EP1224190A1 - Substituted diboron compounds - Google Patents

Substituted diboron compounds

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Publication number
EP1224190A1
EP1224190A1 EP00969107A EP00969107A EP1224190A1 EP 1224190 A1 EP1224190 A1 EP 1224190A1 EP 00969107 A EP00969107 A EP 00969107A EP 00969107 A EP00969107 A EP 00969107A EP 1224190 A1 EP1224190 A1 EP 1224190A1
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EP
European Patent Office
Prior art keywords
reaction
diboron
mmol
penta
hexa
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EP00969107A
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German (de)
English (en)
French (fr)
Inventor
Sebastian Mario Marcuccio
Helmut Weigold
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Commonwealth Scientific and Industrial Research Organization CSIRO
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Commonwealth Scientific and Industrial Research Organization CSIRO
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • This invention relates to a process for the preparation of organic boronic acid derivatives.
  • This invention also relates to a process for covalently coupling organic compounds, in particular to a process for covalently linking organic compounds via formation of an organic boronic acid derivative and coupling to other organic compounds.
  • Substituted bi- and tri-aryl compounds are of great interest to the pharmaceutical and agrochemical industries. A great number of these compounds have been found to possess pharmaceutical activity, while others have been found to be useful herbicides. There is also interest from the polymer industry in polymers prepared by the linking together of organic compounds.
  • organic boronic acid derivatives can be prepared by reacting an organic compound having a halogen or halogen-like substituent with a penta- or hexa- substituted diboron derivative.
  • the organic boronic acid derivatives are useful in the preparation of covalently coupled organic compounds.
  • one aspect of the present invention provides a process for the preparation of an organic boronic acid derivative comprising reacting a penta- or hexa- substituted diboron derivative with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst, such that direct carbon to boron bond is formed between said coupling position and a boron-containing residue of the penta- or hexa- substituted diboron derivative.
  • Another aspect of the present invention provides a process for the preparation of an organic boronic acid derivative comprising:
  • the invention provides a process for the preparation of an organic boronic acid derivative comprising: (A) reacting a tetra-substituted diboron derivative with a nucleophile to form a penta or hexa substituted diboron derivative; and (B) reacting the penta- or hexa- substituted diboron derivative in situ with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst such that a direct carbon to boron bond is formed between said coupling position and a boron-containing residue of the penta or hexa substituted diboron derivative.
  • the present invention provides a process for coupling a first organic compound having at a coupling position a halogen or halogen-like substituent and a second organic compound having at a coupling position a halogen or halogen-like substituent comprising: (A) preparing an organic boronic acid derivative by reacting a penta- or hexa- substituted diboron derivative with said first organic compound in the presence of a
  • Group VIII metal catalyst such that a direct carbon to boron bond is formed between said coupling position and a boron-containing residue of the penta or hexa substituted diboron derivative; and (B) reacting the organic boronic acid derivative with said second organic compound in the presence of a suitable base and a Group VIII metal catalyst, such that a carbon to carbon bond is formed between the respective coupling positions of the organic compounds.
  • the three steps i.e. formation of the penta- or hexa- substituted diboron derivative, the reaction of the derivative with the organic compound to form the organic boronic acid derivative, and the coupling of that derivative with another organic compound are performed in the one pot without isolation of intermediates
  • the invention provides a process for coupling a first organic compound having at a coupling position a halogen or halogen-like substituent and a second organic compound having at a coupling position a halogen or halogen-like substituent comprising:
  • step (C) it is preferable to decompose any unreacted tetra-, penta- or hexa- substituted diboron derivative by adding water and a suitable base.
  • the base should be such that it is strong enough to break the boron to boron bond of the diboron compounds.
  • the base added is preferably one which is capable of catalysing the coupling reaction of step (C).
  • Coupled position refers to a position on an organic compound at which coupling to an organic compound is desired.
  • Each organic compound may have one or more, preferably between 1 and 6, coupling positions.
  • This process conveniently allows for the preparation of both symmetrical and unsymmetrical products by varying the organic compound which is coupled to the organic boronic acid derivative.
  • organic compound having a halogen or halogen-like substituent at a coupling position refers to any organic compound having a carbon to halogen or carbon to halogen-like substituent bond at a position where coupling to the organic compound is desired.
  • the organic compound may be aliphatic, olefmic, aromatic, polymeric or dendritic or any combination thereof.
