyst to its active state or modulate the oxidation state of a moiety in a compound of formula (A), formula (B), or formula (I).

[0159] In some embodiments, a water neutralizer may be included in the reaction mixture. Suitable neutralizers include, for example, liquid phase neutralizers such as trialkyl orthoformate or solid phase neutralizers such as molecular sieves, zeolites and the like. In some embodiments, the reaction is carried out in an environment substantially free of water, where substantially free is defined as that which is necessary to prevent a decrease in reaction yield due to the presence of water.

[0160] In some embodiments, a stepwise or multistep reaction may be appropriate. For example, without limitation, the catalyst may be chemically modified with one or more ligands before being combined with other reaction components. Additional examples include manipulation of protecting groups, ligand exchange, manipulation in an oxidizing environment, or formation of a pseudohalide followed by one-pot coupling. In particular, the carboxylate moiety can be chemically converted in situ. For example, the carboxylic acid may be deprotonated, or the ester, thioester, or acyl halide may be hydrolyzed to form the carboxylate anion. In some embodiments, where X ¹ or X ² is -C(=O)Y and Y is OM, X ¹ or X ² can be formed. Additional examples of suitable transformations are provided in Richard C. Larock Comprehensive Organic Transformations: A Guide to Functional Group Preparations (2nd Ed., Wiley, John & Sons, Inc., Nov. 1999); and Jerry March, (Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th Ed., Wiley, John & Sons, Inc., Jan. 2007).

[0161] In some embodiments, the compound of formula (I) may be an oligomer or polymer.

[0162] Additional processing may be required to isolate and/or purify a compound of formula (I). Standard experiments based on the guidelines provided herein can be used to determine appropriate isolation and/or purification conditions. For example, standard methods are available, such as distributing the reaction mixture between solvents of different hydrophobicity, such as extraction, precipitation, such as crystallization, distillation, and chromatography. Those skilled in the art have the knowledge and skill to enable them to isolate and/or purify compounds of formula (I) using standard techniques following the guidance provided herein.

[0163] In some embodiments, a compound of formula (I) is prepared with at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% yield, based on the starting compound of formula (A).

[0164] The compound of formula (I) can be used in any suitable application, for example, in an agricultural product, drug, material and/or scientific research.

Pharmaceutical compositions

[0165] Some embodiments described herein relate to a pharmaceutical composition that may include an effective amount of one or more of the compounds described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0166] The term "pharmaceutical composition" refers to a mixture of one or more of the compounds and/or salts described herein with other chemical components such as diluents or carriers. The pharmaceutical composition facilitates the administration of the compound to the body. Pharmaceutical compositions can be substantially tailored to the specific route of administration intended for them. In some cases, salts can be obtained by contacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

[0167] The term "physiologically acceptable" refers to a carrier, diluent, or excipient that does not interfere with the biological activity and properties of the compound, and does not cause significant harm or injury to the animal to which the composition is intended to be administered.

[0168] As used herein, the term "carrier" refers to a compound that facilitates the introduction of the compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a widely used carrier that facilitates the uptake of many organic compounds into the cells or tissues of a subject.

[0169] As used herein, the term "diluent" refers to an ingredient in a pharmaceutical composition that has no appreciable pharmacological activity, but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the amount of a potent drug that is too small to manufacture and/or administer. It can also be a liquid for dissolving a drug that is administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, without limitation, phosphate buffered saline, which mimics the pH and isotonicity of human blood.

[0170] As used herein, the term "adjuvant" refers to a substantially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding power, lubricity, disintegrating power, etc. d. compositions. "Diluent" is a kind of excipient.

[0171] The pharmaceutical compositions described herein may be administered to a human patient alone or as pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or with carriers, diluents, excipients, or combinations thereof. The appropriate composition depends on the route of administration chosen. Methods for preparing and administering the compounds described herein are known to those skilled in the art.

[0172] Pharmaceutical compositions disclosed herein may be prepared in a manner that is known per se, for example, by conventional mixing, dissolving, granulating, drageeing, triturating, emulsifying, encapsulating, entrapping, or tableting methods. In addition, the active ingredients are contained in an amount effective to achieve their intended purpose. Many of the compounds used in the pharmaceutical combinations described herein can be presented as salts with pharmaceutically compatible counterions.

