PRODUCTS OBTAINABLE THEREBY, AND THEIR USE

Field of the Invention

The present invention relates to the field of metal insertion in the presence of boron-based compounds to make compounds useful in Suzuki-type cross-coupling reactions.

Background of the Invention

Organometallic reagents are of increasing importance in organic chemistry, especially as key intermediates for the synthesis of biologically active compounds as well as natural products. In particular, transition metal catalyzed cross-couplings such as the Negishi, Stille, Heck and Suzuki -Miy aura types have become widely used synthetic tools for the concise construction of polyfunctional aromatics and

heteroaromatics.

In particular, the Suzuki -Miy aura cross-coupling reactions are highly practical and extensively used for straightforward C-C-bond formation by applying

organoborates as organometallic intermediates. The organoboron compounds such as organotrifluoroborates generally show a high tolerance towards functional groups and thermal stability. Moreover, the Suzuki type reactions can even be conducted in protic or aqueous solvents producing merely non-toxic waste which makes them frequently used reactions in academic institutions and industry.

However, the preparation of these organoboron intermediates has had major drawbacks. Besides commonly used multi-step reactions via highly reactive organometallics, the direct syntheses of organoboron compounds has been difficult, has had a low atom-economy or a low yield due to side-reactions and/or byproducts, or has required expensive transition-metal catalysis or expensive catalytic boranes, such as pinacolboranes and catecholboranes. The known synthetic routes and/or the use of borohydrides have also had a low tolerance towards sensitive functional groups.

Thus, there continues to be a need for a direct, facile and inexpensive route for making polyfunctional and heterocyclic organoborates having a greater tolerance for functional groups which can subsequently be used in cross-coupling reactions. The present invention addresses this and other problems as further described below.

Summary of the Invention

One aspect of the invention is a process for making boron-containing organic compounds (also referred to herein as "organoboron compounds") comprising reacting at least one organic compound having at least one CI, Br, or I atom or at least one nucleophilic leaving group substituent with at least one boron-containing reagent represented by the chemical formula (IA) or (IB):

B(YR ¹ ) ₃ (IA)

[Cat] ⁿ⁺ [B(YR ¹ ) ₄ ^" ]„ (IB)

in the presence of at least one oxidizable metal or oxidizable metal complex, wherein

each Y independently represents an oxygen atom, a sulfur atom, or - R'-, each R ¹ and each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,

Cat is a cation or mixture of cations, and

n is a positive number in the range from 1 to 3.

Another aspect of the invention is a mixture comprising components (A) and

(B):

(A) at least one anion comprising at least one moiety represented by the formula (IIA)

R ² ₂ B(YR ¹ ) ₂ (IIA) and/or a compound or anion comprising at least one moiety represented by formula (ΠΒ)

(B(R ² ) _a (YR ¹ ) _b Y) ₃ (ΠΒ) and

(B) at least one anion comprising at least one moiety represented by the formula (III)

R ² ₄ B (III),

wherein each Y independently represents an oxygen atom, a sulfur atom, or - R'-, each R ¹ and each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,

each R ² independently represents an organic moiety bonded to the boron atom of the anion or compound via a carbon - boron covalent bond,

each "a" and "b" represents an integer in the range from 0 to 2,

each sum of "a" + "b" per boron atom is in the range from 1 to 2, and

the molar ratio of component (B) to component (A) is at least 1 : 100.

A further aspect of the invention is anions comprising at least one moiety represented by the formula (IIA):

R ² ₂ B(YR ¹ ) ₂ (IIA) and/or

compounds and anions comprising at least one moiety represented by formula (IIB)

(B(R ² ) _a (YR ¹ ) _b Y)3 (IIB),

wherein

each Y independently represents an oxygen atom, a sulfur atom or -NR'-, wherein each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,

each R ¹ independently represents an organic group having from 4 to 15 carbon atoms and, optionally, one or more hetero atoms, and

each R ² independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond comprising a saturated aliphatic group, an unsaturated aliphatic group, a vinyl group, an aryl group, or one or more hetero atoms, each "a" and "b" represents an integer in the range from 0 to 2, and

each sum of "a" + "b" per boron atom is in the range from 1 to 2. Yet a further aspect of this invention is compounds comprising at least one moiety represented by formula (IV) and (IIB):

R ² ₂ BYR ¹ (IV) and

(B(R ² ) _a (YR ¹ ) _b Y)3 (IIB), wherein

each Y independently represents an oxygen atom, a sulfur atom, or - R'-, wherein each R' independently represents an organic moiety comprising up to 15 carbon atoms and, optionally, one or more hetero atoms,

each R ¹ independently represents an organic moiety comprising from 4 to 15 carbon atoms and, optionally, one or more hetero atoms,

each R ² independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond comprising an alkynyl group, a benzyl group or one or more hetero atoms,

each "a" and "b" represents zero or 1, and

each sum of "a" + "b" per boron atom is equal to 1 or 2, preferably 1.

Another aspect of this invention is methods for cross-coupling organic compounds comprising reacting the above-described mixture, anion and/or compound with at least one organic compound having at least one CI, Br, I, nucleophilic leaving group or aldehyde substituent.

The organoboron products of the invention are useful for conducting coupling reactions and reactions with aldehydes. Due to their selectivity, such reactions may be conducted in protic solvents, such as water and alcohols, and sensitive functional groups in the reactants are maintained in the final product. The organoboron products are stable, so that they maintain their activity during storage.

Further details regarding the present invention are presented in the following detailed description of the invention.

Brief Description of the Drawings

Fig. 1 shows percent cross-coupling conversion for various catalysts based on the illustrated cross-coupling reaction according to the invention.