  • the organic compound may have one or more, preferably between 1 and 6, halogen or halogen-like substituents at coupling positions.
  • aromatic and aromatic compound(s) refer to any compound which includes or consists of one or more aromatic or pseudoaromatic rings.
  • the rings may be carbocyclic or heterocyclic, and may be mono or poly cyclic ring systems.
  • suitable rings include but are not limited to benzene, biphenyl, terphenyl, quaterphenyl, naphthalene, tetradyronaphthalene, 1-benzylnaphthalene, anthracene, dihydroanthracene, benzanthracene, dibenzanthracene, phenanthracene, perylene, pyridine, 4-phenylpyridine, 3-phenylpyridine, thiophene, benzothiophene, naphthothiophene, thianthrene, furan, pyrene, isobenzofuram, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, indole, indolizine, isoindole, purine, quinoline, isoquinoline, phthalazine,
  • aromatic and aromatic compound(s) include molecules, and macromolecules, such as polymers, copolymers and dendrimers which include or consist of one or more aromatic or pseudoaromatic rings.
  • pseudoaromatic refers to a ring system which is not strictly aromatic, but which is stablized by means of delocalization of ⁇ electrons and behaves in a similar manner to aromatic rings. Examples of pseudoaromatic rings include but are not limited to furan, thiophene, pyrrole and the like.
  • an "olefmic” and “olefinic compound” as used herein refer to any organic compound having at least one carbon to carbon double bond which is not part of an aromatic or pseudo aromatic system.
  • the olefinic compounds may be selected from optionally substituted straight chain, branched or cyclic alkenes; and molecules, monomers and macromolecules such as polymers and dendrimers, which include at least one carbon to carbon double bond.
  • Suitable olefinic compounds include but are not limited to ethylene, propylene, but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, cyclopentene, l-methylpent-2-ene, hex-1-ene, hex-2-ene, hex-3-ene, cyclohexene, hept-1-ene, hept-2- ene, hept-3-ene, oct-1-ene, oct-2-ene, cyclooctene, non-1-ene, non-4-ene, dec-1-ene, dec- 3-ene, buta-l,3-diene, penta- 1,4-diene, cyclopenta-l,4-diene, hex-l,4,diene, cyclohexa- 1,3-diene, cyclohexa- 1,4-diene, cyclohepta-l,3-d
  • optionally substituted means that a group may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, isocyano, cyano, formyl, carboxyl, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diary lamino, benzy lamino, imino, alkylimine, alkenylimine, alkynylimino,
  • the organic compound must include at least one halogen or halogen-like substituent at a coupling position to enable reaction with the penta- or hexa- substituted diboron derivative.
  • Preferred halogen substituents include I, Br and Cl. Cl may also be used although Cl is generally less reactive to substitution by the penta- or hexa- substituted diboron derivative or organic boronic acid derivative. The reactivity of chloro substimted organic compounds can be increased by selection of appropriate ligands on the catalyst.
  • halogen-like substituent and "pseudo-halide” refer to any substituent which, if present on an organic compound, may undergo substitution with a penta- or hexa- substituted diboron derivative in the presence of a suitable catalyst to give an organic boronic acid derivative, or if present on an organic compound may undergo substitution with an organic boronic acid derivative to give a coupled product.
  • halogenlike substituents include triflates and mesylates, diazonium salts, phosphates and those described in Palladium Reagents & Catalysts (Innovations in Organic Synthesis by J. Tsuji, John Wiley & Sons, 1995, ISBN 0-471-95483-7).
  • the process according to the present invention is especially suitable for coupling organic compounds containing substituents which are reactive with organometallic compounds, such as Grignard reagents or alkyl lithiums, therefore unsuitable for reacting using standard Grignard methodology unless these substituents are first protected.
  • organometallic compounds such as Grignard reagents or alkyl lithiums
  • One such class of reactive substituents are the active hydrogen containing substituents.
  • active hydrogen containing substituent refers to a substituent which contains a reactive hydrogen atom.
  • substituents include but are not limited to hydroxy, amino, imino, acetyleno, carboxy (including carboxylato), carbamoyl, carboximidyl, sulfo, sulfinyl, sulfinimidyl, sulfmohydroximyl, sulfonimidyl, sulfoniimidyl, sulfonohydroximyl, sultamyl, phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphono (including phosphonato), hydrohydroxyphosphoryl, allophanyl, guanidino, hydantoyl, ureido, and ureylene.