[0173] There are many routes of administration of a compound, salt, and/or composition in the art, including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral administration, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.

[0174] It is also possible to administer the compound, salt, and/or composition in a local rather than systemic manner, for example, by injection or implantation of the compound directly into the affected area, often as a depot or sustained release composition. Moreover, it is possible to administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will target the organ and be selectively taken up by it. For example, intranasal or pulmonary delivery may be desirable for the treatment of a respiratory disease or condition.

[0175] The compositions may, if desired, be presented in a package or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. The package may, for example, contain a metal foil or a plastic film, such as a blister pack. The package or dispenser may be accompanied by instructions for use. The package or dispenser may also be accompanied by a notice associated with the container in the form prescribed by the government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the form of the drug for human or veterinary administration. For example, such a notice could be a US Food and Drug Administration-approved label for prescription drugs or an approved package insert. Compositions, which may include a compound and/or salt described herein, formulated in a compatible pharmaceutical carrier, may also be prepared, placed in an appropriate container, and labeled for the treatment of said condition.

EXAMPLES

[0176] In the following examples, additional embodiments are disclosed in more detail and are not intended to limit the scope of the claims in any way.

CONNECTIONS

[0177] Table 1 shows the compounds of formula (I), obtained by the methods disclosed in this document.

EXAMPLE 1

Preparation of Compound 1

[0178] Bis(pinacolato)diborane (120 mol %) was added to a vial containing a solution of [1,1,1]propellane (0.25 M in Et ₂ O) at room temperature (RT) and sealed in an atmosphere N2 _. After 3 days, the reaction mixture was filtered and the collected solid was washed with Et ₂ O and dried in vacuo to give Compound 1-1 as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.03 (s, 6H), 1.22 (s, 24H).

[0179] Compound 1-1 was added to a flame-dried vial with a magnetic anchor, followed by Pd(PPh ₃ ) ₄ (20 mol %) and 4-bromoanisole 1-2 (120 mol %). The reaction vial was purged with N ₂ and THF (0.08 M in compound 1-1) was added followed by tert-BuOK (1M in THF, 300 mol %). The mixture was heated at 85°C for 20 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the crude product. Purification of the resulting product by column chromatography (SiO ₂ , hexanes/EtOAc) gave compound 1 as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.12 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 3.78 (s, 3H ), 2.13 (s, 6H), 1.26 (s, 12H).

EXAMPLE 2

Compound 2 preparation

[0180] An oven-dried vial containing a magnetic anchor was placed with 5-bromopyrimidine 2-2, compound 2-1 (300 mol %), 4,4'-di-tert-butyl-2,2'-bipyridine (15 mol %), nickel (II) chloride (dimethoxyethane adduct) (10 mol %), cesium carbonate (300 mol %), iridium catalyst [Ir{dF(CF ₃ )ppy} ₂ (dtbpy)] PF ₆ (1% mol.) and DMF (0.02 M in compound 2-2). The solution was degassed with a cool-pump-heat (3x) cycle, then irradiated with a 3 W blue LED lamp for 4 hours. The mixture was diluted with water and extracted with EtOAc (4x). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give the crude product, which was further purified by column chromatography (SiO ₂ , EtOAc/hexanes) to give compound 2 as a pale yellow residue. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (s, 1H), 8.71 (d, J=5.3 Hz, 1H), 7.34 (d, J=5.3 Hz, 1H ), 7.17 (m, 2H), 7.11 (m, 2H), 2.45 (s, 6H), 2.35 (s, 3H); LC/MS (APCI) m/z 237.1 [C ₁₆ H ₁₆ N ₂ +H] ⁺ .

