Recent Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals - New Trends in Cross-Coupling: Theory and Applications - page 718

15.2.4 Enolate Arylation
The transition metal-catalyzed a-arylation of carbonyl groups had been
scarcely studied 68 before the groups of Hartwig, 69 Buchwald 70 and Miura 71
published their work in the late 1990s on the coupling of ketones with aryl
bromides. Since then, the scope of this technology has been expanded to
include esters, b-keto esters, malononitriles, malonates, amides, aldehydes,
sulfones and nitroalkanes. Also, asymmetric variants of this important
transformation have been developed and applied to aldehydes, ketones,
esters and amides. 72 Several reviews have been published in this area. 72,73 Pd
is the metal of choice, but Ni and Cu have also been employed. Only recently
has this technology begun to be applied by process groups in the pharma-
ceutical industry for the synthesis of drug candidates 74 and examples with
ketones, esters, b-cyano esters, b-ketone esters and lactams have been
reported.
Abele and co-workers at Actelion Pharmaceuticals in Switzerland de-
scribed the large-scale preparation of drug intermediate 39 (Scheme 15.7). 74e
The phenyl group on the molecule was introduced via Pd-catalyzed a-aryla-
tion of enolate 36, generated by treating ester 35 with freshly prepared
LDA at 0-10 1C, with bromobenzene (37). Screening of the reaction con-
ditions showed that either Pd(OAc) 2 or Pd 2 (dba) 3 in combination with
P(t-Bu) 3 HBF 4 gave comparable results and that with chlorobenzene only
Pd 2 (dba) 3 performed satisfactorily. A delayed exotherm was observed for this
reaction (the internal temperature rose to 25-29 1C but was easily controlled
with a constant jacket temperature of 20 1C), but this exotherm remained
constant up to the 4 kg scale. In the plant, neat 35 was added to cold (0-10 1C)
LDA in a hexane-toluene mixture. After 10 min at 5-10 1C, Pd 2 (dba) 3
(1 mol%) and P(t-Bu) 3 HBF 4 (1 mol%) were added, followed by thorough
degassing. Bromobenzene was then added neat over 15 min and, after
warming to 20 1C, the mixture was stirred at this temperature for 2 h 45 min.

i-Pr 2 NH

HexLi (33% in hexane)
PhMe, 0 − 10 ºC, 30 min
5 − 10 ºC, 45 min

O O

O O

+

LDA

CO 2 Me

CO 2 Me

H

H

Li

35

36

i. Pd 2 (dba) 3 (1 mol%)
P( t -Bu) 3 ￿HBF 4 (1 mol%)
20 ºC, 2 h 45 min

O O

Br

O

36 +

CO 2 Me

H

ii. aqueous workup
iii. charcoal treatment (10 wt% per 35 )
iv. concentration
v. dilution with PhMe

38
(4.97 kg;
telescoped as
PhMe solution)
( R )/( S ) ratio: 2:1

37
(1 equiv)

39

Scheme 15.7 Synthesis of intermediate 39 via Pd-catalyzed enolate arylation.