  • alkyl used either alone or in compound words such as “alkenyloxy alkyl”, “alkylthio”, “alkylamino” and “dialky lamino” denotes straight chain, branched or cyclic alkyl, preferably C j _20 a ⁇ yl or cycloalkyl.
  • straight chain and branched alkyl examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1, 1-dimethyl-propyl, hexyl, 4- methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 2,2- dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2,- trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methoxyhexyl, 1-methylhexyl, 2,2- dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3
  • cyclic alkyl examples include mono- or poly cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • alkoxy denotes straight chain or branched alkoxy, preferably C ⁇ 2 o alkoxy. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy and the different butoxy isomers.
  • alkenyl denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined, preferably C2.20 alkenyl.
  • alkenyl examples include vinyl, allyl, 1- methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1- methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1- octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3- butadienyl, l-4,pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3- cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycl
  • alkynyl denotes groups formed from straight chain, branched or cyclic alkyne including alkyl and cycloalkyl groups as previously defined which contain a triple bond, preferably C2 . 20 alkynyl.
  • alkynyl include ethynyl, 2,3-propynyl and 2,3- or 3,4-butynyl.
  • acyl either alone or in compound words such as “acyloxy”, “acylthio”, “acy lamino” or “diacylamino” denotes carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring which is referred to as heterocyclic acyl, preferably CJ_2Q acyl.
  • acyl examples include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; alkoxy carbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t- pentyloxy carbonyl and heptyloxy carbonyl; cycloalkyl
  • phenylacetyl phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl
  • naphthylalkanoyl e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl]
  • aralkenoyl such as phenylalkenoyl (e.g.
  • phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl
  • aralkoxy carbonyl such as phenylalkoxy carbonyl
  • benzyloxy carbonyl aryloxy carbonyl such as phenoxy carbonyl and napthyloxy carbonyl; aryloxyalkanoyl such as phenoxy acetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and napthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazoly
  • heterocyclic refers to aromatic, pseudo-aromatic and non-aromatic rings or ring systems which contain one or more heteroatoms selected from N, S, O and P and which may be optionally substimted.
  • the rings or ring systems have 3 to 20 carbon atoms.
  • the rings or ring systems may be selected from those described above in relation to the definition of "aromatic".
  • aryl as used herein on its own or as part of a group such as “haloaryl” and “aryloxy carbonyl” refers to aromatic and pseudo-aromatic rings or ring systems composed of carbon atoms, preferably between 3 and 20 carbon atoms.
  • the rings or ring systems may be optionally substituted and may be selected from those described above in relation to the definition of "aromatic".
  • tetra-substituted diboron derivative may refer to diboronic acid itself or an ester or other derivative of diboronic acid.
  • suitable esters and derivatives include those of the formula (RX) 2 B-B(RX) 2 where R is hydrogen, optionally substimted alkyl or optionally substimted aryl or -B(XR) 2 represents a cyclic group of formula
  • each X which can be the same or different, can be O, S(O) n where n is 1 or 2 or NR" where R" is hydrogen or C,-C ]2 alkyl
  • R is optionally substimted alkylene, optionally substimted arylene or other divalent group comprising linked aliphatic or aromatic moieties.
  • Preferred tetra-substimted diboron derivatives include bis(pinacolato)diboron (the pinacol ester of diboronic acid), bis(ethanediolato)diboron, bis(n-propanediolato)diboron and bis(neopentanediolato)diboron.
  • the diboron ester derivatives may be made following the method of Brotherton et al. [R.J. Brotherton, A.L. McCloskey, L.L. Peterson and H. Steinberg, J. Amer. Chem. Soc. 82, 6242 (196); R.J. Brotherton, A.L. McCloskey, J.L. Boone and H.M. Manasevit, J. Amer. Chem. Soc. 82, 6245 (I960)].
  • B(NMe 2 ) 3 obtained by reaction of BC1 3 with NHMe ⁇ is converted to BrB(NMe_> 2 by reaction with a stoichiometric amount of BBr 3 .
  • tetra-substimted diboron derivatives are those analogous to the esters above, but where O is substimted by S(O) 2 where n is 1 or 2, or NR" where R" is H or C r C 12 alkyl.
  • the "penta- or hexa- substimted diboron derivative” refers to a diboron derivative having 5 or 6 substituents. It may be a further substimted tetra-substimted diboron derivative, as hereinbefore defined, or an alkali metal salt thereof, wherein one or both of the boron atoms of the tetra-substimted diboron derivative bear a further substituent resulting from reaction between tetra-substimted diboron derivative and a nucleophile.