EXAMPLE 3

Compound 3 preparation

[0181] An oven-dried vial containing a magnetic anchor was placed with Compound 3-2, Compound 2-1 (150 mol %), 4,4'-di-tert-butyl-2,2'-bipyridine (15 % mol.), Nickel (II) chloride (adduct with dimethoxyethane) (10 mol. %), cesium carbonate (150 mol. %), iridium catalyst [Ir{dF(CF ₃ )ppy} ₂ (dtbpy)]PF ₆ (1% mol.) and DMF (0.02 M in compound 3-2). The solution was degassed with a cool-pump-heat (3x) cycle, then irradiated with a 3 W blue LED lamp for 4 hours. The mixture was diluted with water and extracted with EtOAc (4x). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give the crude product, which was further purified by column chromatography (SiO ₂ , EtOAc/hexanes) to give compound 3 as a pale yellow residue. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.66 (d, J=5.0 Hz, 1H), 7.56 (s, 1H), 7.37 (d, J=4.9 Hz, 1H ), 2.37 (s, 6H), 2.35 (s, 3H); LC/MS (APCI) m/z 304.1 [C ₁₈ H ₁₆ F ₃ N+H] ⁺ .

EXAMPLE 4

Compound 4 preparation

[0182] To a solution of compound 4-1 (2.00 g, 11.8 mmol) in DCM (23.5 ml) was added 2 drops of DMF and cooled to 0°C. Oxalyl chloride (1.21 ml, 14.1 mmol) was added slowly and the resulting solution was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure to give the acid chloride, which was dissolved in DCM (58.8 ml) and cooled to 0°C. Et ₃ N (4.91 ml, 35.3 mmol) was added to the solution, followed by compound 4-2 (1.45 g, 11.8 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure to give compound 4-3, which was used without further purification. LC/MS (APCI) m/z 276.1 [C ₁₅ H ₁₇ NO ₄ +H] ⁺ .

[0183] A solution of crude compound 4-3 in AcOH (19.6 ml) and TFA (19.6 ml) was halved and added to 2 microwave synthesis vials and each irradiated at 100°C for 70 minutes. The contents of the two vials were recombined and concentrated under reduced pressure to give the crude product, which was then purified using column chromatography (SiO ₂ , EtOAc/hexanes) to give compound 4-4, which was used without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (d, J=8.3 Hz, 1H), 7.35 (m, 1H), 7.24-7.22 (m, 1H), 3 .76 (s, 3H), 2.63 (s, 6H), 2.50 (s, 3H); LC/MS (APCI) m/z 258.1 [C ₁₅ H ₁₅ NO ₃ +H] ⁺ .

[0184] To a solution of semi-purified compound 4-4 (3.03 g, 11.8 mmol) in THF (29.4 ml) was added 2M NaOH (17.7 ml, 35.3 mmol). The mixture was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure. The main aqueous layer was washed with EtOAc (1×20 ml), and then the aqueous layer was acidified with 1N HCl. The resulting white precipitate was collected by filtration. The filter cake was washed with H ₂ O (20 ml) and dried to give compound 4-5 as a beige solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.68 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.50 (s, 1H), 7.18 (d, J=7.9 Hz, 1H), 2.45 (s, 6H), 2.43 (s, 3H); LC/MS (APCI) m/z 244.1 [C ₁₄ H ₁₃ NO ₃ +H] ⁺ .

[01851 Compound 4-5 (1.98 g, 8.13 mmol), NHPI (1.33 g, 8.13 mmol) and DMAP (0.099 g, 0.813 mmol) were added to the vial and suspended in anhydrous DCM (81 ml ). Then DIC (1.26 ml, 8.13 mmol) was added and the resulting solution was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The resulting residue was taken up on celite and further purified by column chromatography (SiO ₂ , hexanes/EtOAc) to give compound 4-6 as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.97-7.86 (m, 2H), 7.85-7.80 (m, 2H), 7.57 (d, J=8.1 Hz, 1H), 7.31 (s, 1H), 7.15 (d, J=8.2 Hz, 1H), 2.81 (s, 6H), 2.49 (s, 3H); LC/MS (APCI) m/z 389.0 [C ₂₂ H ₁₆ N ₂ O ₅ +H] ⁺ .

[0186] A vial containing a solution of compound 4-6 (1.20 g, 3.09 mmol) and B ₂ cat ₂ (0.92 g, 3.86 mmol) in DMA (31 ml) was purged with N ₂ for 10 minutes, sealed, and then irradiated with a blue LED strip surrounding the vial. After 40 h, triethylamine (12.1 ml, 87.0 mmol) was added to the mixture, followed by pinacol (1.46 g, 12.4 mmol). After 3 hours the mixture was concentrated and purified by column chromatography (SiO ₂ , EtOAc/hexanes) to give compound 4-7 as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53 (d, J=8.1 Hz, 1H), 7.27 (br s, 1H), 7.10 (d, J=8.1 Hz, 1H), 2.46 (s, 3H), 2.40 (s, 6H), 1.27 (s, 12H).

