Mild and Selective Synthesis of an Aryl Boronic Ester by Equilibration of Mixtures of Boronic and Borinic Acid Derivatives

Vanessa F. Hawkins, Mark C. Wilkinson, and Matthew Whiting
Synthetic Chemistry, Chemical DeVelopment, GlaxoSmithKline, Gunnels Wood Road, SteVenage, Hertfordshire SG1 2NY, U.K.

 

Introduction
As part of a synthetic programme a convenient procedure was required for the synthesis of pinacol boronic ester 1 on multikilogram (multi-kg) scale. Aryl boronic acids and esters1 have become ubiquitous in synthetic chemistry in both industrial and academic settings, predominantly due to their straightforward use in a wide range of transition metal-catalysed coupling reactions.2 The most common way to access these compounds is by the electrophilic trapping of aryl metal species (generally the aryllithium or Grignard reagent) with a borate ester. Unfortunately this reaction often leads to borinic acid and borane byproducts which arise from second and third additions of the aryl metal reagent into the borate ester. Several options are available to minimise formation of these generally undesired byproducts, most notably use of cryogenic conditions,3 in situ quenching protocols,4 and/or large excesses of hindered alkyl borate esters3 such as triisopropyl borate or isopropyl pinacol borate. Whilst the necessity for use of such conditions does not prevent the reactions from being carried out on large scale, use of more ambient temperatures and only stoichiometric amounts of the borate esters is highly desirable from a process efficiency and operability point of view.5 Also, in a number of cases, particularly those involving electron-rich aryl groups, the borinic acid is often still formed in significant quantities irrespective of the reaction conditions used.6 We have found that in certain cases mixtures of boronic and borinic acid derivatives formed under relatively mild reaction conditions can be readily equilibrated
to give solely the boronic ester with high selectivity.

 

Results and Discussion
On a small scale, selective formation of the desired boronic ester 1 was readily accomplished in high yield by iodine magnesium exchange of iodide 2 using i-PrMgCl in THF at-10 °C followed by addition of isopropyl pinacol borate (3) (Scheme 1). After warming to room temperature overnight and derivatives 4 were shown to be kept to trace amounts either by very slow addition of 3, maintaining the internal temperature at -10 °C until complete addition had occurred or, alternatively, by very rapid addition of the borolane in one portion. Conversely if only 0.6 equiv of 3 was added and the reaction allowed to warm to room temperature, up to 60% of the borinic acid 4 (R ) H) was formed. This did not look ideal for scale up as very fast addition was likely to be impossible and very slow addition is inefficient from a processing perspective.

 

Interestingly, during our development work we had noticed that the borinic acid derivatives in the crude reaction mixture slowly converted to the desired boronate 1 if the reaction mixture was allowed to stir at room temperature for extended periods of time. Gentle heating of these reaction mixtures accelerated this equilibration, and thus, even a reaction mixture containing artificially high levels of the borinic acid of up to 60% could be completely equilibrated through to the desired boronic ester simply by warming the reaction mixture to 50 °C for 1 h. This observation meant that upon scale up we would be able to carry out the addition in a relatively uncontrolled fashion and still obtain high selectivity for the desired product. As far as we are aware this type of equilibration has not been reported previously;
however, it is not entirely unexpected, as it is known that the boronic acid derivatives are the thermodynamically more stable species.1

 

On scale up to the pilot plant we opted to telescope the boronate formation onto formation of iodide 2 the isolation of which was complicated by a voluminous crystal form. Thus 4-chloro-2-iodophenol (5) was alkylated with 4-chloro-2-fluorobenzyl bromide (6) using K2CO3 in acetone. After concentration, dilution with toluene, and an aqueous workup the toluene solution of 2 was dried by azeotropic distillation before being cooled to -10 °C and treated with i-PrMgCl in THF to effect iodine-magnesium exchange. The Grignard reagent obtained was treated with 3 and allowed to warm to room temperature, giving the desired boronic ester containing up to 30% of the undesired borinic acid derivatives (Scheme 2). Warming this crude reaction mixture to 50 °C for 1 h promoted complete equilibration to the desired product 1 which was isolated by crystallisation from 2-propanol in 78% yield and >99.9% purity.