Detailed Description of the Invention Definitions of terms used herein

The abbreviations used herein are defined in the following table:

The term "metalated" means that the compound that is the subject of this adjective is bonded, coordinated or complexed with a metallic cation or cationic complex. The term "protic" or "protic hydrogen atom(s)" refers to acidic hydrogen atom substituents (i.e., hydrogen atoms the protons of which may be removed through contact with a Lewis base). In general, hydrogen atoms not attached to carbon atoms may be considered protic. Examples of protic hydrogen atoms include the hydrogen atoms of carboxylic acids, aldehydes, phenols, alcohols, and amines. The expression, "standard oxidation potential" refers to the oxidation potential measured at pH 14 under standard temperature and concentration conditions. The oxidation potential is, by definition, the exact opposite of the standard reduction potential reported in the literature (e.g., a reduction potential of - 1.0 V equals an oxidation potential of +1.0 V). Examples of the reduction potentials for metals and metal complexes may be found in Annex VI, page 1843, of Hollemann-Wiberg, LEHRBUCH DER ANORGANISCHEN CHEMIE, 101 ^ST edition (Walter de Gruyter, 1995).

The expression (B(R ² ) _a (YR ¹ ) _b Y)3 refers to a cyclic structure of type

([B(R ² )a(YR ¹ ) _b Y][B(R ² ) _c (YR ¹ ) _d Y][B(R ² )e(YR ¹ )fYR ¹ ]) wherein a+b and c+d and e+f independently is in the range of 1 to 2 and each a,b,c,d,e, and f independently represents an integer in the range of 0 to 2. Unless stated otherwise, the expression "hetero atoms" as used herein refers preferably to the atoms N, O, S, P, B, Si, and Se. More preferred hetero atoms are N, O, S, and P.

Boron reagent

Boron-containing reagents of formulae (IA) and (IB) are reacted with organic compounds having CI, Br, I, and/or nucleophilic leaving groups to make boron- containing compounds.

The organic moieties R ¹ and R' of formulae (IA) and (IB) may be selected from a wide range of moieties having at least 1 , preferably at least 2, more preferably at least 3, and even more preferably at least 4 up to 15, more preferably up to 10, and even more preferably up to 8, carbon atoms and, optionally, one or more hetero atoms. Preferred moieties may be selected from saturated or unsaturated, straight or branched, aliphatic groups, cyclic groups or combinations of the aforementioned aliphatic and cyclic groups. The cyclic groups may be monocyclic or polycyclic, saturated or unsaturated, carbocyclic or heterocyclic ring structures. The polycyclic ring structures may be fused ring structures, bridged ring structures and rings sharing one atom in common preferably comprising up to 3, more preferably up to 2, rings. The aliphatic and/or cyclic moiety may have one or more substituents.

The hetero atoms may be present as chain and/or ring member and/or

substituent. Together with the carbon atoms, the hetero atoms may, for example, form ethers, ketones, amides, amines, nitro, cyano, esters, sulfonyl, etc., which are preferably protected if they would otherwise contain an acidic hydrogen atom, CI, Br, I or nucleophilic leaving group. Some or all hydrogen atoms may be replaced by fluorine atoms.

The organic moiety preferably does not contain protic (i.e., acidic) hydrogen atoms and preferably does not have CI, Br, I, or nucleophilic leaving group

substituents. The organic moiety may be saturated or unsaturated, but is preferably saturated.

Examples of preferred R ¹ groups include ethyl, ^-propyl, isopropyl, «-butyl, sec-butyl, t-butyl, «-pentyl, «-hexyl, «-heptyl, «-octyl, «-nonyl, «-decyl, and n- dodecyl and the foregoing substituted with one or more substituents selected from the group methyl, ethyl, propyl, isopropyl, «-butyl, sec-butyl, and t-butyl. For various reasons including cost, availability and safety, unsubstituted «-butyl, sec-butyl, t-butyl, «-pentyl, «-hexyl, «-heptyl, and «-octyl are particularly preferred.

Examples of preferred R' groups include the above preferred R ¹ groups and methyl. The Cat of formula IA is any cation that does not negatively interfere with, or detract from, the desired reactions and reaction products. Cat may be selected from alkali metal cations such as Li ⁺ , Na ⁺ , and K ⁺ , alkaline earth metal cations such as Mg ²⁺ and Ca ²⁺ , and quaternary amines such as tetralkyl ammonium compounds wherein the alkyl groups have 1 to 4, preferably 1-2, carbon atoms, such as N(«-Bu) ₄ ⁺ and mixtures thereof.

The value of "n" in Formulae (IB) corresponds to the valence, or charge, of the cation(s). When the salt of formula (IB) contains a mixture of cations having different valences or charges, "n" may have a fractional value representing the molar average charge of the cation mixture. Metals and Metal Complexes

The metals and metal complexes used in the process according to this invention may be any metal having a standard oxidation potential greater than the oxidation potential of the boron-containing reagent. The metals and metal complexes preferably have a positive standard oxidation potential at pH 14, more preferably a standard oxidation potential at pH 14 not less than 0.1 V, more preferably not less than 0.4 V, even more preferably not less than 0.7 V, yet more preferably not less than 1 V, even more preferably not less than 1.5 V, and still more preferably not less than 2 V.

The metals are preferably in the zero (i.e., elemental) oxidation state when it is brought into contact with the other reactants. Preferred metals include Mg, Al, Ca, Zn, K, Li, and Na. The metals and metal complexes may be brought into contact with the other reactants in the form of solid metal turnings, shavings or nanoparticles.

The metal complexes are preferably complexes of metals with a ligand. The ligand is an electron donor (i.e., Lewis base) ligand capable of donating a pair of electrons to a metal ion capable of accepting the electrons as a Lewis acid to form a coordination bond. Examples of suitable ligands include N(R') ₃ , 0(R') ₂ , OOC-R', P(0)(R') ₃ , P(R' )3, and multidentate ligands having two or more of the foregoing ligands, preferably bonded to the same or adjacent carbon atoms of an organic compound molecule, wherein each R' independently has the same meaning, including preferred meanings, as defined above. Examples of suitable ligands include PPh ₃ , NEt ₃ , imidazole, pyridine, acetate, and ethers. Multidentate ligands based on one or more of the aforementioned ligands are preferred. Suitable preferred metals include transition elements, such as Co, Cu, Fe, Cr, Mn, Mo, Os, Re and Ru, which have an oxidation state of at least +1.