  • penta- or hexa- substimted diboron derivative may also collectively refer to a mixture of further penta- or hexa-substituted diboron derivatives resulting from reaction between the tetra- substimted diboron derivative and greater than 1 and less than 2 molar equivalents of nucleophile. It is a further advantageous feature of the present invention that the process can be performed with mixtures of penta- and hexa- substimted diboron derivatives. 5
  • Suitable examples of penta- or hexa- substimted diboron derivatives are of general formulae (i) and (ii)
  • M is a counterion and Nu is a nucleophile.
  • M is a Group I or Group II metal ion.
  • each M may be the same or different.
  • Each Nu may be the same or different and may be a strong nucleophile, such as hydroxide, alkoxide, phenoxide, alky lamino or amino, alternatively the nucleophile may be a complex anion such as that from acacH formed by loss of a proton from an OH, or 0 other anions formed by loss of a proton from OH, CH, SH or NH and may be monodentate or bidentate.
  • a strong nucleophile such as hydroxide, alkoxide, phenoxide, alky lamino or amino
  • the nucleophile may be a complex anion such as that from acacH formed by loss of a proton from an OH, or 0 other anions formed by loss of a proton from OH, CH, SH or NH and may be monodentate or bidentate.
  • Nu methoxide, ethoxide, n- propoxide, t ' -propoxide, n-butoxide, t-butoxide, dimethy lamino, diethy lamino, diisopropylamino, fluoride, cyano or thiolate.
  • preferred bidentate 5 nucleophiles include those derived from ethylene glycol, ethanolamine or ethylenediamine.
  • Examples of chiral nucleophiles include those generated from (S)-(-)-l-phenylethanol; (R)-( + )- 1 -phenylethanol ; (- )- 1 ,2 : 5 , 6-Di-O-isopropylidene- ⁇ -D-glucofuranose ; ( + )- 1 ,2:5,6-Di-O-isopropylidene-D-mannitol; (S)-( +)-l ,2-O-Isopropylidene-glycerol; (R)-(-)- 0 1,2-O-Isopropylidene-glycerol; (-l-)-2,3-O-Isopropylidene-L-threitol; (-)-2,3-O-O-
  • Each X which can be the same or different, can be O, S(O) n , where n is 1 or 2 or NR" where R" is hydrogen or C C 12 alkyl, and each R may be the same or different and is independently selected from hydrogen, optionally substimted alkyl, optionally substimted aryl or B(XR) 2
  • the counterion M may be co-ordinated with a compound to further solubilize the base in a particular solvent, for example, crown ethers and cyclams.
  • the penta- on hexa- substimted diboron derivatives may be chiral compounds, and may have an enantiomeric excess of one or more enantoimers or isomers relative to others.
  • the chirality may be derived from any one or more of the substiments of the penta- or hexa- substimted diboron derivatives.
  • the derivatives may be prepared from a suitable tetra- substimted diboron compound, or the chirality may be introduced using a chiral nucleophile to form the penta- or hexa- substimted diboron derivative. Chiral compounds can be used to advantage to produce chiral products.
  • boron-containing residue refers to a group of the general formula
  • Group VIII metal catalyst refers to a catalyst comprising a metal of Group 8 of the periodic table described in CRC Handbook of Chemistry and Physics, 64th edition, 1983-1984, CRC Press.
  • metals include Ni, Pt, Pd and Co.
  • the catalyst is a palladium catalyst as described below, although analogous catalysts of other Group VIII metals may also be used.
  • suitable Ni catalysts include nickel black, Raney nickel, nickel on carbon and nickel clusters or a nickel complex.
  • suitable Pt catalysts include platinum black, platinum on carbon and platinum clusters or a platinum complex.
  • the Group VIII metal catalyst may additionally include other metals.
  • suitable cobalt catalysts include CoCl 2 (dppf), CoCl 2 (PPh 3 ) 2 , CoCl 2 [PPh 2 (CH 2 ) 3 PPh 2 ], and CoCyPPh ⁇ CH ⁇ PP J.
