Chemistry Reference
In-Depth Information
[RuCl
2
(
6
-C
6
H
6
)]
2
(0.5 mol%;
added in 2 portions)
PPh
3
(1 mol%)
K
3
PO
4
(2 equiv)
KOAc (0.1 equiv)
NMP, 110
i.
μ
MeO
F
MeO
F
Br
MeO
F
13 1
−
130ºC,9h
F
3
C
+
N
O
ii. water addition to crystallize
T<25ºC
N
H
F
3
C
O
O
134
anacetrapib
25 ppm Ru
N
96%
F
3
C
CF
3
133
(4.44 kg)
O
132
(1.03 equiv)
F
3
C
Scheme 15.29 Ru-catalyzed biaryl formation via C-H activation.
p,Z
1
interaction in which the Pd enolate behaves as a p-acid that weakens the
C-H bond and facilitates its cleavage.
Ouellet and co-workers at Merck Frosst in Canada described the synthesis
of anacetrapib (134), a potent and selective inhibitor of cholesteryl ester
transfer protein for the prevention and treatment of hypercholesterolemia
(Scheme 15.29).
140
The biaryl core of the molecule was assembled via Ru-
catalyzed cross-coupling between aryl bromide 131 and aryloxazoline 132.
144
Initial experiments with 2.5 mol% [RuCl
2
(m
6
-C
6
H
6
)]
2
, 10 mol% PPh
3
and
K
3
PO
4
(2 equiv.) in NMP at 120 1C for 2 h afforded clean 133 with good
conversion. Further experimentation revealed that alternative ligands such
as PCy
3
(electron rich), P(4-F-C
6
H
4
)
3
(electron poor) or dppf (bidentate) gave
lower yields of 133 compared with PPh
3
. In addition, inorganic bases
(K
2
CO
3
,Cs
2
CO
3
) performed better than organic bases (i-Pr
2
NEt, Et
3
N) and
polar aprotic solvents (DMF, DMAc, NMP) were preferred over toluene or
xylenes. After NMP had been selected as the preferred solvent, it was ob-
served that whereas the reactions carried out with 5 mol% Ru gave con-
sistent results, the reactions with lower Ru loadings (0.5-1 mol%) provided
variable conversions (30-99%). The reason for this variability was ascribed to
the level of g-butyrolactone present in the NMP, as lots of solvent that
contained higher levels of this impurity afforded better conversions. This
assumption was corroborated experimentally when a failed reaction that
employed g-butyrolactone-free NMP was spiked with this impurity, which
then proceeded to high conversion. It was speculated that the reason for this
enhanced catalytic activity in the presence of this impurity could be the
hydrolysis of the lactone to the corresponding hydroxy acid by the K
3
PO
4
in
the reaction medium.
145
A similar activating effect was observed when
additives such as KOAc, TFA, pivalic acid and 4-methylbenzoic acid were
tested.
The final experimental conditions called for the addition of a degassed
NMP solution containing [RuCl
2
(m
6
-C
6
H
6
)]
2
(0.5 mol%) and PPh
3
(1 mol%,
added as two equal portions) to a degassed solution of 131, 132,K
3
PO
4
and
KOAc in NMP at 130 1C. After the first catalyst portion had been added, the
mixture was stirred at 130 1C for 2 h, followed by the addition of the second
portion of catalyst and an additional 7 h at 110 1C. Upon completion of
reaction, the mixture was cooled to room temperature and water was added
Search WWH ::
Custom Search