The metal and/or metal complex is preferably introduced into the reaction mixture when the other reactants are already present in admixture with each other, preferably in a solvent. An amount of metal and/or metal complex is introduced which is preferably sufficient to drive the reaction to completion. This can generally be assured by providing an excess amount of metal and/or metal complex, so that solid metal and/or metal complex remains in the reaction mixture when no further reaction activity is observed.

Organic compound

The substrate for the reaction is at least one organic compound having at least one CI, Br, or I atom or at least one nucleophilic leaving group substituent. Each nucleophilic leaving group is preferably selected from the group consisting

of -OS(0) ₂ -R ^A , -N=N-R ^B , -OP(0)(OR ^c ) ₂ , -OC(0)R ^D , -SR ^E , and -N(R ^F ) ₃ R ^G , wherein R ^A , R ^c , R ^D , R ^E , and R ^F each independently represents an hydrocarbyl group or a fluorocarbyl group, wherein the hydrocarbyl or fluorocarbyl group preferably has B G

from 1 up to 10, preferably up to 7, carbon atoms, and R and R each represent BF ₄ . Preferred hydrocarbyl groups include methyl, branched-chain and straight-chain aliphatic hydrocarbons such as ethyl, propyl, isopropyl, «-butyl, sec-butyl and t-butyl, and aromatic hydrocarbons such as phenyl and benzyl. Preferred fluorocarbyl groups include -(CF ₂ ) _m CF ₃ , wherein "m" represents an integer in the range from zero to 4 and fluorinated aryl groups, such as fluorinated benzyl groups.

Preferred nucleophilic leaving groups include triflates (-OS(0) ₂ CF ₃ ); mesylates (-OS(0) ₂ CH ₃ ); nonaflates (-OS(0) ₂ (CF ₂ ) ₃ CF ₃ ); tosylates (-OS(0) ₂ C ₆ H ₅ CH ₃ );

diazonium salts such as ArN ₂ BF ₄ , wherein Ar represents an aryl group such as phenyl, benzyl, tolyl, xylyl, or naphthyl; acetate; pivalate; thiomethyl; and thioaryl, such as thiobenzyl.

Preferred organic compounds may be represented by formula (V):

R ⁵ L _P (V)

wherein R ⁵ represents an organic residue comprising one or more carbon atoms and, optionally, one or more hetero atoms;

L represents CI, Br, I, or a nucleophilic leaving group, such as the preferred

nucleophilic leaving groups described above; and

"p" represents an integer in the range from 1 up to 10, preferably up to 4, more preferably up to 2, and even more preferably up to 1.

The organic residue, R ⁵ , preferably does not comprise protonated hetero atoms such as, for example, OH, H, or SH and preferably comprises one or more cyclic groups and/or one or more aliphatic groups.

The cyclic groups may comprise carbocyclic groups, such as cycloalkyl groups and aryl groups, and heterocyclic groups, such as heteroaryl groups and partially or fully saturated heterocyclic compounds. Preferred cyclic groups have at least 4, more preferably at least 5, and even more preferably at least 6, up to 20, more preferably up to 15, and even more preferably up to 10, carbon atoms and optionally from 1 preferably up to a number of hetero atoms equal to the number of carbon atoms in the cyclic group. The heteroatoms are preferably selected from B, O, N, S, Se, P and Si, and more preferably selected from O, N and S. The cyclic group may comprise a monocyclic or polycyclic ring system. The polycyclic ring system may comprise fused ring systems, bridged ring systems and rings having one atom in common.

Preferred carbocyclic groups are aryl cycloalkyl groups,and cycloalkenyl groups, such as phenyl groups, napththalene rings, cyclohexyl groups, cyclohexenyl groups, cyclopentyl groups, cyclopentenyl groups, etc.

Preferred heterocyclic groups include heteroaryl groups having 5, 6, or 7 ring members and 1, 2, or 3 hetero atoms. Examples of heterocyclic groups containing one or more nitrogen atoms as ring members include pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isothiazolyl, isoxazolyl, furazanyl, pyridinyl, piperidyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, morpholinyl or morpholino, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalizinyl, naphthyridinyl, carbazolyl, phenazinyl, phenanthradinyl, acridinyl, phenothiazinyl, perimidinyl, phenanthrolinyl, and phenoxazinyl. Examples of oxygen-containing heterocyclic groups other than those previously mentioned among nitrogen atom-containing heterocyclic groups include furyl, pyranyl, isobenzofuranyl, chromenyl, chromanyl, iaochromanyl, and xanthenyl.

The aliphatic group preferably comprises at least 2, more preferably at least 3, and even more preferably at least 4, up to 20, more preferably up to 12, and even more preferably up to 8, and even more preferably up to 6, carbon atoms. The aliphatic group may be straight-chained or branched, may comprise one or more heteroatoms representing up to half, more preferably up to one-fourth, the total number of atoms in the aliphatic group, and may comprise one or more unsaturated bonds. The heteroatoms are preferably selected from B, O, N, S, Se, P and Si, and more preferably selected from O, N and S. The unsaturated bonds are preferably double bonds and triple bonds. Preferred aliphatic groups include alkyl groups, alkenyl groups and alkynyl groups. The aliphatic groups are preferably saturated (i.e., do not contain unsaturated bonds).

The substituents, when present, are preferably selected from among the aforementioned preferred R ¹ cyclic and aliphatic groups bonded directly to the aforementioned cyclic or aliphatic groups or bonded indirectly to the same via a Y group as defined above. Preferred substituents also include fluorine atoms and nonprotic functional groups.

Preferred functional group substituents are nitrile, nitro, ester, amide, protected alcohol, protected amine and protected amide. The ester group is preferably represented by the formula -C(0)OR ³ , wherein R ³ is an organic moiety, which may be selected from each and every option presented for R ¹ of Formula (I) above.

