Chemistry Reference
In-Depth Information
i.
Pd(PPh
3
)
4
(0.5 mol%)
(
S
)- BINAP (1 mol%)
KOH, IPA, 83 ºC, 18 h
SH
CN
S
CN
Br
+
ii.
iii.
Crystallization from H
2
O/IPA
Crystallization from H
2
O/AcOH
O
O
F
163
164
(1.0 equiv)
F
81%
165
O
N
O
Me
S
NH
2
S
NH
2
167
N
O
O
Cs
2
CO
3
,KOH
DMSO, 125
−
130 ºC
N
Me
F
166
(45.2 kg)
168
N
Scheme 15.38 Migita coupling en route to diaryl ether 168.
Pd(PPh
3
)
4
to afford diaryl thioether 165 in 62% yield. However, additional
development work revealed that the addition of catalytic amounts of
bidentate phosphorus ligands accelerated the rate of reaction and increased
the yield. Thus, additional PPh
3
provided 165 in 74% yield, whereas with (S)-
BINAP the yield increased to 82%. Interestingly, while (R)- and (S)-BINAP
performed similarly well in the reaction, (
)-BINAP displayed a kinetic
profile faster than without additional ligand but slower than with enantio-
merically pure BINAP. The reason for this rate difference was unclear, but it
may be related to the different solubilities of the optically pure and racemic
ligand in the reaction medium. Another interesting observation was that, in
the absence of additional ligand, nitrile hydrolysis to the amide preceded the
cross-coupling step as the dominant pathway, whereas with added (S)-
BINAP, diaryl thioether formation took place preferentially before nitrile
hydrolysis.
The large-scale campaign was carried out by charging the two reactants,
Pd precatalyst, ligand, base and solvent and heating the resulting mixture to
a steady reflux (internal temperature of 83 1C). Upon completion of reaction,
water was added to crystallize the product, which, after heating to 50-55 1C
and cooling to 20 1C, was isolated by filtration. The wet cake was then dis-
solved in AcOH at 95-100 1C and treated with activated charcoal (5 wt% per
163) and filter aid (6.7 wt% per 163) for 30 min. After cooling to 65 1C, the
mixture was filtered and to the filtrates was added water to crystallize 45.2 kg
of Migita product 166 in 81% yield. No information was provided on the level
of residual Pd in purified 166.
The catalytic cycle shown in Scheme 15.39 was proposed. Initially, the four
PPh
3
groups in Pd(PPh
3
)
4
(I) would be displaced by BINAP to afford an 18-
electron species II that can exist in equilibrium with a 16-electron species III.
Dissociation of one of the BINAP ligands can provide a 14-electron species IV
(believed to be the active catalyst) that can then undergo oxidative addition
with ArBr to provide Fitton Rick intermediate V (usually a trans complex with
monodentate ligands but cis with bidentate ligands).
170
Replacement of the
Search WWH ::
Custom Search