Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
PREPARATION OF DIBORONIC ESTERS
Document Type and Number:
WIPO Patent Application WO/2004/076467
Kind Code:
A1
Abstract:
This invention relates to a process for the preparation of an ester of diboronic acid comprising reacting a tetrakis(dialkylamino)diboron with an alcohol to form the ester and a volatile dialkylamine, wherein the volatile dialkylamine is liberated from the reaction mixture in gaseous form.

Inventors:
MARCUCCIO SEBASTIAN MARIO (AU)
MOORHOFF CORNELIS MATTHIJS (AU)
Application Number:
PCT/AU2004/000255
Publication Date:
September 10, 2004
Filing Date:
February 27, 2004
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
BORON MOLECULAR PTY LTD (AU)
MARCUCCIO SEBASTIAN MARIO (AU)
MOORHOFF CORNELIS MATTHIJS (AU)
International Classes:
C07F5/02; C07F5/04; (IPC1-7): C07F5/04
Foreign References:
US3062823A1962-11-06
US6603004B22003-08-05
Other References:
NAKAMURA H. ET AL.: "A concise synthesis of enantiometrically pure L-(4-boronophenyl)alanine from L-tyrosine", J. ORG. CHEM., vol. 63, 1998, pages 7529 - 7530
Attorney, Agent or Firm:
Caine, Michael J. (1 Nicholson Street Melbourne, VIC 3000, AU)
Download PDF:
Claims:
THE DEFINING THE INVENTION ARE AS FOLLOWS:
1. A process for the preparation of an ester of diboronic acid comprising reacting a tetrakis (dialkylamino) diboron with an alcohol to form said ester and a volatile dialkylamine, wherein the volatile dialkylamine is liberated from the reaction mixture in gaseous form.
2. A process according to claim 1 wherein the tetrakis (dialkylamino) diboron is represented by formula (I): wherein R and R each independently represent Clalkyl groups.
3. A process according to claim 1 or claim 2 wherein the tetrakis (dialkylamino) diboron is selected from the group consisting of tetrakis (dimethylamino) diboron, tetrakis (diethylamino) diboron and tetrakis (dipropylamino) diboron.
4. A process according to any one of claims 1 to 3 wherein the alcohol is represented by formula IIa : QOH (IIa) wherein Q is selected from optionally substituted ClC6 alkyl, optionally substituted C2C6 alkenyl, optionally substituted C2C6 alkynyl, optionally substituted aryl group, or optionally substituted aliphatic ring.
5. A process according to any one of claims 1 to 3 wherein the alcohol is represented by formula II: HO (CRR) nOH (II) where n is 2 or 3 and each R is an independently selected from hydrogen, optionally substituted ClC6alkyl, optionally substituted C2C6alkenyl, optionally substituted C2 C6alkynyl, optionally substituted ClC6alkoxycarbonyl, optionally substituted Cl C6alkoxy, and optionally substituted aryloxy, or any two R groups together with the carbon atom (s) to which they are attached represent an optionally substituted CsC8cycloalkyl or C5C8cycloalkenyl group.
6. A process according to claim 5 wherein each R is selected from H and methyl.
7. A process according to any one of claims 1 to 3 wherein the alcohol is selected from pinacol, neopentylglycol, hexyleneglycol, (+)pinanediol and ()pinanediol.
8. A process according to claim 1 conducted neat.
9. A process according to any one of the preceding claims wherein the tetrakis (dialkylamino) diboron and the alcohol are reacted at a temperature of from 80°C to 140°C.
Description:
PREPARATION OF DIBORONIC ESTERS FIELD OF THE INVENTION The invention relates to boronic compounds, in particular to a process for the preparation of diboronic acid and its esters. Diboronic acid and its esters are useful in the preparation of organoboronic acids and esters, which are themselves useful in processes for covalently linking organic compounds.

BACKGROUND OF THE INVENTION 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.

The catalyzed cross-coupling of organoboronic acids and esters with alkyl, alkenyl or aryl halides, which is generically known as the Suzuki reaction, has shown great synthetic versatility. This is especially so for the production of substituted biaryl compounds due to the large variety of arylboronic compounds that are currently commercially available.

Many of the previously reported Grignard or analogous zinc methologies for C-C bond formation involve the direct coupling of organometallic regents of high reactivity in the presence of a catalyst. The utility of such reactions has been limited due to the inability of the organometallic reagents to tolerate sensitive functionalities. In the preparation of biaryl compounds under Suzuki conditions aryl boronic acids are reacted with aryl halides in the presence of a base and catalyst. Unlike most organometallic reagents, aryl boronic acids are generally air-stable and exhibit low toxicity. They are also especially noted for undergoing C-C bond formation in the presence of a wide variety of functional groups.