Protected alcohol, protected amine and protected amide are alcohol, amine and amide groups in which each proton bonded to an oxygen atom or nitrogen atom has been replaced with a group that is less reactive than the proton and yet capable of being removed to permit reactions to take place on the respective groups. Suitable protecting groups for those functionalities are well known in the state of the art. A description of suitable protective groups is provided, for example, in "Protective groups in organic synthesis" T. W. Greene, P. G. M: Wuts, Wiley. An example is TIPS to protect alcoholic and phenolic OH groups. Reaction conditions

The syntheses of organoboron compounds is preferably conducted at a temperature in the range from -30°C, more preferably from -10°C, up to, but not including, the decomposition temperature of the reactant having the lowest

decomposition temperature. In most cases, the reaction may preferably be conducted at temperatures in the range from 10°C, more preferably from 20°C up to 50°C, more preferably up to 30°C, such as at ambient (e.g., room) temperature.

The reaction is generally conducted under the exclusion of oxygen, or air, in an nonprotic, preferably inert, solvent under an inert atmosphere, such as argon gas, until conversion is complete. Suitable inert nonprotic solvents include, but are not limited to, cyclic, linear or branched mono- or polyethers such as THF, Me-THF, dibutyl ether, diethylether, tert-butylmethylether, dimethoxyalkylether, and dimethoxyalkanes; thioethers such as dimethyl sulfide and dibutyl sulfide; tertiary amines such as triethylamine, and ethyldiisopropylamine; phosphines; aromatic hydrocarbons, such as benzene, toluene and xylene; heteroaromatic hydrocarbons such as pyridine, N- methyl -2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone ( EP), N-butyl-2-pyrrolidone ( BP); aliphatic hydrocarbons, such as pentane, hexane, or heptane; cycloalkyls such as cyclohexane; dialkyl sulfoxides such as dimethylsulfoxide, amides such as dimethylformamide, Ν,Ν-dimethylacetamide and hexamethylphosphortriamide (HMPA); cyclic, linear or branched alkanes in which one or more hydrogen atoms are replaced by halogen atoms, such as dichloromethane, tetrachloromethane,

hexachloroethane; urea derivatives such as Ν,Ν'-dimethylpropylene urea (DMPU) and Ν,Ν,Ν',Ν'-tetram ethyl urea; acetonitrile; and CS ₂ either individually or two or more in combination. Cyclic ethers, such as THF and Me-THF, are preferred.

This reaction is preferably carried out in the substantial absence of protic solvents, such as water. Unless stated otherwise, the solvent has been dried to minimize the presence of protic solvents such as water. The reaction vessel, reactants and solvent are preferably dried or distilled before use to ensure that water is not present during the reaction.

Synthesis of the organoboron compounds is preferably conducted in the presence of LiX, wherein X represents halide selected from CI, Br, and I. X is preferably CI. LiX has an accelerating effect on the synthesis of the organoboron compounds. The reaction rate is generally sufficient without a further catalyst, so that in a preferred embodiment the reaction is carried out in the absence of a transition metal catalyst.

The reaction is preferably carried out in a one pot procedure. In other words, the reaction is preferably carried out by contacting a solution containing the organic compound substrate, at least one boron reagent and, preferably, LiX with the metal to generate the desired organoboron compound(s) in situ (i.e., without conducting transmetallation of the organic compound substrate in a separate step prior to reacting the metalated organic compound with a boron-containing compound).

Organoboron products

The process according to the invention produces organoboron compounds wherein the organic substrate molecules form bonds between the carbon atoms to which CI, Br, I, or an nucleophilic leaving group were attached and the boron atoms of the boron reagent to form various neutral or anionic species depending on the ratio of equivalents of the CI, Br, I, and nucleophilic leaving groups to boron atoms present in the reaction mixture and the nature of the solvent used to conduct the reaction.

The ratio of equivalents influences the degree to which the organic compound substrate is substituted on the boron-containing reagents. Increasing the ratio of organic compound substrate to boron atoms increases the molar average number of organic compound substrate molecules bonded to the boron atoms of the boron- containing reagents. When the ratio of equivalents is greater than 1 : 1, a mixture of organoboron compounds may be produced having various degrees of organic compound substrate substitution.

When the organoboron product is neutral, the organoboron product may comprise a mixture of one or more components comprising the following moieties:

R ² B(YR ¹ ) ₂ ,

R ² ₂ BYR ^X ,

R ² ₃ B, and/or

(B(R ² ) _a (YR ¹ ) _b Y) ₃ ,

wherein

each "a" and "b" represents an integer in the range from 0 to 2 and each sum of "a" + "b" per boron atom is 1 or 2.

In a preferred aspect of this invention, the neutral compounds may comprise moieties represented by formula (IV) and (IIB):

R ² ₂ BYR ¹ (IV) and

(B(R ² ) _a (YR ¹ ) _b Y) ₃ (IIB),

wherein

each Y and R ¹ have the same meaning as defined in formulae (IA) and (IB) above. Each R ¹ independently preferably represents an organic moiety comprising from 4 to 15 carbon atoms and, optionally, one or more hetero atoms,

each R ² independently represents an organic moiety comprising an alkynyl group, a benzyl group or one or more hetero atoms, wherein the organic group is bonded to the boron atom of the moiety represented by formula (IIA) or (IIB) via a carbon - boron covalent bond, each "a" and "b" represents zero or 1, and

each sum of "a" + "b" per boron atom is equal to 1. Conducting the reaction in nonprotic polar solvents tends to generate anionic organoboron species charge-balanced by cationic species generated in situ. This is in contrast to conducting the reaction in nonpolar solvents such as toluene, which tends to generate a greater proportion of neutral species. To maximize yield and reaction rates under mild conditions, the generation of anionic organoboron species in nonprotic polar solvents, such as THF, is preferred.

