4
B. C. Duffy et al. / Tetrahedron Letters xxx (2014) xxx–xxx
NH
CCl3
formation of the imidate is a well-known process often used in
allylic trichloroacetimidates before Overman rearrangement.18
R
R
R
SH +
R'
R'
A
O
series of alcohols were first subjected to imidate formation condi-
tions in anhydrous THF followed by addition of the thiol and sim-
ple heating. While the yields for this two-step procedure are
slightly lower than for the substitution reaction itself (Table 4)
the advantage of substitution without the need for isolation of
the trichloroacetimidate is clear.
NH2
CCl3
+
1
NH2
SN
S-
R
+
R'+
+
S-
+
R
O
O
CCl3
2
SN
We hypothesized that the more moderate yield of the sulfide
products in the case of the isopropyl sulfide 35 may be due to com-
peting elimination reactions to from the volatile alkene as a side
product, as the substitution reaction in these cases may be sluggish
due to sterics. To explore this idea the single flask substitution pro-
cedure was performed on dihydrocholesterol 38 with thiol 18, as
the alkene byproduct in this case should not be volatile (Scheme 2).
Exposing steroid 38 to the in situ substitution reaction in refluxing
THF did not give product, returning the imidate 40 instead. This
result is consistent with the reactions of isopropyl trichloroacetim-
idate, which required heating in toluene to form sulfide 35. Forma-
tion of the imidate of 38 in toluene followed by addition of thiol 18
and heating to reflux gave a much faster reaction, and lead to the
isolation of sulfide 39 in 44% yield. None of the b-isomer was
observed in the crude 1H NMR, with the balance of the material
being unreacted trichloroacetimidate 40 (24%) and a mixture of
alkenes 41 (30%).
Given the results described above the direct displacement of tri-
chloroacetimidates with thiols seems to proceed under either a SN2
or S1N mechanism. Supporting an S2N mechanism, the methyl trichlo-
roacetimidate provided good yield of methyl sulfide 36. Addition-
ally, the displacement of the chiral alcohol 39 proceeded with
inversion, as none of the other diastereomers could be detected
in the crude 1H NMR. Support for an S1N type mechanism comes
from the ability to form sulfide 33 from diphenylmethyl trichloro-
acetimidate, as substitution at this center typically proceeds
through an S1N pathway. Therefore we propose that the substitution
reaction can proceed under either an S2N or SN1 manifold (Fig. 1)
depending on the structure of the electrophile. This is different
mechanistically than previous uncatalyzed substitution reactions
NH2
S
S
+
R'
O
CCl3
R'
Figure 1. Mechanistic possibilites.
with carboxylic acids,9 that appeared to go through carbocation
intermediates.
In summary, a new methodology for alkylating thiols under
neutral conditions without the need of an acid, base, or metal cat-
alyst by utilizing a trichloroacetimidate as an electrophile has been
demonstrated. No precedence has shown that this displacement
can be performed solely under thermal conditions without an
added catalyst. The scope and optimal conditions of these trichlo-
roacetimidate displacements to generate sulfides have been inves-
tigated. Aromatic thiols provide better conversions than alkyl
thiols, likely due to their greater acidity. Using tetrazole thiol 18
as the test substrate, we have shown that the reaction tolerates
considerable variation of substrate with alkyl, allylic, propargylic,
and benzylic trichloroacetimidates (with both electron donating
and electron withdrawing groups) all participating in the substitu-
tion reactions. Reactions with more sterically hindered trichloro-
acetimidates tended to provide lower yields than less hindered
substrates, and in the case of the tert-butyl imidate lead to the tet-
razolothione product instead of the sulfide. Conditions have also
been developed to directly convert primary alcohols to their corre-
sponding sulfides in a single flask procedure going through a tran-
siently formed trichloroacetimidate intermediate. These conditions
are notable as many other methods for the direct conversion of
alcohols to sulfides are dependent on pathways that proceed
through carbocation intermediates, and therefore do not allow
for the use of unactivated primary and secondary alcohols. Based
on the available information, it is likely that the displacement of
the imidate under these conditions may proceed through either
an S1N or S2N pathway depending on the structure of the electrophile.
The major byproduct of the reaction, trichloroacetamide, can be
conveniently removed by washing with aqueous NaOH solutions.
Additionally, trichloroacetonitrile is quite inexpensive, especially
when purchased in quantity, making this new protocol economical.
This method may find wide application in the synthesis of sulfides
from alcohols, a common functional group transformation.
H
38
H
H
H
HO
i) 10 mol % DBU
Cl3CCN,toluene
ii) Thiol 18
H
then heat to reflux
H
H
39
Ph
N
N
Acknowledgments
H
H 44%
N
N
S
H
H
H
+
Acknowledgement is made to the Donors of the American
Chemical Society Petroleum Research Fund for a recent New Direc-
tions award (54823-ND1). Support for the Syracuse University
NMR facility was provided by the National Science Foundation
(CHE-1229345), which is gratefully acknowledged.
H
40
H
NH
24%
H
H
H
H
Cl3C
O
+
Supplementary data
H
41
H
30%
Supplementary data (detailed experimental procedures and
NMR data (1H and 13C spectra)) associated with this article can
Scheme 2.