Of particular synthetic importance in the Suzuki methodology are the precursor aryl boronic esters which can be readily hydrolysed to the corresponding aryl boronic acid. A

great many aryl and alkene boronic acids and esters are most conveniently prepared from the corresponding tetrahydroxydiboron and its ester. For example Miyaura (Ishiyama, T et al. 3. Org. Chem. , 1995,60, 7508) has reported that the diboron ester, bis (pinacolato) diboron, reacts readily with aryl halides in the presence of palladium catalysts to produce arylboronic esters which are then readily converted to arylboronic acids. As such, the diboronic esters are important intermediates in the preparation of diboronic compounds for Suzuki coupling with alkene or aryl halides. Many useful reactions involving diboronic esters and organoboronic ester, including aryl and alkenyl boronic esters have been disclosed by Marcuccio et al in the following patent applications by Commonwealth Scientific and Industrial Research Organisation: WO 98/45265, WO 98/58935, WO 99/33845, WO 00/21966 and WO 01/29051.

Diboronic esters can be used directly in Suzuki methodology without converting them to their corresponding diboronic acid. In some applications the esters are actually favoured over the analogous acids. For example unlike many parent organoboronic acids the corresponding pinacol esters are discrete molecules which are more easily characterised and may often be purified by chromatography. Furthermore these pinacol esters are generally more soluble in organic solvents. In some instances the pinacol esters can be used as protecting groups to eliminate unwanted side reactions. Also, the use of diboronic esters has been recommended for Suzuki coupling (reaction) in cases where the organoboronic acids are sensitive to hydrolytic deborination.

Diboronic esters are generally made following the method of Brotherton et al. [R. J.

Brotherton, A. L. McCloskey, L. L. Peterson and H. Steinberg, J. Amer. Chez. Soc. 82, 6242 (1960) ; R. J. Brotherton, A. L. McCloskey, J. L. Boone and H. M. Manasevit, J. Amer.

Chem. Soc. 82,6245 (1960), Progress in Boron Chemistry by H. Steinberg and A. L.

McClosky, Pergamon Press, 1964, Library of Congress Catalog Number 64-13501 pages 14 and 15]. In this process B (NMe2) 3, obtained by reaction of BCl3 with NHMe2, is converted to BrB (NMe2) 2 by reaction with a stoichiometric amount of BBr3. Reduction in refluxing toluene with sodium metal gives the diboron compound [B (NMe2) 2] 2 which, after purification by distillation, can be reacted with the alcohol (for example, pinacol or

neopentanediol) in the presence of a stoichiometric amount (four equivalents) of HCl to give the desired ester product.

In this process it is believed that the addition of the HCl drives the reaction to completion by converting the continuously released dimethylamine to dimethylammonium hydrochloride salt (Me2NH+2Cl-), as a white precipitate. The conversion of the dimethylamine as its hydrochloride salt has a positive effect on the equilibrium of the reaction, favouring the formation of the product diboronic ester. This reaction, however, presents a number of practical problems, especially if large quantities of diboronic ester are required. For example the reaction is extremely exothermic which presents safety concerns, especially when the reaction is performed in the volatile solvent, diethyl ether, the usual solvent for the reaction. Also, the reaction requires the use of anhydrous HCl which requires the use of specialized equipment that is anti-corrosive in nature. This is especially important for moisture sensitive esters, like the diboronic neopentyl glycolato ester which is susceptible to moisture and prone to lose neopentylglycol. In a reaction where the alcohol is acid sensitive it is important to have the HCl content standardized since excess HCl may attack the acid sensitive moiety. For instance in the Miyaura et al example mentioned previously, excessive acid may attack the pinacol ester resulting in pinacol-pinacolone rearrangement.

A further problem with the conventional process is that the solid dimethylammonium hydrochloride salt product usually forms in lumps which complicates the reaction workup and requires mechanical stirring. Also this salt byproduct is hygroscopic which is again undesirable if one is trying to keep the reaction conditions anhydrous for moisture sensitive diboron esters.

The present invention attempts to overcome or eliminate these problems by providing a process for the preparation of diboronic esters which does not require the use of HCl and does not produce a salt byproduct.

SUMMARY OF THE INVENTION It has now been surprisingly found that diboronic acid (tetrahydroxydiboron) and esters of diboronic acid can be conveniently and efficiently prepared by simply reacting a tetrakis (dialkylamino) diboron with a suitable alcohol under conditions which liberate an alkylamine without using HCI.