  • Suitable palladium catalysts include but are not limited to Pd 3 (dba) 3 , PdCl 2 , Pd(OAc) 2 , PdCl 2 (dppf)CH 2 Cl 2 , Pd(PPh 3 ) 4 and related catalysts which are complexes of phosphine ligands, (such as (Ph 2 P(CH 2 ) n PPh 2 ) where n is 2 to 5, P(o-tolyl) 3 , P(i-Pr) 3 , P(cyclohexyl) 3 , P(o-MeOPh) 3 , P(p-MeOPh) 3 , dppp, dppb, TDMPP, TTMPP, TMPP, TMSPP, 2-(di-t-butylphosphino)biphenyl, (R,R)-Me-DUPHOS, (S,S)-Me-DUPHOS, (R)- BINAP, (S)
  • phosphite ligands such as P(OEt) 3 , P(O-p-tolyl) 3 , P(O-o-tolyl) 3 , P(O-iPr) 3 , tris(2,4-di-t- butylphenyl)phosphite and other examples described in the STREM Catalogue No.
  • ligands including those containing P and/or N atoms for co-ordinating to the palladium atoms, (such as for example pyridine, alkyl and aryl substituted pyridines, 2,2'- bipyridyl, alkyl substimted 2, 2 '-bipyridyl and bulky secondary or tertiary amines), and other simple palladium salts either in the presence or absence of ligands.
  • the palladium catalysts include palladium and palladium complexes supported or tethered on solid supports, such as palladium on carbon, as well as palladium black, palladium clusters, palladium clusters containing other metals, and palladium in porous glass as described in J. Li, A. W-H. Mau and C.R. Strauss, Chemical Communications, 1997, pl275.
  • the same or different palladium catalysts may be used to catalyse different steps in the process.
  • the palladium catalyst may also be selected from those described in U.S. Patent 5,686,608. In certain reactions there are advantages in using ligands with altered basicity and/or steric bulk.
  • Suitable catalysts also include metallocyclic compounds and compounds that can form metallocyclic species in situ in the reaction medium.
  • the catalysts according to the present invention may be prepared in situ.
  • catalysts consisting of phosphine complexes of palladium can be prepared in situ by addition of a palladium (II) salt such as the acetate and the desired mono- or di-phosphine in a ratio such that the Pd/P atom ratio is approximately 1:2.
  • Arsines, such as for example bis(diphenylarsino) ethane and the like can also be used in conjunction with Pd to make active catalysts for the boronation of aryl halide type species.
  • the process may be performed in any suitable solvent or solvent mixmre provided that it is anhydrous.
  • suitable solvents include amides of the lower aliphatic carboxylic acids and lower aliphatic secondary amines, DMSO, aromatic hydrocarbons, nitromethane, acetonitrile, benzonitrile, ethers, poly ethers, cyclic ethers, lower aromatic ethers, lower alcohols, and their esters with the lower aliphatic carboxylic acids, pyridine, alkylpyridines, cyclic and the lower secondary and tertiary amines, and mixtures thereof, including mixtures with other solvents.
  • the process is performed in a protic solvent.
  • suitable protic solvents include lower alcohols. Most preferably the solvent is ethanol, methanol, isopropanol or mixtures thereof and with other solvents.
  • the temperature at which each step of the process according to the invention is conducted will depend on a number of factors including the desired rate of reaction, solubility and reactivity of the reactants in the selected solvent, boiling point of the solvent, etc.
  • the temperamre of the reaction will generally be in the range of -100 to 250°C. In a preferred embodiment the process is performed at a temperamre between 0 and 80°, more preferably between 0 and 40°C.
  • nucleophile and nucleophile refer to a compound which, when present in the reaction mixmre, is capable of nucleophilically reacting with a "tetra- substimted diboron derivative” to form a "penta- or hexa- substimted diboron derivative” as hereinbefore defined. It is also preferable that a nucleophile is chosen which is soluble in the solvent to which it is added.
  • nucleophiles examples include hydroxides, fluorides, cyanides and thiolates of Li, Na, K, Rb, Cs, ammonium and the group II metals Mg, Ca, & Ba, and their alkoxides and phenoxides, thallium hydroxide, alkylammonium hydroxides and as well as amides such as LiNMe 2 and NaNH 2 .
  • Some of these nucleophiles may be used in conjunction with a phase transfer reagent, such as for example tetraalkylammonium salts or the crown ethers.
  • Nucleophiles that may be used also includes alkali metal salts of potentially chelating ligands, for example acetylacetone.
  • suitable bases for catalysing the reaction between the organic boronic acid derivative and a further organic compound include the bases listed above as well as caesium carbonate, and potassium carbonate.