 

Several experiments were run to further probe this interesting observation. The parent system, using phenyl magnesium chloride (7a), along with simply substituted derivatives using both p- and o-methoxy phenylmagnesium bromide (7b and 7c) were investigated. Solutions of the desired boronates (8a-c) containing artificially elevated levels of the borinic acid derivatives 9a-c were prepared by addition of 1 equiv of Grignard reagent to a solution of 0.6 equiv of the borolane at 0 °C. After stirring for 30 min a further 0.6 equiv of borolane was added, and the mixtures were then warmed to promote equilibration
to the boronate. The relative amounts of borinic acid and boronic acid derivatives were monitored by LC/UV analysis using dimethoxybenzene as an internal standard (Table 1).

 

The parent case using phenyl magnesium chloride initially gave a 1.2:1 mixture of borinic and boronic acid derivatives; upon warming no change in this mixture was observed even after extended periods at reflux (Table 1, entry 1). Using p-methoxyphenylmagnesium bromide, a 1:1.2 mixture of borinic and boronic acid derivatives was formed, and again no conversion was observed upon heating the reaction mixture (entry 2). In contrast upon gentle warming of the reaction mixture derived from o-methoxyphenylmagnesium bromide rapid equilibration to almost entirely the boronate 8c was observed (entry 3).

 

In this series of experiments it therefore appears that the presence of an o-alkoxy group is vital for this equilibration to proceed.

We next briefly investigated use of alternative borate esters (Table 2) in the hope we would be able use a more readily available derivative in place of the relatively expensive isopropyl pinacol borate (3).
The mixture of borinic and boronic acid derivatives derived from isopropyl pinacol borate, as has been seen, readily equilibrated with gentle warming to give almost exclusively boronate 9c (Table 2, entry 1). When triisopropyl borate is used instead, equilibration did occur; however, it was very slow, and competitive proto-deboronation occurred (entry 2). When the simplest borate ester trimethyl borate was used, no equilibration of the initially formed mixture was observed (entry 3); it thus appears that the use of isopropyl pinacol borate is a necessity for efficient equilibration.

 

In summary we have shown that in certain cases reaction mixtures containing both borinic and boronic acid derivatives, obtained by the quenching of aryl Grignard reagents with isopropyl pinacol borate, undergo equilibration upon gentle warming to give only the boronic ester with high selectivity. This observation enables the selective synthesis of certain boronic esters under milder conditions than previously realisable, thus facilitating reaction scale up. We have demonstrated this process on multi-kg scale by the successful synthesis of pinacol boronic ester 1 and expect it to be applicable to the synthesis of a range of other building blocks in the pharmaceutical and fine chemicals industries.
 

Aryl boronic acids and esters1 have become ubiquitous in synthetic chemistry in both industrial and academic settings, predominantly due to their straightforward use in a wide range of transition metal-catalysed coupling reactions:

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CAS No. 101580-70-5 Benzene, 1,2-dibromo-4-methyl-5-nitro- Catalog No.:AG0004UP MDL No.:MFCD23135744 MF:C7H5Br2NO2 MW:294.9281	CAS No. 101580-93-2 Acetic acid, 2-chloro-, 3,4-dichlorophenyl ester Catalog No.:AG0004UO MDL No.: MF:C8H5Cl3O2 MW:239.4831	CAS No. 101581-02-6 2-Oxabicyclo[3.2.1]octan-3-one, 1-methyl- Catalog No.:AG0004UN MDL No.: MF:C8H12O2 MW:140.1797
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CAS No. 101582-69-8 Ethanol, 2,2'-[[4-(phenylmethoxy)phenyl]imino]bis- Catalog No.:AG0004UJ MDL No.: MF:C17H21NO3 MW:287.3535	CAS No. 101584-40-1 Carbamic acid, N,N-bis(phenylmethyl)-, ethyl ester Catalog No.:AG0004UI MDL No.: MF:C17H19NO2 MW:269.3383	CAS No. 1015844-72-0 1H-Pyrazol-5-amine, 3-(3-fluorophenyl)-1-phenyl- Catalog No.:AG0004UC MDL No.:MFCD06738763 MF:C15H12FN3 MW:253.2743
CAS No. 1015845-52-9 1H-Pyrazole-4-carboxaldehyde, 1-(2-fluorophenyl)- Catalog No.:AG0004UB MDL No.:MFCD05864518 MF:C10H7FN2O MW:190.1738	CAS No. 1015845-54-1 1H-Pyrazole-4-methanamine, 1-(3-methoxyphenyl)- Catalog No.:AG0004UA MDL No.:MFCD08059756 MF:C11H13N3O MW:203.2404	CAS No. 1015845-56-3 Benzaldehyde, 5-methoxy-2-(1H-pyrazol-1-yl)- Catalog No.:AG0004U9 MDL No.:MFCD08059860 MF:C11H10N2O2 MW:202.2093
CAS No. 1015845-57-4 1H-Pyrazole-4-methanamine, 1-ethyl-N-(2-methoxyethyl)-3,5-dimethyl- Catalog No.:AG0004U8 MDL No.:MFCD08691489 MF:C11H21N3O MW:211.3039	CAS No. 1015845-58-5 1H-Pyrazole-4-methanamine, N-(2-methoxyethyl)-1,3,5-trimethyl- Catalog No.:AG0004U7 MDL No.:MFCD08691493 MF:C10H19N3O MW:197.2774	CAS No. 1015845-60-9 1H-Pyrazole-4-methanamine, N-(2-methoxyethyl)-1-methyl- Catalog No.:AG0004VK MDL No.:MFCD08691494 MF:C8H15N3O MW:169.2242
CAS No. 1015845-62-1 1H-Pyrazol-5-amine, 4-methyl-1-[(3-methylphenyl)methyl]- Catalog No.:AG0004VJ MDL No.:MFCD08457369 MF:C12H15N3 MW:201.2676	CAS No. 1015845-64-3 1H-Pyrazol-5-amine, 1-[(3-fluorophenyl)methyl]-4-methyl- Catalog No.:AG0004VI MDL No.:MFCD08691580 MF:C11H12FN3 MW:205.2315	CAS No. 1015845-66-5 1H-Pyrazol-5-amine, 1-(1-methylbutyl)- Catalog No.:AG0004VH MDL No.:MFCD08457390 MF:C8H15N3 MW:153.2248
CAS No. 1015845-68-7 1H-Pyrazol-5-amine, 1-[(2-chlorophenyl)methyl]-4-methyl- Catalog No.:AG0004VG MDL No.:MFCD08457375 MF:C11H12ClN3 MW:221.6861	CAS No. 1015845-70-1 1H-Pyrazol-5-amine, 1-[(3-chlorophenyl)methyl]-4-methyl- Catalog No.:AG0004VF MDL No.:MFCD08457374 MF:C11H12ClN3 MW:221.6861	CAS No. 1015845-71-2 Pyrimidine, 4-chloro-6-(4-methyl-1H-pyrazol-1-yl)- Catalog No.:AG0004VE MDL No.:MFCD08691760 MF:C8H7ClN4 MW:194.6210