Accordingly, the present invention provides a process for the preparation of an ester of diboronic acid comprising reacting a tetrakis (dialkylamino) diboron with an alcohol to form said ester and a volatile dialkylamine, wherein the volatile dialkylamine is liberated from the reaction mixture in gaseous form.

This process allows for the preparation of diboronic acid esters without using HCI, and without producing significant salt products. The process can also be performed in such a way that liberated amine can be trapped and recycled. These advantages can be translated into a reduction of the overall cost of making diboronic acid esters on an industrial scale.

The preferred tetrakis (dialkylamino) diboron compounds suitable for use in accordance with the present invention may be represented by formula (I) ; wherein R and R each independently represent Cl-C2 alkyl groups. In a preferred embodiment each R and R is identical and is selected from methyl, ethyl, and propyl or R and R together are joined to form a 5 or 6 membered ring system for example a piperidine, or pyrrolidine.

In the prior art procedure the reaction is driven by the concomitant production of the ammonium hydrochloride salt. The present process however does not form a similar salt product. Instead, the process of the present invention is thought to be driven by the liberation of a volatile amine from the reaction mixture. As such the preferred compounds of formula I bear R and R substituents which are small enough to produce volatile amines of the formula HNRR.

The alcohol may be any organic alcohol which is capable of reacting with a tetrakis (dialkylamino) diboron to form an ester of diboronic acid.

Preferably the alcohol is a compound of formula (IIa) : QOH (IIa) wherein Q is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl group, or optionally substituted aliphatic ring.

More preferably the alcohol is a diol of formula (II): HO- (CRR) n-OH (II) where n is 2 or 3 and each R is independently selected from hydrogen, optionally substituted Cl-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Cl-C6alkoxycarbonyl, optionally substituted C1-C6alkoxy, and optionally substituted aryloxy or any two R groups together with the carbon atoms (s) to which they are attached represent an optionally substituted Cs-csoycloalkyl or Cs- Cscycloalkenyl group.

In a particular embodiment each R is selected from H and methyl. Preferably R is not aryl.

Preferred diols include pinacol, neopentylglycol, hexyleneglycol and (+)-pinanediol.

Also preferred are diols of formula (I) which bear chiral substituents. Examples of chiral diols for use in the present invention include (-) or (+) -pinanediol or (D) or (L)-tartrate esters.

In the above definitions, the term"alkyl", used either alone or in compound words such as "alkenyloxyalkyl","alkylthio","alkylamino"and"dialkylamino"d enotes straight chain or branched alkyl, preferably Cl-6 alkyl. Examples of straight chain and branched alkyl 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, and 1,1, 2- trimethylpropyl.

The term"cycloalkyl"denotes cyclic alkyl groups, preferably Ces-8 cycloalkyl. Examples of cycloalkyl include mono-or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term"alkenyl"denotes groups formed from straight chain, or branched alkenes including ethylenically unsaturated alkyl or groups as previously defined, preferably 2-6 alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3- methyl-2-butenyl, 1-pentenyl, 1-hexenyl, and 3-hexenyl.

The term"cycloalkenyl"denotes cyclic alkene groups, preferably Ces-8 cycloalkenyl.

Examples of cycloalkenyl include cyclopentenyl, methyl cyclopentenyl, cyclohexenyl, cyclooctenyl, 1,3-cyclopentadienyl, 1, 3-cyclohexadienyl, and 1,4-cyclohexadienyl.

The term"aryl"is used herein in the broadest sense to refer to any aromatic ring or ring system, preferably having 3 to 20 carbon atoms. The ring or ring system may contain one

or more heteroatoms selected from N, S, and O. The aromatic rings may be carbocyclic, heterocyclic or pseudo aromatic, and may be mono or polycyclic ring systems. Examples of suitable rings include but are not limited to benzene, biphenyl, naphthalene, tetrahydronaphthalene, 1-benzylnaphthalene, pyridine, 4-phenylpyridine, 3-phenylpyridine, thiophene, benzothiophene, naphthothiophene, furan, pyrene, isobenzofuram, chromene, pyrrole, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, indole, indolizine, isoindole, purine, quinoline, isoquinoline, isothiazole, isooxazole, phenoxazine and the like, each of which may be optionally substituted. The term"pseudoaromatic"refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of 7r 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. Preferably the aryl group is an optionally substituted 5 or 6 membered aromatic ring.

The term"aliphatic ring or ring system"as used herein refers to a non-aromatic carbocyclic or heterocyclic ring or ring system, preferably having from 3 to 20 carbon atoms. The ring or ring system may have one or more double or triple bonds. Examples of suitable aliphatic rings include but are not limited to cyclobutane, cyclopentadiene, cyclohexanone, cyclohexene, spiro- [4, 5-decane] and hydrogenated or partially hydrogenated aromatic rings as described above.

