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.
Preparation of Pinacol Boronic Ester 1. To a solution of
4-chloro-2-iodophenol (5) (21.5 kg, 84.5 mol) and 4-chloro-2-
fluorobenzyl bromide (6) (18.9 kg, 84.5 mol, 1 equiv) in acetone
(215 L) at 21 °C was added anhydrous 325 grade potassium
carbonate (23.4 kg, 169 mol, 2 equiv). The stirred suspension
was heated at reflux for 1 h. The solution was concentrated to
75 L by atmospheric pressure distillation, and toluene (150 L)
was added before the organic solution was washed with water
(2 × 172 L). Additional toluene (194 L) was added and the
solution concentrated to 172 L by atmospheric pressure
distillation.
Table 2. Use of alternative borate esters
The obtained solution was cooled to -10 °C (causing partial
precipitation of iodide 2) and then treated with isopropylmag-
nesium chloride in THF (47.3 kg, 48.6 L of a 20% w/w solution
in THF, 92.0 mol, 1.09 equiv) at a rate that maintained the
temperature between -5 and -12 °C. During this addition the
SM initially completely redissolved, and towards the end of
the addition the aryl Grignard reagent partially precipitated.
2-Isopropoxy-4,4,5,5-tetramethyldioxaborolane (19.6 kg, 21.5
L, 105 mol, 1.24 equiv) was added, causing the temperature to
rise to ∼10 °C. The reaction mixture was allowed to warm to
21 °C and then was further warmed to 50 °C for 1 h before
being cooled to 21 °C and quenched with 50% saturated NH4Cl
solution (183 L). The aqueous phase was separated, and the
organics were filtered before being washed with water (2 ×
172 L) and then concentrated by distillation at atmospheric
pressure to ∼65 L. IPA (366 L) was added and the solution
concentrated to 129 L by atmospheric pressure distillation and
then cooled to 70 °C before being seeded. The mixture was
held at 70 °C for 1 h, before being further cooled to 0 °C, and
held at that temperature for 1 h. The product was collected by
filtration and the cake washed with cold IPA (130 L at 0 °C).
The damp product was dried overnight in a vacuum oven at 30
°C to furnish 1 as a white solid, 26.3 kg, 78.4%, >99.9% a/a
purity by LC/UV. 1H NMR (400 MHz, CDCl3) δ 1.36 (s, 12
H), 5.08 (s, 2 H), 6.86 (d, J ) 8.8 Hz, 1 H), 7.08 (dd, J ) 9.8,
2.0 Hz, 1 H), 7.17 (dd, J ) 8.3, 1.7 Hz, 1 H), 7.35 (dd, J )
8.8, 2.7 Hz, 1 H), 7.67 (d, J ) 2.7 Hz, 1 H), 7.94 (t, J ) 8.2
Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ 24.9, 63.8, 83.8,
113.3, 115.6 (d, J ) 24 Hz), 123.3 (d, J ) 13 Hz), 124.3 (d, J
) 3 Hz), 126.2, 130.0 (d, J ) 5 Hz), 132.2, 133.9 (d, J ) 10
Hz), 136.4, 159.4 (d, J ) 247 Hz), 161.3. HRMS (EI+)
calculated for C13H9O35Cl2F (MH+ - BC6H12O2) 270.0014;
found 270.0003. Anal. Calcd for C19H20BCl2FO3: C, 57.36; H,
5.07; B, 2.97; Cl, 17.26; F, 3.36. Found: C, 57.42; H, 4.98; B,
3.01; Cl, 17.49; F, 3.11.
a Ratio of products after 1.5 h at 50 °C. b Ratio of products after 30 h at reflux,
under these conditions approximately 20% of the proto-deboronated product was
also observed. c No conversion observed even after 16 h at reflux.
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.
Experimental Section
Reagents and solvents were purchased from commercial
sources and were used as received. 1H NMR spectra were
recorded at 400 MHz. Data are presented as follows:
chemical shift (ppm), multiplicity (s ) singlet, d )
doublet, t) triplet, q ) quartet, quin ) quintet, sep )
septet, m ) multiplet, b ) broad), coupling constant, J
(Hz) and integration. 13C NMR spectra were recorded at
100 MHz. Data for 13C NMR are reported in terms of
chemical shifts (ppm), and multiplicity (as above) followed
by coupling constant (Hz) for fluorine-containing com-
pounds. High-resolution mass spectra (HRMS) were re-
corded by the Chemical Development Analytical Sciences
department at GSK, Stevenage. Elemental analysis was
carried out at Butterworth Laboratories Ltd., Teddington.
Preparation of Borinic Acid 4 (R ) H). An authentic
sample of 4 (R ) H) was isolated by preparative chromatog-
raphy from a mixture of the boronate and borinic acid: A
solution of iodide 2 (5 g, 12.6 mmol, 1 equiv) in toluene 40
mL was cooled to -10 °C before being treated with a 2 M
solution of isopropylmagnesium chloride in THF (6.9 mL, 13.8
mmol, 1.1 equiv) at a rate that maintained the temperature below
-3 °C. The reaction was allowed to warm to 0 °C before being
treated with 2-isopropoxy-4,4,5,5-tetramethyldioxaborolane (1.55
mL, 7.6 mmol, 0.6 equiv) and then being allowed to warm
further to room temp. After 10 min at room temp the reaction
was quenched by addition of saturated NH4Cl solution (40 mL).
Vol. 12, No. 6, 2008 / Organic Process Research & Development
•
1267