CAS No. 1015845-73-4 1H-Pyrazol-3-amine, 4-[4-(1,1-dimethylethyl)phenyl]- Catalog No.:AG0004VD MDL No.:MFCD19317394 MF:C13H17N3 MW:215.2942	CAS No. 1015845-74-5 1H-Pyrazole-4-methanamine, 1-(2-methoxyphenyl)-α-methyl- Catalog No.:AG0004VC MDL No.:MFCD08691422 MF:C12H15N3O MW:217.2670	CAS No. 1015845-75-6 1H-Pyrazole-5-carboxylic acid, 1-ethyl-3-(2-methylpropyl)- Catalog No.:AG0004VB MDL No.:MFCD08059761 MF:C10H16N2O2 MW:196.2462
CAS No. 1015845-77-8 1H-Pyrazole-4-carboxylic acid, 1-(2-methoxyphenyl)- Catalog No.:AG0004VA MDL No.:MFCD05864512 MF:C11H10N2O3 MW:218.2087	CAS No. 1015845-78-9 1H-Pyrazol-5-amine, 4-(2-methoxyphenyl)-1,3-dimethyl- Catalog No.:AG0004V9 MDL No.:MFCD08059786 MF:C12H15N3O MW:217.2670	CAS No. 1015845-79-0 1H-Pyrazole-4-methanamine, 1-ethyl-N-(1-methylethyl)- Catalog No.:AG0004V8 MDL No.:MFCD08691485 MF:C9H17N3 MW:167.2514
CAS No. 1015845-80-3 1H-Pyrazole-4-methanamine, 1-methyl-N-(2-methylpropyl)- Catalog No.:AG0004V7 MDL No.:MFCD08691488 MF:C9H17N3 MW:167.2514	CAS No. 1015845-81-4 1H-Pyrazole-4-methanamine, 1-ethyl-N-(2-methoxyethyl)- Catalog No.:AG0004V6 MDL No.:MFCD08691495 MF:C9H17N3O MW:183.2508	CAS No. 1015845-83-6 1H-Pyrazole-4-carboxaldehyde, 1-[4-(1-methylethyl)phenyl]- Catalog No.:AG0004V5 MDL No.:MFCD08691536 MF:C13H14N2O MW:214.2631
CAS No. 1015845-84-7 Benzaldehyde, 5-fluoro-2-(1H-pyrazol-1-yl)- Catalog No.:AG0004V4 MDL No.:MFCD08059861 MF:C10H7FN2O MW:190.1738	CAS No. 1015845-86-9 Benzaldehyde, 2,4-dimethyl-6-(1H-pyrazol-1-yl)- Catalog No.:AG0004V3 MDL No.:MFCD08059862 MF:C12H12N2O MW:200.2365	CAS No. 1015845-87-0 Benzaldehyde, 3,5-dimethyl-2-(1H-pyrazol-1-yl)- Catalog No.:AG0004V2 MDL No.:MFCD08059863 MF:C12H12N2O MW:200.2365
CAS No. 1015845-89-2 Benzaldehyde, 2-methyl-4-(1H-pyrazol-1-yl)- Catalog No.:AG0004V1 MDL No.:MFCD08059904 MF:C11H10N2O MW:186.2099	CAS No. 1015845-91-6 1H-Pyrazol-5-amine, 1-(1,2-dimethylpropyl)- Catalog No.:AG0004V0 MDL No.:MFCD08457391 MF:C8H15N3 MW:153.2248	CAS No. 1015845-93-8 1H-Pyrazol-5-amine, 1-(3-cyclohexen-1-ylmethyl)- Catalog No.:AG0004UZ MDL No.:MFCD08457377 MF:C10H15N3 MW:177.2462
CAS No. 1015845-94-9 1H-Pyrazol-5-amine, 1-[(3-fluorophenyl)methyl]- Catalog No.:AG0004UY MDL No.:MFCD08691578 MF:C10H10FN3 MW:191.2049	CAS No. 1015845-95-0 1H-Pyrazol-5-amine, 3-methyl-1-[(3-methylphenyl)methyl]- Catalog No.:AG0004UX MDL No.:MFCD08457368 MF:C12H15N3 MW:201.2676	CAS No. 1015845-96-1 1H-Pyrazol-5-amine, 1-[(4-fluorophenyl)methyl]-4-methyl- Catalog No.:AG0004UW MDL No.:MFCD08691581 MF:C11H12FN3 MW:205.2315
CAS No. 1015846-01-1 1H-Pyrazol-5-amine, 1-[(4-chlorophenyl)methyl]-4-methyl- Catalog No.:AG0004W6 MDL No.:MFCD08457373 MF:C11H12ClN3 MW:221.6861	CAS No. 1015846-02-2 1H-Pyrazol-5-amine, 1-(1-ethylpropyl)-4-methyl- Catalog No.:AG0004W5 MDL No.:MFCD08457388 MF:C9H17N3 MW:167.2514	CAS No. 1015846-03-3 Benzaldehyde, 4-[[6-(1H-pyrazol-1-yl)-4-pyrimidinyl]oxy]- Catalog No.:AG0004W4 MDL No.:MFCD00299070 MF:C14H10N4O2 MW:266.2548