In this specification"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, aryloxyalkyl, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, isocyano, cyano, formyl, carboxyl, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, imino, alkylimino, alkenylimino, alkynylimino, arylimino, benzylimino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy mercapto,

alkylthio, benzylthio, acylthio, sulphonamido, sulfanyl, sulfo and phosphorus-containing groups.

Preferably Q is an optionally substituted C1-C6 alkyl group. More preferably Q is an C1-C6 alkyl group.

In one embodiment, one or more of the R groups on compounds of formula (II) represents or includes at least one reactive functionality, for example, acid, alcohol, amine, etc. Such functionalities can be protected according to standard protection group chemistry. (See Greene and Wutz, "Protective Group Chemistry", 3rd Edition, 1999, John Wiley & Sons.) One of the many advantages of the present HCl free process is that acid sensitive protecting groups, like methoxymethyl (MOM) and benzyloxymethyl (BOM) ethers, are not susceptible to cleavage. As such the present process is amenable to the preparation of esters of diboronic acid which have acid sensitive groups. The synthesis of diboronic esters with diols possessing basic functionalities (for example, when one or more R is an amine) is generally difficult with the conventional HCl method since the products obtained are partially or fully protonated on their basic functionalities. The process according to the present invention does not have this inherent problem.

As used herein the term"liberated"refers to the process by which the produced HNR'R"is removed from the reaction process. The liberation of the volatile amine produced as a product in the present reaction can be achieved in a multitude of ways using standard laboratory equipment. In a preferred embodiment the amine product is produced at a reaction temperature which is greater than the boiling temperature of the amine. As such, it will be understood that the concept of"volatility"as used herein merely requires the resultant amine to have a boiling point which is lower than the boiling point of the reaction solvent. In such an instance the volatile amine can be liberated as a gas by passing a stream of inert gas into the reaction mixture. Preferably nitrogen is used for this purpose.

Alternatively, the volatile amine can also be removed under vacuum during the reaction.

Another of the advantages of the present invention is that the amine product can be easily collected. It can then be reused again to prepare further compound of formula I by the

Brotherton method which has already been discussed. The amine can be collected by distillation and direct condensation from the reaction mixture either at atmospheric or under reduced pressure. As such the process of the present invention also provides for the product amine to be readily collected and recycled as it is not converted to its hydrochloride salt The process is preferably performed at a reaction temperature which is higher than the boiling point of the produced amine. Preferably the reaction is performed at a temperature between 80°C-140°C. However, as mentioned previously, the reaction temperature will be dependant on both the boiling points of the reaction solvent and resulting amine byproduct.

Preferably the reaction is performed in a refluxing solvent. Preferred solvents are those which solubilise the reactants. A further advantage of the present invention is that it is not solvent specific. The reaction works well in both non-polar and polar solvents. Preferred solvents include toluene, xylene, heptane, dioxane, diethyl ether, dichloromethane, dimethyl sulphoxide, butyl acetate or benzene. More preferred solvents are toluene or xylene.

In another preferred embodiment the process is carried out without a solvent. In this embodiment the reactants are simply added together and heated for such a time as to produce the amine which is liberated as a gas. The main advantage of this method stems from the absence of a solvent, as the volatile amine can be collected in a substantially pure state, that is, without any accompanying solvent.

A further advantage of the process of the present invention is that after the liberation of the volatile amine the reaction mixture contains essentially only the desired diboronic ester.

Accordingly, the present process avoids the conventional steps of filtering off and washing the resultant ammonium salt.

A general procedure of a process of the invention utilizing a diol of formula II as the alcohol and a tetrakis (dialkylamino) diboron of formula I is set out below in Scheme 1.

Scheme 1 Accordingly in this generalized procedure the tetrakis (dialkylamino) diboron is added to a solution of diol (2 mol equivalent) in an appropriate solvent at room temperature or at ~5°C to 10°C below boiling point of the solvent. When the addition is carried out at room temperature, the mixture is then slowly heated. A slow stream of nitrogen can be used to disperse RRNH. When the addition is carried at-5°C to 10°C below boiling point of the solvent (after an induction time of about 5 to 120 seconds or even longer), a vigorous to mild evolution of RRNH is expected to occur. Preferably, the more vigorous the evolution of RR NH the faster the reaction. For diboronic ester compounds which are soluble in the reactant solvent at room temperature, the reactant solution can be filtered, for example on a No-2 sintered glass funnel. The solution can then be analysed by GC to establish purity. Usually the purity ranges between 95-99%. The solvent is then removed in vacuo to give the ester of the diboronic acid. Further purification may be accomplished using recrystallisation from an appropriate solvent or by chromatographic techniques.