When the organoboron product is anionic and the ratio of equivalents of organic compound substrate to boron-containing reagent is greater than 1 : 1, the organoboron product may comprise a mixture of one or more of anionic components comprising the following moieties:

R^YR ¹ ^,

R ² ₂ B(YR ¹ ) ₂ ,

R ² ₃ B(YR ¹ ),

R ² ₄ B, and/or

(B(R ² ) _a (YR ¹ ) _b Y) ₃ ,

wherein

each Y, R ¹ , and R ² have the same meaning as defined above,

each "a" and "b" represents an integer in the range from 0 to 2,

each sum of "a" + "b" per boron atom is in the range from 1 to 2, and

the sum of "a" + "b" per molecule is at least 4.

In a preferred embodiment, the product of the reaction is a mixture comprising components (A) and (B):

(A) at least one anion comprising at least one moiety represented by the formula (IIA)

R ² ₂ B(YR ¹ ) ₂ (IIA) and/or

a compound or anion comprising at least one moiety represented by formula (ΠΒ)

(B(R ² ) _a (YR ¹ ) _b Y) ₃ (ΠΒ) and (B) at least one anion comprising at least one moiety represented by the formula (III)

R ² ₄ B (III),

wherein

each Y and R ¹ have the same meanings as defined above in formulae (IA) and (IB), each R ² independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond, each "a" and "b" represents an integer in the range from 0 to 2,

each sum of "a" + "b" per boron atom is in the range from 1 to 2, and

the molar ratio of component (B) to component (A) is at least 1 : 100, preferably at least 1 :50, and more preferably at least 1 :20.

In the same or different preferred embodiment, the preferred anions comprise moieties represented by the formula (IIA) and/or (IIB):

R ² ₂ B(YR ¹ ) ₂ (IIA) and/or

(B(R ² ) _a (YR ¹ ) _b Y)3 (IIB),

wherein

each Y and R ¹ has the same meaning as in formulae (IA) and (IB) above. R ¹ preferably represents an organic group having from 4 to 15 carbon atoms and, optionally, one or more hetero atoms,

each R ² independently represents an organic moiety bonded to the boron atom of the anion via a carbon - boron covalent bond comprising a saturated aliphatic group, an unsaturated aliphatic group, a vinyl group, an aryl group, or one or more hetero atoms, each "a" and "b" represents an integer in the range from 0 to 2,

each sum of "a" + "b" per boron atom is in the range from 1 to 2, and

the sum of "a" and "b" per formula (IIB) molecule is at least 4, preferably at least 5.

The anions are accompanied by a charge-balancing amount of cations. The cations comprise the metallic cations formed by oxidizing the metal during the reaction, cations introduced via salts of formula (IB), when present, and Li ⁺ introduced via LiX. The organoboron-containing mixtures, salts and compounds may be isolated and, if necessary, dried or dispersed or dissolved in a wide range of solvents. Once formed, the products are stable not only in the solvents used to synthesize the product, but also in a variety of protic solvents as well, such as water and various alcohols, for example.

End use applications

The above-described organoboron mixtures, anions and compounds are useful for conducting coupling reactions with electrophiles, such as the Suzuki-type cross- coupling reactions and, in particular, the Suzuki-Miy aura-type cross-coupling reactions. In a preferred embodiment, the electrophiles are organic compounds having at least one CI, Br, I, or nucleophilic leaving group. The nucleophilic atoms and groups react with the organoboron anions and compounds disclosed herein to make organic compounds that are larger and/or more complex than the organic compound substrate that was used to make the organboron anions and compounds. The electrophile may be reacted with the above-described organoboron compounds in the presence of a cross-coupling catalyst to couple the electrophile residue with the organo portion of the organoboron compound.

Due to their stability, the organoboron products may be used to conduct cross- coupling with organic compounds that have, in addition to the electrophilic atom(s) or group(s), functional groups having sensitive functional groups, such as -OH groups, carboxylic acid groups, and the like, without requiring replacement of the protic hydrogen atoms with protective groups prior to conducting the reaction. The choice of electrophiles is therefore much broader than the choice of organic compound substrates for synthesizing the organoboron compounds of the invention.

Examples of sensitive functional groups on the electrophile tolerated during cross-coupling include, for example, nitrile groups, -OH groups, acid groups, ester groups, amide groups, aldehyde groups, keto groups and cyano groups.

The ability to conduct such cross-coupling reactions with unprotected sensitive functional groups is a surprising and unexpected advantage over state of the art cross- coupling reactions. Cross-coupling is conducted with a catalyst and a base. The cross-coupling catalyst and base is preferably selected from the types used in state of the art Suzuki- type, or in particular the Suzuki-Miyaura-type, cross-coupling reactions. Appropriate catalysts and bases are well-known. Preferred catalysts comprise one or more palladium or nickel atoms. Examples of preferred catalysts include PdCl ₂ , Pd(PPh ₃ ) ₄ , Pd(OAc) _2> PdCl ₂ , which surprisingly may be used without stabilizing ligands, and NiBr ₂ (PPh ₃ ) ₄ . An example of a base is a basic alkali metal salt, such as an alkali metal phosphate. An example is potassium phosphate.

The reaction conditions for conducting cross-coupling are the same as, or analogous to, the preferred conditions for synthesizing the organoboron mixtures, anions, and compounds according to the invention. Further details on how to conduct such cross-coupling reactions are provided in S. R. Chemler, D. Trauner, S. J.

Danishefsky, Angew. Chem. Int. Ed. 2001, 40, 4544-4568; A. C. Frisch, M. Beller, Angew. Chem. Int. Ed. 2005, 44, 674 -688; G. A. Molander, B. Canturk, Angew. Chem. Int. Ed. 2009, 48, 9240 - 9261; and N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483, which are incorporated herein by reference for their relevant disclosures. .