CAS No. 1015846-04-4 Benzoic acid, 3-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)- Catalog No.:AG0004W3 MDL No.:MFCD08691860 MF:C12H13N3O2 MW:231.2505	CAS No. 1015846-06-6 1H-Pyrazole-4-carboxylic acid, 3,5-dimethyl-1-(2-propen-1-yl)- Catalog No.:AG0004W2 MDL No.:MFCD08691921 MF:C9H12N2O2 MW:180.2038	CAS No. 1015846-07-7 Ethanone, 1-[1-(2-methylphenyl)-1H-pyrazol-4-yl]- Catalog No.:AG0004W1 MDL No.:MFCD09055191 MF:C12H12N2O MW:200.2365
CAS No. 1015846-08-8 Ethanone, 1-[1-(3-methylphenyl)-1H-pyrazol-4-yl]- Catalog No.:AG0004W0 MDL No.:MFCD09055192 MF:C12H12N2O MW:200.2365	CAS No. 1015846-09-9 Ethanone, 1-[1-(4-methoxyphenyl)-1H-pyrazol-4-yl]- Catalog No.:AG0004VZ MDL No.:MFCD09055193 MF:C12H12N2O2 MW:216.2359	CAS No. 1015846-11-3 Ethanone, 1-[1-(3-methoxyphenyl)-1H-pyrazol-4-yl]- Catalog No.:AG0004VY MDL No.:MFCD09055194 MF:C12H12N2O2 MW:216.2359
CAS No. 1015846-12-4 Ethanone, 1-[1-(2-methoxyphenyl)-1H-pyrazol-4-yl]- Catalog No.:AG0004VX MDL No.:MFCD09055195 MF:C12H12N2O2 MW:216.2359	CAS No. 1015846-14-6 1H-Pyrazole-4-methanamine, 1-(3-methoxyphenyl)-N-methyl- Catalog No.:AG0004VW MDL No.:MFCD09055227 MF:C12H15N3O MW:217.2670	CAS No. 1015846-17-9 1H-Pyrazole-4-methanamine, 3-(4-fluorophenyl)- Catalog No.:AG0004VV MDL No.:MFCD09802305 MF:C10H10FN3 MW:191.2049
CAS No. 1015846-18-0 1H-Pyrazol-5-amine, 4-(4-methoxyphenyl)-1,3-dimethyl- Catalog No.:AG0004VU MDL No.:MFCD09055260 MF:C12H15N3O MW:217.2670	CAS No. 1015846-20-4 1H-Pyrazole-4-ethanamine, 1-ethyl-3,5-dimethyl- Catalog No.:AG0004VT MDL No.:MFCD06804128 MF:C9H17N3 MW:167.2514	CAS No. 1015846-23-7 1H-Pyrazole-4-methanamine, 1-methyl-N-(1-methylethyl)- Catalog No.:AG0004VS MDL No.:MFCD09055384 MF:C8H15N3 MW:153.2248
CAS No. 1015846-31-7 Pyrimidine, 4-chloro-2-methyl-5-(1-methylethyl)- Catalog No.:AG0004VR MDL No.:MFCD09971217 MF:C8H11ClN2 MW:170.6393	CAS No. 1015846-32-8 Pyrimidine, 4-chloro-5-(1-methylethyl)- Catalog No.:AG0004VQ MDL No.:MFCD09971218 MF:C7H9ClN2 MW:156.6128	CAS No. 1015846-36-2 Cyclobutanemethanamine, 1-(2-methylpropyl)- Catalog No.:AG0004VP MDL No.:MFCD09971229 MF:C9H19N MW:141.2539
CAS No. 1015846-38-4 Cyclopropanemethanamine, 1-[(2-ethyl-1H-imidazol-1-yl)methyl]- Catalog No.:AG0004VO MDL No.:MFCD09971231 MF:C10H17N3 MW:179.2621	CAS No. 1015846-40-8 2-Pyridinemethanamine, α-ethyl-3-methyl- Catalog No.:AG0004VN MDL No.:MFCD09971238 MF:C9H14N2 MW:150.2209	CAS No. 1015846-43-1 1H-Indazole, 3-iodo-1,5-dimethyl- Catalog No.:AG0004VM MDL No.:MFCD09971246 MF:C9H9IN2 MW:272.0856