Chemistry Reference
In-Depth Information
15.3.2 Carbon-Sulfur Bond Formation (Migita Thioether
Synthesis)
The Pd-catalyzed arylation of sulfides, also known as the Migita reaction,
160
has attracted less attention in industrial and academic settings than
similar transformations with amines, amides and alcohols, most likely due
to the limited presence of the sulfide, sulfoxide and sulfone functionalities
in pharmaceuticals and natural products. Even more scarce are reports
from process groups in the pharmaceutical industry.
161
However, a very
detailed mechanistic study of this reaction using palladium complexes of
Josiphos ligand CyPF-t-Bu (Josiphos SL-J009-1) was reported by Hartwig's
group.
162
Thiols are stronger nucleophiles than alcohols and amines,
which should favor the transmetallation step. However, they are prone to
oxidation and avoiding disulfide formation still remains a challenge in this
reaction.
Since the original reports by Migita and co-workers,
160
numerous
improvements have been described, such as the work by Murata and
Buchwald
163
and Hartwig and co-workers
164
on the use of phosphine ligands
(dippf and CyPF-t-Bu, respectively) in combination with Pd(OAc)
2
which now
allows the use of aryl chlorides or bromides and also aliphatic and aromatic
thiols. Many other ligands have been tested in this transformation.
163,165
Copper has been shown to be an effective substitute for Pd for C-S bond
formation.
166
CuBr in the presence of a phosphazene base
167
or CuI with 2,9-
dimethyl-1,10-phenanthroline (neocuproine) has been shown to promote
diaryl thioether formation.
168
Transition metal-catalyzed C-S bond for-
mation was previously reviewed in 2000.
169
A recent example by Yang and co-workers at AMRI involved the prepa-
ration of 162, a potent tubulin inhibitor for the treatment of leukemia and
lymphoma (Scheme 15.37).
161e
Compound 162 is a derivative of vinblastine,
a natural product belonging to the vinca alkaloids family. The first two
members of this family, vinblastine and vincristine, were isolated from
Catharanthus roseus (Madagascar periwinkle) in the 1950s and, since then,
several members of this family have been prepared through total synthesis.
However, owing to the molecular complexity of the carbon skeleton in this
series of compounds, structural modification of the natural products is a
more straightforward approach to synthesize vinca derivatives as potential
therapeutic agents. Thus, starting from vinblastine sulfate, iodination with
NIS afforded iodoarene 161, which was telescoped as an NMP solution into
the thiomethylation step (Migita coupling). When this transformation was
performed in a sealed tube at 65 1C with 15 equiv. of MeSH, the reaction
proceeded to completion to generate methyl thioether 162. However, when
the reaction was carried out in an open vessel under a nitrogen sweep, in-
complete conversion was observed due to the loss of MeSH. On a large scale,
the NMP solution of 161 was sparged with nitrogen gas for 30 min, which
allowed for a lower Pd precatalyst loading (7.5 mol% versus the original
10 mol%) to accomplish complete consumption of 161 with 1.5-1.7 equiv. of
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