  • organic boronic acid derivative refers to the product of the Group VIII metal catalysed reaction between an organic compound having a halogen or halogen-like substiment at a coupling position and a "penta- or hexa- substimted diboron derivative", the product including a carbon to boron bond between the coupling position and a boron-containing residue of the penta- or hexa- diboron derivative.
  • the term includes organic boronic acids, as well as their esters and other derivatives.
  • an organic boronic acid derivative comprising reacting a penta- or hexa- substimted diboron derivative with an organic compound having a halogen or halogen-like substiment and an active hydrogen containing substiment in the presence of a Group VIII metal catalyst.
  • organic boronic acid derivative is an ester
  • a process for the preparation of an organic boronic acid by the hydrogenolysis or hydrolysis, using established procedures, of the organic boronic acid derivative obtained as hereinbefore described is provided.
  • the process according to the present invention is applicable to chemistry on solid polymer support or resin bead in the same manner as conventional chemistry is used in combinatorial chemistry and in the preparation of chemical libraries.
  • a suitable organic compound having a halogen or halogen-like substiment at a coupling position which is chemically linked to a polymer surface may be reacted with an organic boronic acid derivative in the presence of a palladium catalyst and a suitable base to form a coupled product linked to the surface of the polymer. Excess reagents and by-products may then be washed away from the surface leaving only the reaction product on the surface. The coupled product may then be isolated by appropriate cleavage of the chemical link from the polymer surface.
  • the process is also possible using the alternative strategy of reacting an organic compound or an organic compound having a halogen or halogen-like substiment linked to a polymer surface with a penta- or hexa- substimted diboron derivative in the presence of a suitable catalyst to form an organic boronic acid derivative chemically linked to the polymer surface.
  • This derivative may then be reacted with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base to prepare the coupled product chemically linked to the polymer.
  • Excess reactants and by-products may be removed by suitable washing and the coupled product may be isolated by chemically cleaving the link to the polymer.
  • a polymer e.g. polystyrene
  • a halogen, or halogen-like substiment it is also possible to directly functionalise the surface of a polymer, e.g. polystyrene, with a halogen, or halogen-like substiment and then convert this mnctionalised surface to an organic boronic acid derivative surface by reaction of the functionalised polymer with a penta- or hexa- substimted diboron derivative in the presence of a suitable catalyst.
  • the organic boronic acid derivative surface may then be reacted with any suitable organic compound having a halogen or halogen-like substiment. If the organic compound contains other functional groups, for example carboxylic ester, they may be used as linking groups to further extend the chemical reactions applied to the polymer surface.
  • linking group refers to any chain of atoms linking one organic group to another.
  • Examples of linking groups include polymer chains, optionally substimted alkylene group, carboxylic esters and any other suitable divalent group.
  • polyorganic compounds or other polymers by reaction of organic compounds having more than one halogen or halogen-like substiment.
  • organic compounds may be reacted with a penta- or hexa- substimted diboron derivative in the presence of a palladium catalyst to form an organic boronic acid derivative having more than one boron functionality.
  • organic boronic acid derivative having more than one boron functionality.
  • organic compounds or organic compounds having more than one halogen or halogen-like substiment to form a polymer.
  • the organic compound has three or more halogen or halogen-like substiments which react with the penta- or hexa- substimted diboron derivative then it is possible to prepare dendritic molecules in accordance with the process of the present invention.
  • the organic compound may be separate molecules or may be linked together such that the organic boronic acid derivative formed after reaction with the penta- or hexa- substimted diboron derivative is able to react at a coupling position located elsewhere in the molecule so as to provide for an intramolecular reaction, such as a ring closure reaction.
  • the process according to the invention allows intramolecular linking to occur within different organic compounds bearing halogen or halogen-like substiments located at different parts of the molecule. Reaction of one halide substiment with a second penta- or hexa-substituted diboron derivative to form an organic boronic acid derivative allows reaction of that derivative with the halide substiment on the other compound to thereby link the organic compounds.
  • the process according to the invention is also useful for the preparation of reactive intermediates which are capable of taking part in further reactions or rearrangements.
  • reactive intermediates may be the organic boronic acid derivative or the coupled products.
  • aryl organic boronic acid derivatives may take part in one or more of the palladium catalysed reactions of aryl boron compounds described by Miyaura and Suzuki in Chem. Rev. 1995, 95 2457-2483.