The invention will now be described with reference to the following examples which illustrate some preferred embodiments of the invention. It is to be understood that the particularity of the following description is not to supersede the generality of the preceding description of the invention.

Example 1 Preparation of bis (pinacolato) diboron

a) In toluene Tetrakis (dimethylamino) diboron (FW: 197.926) (50.0 g, 0.2526 mol) was added neat within 10 minutes to a solution of pinacol (FW: 118.18) (60.0 g, 0.5077 mol) in toluene (250 mL) at room temperature. This mixture was then slowly heated to 85°C. Me2NH gas started to come off and after 20 minutes the temperature was slowly raised to 105°C and maintained for 30 minutes. A slow stream of nitrogen was used to disperse Me2NH. The solution was filtered on a sintered glass funnel. The solution was analysed by GC (98.1 % pure; 0.15% pinacol was left). The toluene** was removed in vacuo to give a colourless solid of bis (pinacolato) diboron*** (MF: C12H24B204 ; FW : 253.94) 64.10 g, 99.9 % of 98. 1% purity by GC. The resultant solid was recrystallised from petroleum (80°C-100°C) (0.5 L): 53.89 g, 84.0 %, 99.7% pure by GC. mp. 137°C-140 °C.'H 5 (CDCl3, 200 MHz) 1.23 (s, 24H) ppm. 13C 8 (CDCl3, 50 MHz) 24.9 (8x CH3); 83.4 (4x C) ppm. The mother liquor was kept for further recrystallization. * This method was fast and easy to perform.

* It was sufficient to keep the reaction mixture under a blanket of nitrogen.

** Recrystallisation of the product was carried out using either petroleum (80°C-100°C) [fine pearly crystals], or toluene: petroleum (60°C-80°C) (1: 9) [coarser crystals of 3-5 mm]. In last mentioned case total removal of toluene from the crude reaction mixture is thus not necessary.

*** In one case the crude product was dissolved in an organic solvent and an aqueous wash was included to remove traces of pinacol.

b) In heptane Tetrakis (dimethylamino) diboron (3.96 g, 20 mmol) was added neat within one minute to a mixture of pinacol (4.72 g, 40 mmol) in heptane (20 mL) at 40°C. The temperature was raised to 98°C. After an induction period of 5 minutes a vigorous evolution of Me2NH resulted. The temperature was maintained for 30 minutes at 98° C. Heptane (-20 mL) was used to decant and wash the solid residues (-29 mg) *. The combined solution was subjected to a slow stream of nitrogen to disperse the Me2NH and some solvent (maximum volume 30 mL). GC revealed 97.7% purity. The solution was allowed to stand at room temperature for 18 hours and 1 hour at 0° C. A Pasteur pipette was used to remove the liquid from the crystals. The crystals were dried in a steady stream of nitrogen and heptane was removed in vacuo to give a colourless solid of bis (pinacolato) diboron (4.60 g, 90.5 % of >98 % purity by GC). The mother liquor was kept for further recrystallisations.

*Note: This material was insoluble in heptane and caused a solubility problem. It is possible that this material is formed from hydrolysis of a small amount of starting material. c) In dioxane Tetrakis (dimethylamino) diboron (3.96 g, 20 mmol) was added neat (within one minute) to a mixture of pinacol (4.72 g, 40 mmol) in dioxane (20 mL) at 40°C. The temperature was raised to 100°C. After an induction period of-10 minutes a vigorous evolution of Me2NH resulted. The temperature was maintained for 30 minutes at 100°C. The solvent was removed on the rotary evaporator to give a quantitative yield of bis (pinacolato) diboron.

The solid was dissolved in petroleum (60°C-80°C) (40 mL) and hot filtered to remove residues (-100 mg). The filtrate was further washed with petroleum (60°C-80°C). The combined solution was subjected to a slow stream of nitrogen to disperse Me2NH and some solvent (maximum volume 35 mL). GC revealed 97.4% purity. The solution was allowed to stand at room temperature for 18 hours and 1 hour at 0°C. A Pasteur pipette was used to remove the liquid from the crystals. The crystals were dried in a steady stream of nitrogen and the petroleum was removed in vacuo to give a colourless solid of

bis (pinacolato) diboron (-4. 6 g, 90 % of >99 % purity by GC). The mother liquor was kept for further recrystallisations. Note: For this procedure, the reaction is somewhat sluggish to start. d) In diethyl ether Tetrakis (dimethylamino) diboron (1.00 g, 5.05 mmol) was added neat (within one minute) to a mixture of pinacol (1.20 g, 10.15 mmol) in diethyl ether (10 mL) at room temperature and stirred for 18 hours. Nitrogen was used to blow off Me2NH and diethyl ether removed Yield: quantitative 97% pure by GC. The aforementioned recrystallization procedure gave bis (pinacolato) diboron 99% pure by GC. e) In dichloromethane Tetrakis (dimethylamino) diboron (1.00 g, 5.05 mmol) was added neat (within one minute) to a mixture of pinacol (1.20 g, 10.15 mmol) in dichloromethane (10 mL) at room temperature and stirred for 18 hours. Fine, white needles precipitated. Addition of petroleum spirits (40°C-60°C) (50 mL) gave a further precipitate of (Me2NH+) 2CH2. 2Cl-.