[0187] Compound 4-7 (50.0 mg, 0.15 mmol) was added to a vial with a magnetic anchor, followed by Pd(PPh ₃ ) ₄ (17.8 mg, 0.015 mmol) and 4-bromoanisole 4-8 (38 .0 µl, 0.31 mmol). The reaction vial was purged with N ₂ and DME (1.1 ml) was added followed by t-BuOK (0.46 ml, 0.46 mmol, 1M in t-BuOH). The mixture was heated at 85°C for 20 hours Then the reaction mixture was cooled to room temperature and concentrated to obtain the crude product. Purification of the crude product by column chromatography (SiO ₂ , hexanes/EtOAc) gave compound 4 as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (d J=8.0 Hz, 1H), 7.31-7.29 (m, 1H), 7.23-7.20 (m, 2H ), 7.14-7.11 (m, 1H), 6.90-6.86 (m, 2H), 3.81 (s, 3H), 2.54 (s, 6H), 2.48 (s, 3H). LC/MS (APCI) m/z 306.1 [C ₂₀ H ₁₉ NO ₂ +H] ⁺ .

EXAMPLE 5

Compound 5 preparation

[0188] Compound 4-7 (100 mg, 0.31 mmol) was added to a vial with a magnetic anchor, followed by Cs ₂ CO ₃ (301 mg, 0.92 mmol), Pd(dppf)Cl ₂ (45.0 mg, 0.061 mmol) and 2-bromoquinoline 5-1 (84.0 µl, 0.62 mmol). The reaction vial was purged with N ₂ and DME (2.8 ml) was added followed by H ₂ O (0.28 ml). The mixture was heated at 85°C for 20 hours Then the reaction mixture was cooled to room temperature and concentrated to obtain the crude product. Purification of the crude product by column chromatography (SiO ₂ , hexanes/EtOAc) followed by reverse phase column chromatography (C18, H ₂ O/CH ₃ CN) gave compound 5 as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.89 (d, J=2.2 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 8.00 (apparent dd, J=2.2, 0.8Hz, 1H), 7.83-7.81(m, 1H), 7.70(ddd, J=8.4, 6.9, 1.5Hz, 1H) , 7.58 (d, J=8.1 Hz, 1H), 7.56 (ddd, J=8.4, 7.0, 1.3 Hz, 1H) 7.33-7.32 (m, 1H), 7.17-7.14 (m, 1H), 2.73 (s, 6H), 2.50 (s, 3H). LC/MS (APCI) m/z 327.1 [C ₂₂ H ₁₈ N ₂ O+H] ⁺ .

EXAMPLE 6

Compound 6 preparation

[0189] NiCl ₂ ⋅DME (0.028 g, 0.127 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.068 g, 0.254 mmol) and compound 6-1 (0.200 g , 0.634 mmol) and then purged with N ₂ . Anhydrous DMF (2.53 ml) was added and the mixture was stirred for 2 minutes before adding the arylzinc reagent. In a separate vial, the arylzinc reagent was prepared by adding a solution of p-tolylmagnesium bromide (1.90 ml, 1.90 mmol) to a solution of ZnCl ₂ (1 M in diethyl ether) (1.90 ml, 1.90 mmol) and the mixture was allowed to stir for 10 minutes. The arylzinc solution was then added in one portion to the vial containing the catalyst solution. The resulting mixture was allowed to stir at room temperature overnight. The mixture was concentrated and purified by column chromatography (SiO ₂ , EtOAc/hexanes) to give compound 6 as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.12 (s, 4H), 3.71 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H); LC/MS (APCI) m/z 217.1 [C ₁₄ H ₁₆ O ₂ +H] ⁺ .

[0190] Table 2 shows the compounds of formula (A), obtained by the methods disclosed in this document.