Exceptionally, aldehyde groups react with the organoboron via a secondary addition reaction to link the organo portion of the organoboron with the organic compound bearing the aldehyde via a secondary alcohol. When it is desired to link organic compounds via this route, the organic compound to be added to the organo portion of the organoboron compound does not need to undergo cross-coupling and therefore does not require an electrophilic atom or group substituent, nor cross- coupling catalyst or base. The invention is now illustrated by the following examples.

Example 1:

Preparation of ethyl 4-(l-phenylvinyl)benzoate (6i)

A dry, argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with magnesium turnings (78 mg, 3.2 mmol) and LiCl (93 mg, 2.2 mmol). The LiCl was dried in vacuo using a heat gun (450 °C, 5 min). After addition of THF (2 mL), the magnesium was activated with 1,2-dibromoethane (2 mol%) and Me ₃ SiCl (5 mol%). Stirring for 5 min was followed by addition of B(OBu) ₃ (230 mg, 1 mmol). Thereafter, the suspension was cooled to 0 °C, a solution of (l-bromovinyl)benzene (4d, 366 mg, 2 mmol) in THF (2 mL) was added and the reaction mixture was strirred for 30 min at 0 °C to make the arylvinylborates.

To demonstrate the suitability of the arylvinylborates for cross-coupling reactions, the supernatant solution was then cannulated dropwise into a new argon- flushed Schlenk flask charged with ethyl 4-bromobenzoate (7g, 1.6 mmol, 367 mg), PdCl ₂ (4 mol%, 14 mg), dppf (4 mol%, 44 mg) and Cs ₂ C0 ₃ (652 mg, 2 mmol) in EtOH (4 mL) followed by stirring at 65 °C for 6 h. Subsequently, the reaction mixture was diluted with 5 mL EtOAc and quenched with brine (10 mL). The aqueous layer was extracted with CH ₂ C1 ₂ (3x 15 mL). The combined organic phases were dried over Na ₂ S0 ₄ and the solvent was removed in vacuo.

The crude product was purified by flash column chromatography (Si0 ₂ , pentane/Et ₂ 0 = 95:5) affording 6i as pale yellow solid (383 mg, 95%).

Example 2:

Preparation of 2-chloro-3-(3-thienyl)pyridine (6m)

A dry, argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with magnesium turnings (78 mg, 3.2 mmol) and LiCl (93 mg, 2.2 mmol). The LiCl was dried in vacuo using a heat gun (450 °C, 5 min). After addition of THF (2 mL), the magnesium was activated with 1,2-dibromoethane (2 mol%) and Me ₃ SiCl (5 mol%). Stirring for 5 minutes was followed by addition of B(OBu) ₃ (230 mg, 1 mmol). Thereafter, the suspension was cooled to 0 °C, a solution of 3-bromothiophene (4h, 326 mg, 2 mmol) in THF (2 mL) was added and the reaction mixture was strirred for 30 min at 0 °C to make the thiophene- substituted borates.

To demonstrate the suitability of the thiophene- substituted borates for cross- coupling, the supernatant solution was then cannulated dropwise into a new argon- flushed Schlenk flask charged with 2-chloro-3-iodopyridine (7k, 1.6 mmol, 383 mg), PdCl ₂ (4 mol%, 14 mg), dppf (4 mol%, 44 mg) and Cs ₂ C0 ₃ (652 mg, 2 mmol) in EtOH (4 mL) and DMF (1 mL) followed by stirring at 65 °C for 1 h. Subsequently, the reaction mixture was diluted with 5 mL EtOAc and quenched with brine (10 mL). The aqueous layer was extracted with CH ₂ CI ₂ (3x 15 mL). The combined organic phases were dried over Na ₂ S0 ₄ and the solvent was removed in vacuo.

The crude product was purified by flash column chromatography (Si0 ₂ , pentane/EtOAc = 9: 1 with 0.5% NEt ₃ ) affording 6m as pale yellow solid (291 mg, 93%).

Example 3

Preparation of organoborates

Organoborates were prepared by reacting 4-bromo-o-xylene (1 equivalent) with various borates (0.33 equivalent) and magnesium turnings (1.6 equivalent) in the presence of LiCl (1.1 equivalent) for 20 minutes at 25°C in dry THF as the solvent. The reaction produced a reaction mixture containing reaction products in which the boron atom of the former borate reactant has from 1 to 4 o-xylene substituents bonded at the o-xylene 4-position and from 1 to 3 of the alkoxy or aceto groups of the organoborate was replaced by o-xylene at the o-xylene 4-position. The boron product was substantially anionic (i.e., boron with 4 subsituents) with Mg ²⁺ generated via oxidation of the magnesium turnings as the primary cationic counter-ion. The most prevalent organoborate anion had two o-xylene groups, wherein one of the o-xylene groups replaced an alkoxy or acetoxy substituent formerly on the borate reactant.

The percent conversions of the substrate to the organoborate (i.e., yield) for the respective borate reactants tested are shown in Table 1.

Table 1

Preparation of organoborates using various borate sources

Entry Borate Product

Reactant (conversion)

1 B(OMe) ₃ 33%

2 B(OEt) ₃ 49%

3 B(OiPr) ₃ 51%

4 B(OBu) ₃ 64%

5 B(OAc) ₃ 43%

6 Na ⁺ B(OMe) ₄ ^" 28% Li B(OMe) ₄ 41%

As shown in table 1, the selection of borate additive influences the conversion rate.

The conversion rate is also affected by the ratio of equivalents between organohalide substrate and the borate reactant. Organoborates were prepared by reacting 4-bromo-o-xylene (1 equivalent, referred to below as the "substrate") with tributylb orate (referred to below as the "borate") and magnesium turnings (1.6 equivalent) in the presence of LiCl (1.1 equivalent) for 30 minutes at 25°C in dry THF as the solvent. The respective substrate to borate equivalent ratios and the percent conversions of the 4-bromo-o-xylene to the organoborate are shown in Table 2.

