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N
N
N
Me
O
F
HO
2
C
CO
2
H
F
CO
2
H
5
6
7
Figure 15.1
Impurities from the Suzuki coupling of bromide 1 and boronic acid 2.
The A-Phos ligand proved to be the most effective at suppressing the for-
mation of by-products desbromo 5, homocoupled 6 and deboronated 7
(Figure 15.1).
On the kilogram scale, bromide 1 and boronic acid 2 in IPA were treated
with aqueous K
3
PO
4
to form a biphasic mixture (whereas IPA and H
2
O
typically form one phase, the presence of salts in the aqueous layer
made the two phases immiscible). The biphasic mixture was charged with
PdCl
2
(A-Phos)
2
and the atmosphere was made inert before heating at 85 1C
for 1 h. The Suzuki product 3 was formed as the potassium salt and resided
predominantly in the aqueous phase. Washing the aqueous layer with
toluene purged the Pd-ligand complex and subsequent acidification with
aqueous HCl crystallized the Suzuki product as the acid. This pH adjustment
was carried out at 70 1C with slow cooling to crystallize 3 with large particle
size for easy filtration. Without acidification at elevated temperature, the
crystallization of 3 was nucleation dominated and the resulting small
particle size resulted in a very slow filtration. Ultimately, this process
provided over 2 kg of Suzuki product 3 containing
o
0.5 ppm of Pd.
Fiorelli and co-workers at the Istituto Italiano di Tecnologia in Genova, Italy,
developed the Suzuki coupling of boronic ester 10 and bromide 11 for their
multi-gram synthesis of fatty-acid amide hydrolase inhibitor 13 for the treat-
ment of nociceptive and inflammatory pain (Scheme 15.2).
53be
This cross-
coupling was complicated by the hydrolytic lability of the carbamate found in
both the bromide and Suzuki product 12. For example, 11 hydrolyzed quickly
in very polar solvents (DMF, MeCN) using acetate bases common to Suzuki
couplings, but the carbamate proved much more stable in less polar solvents
such as THF, dioxane and toluene. Initial couplings of boronic acid 8 and 11
in dioxane were sluggish at 80 1C and it was suspected that the low solubility
of 8 in dioxane contributed to its poor conversion. The addition of water could
improve the solubility of 8; however, this benefit was offset by increased
carbamate hydrolysis. As a result, the team investigated boronic esters such as
10, which have better solubility in dioxane and better conversion in the Suzuki
reaction. On the multi-gram scale, the boronic acid was converted to 10 by
heating with ethylene glycol in dioxane and the boronic ester was treated with
a mixture of bromide, CsOAc and PdCl
2
(dppf) at 80 1C to generate the Suzuki
product 12 with only 7% combined by-product from carbamate hydrolysis of
11 and 12. The reaction mixture was washed with aqueous citric acid solution
to neutralize the base and sequester Pd and ultimately the Suzuki product was
recrystallized from MeCN to afford 39 g of material in 66% yield. No infor-
mation was provided on the amount of residual Pd in 12.
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