The clear solution was evaporated to dryness to give bis (pinacolato) diboron (1.12 g, 87. 5% and 97.7% pure by GC). Although this method worked, it is not a preferred method. f) In dimethylsulfoxide Tetrakis (dimethylamino) diboron (0.50 g, 5.077 mmol) was added neat (within one minute) to a mixture of pinacol (0.60 g, 2.53 mmol) in dimethylsulfoxide (10 mL) at 80°C. and heated for 10 minutes at 110° C. The mixture allowed to stand for 18 hours at room temperature. Fine, white needles had precipitated. Addition of petroleum spirits (40°C- 60°C) (5x 5 mL) extracted bis (pinacolato) diboron which was evaporated to dryness (0.37 g, 57.8% and 98.9% pure by GC). Some residual solvent (DMSO) makes this procedure less desirable for high purity production.

g) In butyl acetate Tetrakis (dimethylamino) diboron (0.50 g, 2.53 mmol) was added neat (within one minute) to a mixture of pinacol (0.60 g, 5.08 mmol) in butyl acetate (5 mL) at 80°C and then heated to 110° C for 10 minutes. This mixture was kept 18 hours at room temperature. Nitrogen was used to blow off Me2NH and butyl acetate was removed. Crude yield: (0.61 g, 95.2% ; 96% pure by GC). The usual recrystallization procedure gave bis (pinacolato) diboron (0.32g, 49.9% ; 99% pure by GC). The mother liquor was kept for further recrystallisations.

Some crystalline dimethyl acetamide as byproduct was also obtained. h) Without solvent Pinacol (4.72 g, 40 mmol) was heated to 50°C, whereby it melted.

Tetrakis (dimethylamino) diboron (3.96 g, 20 mmol) was added to this melt (within two minutes) and thoroughly mixed. After five minutes at 50°C, the reaction temperature was raised to 100°C. During the heating process, a milkiness started to appear with the simultaneous evolution of Me2NH over a period of fifteen minutes. The reaction mixture had then totally solidified but was kept for a further 15 minutes at 100°C. A stream of nitrogen was used to remove Me2NH. Yield : 4.99 g, 98. 3%, 98.3% pure of soluble material. The solid was dissolved in petroleum (60°C-80°C) (40 mL) and filtered hot to remove residues (-290 mg). The filtered residue was further washed with petroleum (60°C-80°C). The combined solution was subjected to a slow stream of nitrogen to evaporate some solvent (maximum volume 35 mL). The solution was allowed to stand at room temperature for 18 hours and 1 hour at 0°C. A Pasteur pipette was used to remove the liquid from the crystals. The crystals were dried in a steady stream of nitrogen and evacuated to remove any residual petroleum to give bis (pinacolato) diboron as a colourless solid (4.78 g, 94.2 % of >99 % purity by GC). The mother liquor was kept for further recrystallisations.

Example 2 Preparation of bis (neopentylglvcolato) diboron Tetrakis (dimethylamino) diboron (9.89 g, 52.65 mmol) was added to a solution of 2,2- dimethyl-1, 3-propanediol [neopentylglycol] (10.42 g, 100 mmol) in toluene (40 mL) at room temperature within two minutes. The mixture was heated to 105°C and an evolution of dimethylamine started to occur at 85°C. The mixture was heated for 60 minutes at 105°C then the toluene was removed to give a white solid: 11.39 g, 95.8%.

Recrystallisation from toluene gave bis (neopentylglycolato) boron (MF: CloH20B204 ; FW: 225.89) 6.48 g, 54.5%. mp 182.5-184. 5 °C. 8 (CDCl3, 200 MHz) 0.94 (s, 12H); 3.58 (s, 6H) ppm. 13C 8 (CDCl3, 50 MHz) 22.3 (4x CH3) ; 31.9 (2x C), 71.7 (4x CH2) ppm. The mother liquor was kept for further recrystallization.

