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followed by further heating to 80 1C once the exotherm had subsided. After
1.5 h, the reaction was subjected to an aqueous work-up followed by a hot
slurry in i-PrOAc and a silica plug using EtOAc as eluent to remove inorganic
impurities. Racemic a-arylation product 42 was obtained in 66% yield as a
brown solid (480 g). No information was provided on the level of residual Pd
in 42, but API 43 was isolated with 5 ppm Pd.
15.2.5 Sonogashira Coupling
The Cu and Pd co-catalyzed Sonogashira reaction (also known as the
Sonogashira-Hagihara reaction)
75
has found an important niche in the
toolbox of process chemists,
76
since it is the most useful method for pre-
paring conjugated arenynes and enynes via coupling of terminal alkynes and
sp
2
-hybridized carbons (aryl, heteroaryl and alkenyl halides). In addition to
pharmaceuticals, the products derived from this reaction find applications
in the synthesis of natural products, agrochemicals and molecular materials.
Some of the advantages of the Sonogashira reaction are its technical sim-
plicity, high functional group compatibility and the typically high yields of
products. In addition to the Cu-Pd combination, this coupling can also be
carried out by other metal-ligand complexes derived from Fe, Ru, Co, Ni, Ag,
Au and In.
77
The applications of the Sonogashira reaction have been recently reviewed.
78
Variations using only substoichiometric Pd
78c
or Cu (catalytic Stephens-
Castro reaction
79
) have also been reported. The Sonogashira reaction has
been employed in the synthesis of heterocycles containing nitrogen, oxygen
and sulfur.
79a
In general, milder conditions can be employed with electron-
rich acetylenes in comparison with less reactive electron-poor substrates.
A common side reaction in Sonogashira couplings arises from alkyne
homocoupling, but the levels of homocoupling by-products can be minimized
by thorough degassing of the reaction mixture and through the use of high
concentrations of a secondary or tertiary amine base to promote reduction of
Pd(II) to Pd(0).
The process group at Wyeth Research described an application of a
Sonogashira coupling for the large-scale preparation of GRN-529 (47), an
mGluR5 negative allosteric modulator for the treatment of central nervous
system disorders (Scheme 15.9).
76s
The original medicinal chemistry con-
ditions for the coupling of aryl iodide 44 with 2-ethynylpyridine (45) neces-
sitated very high PdCl
2
(PPh
3
)
2
(20 mol%) and CuI (20 mol%) loadings,
employed Et
3
N as base and required chromatography to purify alkyne 46.All
these factors led to reaction optimization for developing a scalable and more
economical process. Thus, a solvent screen revealed that when the reaction
was carried out in 2-MeTHF, a dicult phase cut was encountered owing to
the very dark color of both the organic and aqueous phases. In addition, the
crystallization of 46 from heptane-2-MeTHF gave material contaminated
with black tar and very high levels of Pd (41900 ppm). Switching to NMP as
solvent maintained the dark impurities in solution while 46 could be
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