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employed, which afforded complete consumption of chloroazaindole 23 and
provided an adequate reaction rate (8 h reaction time). The Negishi coupling
between the organozinc reagent (1.5 equiv. of diarylzinc species) and 23 was
carried out in the presence of PdCl
2
(dppf)
CH
2
Cl
2
(10 mol%) at 58 1C for
8 h. The use of an excess of organozinc ensured complete consumption of
23. Upon completion of reaction, an aqueous work-up to remove inorganic
salts followed by the addition of 1.5 M aqueous HCl afforded 24
HCl.
Freebasing with aqueous Na
2
CO
3
, extraction into CH
2
Cl
2
and crystallization
from MeOH provided 158 g of 24 in 60% overall yield. No information was
provided regarding the need for the very high Pd precatalyst loading or the
residual Pd content in 24. This protocol was repeated several times to pro-
duce over 2 kg of Negishi product 24.
15.2.3 Kumada-Corriu Coupling
Owing to the very high reactivity and basicity of Grignard reagents, the
Kumada-Corriu cross-coupling
62,63
has seen very limited use in process
chemistry and has only been applied to relatively simple substrates, in both
its Pd- and Ni-catalyzed versions.
64
It is worth pointing out that the Kumada
reaction is, at least on a large scale, the only type of cross-coupling where a
non-precious metal, Ni, has been employed in more instances than Pd. In
addition to these two metals, Fe,
65
Co
66
and Mn
67
can catalyze this trans-
formation but no applications in process chemistry have been found for Co
or Mn. Some industrial applications of Kumada coupling for fine chemical
production have been reviewed.
63h
Zacuto and co-workers at Merck reported the preparation of 4-allyli-
soindoline (28) as a key component of a drug candidate (Scheme 15.5).
64f
The
researchers implemented a Pd-catalyzed Kumada coupling to install the allyl
moiety using commercially available allyl-Grignard reagents. High-
throughput screening was applied to find the optimal Pd(OAc)
2
-ligand
combination and several ligand hits were identified: XPhos, PCy
2
[(o-tol)in-
dole], P(neopentyl)(t-Bu)
2
HBF
4
, dippf, P(t-Bu)
2
(Ph)
HBF
4
, PCy
2
(Mes) and
P(t-Bu)
3
HBF
4
. Based on cost and availability on scale, P(neopentyl)
(t-Bu)
2
HBF
4
was selected for further development. Additional screening
showed that better conversions were observed with a 1:2 metal:ligand ratio
and that higher processing temperatures (445 1C) and THF:toluene ratios
i. Pd(OAc)
2
(0.5 mol%)
P(neopentyl)(
t
-Bu)
2
HBF
4
(1 mol%)
PhMe, 45
NH
NH
NHHCl
−
50 ºC, 16 h
+
MgCl
27
1.7 Min THF
(3.2 equiv)
ii. aqueous workup
ii i. HCl i n IPA (5.1 M)
T<40ºC
iv. Cooling to 0 ºC
Br
26
28
HCl
(70 g)
29
96%
Scheme 15.5
Synthesis of 4-allylisoindoline (28) via Pd-catalyzed Kumada-Corriu
cross-coupling.
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