Example 3 Preparation of bis (hexylen glycolato) diboron Hexyleneglycol (2-methyl-2,4-pentanediol) (FW: 118. 18. 12.0 g, 101. 6 mmol) in toluene (40 mL) was treated with tetrakis (dimethylamino) diboron (FW: 197.926 ; 9.9 g, 50 mmol) at room temperature and the reaction mixture stirred. The temperature was raised to 100°C within 10 minutes while the release of dimethylamine started to occur after about 5 minutes. The temperature was maintained at 100°C. for 60 minutes at which time for 30 minutes the evolution of dimethylamine occurred. Toluene was removed to give a solid (99.6% pure by GC). The solid was recrystallised from toluene: petroleum (80°C-100 °C) (1: 9) to give a colourless solid of bis (hexylene glycolato) diboron (MF: C12H24B204 ; FW : 253.94) : 8. 83 g, second crop: 3.69 g, combined yield 12.52 g, 98. 6%; 99.6% pure by GC. mp 99-101. 6 °C. 8 (CDC13, 200 MHz) 1.21 (d, J= 7Hz, 6H); 1.28 (s, 12H); 1.47 (dd, J=12,14 Hz, 2H); 1.70 (dd, J=14,3 Hz; 2H) 4.14 (dm, 2H) ppm. 13C 8 (CDCl3, 50 MHz) 23.1 ; 28.3 ; 31.2 ; 46. 2 ; 64.1 ; 70.3 ppm.

Example 4 Preparation of bis ((lS2S, 3R, 5R) (+)-pinanediolato) diboron (+) -Pinanediol (5.00 g, 29.37 mmol) in toluene (20 mL) was heated to 50°C and treated with tetrakis (dimethylamino) diboron (2.90 g, 14.65 mmol) within two minutes. This mixture was then slowly heated to 100°C. and after an induction period of about 5 minutes evolution of Me2NH gas commenced. The mixture was maintained at 100°C. for 30 minutes. A slow stream of nitrogen was used to disperse Me2NH. The toluene was removed (rotary evaporation) to give in quantitative yield a white solid bis ((lys, 2S, 3R, 5R) (+) -pinanediolato) diboron of 99.7% purity. The solid was recrystallised from toluene: petroleum (80°C-100°C) (1: 9) (20 mL) and after standing at room temperature for 18 hours bis ((lS, 2S, 3R, 5R) (+) -pinanediolato) diboron (MF: C2oH32B204 ; FW: 358. 1) 4. 51 g, 86. 6%; 99.6% pure. mp. 150°C. 1H 6 (CDCl3, 200 MHz) 0.82 (s, 6H); 1.08 (d, J=6Hz, 2H); 1.26 (s, 6H); 1.38, (s, 6H); 1. 8-2. 4 (m, 10H) ; 4.24 (dd, J=6, 1 Hz, 2H) ppm. The mother liquor was subjected to further recrystallization (0.31 g, 5.9%, 99.6% purity).

Example 5 Preparation of bis (diethyl-L-tartrate glycolato) diboron Tetrakis (dimethylamino) diboron (5.0 g, 25.2 mmol) was added neat within 2 minutes to a solution of diethyl L-tartrate (10,4 g, 50.44 mmol) in toluene (40 mL) at-105°C within 5 minutes. An immediate vigorous evolution of Me2NH occurred (CAUTION). The solution was cooled to room temperature and analysed by GC and shown to be quantitative with 88% purity. The solution was dried on the high vacuum pump to give a colourless viscous oil of bis (diethyl-L-tartrate glycolato) diboron (MF: C16H24B2012 ; FW : 429.99).

This oil slowly partially crystallised at room temperature. 8 (CDCl3, 200 MHz) 1.30 (t, J= 7Hz, 12H); 4.26 (q, J=7Hz; 8H); 4.92 (s, 4H) ppm.

Example 6 Preparation of bis (di-n-butyl-L-tartrate glvcolato) diboron Di-n-butyl L-tartrate (2.65 g, 10.10 mmol) in toluene (20 mL) was heated to 100°C Tetrakis (dimethylamino) diboron (1.0 g, 5.05 mmol) was added neat within 2 minutes to this solution. After an induction period of between 5 and 10 minutes a slow (sluggish) release of Me2NH occurred. The mixture was kept at 100 °C for 60 minutes. The solution was cooled to room temperature and analysed by GC and shown to be only 78. 8% pure.

The solution was evaporated and then dried on the high vacuum pump to give a colourless viscous oil of bis (di-n-butyl-L-tartrate glycolato) diboron (MF: C24H40B2012). S (CDC13, 200 MHz) 0.88 (t, J= 7Hz, 12H); 1.32 (m, 8H) ; 1.64 (m, 8H), 4.10 (q, J=7Hz; 8H); 4.80 (s, 4H) ppm.