Table 2

Preparation of organoborates using various ratios of reactants

Entry Substrate / Borate Ratio Organoborate

(conversion)

1 0.25 eq 71%

2 0.33 eq 79%

3 0.5 eq 83%

4 1.0 eq 82%

Example 4:

Preparation of organoborates using Li, Na, Ca, K, Al and Zn

Tributylb orate (0.5 equivalent) and Li, Na and K are reacted with

4-bromoxylene (1 equivalent) in the presence of LiCl in dry THF according to the conditions shown in entries 1 to 3 of Table 3.

Tributylb orate (0.5 equivalent) and Ca, Al and Zn are reacted with 1-bromo- bis(trifluoromethyl)-benzene (1 equivalent) in the presence of LiCl in dry THF according to the conditions shown in entries 4 to 6 of Table 3. Table 3

Preparation of organoborates using various metals

1 Li >95% 0.5 25

2 Na >95% 12 25

3 K >83% 8 25

4 Ca >90% 2 25

5 Al >95% 0.5 65

6 Zn 84% 12 65

As can be seen from the data in the above table, the metal used to drive the reaction may be selected from any one of the metals listed in Table 3. Of those metals, the highest reaction rates and yields for this reaction are obtained with Li and Al followed by Ca and Na. Yields greater than 80%> are attained for K and Zn in 12 hours or less.

Example 5

Synthesis of Ethyl 4-(3,4-dimethylphenyl)-benzoate (6a)

Tributylb orate (0.5 equivalent) and Mg are reacted with 4-bromoxylene (1 equivalent) in the presence of LiCl in dry THF at 25°C for 30 minutes to make the xylene- substituted boron compound with 90% yield. The reaction mixture is then reacted with ethyl 4-iodophenylcarboxylate (4-iodophenylpropionate) in a 3 : 1 mixture of THF to methanol in the presence of 4 mol% catalyst selected according to Fig. 1 and 1 equivalent potassium phosphate for 12 hours at 65°C to form the title compound 6a

As shown in Fig. 1, the organoborates of the invention can be cross-coupled to produce the desired product in high yield using a wide variety of palladium and nickel catalysts, including catalysts in which the metal atom is not stabilized by ligands such as dppp, dppe, dba, TTMPP, and acac.

Example 6 To demonstrate the suitability of the organoborates for cross-coupling functionalized organic compounds, functionalized aryl bromides 4a-e are reacted with magnesium turnings (1.6 equiv) in the presence of B(OBu) ₃ (0.5 equiv) and LiCl (1.1 equiv) in a 1 : 1 mixture of THF and ethanol providing the corresponding arylborates 5a-e in ca. 90% yield. Subsequent Suzuki type cross-couplings with aryl iodides or bromides in a 1 : 1 mixture of THF and ethanol or DMF at 65°C according to conditions [a] to [d] described in the footnotes below furnished the polyfunctional aromatics 6b-k in 79-96% yield (Table 4, entries 1-10).

Table 4

Preparation of poly substituted aromatics via functionalized arylborates of type 5 prepared by direct magnesium insertion in the presence of B(OBu) ₃

[a] Obtained after cross-coupling in 1 : 1 mixture of THF and ethanol in the presence of Pd(PPh ₃ ) ₄ (4 mol%) as Pd catalyst and with Cs ₂ C0 ₃ (1 equiv) as base for 2 h

[b] Obtained after cross-coupling in DMF in the presence of PdCl ₂ (dppf) (4 mol%), as Pd catalyst and with Cs ₂ C0 ₃ (2 equiv) as base for 12 h

[c] Obtained after cross-coupling in 1 : 1 mixture of THF and ethanol in the presence of PdCl ₂ (4 mol%) as Pd catalyst and with K ₃ P0 ₄ (2 equiv) as base for 2 h

[d] Obtained after cross-coupling in 1 : 1 mixture of TFIF and ethanol in the presence of PdCl ₂ (dppf) (4 mol%) as Pd catalyst and with Cs ₂ C0 ₃ (1 or 2 equiv) as base for 6 h

As can be seen from the results shown in Table 4, compounds may be synthesized with a variety of sensitive functional group substituents without intervening protection and deprotection of those substituents, thereby simplifying the process for obtaining those compounds and reducing the quantity of wasteful byproducts.

Example 7

Synthesis of polysubstituted heteroaromatic and aromatic compounds starting from heteroaryl and benzyl compounds

Functionalized heteroaryl bromides and benzyl chlorides 4g-j may also be reacted with magnesium in the presence of B(OBu) ₃ to furnish, after subsequent cross-coupling with substituted aryl iodides or bromides 7g and 7j-m in a 1 : 1 mixture of THF and ethanol or DMF at 65°C according to conditions [a] to [d] described in the footnotes below, polyfunctional aromatics 61-p (Table 5, entries 1-5).

Table 5

Preparation of polysubstituted heteroaromatics and aromatics via functionalized heteroaryl and benzylborates prepared by direct magnesium insertion in the presence of B(OBu) ₃ .

Conditions

Entry Substrate Electrophile Product (Yield, %)

[a] Obtained after Pd-catalyzed cross-coupling (PdCl ₂ (dppf) (4 mol%), Cs ₂ C0 ₃ (2 equiv), THF/EtOH (1 : 1), DMF, 65 °C, 12 h)

[b] Obtained after Pd-catalyzed cross-coupling (PdCl ₂ (dppf) (4 mol%), Cs ₂ C0 ₃ (2 equiv), THF/EtOH (1 : 1), DMF, 65 °C, 1 h)

[c] Obtained after Pd-catalyzed cross-coupling (Pd(PPh ₃ ) ₄ (4 mol%), K ₃ P0 ₄ (2 equiv), THF/EtOH (1 : 1), 65 °C, 2 h)

[d] Obtained after Pd-catalyzed cross-coupling (PdCl ₂ (dppf) (4 mol%), Cs ₂ C0 ₃ (2 equiv), THF/EtOH (1 : 1), 65 C, 6 h)

As can be seen from the results in Table 5, functionalized heteroaryl bromides or benzyl chlorides 4g-j react outstandingly fast with magnesium in the presence of B(OBu) ₃ and furnish after subsequent cross-coupling with substituted aryl iodides or bromides 7g and 7j-m the desired polyfunctional aromatics 61-p (Table 5, entries 1- 5).