EXAMPLE 7

Compound 7 preparation

[0191] A heterogeneous solution of compound 1-1 (150 mg, 0.47 mmol) and N-methyliminodiacetic acid (103 mg, 0.7 mmol) in DMSO (4.7 ml) and 1,2-DCE (2.0 ml) was heated at 120° C. in a Biotage® Initiator+ microwave reactor for 1 hour. The reaction mixture was then cooled to room temperature, diluted with water and extracted with EtOAc (3x). The combined organic layers were dried (MgSO ₄ ) and concentrated to give the crude product, which was further purified using column chromatography (SiO ₂ , DCM/CH ₃ CN) to give compound 7 as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.75 (d, J=16.1 Hz, 2H), 3.61 (d, J=16.0 Hz, 2H), 2.98 (s, 3H ), 2.00 (s, 6H), 1.22 (s, 12H).

EXAMPLE 8

Compound 8 preparation

[0192] A solution of methoxyamine (1.91 ml, 1.88 mmol, 0.98 M in THF) was diluted with THF (4 ml), cooled to -78°C and treated with t-BuLi (1.14 ml, 1.94 mmol, 1.7 M in pentane). After 30 minutes, compound 1-1 (200 mg, 0.63 mmol) was added to the reaction mixture in one portion. After 5 minutes, the reaction mixture was sealed, heated to room temperature, and then heated to 60°C. After 16 hours the reaction mixture was cooled to room temperature and treated with Boe anhydride (477 mg, 2.19 mmol). After 1 hour, DCM was added to the reaction mixture and the reaction mixture was filtered through a pad of celite. The Celite layer was washed with DCM and the combined filtrates were concentrated to give the crude product. Purification of the crude product by column chromatography (SiO ₂ , hexanes/EtOAc) gave compound 8 as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.85 (s, 1H), 2.07 (s, 6H), 1.44 (s, 9H), 1.24 (s, 12H);

EXAMPLE 9

Compound 9 preparation

[0193] A solution of compound 8 (127.9 mg, 0.41 mmol) in THF (2.2 ml) and H ₂ O (0.55 ml) was treated with sodium periodate (265 mg, 1.241 mmol). After 5 minutes IN HCl (aqueous) (0.83 ml) was added. After 1 h, the reaction mixture was extracted with EtOAc (2x) and the combined organic layers were washed with water and concentrated to give compound 9 as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.84 (s, 6H), 1.37 (s, 9H).

EXAMPLE 10

Preparation of Compound 10

[0194] A solution of compound 7 (290.4 mg, 0.94 mmol) in MeOH (6.5 ml) was treated with KHF ₂ (1.69 ml, 4.23 mmol, 2.5 M in H ₂ O) at room temperature. After 2 hours the reaction mixture was concentrated, dissolved in 1:1 MeOH:H ₂ O (8 ml) and re-concentrated. This procedure was repeated 1 additional time. Then, acetone was added to the reaction mixture. The reaction mixture was filtered and the collected solid was washed with more acetone. The combined filtrate was concentrated to give a white solid which was then washed with Et ₂ O to remove residual pinacol to give compound 10 as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.46 (s, 6H), 1.35 (s, 9H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ , no internal standard) δ - 141.09.

[0195] Moreover, although the foregoing has been described in more detail by way of illustration and examples for purposes of clarity of understanding, it will be apparent to those skilled in the art that numerous and varied changes can be implemented without departing from the spirit or scope of the present invention. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present invention, but rather to cover all changes and alternatives, based on the true scope and spirit of the present invention.

Claims (45)

1. A method for producing a substituted bicyclo[1,1,1]pentane of formula (I), including: contacting a compound of formula (A) with a compound of formula (B) in the presence of a first transition metal catalyst, optionally a second transition metal catalyst, and optionally a base, under conditions chosen to form a compound of formula (I); wherein the compound of formula (A) has the structure:

where R ¹ is selected from the group consisting of C _6-10 aryl substituted with unsubstituted C _1-4 alkyl, benzoxazole substituted with unsubstituted C _1-4 alkyl, C-carboxy substituted with unsubstituted C _1-4 alkyl,

and the first boron-containing fragment, and the first boron-containing fragment is connected through boron; wherein the first boron-containing moiety is selected from the group consisting of

and

; where X ¹ is selected from the group consisting of –C(=O)Y,

and a second boron-containing fragment; wherein the second boron-containing moiety is selected from the group consisting of

