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P. R. Mullens / Tetrahedron Letters 50 (2009) 6783–6786
i) nBuLi
ii) B(OMe)3
Br
(HO)2B
O
B
HO OH
N
N
O
iii) NH4Cl
THF, -90 °C
N
N
N
THF, 4 Å MS
80%
N
3
2
1
38%
Scheme 1. The literature synthesis of ester 1.3
As expected, the more electron-poor aryl chlorides (7a, 8a, 9a and
13a, entries 1, 2, 3 and 7) had the fastest reaction rates, achieving
complete conversion in an hour or less. In general, the electron-
rich aryl chlorides (10a, 12a and 14a, entries 4, 6 and 8) required
2 h to reach complete conversion which is still favourable when
compared with the typical 80–90% conversion in 24 h observed
when the ester 1 and KF are used.
OH
B
Li
N
O
Li
N
Li
HO
HO
O
B
HO
OH
OH
B
N
N
OH
6
5
4
When KF was replaced with LiOH in a Suzuki reaction using es-
ter 1, the rate of reaction observed was comparable to when lith-
ium hydroxy ate complex 5 was used directly suggesting that
LiOH is an excellent choice of base for these examples.
Figure 1. Lithium hydroxy ate complexes.
and by ageing at room temperature; however, 4 was always con-
taminated with small amounts of lithium hydroxybutyl boronic
acid 6 which led us to pursue scale-up of the lithium hydroxy ate
complex 5. The synthesis was found to be scaleable and high yield-
ing, affording complex 5 in a single pot from 4-bromopyrazole 2 in
88% yield on a multi-gram scale (Scheme 2).6 This process was later
demonstrated on multi-kilo scale in 77% yield and on multiple
occasions by a third party vendor.
An improved synthesis of the desired pinacol ester 1 has been
demonstrated utilising a scaleable one-pot reverse addition proto-
col to generate the boronic acid 3 and subsequent lithium hydroxy
ate complex 5 which was easily isolated in high yield by filtration.
Simple neutralisation then afforded ester 1 in an improved overall
70% yield from pyrazole bromide 2 compared with the 30% yield
obtained earlier. However, the excellent reactivity with both elec-
tron-rich and electron-poor aryl chlorides, and long-term bench
stability of lithium hydroxy ate complex 5 show that it is a more
easily accessible and useful reagent than ester 1 with the added
advantage that no additional base is required to carry out the Su-
zuki couplings.
Neutralisation of the lithium hydroxy ate complex 5 to ester 1
(methyl tert-butyl ether, acetic acid, followed by drying over so-
dium sulfate) was achieved in 80% yield. This constitutes an im-
proved procedure for the synthesis of ester 1 from pyrazole
bromide 2 in 70% yield over two steps, compared with the previ-
ously reported synthesis which achieved a 30% yield. However,
we were pleased to find that the neutralisation step was found to
be unnecessary as the lithium hydroxy ate complex 5 was shown
to be active in the desired Suzuki coupling; moreover, this reaction
proceeded without the need for added base providing a straightfor-
ward and convenient method to carry out the Suzuki reaction.
The reaction of 5 with a range of aryl chlorides was examined to
determine if this was a generally useful reagent for Suzuki cou-
plings with aryl chlorides. The conditions developed by Fu were
employed and the reactions of lithium hydroxy ate complex 5 were
compared with those of ester 1 using KF as the base (Table 1).7a,7b
Instead of being merely comparable with ester 1 and KF, the
lithium hydroxy ate complex 5 was shown to give superior perfor-
mance in all the examples studied. The series of electron-rich, elec-
tron-poor, aryl, and hindered aryl chlorides showed a greater than
10 time increase in the reaction rate using the lithium hydroxy ate
complex 5 compared with the ester 1 using KF as the base. In most
cases, complete conversion was achieved using complex 5 in less
than 2 h, the exception to this being the highly electron-rich 2,4-
dimethoxychlorobenzene (11a, entry 5), the reaction of which slo-
wed significantly and then stalled after around 5 h at 75% conver-
sion due to decomposition of the lithium hydroxy ate complex 5.8
4-Bromo-1-methyl-1H-pyrazole (2)
Potassium hydroxide (306 g, 3.67 mol) was carefully added to a
mixture of pyrazole (200 g, 2.94 mol) in water (300 mL) whilst
maintaining the internal temperature below 30 °C. Iodomethane
(230 mL, 3.67 mol) was added over 70 min whilst maintaining
the internal temperature below 37 °C. The mixture was allowed
to slowly cool to rt and aged for 2 h. CH2Cl2 (250 mL) was added
and the layers were separated. The aqueous layer was extracted
twice with CH2Cl2 (2 Â 250 mL). The combined organics were then
washed with brine (50 mL) and concentrated to a volume of
approximately 900 mL (85% yield for 1-methylpyrazole). To the
CH2Cl2 solution of 1-methylpyrazole was added a solution of bro-
mine (151 mL, 2.94 mol) in CH2Cl2 (350 mL) over 45 min; the inter-
nal temperature was kept below 29 °C with cooling. After 1 h
ageing at 25 °C, the reaction was quenched with 10% sodium sulfite
(700 mL) and the layers were separated. The aqueous layer was ex-
tracted twice with CH2Cl2 (2 Â 250 mL) and the combined organics
were washed with saturated brine (150 mL) and then dried over
anhydrous sodium sulfate, filtered and concentrated to a colourless
oil (368 g, 96 wt %, 75%).9 1H NMR (400 MHz, CDCl3) d 7.40 (s, 1H),
7.34 (s, 1H), 3.85 (s, 3H). 13C NMR (100 MHz, CDCl3) d 139.7, 130.0,
92.9, 39.4.
Li
i) nBuLi
Br
O
B
THF/toluene, -70 °C
(1-Methyl-1H-pyrazol-4-yl)boronic acid pinacol ester lithium
B(OiPr)3
N
ate complex (5)
O
ii) pinacol, -70 °C to rt
iii) H2O, 5 equiv.
N
HO
N
N
4-Bromo-1-methylpyrazole (2, 101 g, 96 wt %, 600 mmol) was
placed in a 3 L three-neck flask equipped with an overhead stirrer,
a temperature probe and a nitrogen bubbler. Tetrahydrofuran
(600 mL) and toluene (600 mL) were added and the stirred solution
88% yield
2
5
Scheme 2. One-pot synthesis of 5 from 2.