In the absence of borate, only dimeric products can be obtained by the direct magnesium insertion into benzylic carbon-halide bonds. Surprisingly, no dimeric homo-coupling product was observed during the preparation of benzylborates.

The obtained product is water-stable, hence convenient for subsequent reactions.

Example 8

Preparation of alkylborates and allylborates by direct magnesium insertion

Functionalized primary and secondary alkylborates as well as allylborates may also be prepared by direct magnesium insertion as shown in Table 6 below.

Magnesium metal is contacted with respective substrate mixed with 0.5 equivalent tributylb orate per equivalent of the substrate and lithium chloride in THF to make the organoborate. The results are shown in Table 6. Table 6

Preparation of alkylborates, allylborates and benzylborate by direct

magnesium insertion

Entry Substrate Conditions Borate (Yield, %)

(t , T)

Et0 ₂ C ^

1 h, 25 °C Et0 ₂ C ^^B DBu)

8a 9a (>90)

Me Me

EtO,C EtOpC

Br 1 h, 25 °C 2 B(OBu)

8b 9b (>90)

P Ph

EtOpC EtO,C

30 min, 0 °C 2 B(OBu)

8c 9c >90)

, Br B(OBu)

2

30 min, 0 °C

8e 9e (>85)

CQ ₂ Et C0 ₂ Et

,Br 30 min, 0 °C

8f 9f (>85)

As shown by Table 6, functionalized primary and secondary alkyl bromides 8a- d reacted efficiently under standard conditions with magnesium turnings in the presence of LiCl and B(OBu) ₃ to produce the corresponding alkylborates 9a-d (Table 6, entries 1-4). Also, otherwise difficult to prepare allylborates 9e-f could efficiently be prepared via the described method (Table 6, entries 5 and 6).

Example 9

Preparation of polysubstituted organic compounds starting from 4-bromophenol substrate without the use of protective groups

4-Bromophenol in THF is converted to the sodium salt by introducing sodium hydride (NaH) and allowing the reaction to take place for 20 minutes at 0°C. 0.5 equivalent of tributylb orate is then added per equivalent of the resulting phenolic salt product and the temperature of the solution is raised to 25°C over a period of one hour.

Lithium chloride is then added to the above room temperature solution and the solution is contacted with magnesium metal turnings for 2 hours at 25°C to form the arylborates. The arylborates are then combined with 1 equivalent of 4-cyano-2-iodo- aniline (electrophile) per 0.5 equivalent of the arylborate, 2 equivalent cesium carbonate (base) per equivalent of electrophile and enough methanol to provide a mixture with THF in a 1 : 1 ratio and the components of this mixture are reacted in the presence of 4 mol% Pd(PPh ₃ ) ₄ (catalyst) for 1 hour at 65°C.

The above reaction sequence produces 4-cyano-2-(4-hydroxyphenyl)aniline with a yield of 75%.

Example 10

Preparation of ethyl 4-[3,5-6is(trifluoromethyl)phen-l-yl)benzoate (15a) via direct aluminium insertion and subsequent Pd-catalyzed cross-couplings

The substrate l-bromo-fos(trifluoromethyl)benzene 4a is combined with 0.5 equivalent tributylb orate and 1.5 equivalent LiCl per equivalent of substrate 4a in THF and contacted with 3 equivalents aluminum metal per equivalent substrate 4a at 65°C for 1 h to make the /s(trifluoromethyl)phenylborate 5a in ca. 90% yield.

The arylborate 5a is then subjected to Pd-catalyzed cross-coupling with ethyl 4- iodobenzoate (7a); together with 2 equivalent cesium carbonate (base) per equivalent of 7a in a 1 : 1 mixture of THF and ethanol in the presence of 4 mol% Pd(PPh ₃ ) ₄ (catalyst) at 65 °C for 12 h to produce the title polyfunctional arene 15a in 68% yield.

Example 11 Preparation of ethyl 3-(4-cyanobenzyl)-4-ethoxycarbonylbenzoate (15b) via direct aluminium insertion and subsequent Pd-catalyzed cross-couplings

The substrate ethyl 2-bromo-4-ethoxycarboxybenzoate 4k is combined with 0.5 equivalent tributylb orate and 1.5 equivalent LiCl per equivalent of substrate 4k in THF and contacted with 3 equivalents aluminum metal per equivalent substrate 4k at 65°C for 7 h to make the 2,5-di(ethoxycarboxy)phenylborate 5k in ca. 90% yield.

The arylborate 5k is then subjected to Pd-catalyzed cross-coupling with 4- bromobenzonitrile (7j); together with 2 equivalent cesium carbonate (base) per equivalent of 7j in a 1 : 1 mixture of THF and ethanol in the presence of 4 mol% PdCl ₂ (dppf) (catalyst) and DMF at 65 °C for 12 h to produce the title polyfunctional arene 15b in 73% yield.

Example 12

Preparation of a secondary alcohol 14 via addition of arylborate 13 to a benzaldehyde derivative (7n) 4-bromo-o-xylene (substrate) is reacted with 0.5 equivalent of tributylb orate per equivalent of substrate andl .6 equivalent magnesium turnings per equivalent of substrate in the presence of 1.1 equivalent of LiCl per equivalent of substrate for 30 minutes at 25°C in dry THF as the solvent. 0.6 equivalent of the arylborate product is then reacted with 1 quivalent of 4-chlorobenzaldehyde (7n) for 1 h at 25°C to form 1- (3,4-dimethylphenyl)-l-(4-chlorophenyl)methanol (14) with a yield of 81%.

The aldehyde addition reaction proceeds without the use of catalysts or promoters.