,

and

; moreover, the compound of formula (B) has the structure R ² -X ² ; where R ² is selected from the group consisting of C _6-10 aryl substituted with unsubstituted C _1-4 alkyl or C _1-4 alkoxy, pyridine substituted with C _1-6 haloalkyl, pyrimidine and quinoline; where X ² is selected from the group consisting of chloride, bromide, iodide, and pseudohalide, where the pseudohalide is a sulfonate, phosphate, cyanide, azide, isocyanate, thioisocyanate, or a quaternary nitrogen moiety; wherein the first transition metal catalyst is selected from the group consisting of a Pd catalyst and a Ni catalyst, where the Pd catalyst is selected from the group consisting of Pd(PPh ₃ ) ₄ and PdCl ₂ (dppf); and where Ni catalyst is NiCl ₂ ⋅dimethoxyethane; wherein the second transition metal catalyst is an Ir catalyst, wherein Ir is Ir[dF(CF ₃ )ppy] ₂ (dtbpy)PF ₆ ; wherein the compound of formula (I) has the structure:

(I) wherein the bond between R ² and bicyclo[1,1,1]pentane in the compound of formula (I) is a carbon-carbon bond; wherein Y is selected from the group consisting of OR ⁶ and OM; wherein R ⁶ is hydrogen; and where M is a monovalent cation; with the proviso that at least one of X ¹ and X ² is not a boron moiety; and with the proviso that if a second transition metal catalyst is present, then either X ¹ or X ² is -C(=O)Y. 2. The method of claim 1, wherein the first transition metal catalyst is selected to undergo oxidative addition to a compound of formula (A) or a compound of formula (B). 3. The method according to any one of paragraphs. 1, 2, in which the compound of formula (A) has the structure:

,

,

or

; and: each of R ^1A and R ^1B is hydrogen, or OR ^1A , OR ^1B and the boron atom to which they are attached together form

; R ^1C is methyl; OR ^2A and OR ^2B and the boron atom to which they are attached together form

. 4. The method according to any one of paragraphs. 1, 2, in which the compound of formula (A) has the structure:

or

; where Q ₁ represents benzoxazole; where R ¹¹ and R ¹² represent C _1-4 alkyl; and where each n is independently an integer between 0 and 1. 5. The method according to any one of paragraphs. 1, 2, in which the compound of formula (A) has the structure:

, where R ⁶ represents hydrogen. 6. The method according to any one of paragraphs. 1, 2, where the compound of formula (A) is selected from the group consisting of:

,

,

,

,

and

. 7. The method according to any one of paragraphs. 1-6, wherein X ² is selected from the group consisting of zinc chloride, zinc bromide, zinc iodide, and zinc pseudohalide. 8. The method according to any one of paragraphs. 1-6, wherein X ² is selected from the group consisting of magnesium chloride, magnesium bromide, magnesium iodide, and magnesium pseudohalide. 9. The method according to any one of paragraphs. 1-3 or 5-8, wherein R ¹ is C _6-10 aryl substituted with unsubstituted C _1-4 alkyl, or benzoxazole substituted with unsubstituted C _1-4 alkyl. 10. The method according to any one of paragraphs. 1-3 or 5-8, wherein R ¹ is

. 11. The method according to any one of paragraphs. 1-3 or 5-8, in which R ¹ represents the first boron-containing fragment selected from the group consisting of

and

. 12. The method according to any one of paragraphs. 1-11, wherein the contacting of a compound of formula (A) with a compound of formula (B) is carried out in the presence of a base, and the base is selected from the group consisting of Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , Li ₂ CO ₃ , NaHCO ₃ , KHCO ₃ , CsHCO ₃ , LiHCO ₃ , KOtBu, NaOtBu and LiOtBu. 13. The method according to any one of paragraphs. 1-12, wherein M is a monovalent cation selected from the group consisting of Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ and a quaternary nitrogen atom. 14. The method according to any one of paragraphs. 1-13, in which said bringing into contact occurs when irradiated with visible light.

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