  • the present invention allows the formation of organic boronic acid derivatives under exceptionally mild conditions. It is possible to form desired products in good yield at room temperamre and below, and with functionalities which may be susceptible to attach by free bases and/or nucleophiles.
  • the process according to the present invention allow the linking of organic compounds under mild conditions and avoids the use of expensive, difficult to remove and/ or toxic reagents and solvents.
  • boron and boron compounds are generally non-toxic.
  • the reactions may also be performed in relatively cheap solvents such as methanol and ethanol and, in view of the improved control over the reaction steps, it is envisaged that it would be possible to perform the reactions on an industrial scale.
  • the process also allows the linking of organic compounds which contain active hydrogen substiments without the need to protect those substiments during the reaction.
  • the amount of base required for the formation of arylboronic acid ester in methanol is between one and two mole equivalents based on the diboron compound.
  • the added base concentration must be at least one equivalent.
  • Reactions in which more than two equivalents of LiOMe were used (viz. four equivalents) still led predominantly to the formation of the arylboronic acid species.
  • the reaction is considerably more facile when two equivalents, rather than one, of the base are used, the reaction can be gainfully carried out using just under two equivalents of base without forming significant amounts of symmetrical biaryl side product.
  • a further advantage of the above reaction system is that the reaction temperamre is low, which reduces possible dehalogenation of the substrate.
  • the GC of the reaction solution showed a major peak (92%) identified as the aryl borate by GC/MS and only a trace of dimer (1 %).
  • reaction solvent was found to affect the reaction.
  • DMSO at 30°C using approx. equimolar amounts of bis(pinacolato)diboron and l-bromo-3,4-methylenedioxybenzene, with PdCl 2 (dppf).CH 2 Cl 2 as catalyst, the formation of the arylboronic acid ester was incomplete (approx. 50% yield) when one equivalent of lithium methoxide base (per bis(pinacolato)diboron ) was used in the reaction. With two equivalents of lithium methoxide the reaction progressed to completion but the formation of coupled product (biaryl) was significantly larger (in one run it formed to around 50% of the arylboronic acid ester concentration).
  • Bi coupled product
  • reaction mixmre was added to water, extracted into dichloromethane and then dried over MgSO 4 .
  • the GC of the reaction solution showed a major peak identified as the aryl borate. Unreacted aryl halide and diboron compound were also present. Only a trace of dimer was formed.
  • reaction mixmre was added to water, extracted into dichloromethane and then dried over MgSO 4 .
  • the GC of the reaction solution showed a major peak (74%) identified as the aryl borate by GC/MS.
  • dimer 7%) was also formed.
  • reaction mixmre was added to water, extracted into dichloromethane and then dried over MgSO 4 .
  • the GC of the reaction solution showed a major peak identified as the aryl borate by GC/MS. Unreacted aryl halide and diboron compound were also present. Only a trace of dimer was formed.
  • reaction mixmre was added to water, extracted into dichloromethane and then dried over MgSO 4 .
  • the GC of the reaction solution showed a major peak (86%) identified as the aryl borate by GC/MS.
  • a small amount of dimer (5%) was formed.
  • Acetylacetone was converted into the Li compound by reacting a slight excess of acetylacetone with LiOMe in methanol. One equivalent of bis(pinacolato)diboron was then added and the solution stirred at room temp. The solvent was removed and the white powder remaining was used in the reaction.
  • the reaction can also be carried out without attempting the prior isolation of the product from lithium methoxide, acetylacetone and bis(pinacolato)diboron.
  • 0.205 ml acetylacetone was added to a solution of 3 ml methanol and 2 ml 1 m LiOMe in methanol. After ca. 20 mins, 282 mg (1.11 mmol) bis(pinacolato)diboron was added. The clear solution was then treated with 25 mg (0.03 mmol) PdCl 2 (dppf).CH 2 Cl 2 A red solution was formed, to which 248 mg (1.0 mmol) l-iodo-3,4-methylenedioxybenzene was added.
  • n B nmr shows that when bis(pinacolato)diboron reacts with 2 equivalents of LiOMe, the n B resonance moves upfield from 30.9 ppm to 4.67 ppm (external ref.BF 3 .OEt 2 ; solvent methanol).
  • the main product was the arylboronic acid ester.
  • the ratio of arylboronic acid ester to biaryl was greater than 91 : 9 assuming like fid/gc detection factors. Very little dehalogenated material was observed.

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  • Chemical & Material Sciences (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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