Recent Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals - New Trends in Cross-Coupling: Theory and Applications - page 741

years 137 and they have the potential to change and streamline the way in
which chemical syntheses are planned and executed since no additional
functionalization needs to be introduced in the molecule. However, two
major challenges exist to turn C-H activation into a more practical synthetic
method: (a) the lack of reactivity of the C-H bond; and (b) the need to
discriminate between several of these bonds within the same molecule to
obtain the desired regioselectivity. As with many other transition metal-
catalyzed reactions, Pd is the metal of choice, but other metals such as Pt, Au
and Cu can also promote this transformation. 138
The novelty of the C-H activation protocols has prevented them from
being customarily incorporated into process chemistry. Only four large-scale
examples were found in the literature, two of them for oxindole synthesis, 139
one for biaryl formation 140 and one for direct benzylation of a heteroaryl
chloride. 141
Magano and co-workers at Pfizer described the kilogram-scale preparation
of oxindole 129, a key intermediate in the synthesis of serine palmitoyl
transferase enzyme inhibitor 130, a candidate for the treatment of cardio-
vascular diseases (Scheme 15.27). 139b,c The medicinal chemistry preparation
of 129 afforded this material in 41% yield after five steps from commercially
available but expensive 3-fluoro-4-nitrobenzoic acid. 142 With the goal of re-
ducing the cost and number of steps, the researchers focused on an alter-
native approach that relied on C-H activation for oxindole synthesis from
a-chloroacetanilides, as described by Hennessy and Buchwald a few years
earlier. 143 The required precursor, intermediate 127 was readily synthesized
in two steps from inexpensive methyl p-aminobenzoate. With 127 at hand,
the cyclization step to 129 was attempted in toluene, following the con-
ditions reported by Hennessy and Buchwald, but sticky mixtures were ob-
tained owing to the low solubility of 127 in this solvent, which also led to
considerable impurity formation. A solvent screen [DMF, MeCN, 2-MeTHF,
2-MeTHF-IPA (1:1, 4:1)] revealed that the latter combination gave homo-
geneous mixtures and complete conversion in 1 h was observed to afford 129
in 70% yield with good purity on a 60 g scale. However, high Pd(OAc) 2

i. Pd(OAc) 2 (10 mol%)
JohnPhos ( 128 , 20 mol%)
Et 3 N (1.5 equiv)
2- MeTHF/IPA ( 4:1 vol/vol )
70

Cl

O

O

P( t -B u) 2

75 ºC, 2.5 h
hot filtration
recrystallization from IPA
76%

−

N

N

NCbz

ii.
iii.

NC bz

MeO 2 C

MeO 2 C

128
JohnPhos

127 129

(7.70 kg)
100 − 800 pm Pd

O

O

N

N

N

MeHNOC

130
<20 ppm Pd

Scheme 15.27 Pd-catalyzed C-H activation for synthesis of oxindole 129.