Example 7 Preparation of bis (diisopropyl-D-tartrate slycolato) diboron Diisopropyl D-tartrate (FW: 234. 25 ; 2.34 g, 9.99 mmol) in toluene (20 mL) was heated to 100° C. Tetrakis (dimethylamino) diboron (1.0 g, 5.05 mmol) was added neat within 2 minutes to this solution. After an induction period of about 10 minutes a slow release of Me2NH was observed. The mixture was kept at 100°C for 60 minutes. The solution was cooled to room temperature and analysed by GC and shown to be 78.8% pure. The solvent was removed in vacuo to give a colourless viscous oil of bis (diisopropyl-D-tartrate glycolato) diboron (MF : C2oH32B2012 ; FW: 486.106). This oil slowly crystallised at room temperature or at 0 °C. Yield: quantitative; 91.5% pure by GC. mp 85°C. 8 (CDCl3, 200 MHz) 1.26 (d, J=6Hz, 24H); 4.82 (s, 4H); 5.08 (h, J=6Hz; 4H) ppm. 13C 8 (CDCl3, 50 MHz) 21.4 ; 69.9 ; 77.8 ; 168.2 ppm.

Example 8 Preparation of bis (diethyl-D-tartrate glycolato) diboron This compound was prepared in accordance with the method described.

The combined solutions were rotavaporated and then further dried on the high vacuum pump to give a colourless viscous oil of bis (diethyl-D-tartrate glycolato) diboron (MF: C16H24B2012 ; FW: 429.99) 21.20 g, 96.8 % of 99.6% purity by GC which crystallised within 15 hours at 15°C ; mp 45°C. The white solid was recrystallised from toluene: petroleum (80°C-100°C.) (2: 3) (60 mL). 8 (CDCl3, 200 MHz) 1.30 (t, J= 7Hz, 12H); 4.26 (q, J=7Hz; 8H); 4.92 (s, 4H) ppm.

A summary of the results of Examples 1 to 8 is provided in tables I, II and III.

TABLE 1.

Preparation of Diboronic esters in solvent

Ex Diboronic ester. Analysis of crude Analysis of Solvent, temperature product recrystallised product Yield Purity Yield Purity by GC by GC la 0 O 99. 9 % 98. 1% 84. 5% 99. 7% - -B r" \buzz O O in toluene/105 °c 95. 8 % 99. 1 % 54. 5%"99% vt BBs 9s A-o'o-A in toluene/105 °C 3-99% 99. 3% 98. 6% 99. 6% O O s B-B 0 0 in toluene/105°c q. 99 %, 99. 7 % 92. 5% 99. 6 OU B-B O \O in toluene/105 °c 5 EtO2C///Co\/O_co2Et 99% 88 % ! B-B ! EtOC O O tlIICO2Et in toluene/105 °c 6 Bu02C/>O\/OrCO2Bu 99% 78. 8% B-B/-' Bu02C O O ll/CO2Bu in toluene/105 °c 7 PrlO2CgO\/O, \\\CO2Pri 99% 91. 5% Bob i I i Pr0 C1 O 0I _CO Pr z z in toluene/105 °c EtOpC O O, pCOzEt 91% /B--B EtO2C\'QO OjCO2Et z in xylenes/130 °C "The mother liquor contained more compound.

TABLE II.

Solvent (and temperature) effect on the preparation of bis (pinacolato) diboron Ex solvent Reaction temperature GC purity Crude Recrystallised Purity and time solution yield yield by GC 1 a toluene 110 °C/30 min 98.1 84. 5% # 99. 7% lb heptane 98 °C/60 min 97. 7% 90. 6 97. 3* 1 c dioxane 100 °C/90 min 97. 4% >90% >99% 1d Et2O 20°C/18 hours 96.8% #99% 1e CH2Cl2 20°C/18 hours 97.7% 87. 5% lf DMSO 110°C/10 min 98 % 57.8% 98.9% 18 h room temp. 1g BuOAc 110°C/10 min. 96% 95.2% 49.9% #99% 18h room temp. &num Mother liquor contains more compound.

TABLE III.

Reaction without solvent

Ex Diboronic ester. Analysis of crude Analysis of recrystallised at temperature in °C. product product Yield Purity by Yield Purity by GC GC lh p p 98. 3% 98. 4% 94. 2% 99. 0% B-B O \O 100°C

Throughout this specification and the claims which follow, unless the context requires otherwise, the word"comprise", or variations such as"comprises"or comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions, and referred to or indicated in the specification, individually or collectively, and any and all combinations of any two or more said steps or features.