A. K. Yadav et al. / Tetrahedron Letters 53 (2012) 7113–7116
7115
R1
R2
H
N
R2
3
OH
R
H
R
H
R
H
R1
HONH .HCl
AcONa
2
OH2
O
O
N
N
S
P
S
P
2
S
S
OEt
OEt
OEt
OEt
HS
O
OEt
OEt
HONH .HCl
AcONa
-
S
2
HO P
HS
N R1
R2
S
-H2O
SH
R1
OEt
O P
H
N
OEt
OEt
H
R2
P
R2
S
S
OH
OEt
OEt
OEt
O
S
9
S
HS
P
R1
NH
OEt
OEt
H
H
N R1
P
2
R2
+
S
P
2
7
R
HS
S
S
R
OEt
OEt
S
HS
N
OEt
OEt
2
NH
NH
R
C
N
S
P
H N
R
2
4
10
R1
R2
6
H
R2
N
R1
R2
N R1
H2O
C
5
8
OH2 -H O
2
O
(a) Ketones to thioamides
(
b) Aldehydes to thioamides
Scheme 2. Plausible mechanism for thioamidation.
and aldehydes (Tables 2 and 3). Both electron-donating and with-
drawing groups are tolerated. In general, the presence of an aryl
moiety bearing an electron-donating group in the substrates ap-
pears to enhance the yield of thioamides (Table 2, entries 2 and
generated via activation of the corresponding oximes by proton-
ation with dithiophosphoric acid 2 followed by loss of water. Then,
the cationic intermediate 5 combines with the nucleophile 6 pres-
ent in the reaction mixture to form dithiophosphoric ester 7, which
is hydrolyzed to afford secondary thioamides 3. Alternatively, nitri-
lium ion 5 could react with water to form amides 8 which react
with 2 to give thioamides 3 via 9 (Scheme 2(a)). In case of alde-
hydes the corresponding oximes are dehydrated to nitriles 10 via
protonation with 2. The subsequent addition of 2–10 followed by
hydrolysis affords primary thioamides 4 (Scheme 2 (b)).
7
, compared to entries 1 and 8; Table 3, entries 2 and 5, compared
to entries 1, 3, 4, and 6). Cycloalkanones afforded good to excellent
yield of the corresponding thiolactams (Table 2, entries 5 and 6).
In case of unsymmetrical ketones, the usual migratory aptitude
of groups in the Beckmann rearrangement of the ensuing ketoxi-
mes was followed. For example, in all substituted acetophenones
(
Table 2, entries 1, 2, 7, and 8), only migration of aryl group was ob-
In conclusion, we have developed a convenient and efficient
one-pot procedure for the synthesis of thioamides from aldehydes
and ketones. The protocol involves oximation of aldehydes and ke-
tones followed by deoxygenative thioamidation of oximes with
O,O-diethyl dithiophosphoric acid which acts as an acid as well a
source of sulfur. Importantly, this reagent is also applicable to
the conversion of amides and nitriles into thioamides. We believe
that the present operationally simple method would be a practical
alternative to the existing procedures for the synthesis of
thioamides.
served with no product formation via migration of the methyl
group was found. These results imply that the electron-rich aryl
groups have a better migratory aptitude than the alkyl group to-
ward the oximino nitrogen terminus, thus a cationic species on
the oximino nitrogen terminus is involved (Scheme 2). The ensuing
oximes in the present study are expected to be a mixture of syn and
anti isomers (where applicable), but in all cases a single thioamide
isomer was obtained as the product depending on the migratory
aptitude of the groups. This indicates that O,O-diethyl dithiophos-
phoric acid (2) is also capable of catalyzing the syn–anti isomeriza-
tion of oximes under the present reaction conditions. The reaction
of an isolated 3:1 mixture of anti- and syn-1-phenylpropan-2-one
Acknowledgments
1
5
oximes with 2 in dioxane at 80 °C for 2 h afforded a single thio-
amide 3 (R = PhCH , R = Me) in 91% yield. This provides a conclu-
2
We sincerely thank the SAIF, Punjab University, Chandigarh, for
providing spectra. One of us (A.K.Y.) is grateful to the CSIR, New
Delhi, for the award of a Junior Research Fellowship.
1
2
sive proof for the syn–anti isomerization of oximes under the
present reaction conditions. The equilibrium between the isomers
is apparently established faster than the Beckmann rearrangement,
thereby the product composition is determined by the relative
rates of migration of the groups involved and is independent on
the stereochemistry of the ketoximes formed. In case of aldehydes
containing an electron-withdrawing group longer reaction time
was required and yield of the corresponding thioamides was also
lower in comparison to aldehydes bearing an electron-donating
group (Table 3). This might be attributed to the difficulty in proton-
ation of nitriles containing an electron-withdrawing group
References and notes
1
.
.
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2
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3
4
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McManus, S. P.; Lee, K. Y.; Pittman, C. U. J. Org. Chem. 1974, 39, 3041.
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J. Org. Chem. 2007, 72, 4440.
(Scheme 2a). Importantly, the present reagent 2 is also applicable
to the conversion of amides and nitriles into the corresponding
thioamides under the same reaction conditions. Furthermore, the
described method does not generate any foul odors but the reagent
5. (a) Ozturk, T.; Ertas, E.; Mert, O. Chem. Rev. 2007, 107, 5210; (b) Jesberger, M.;
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Pandey, L. K.; Suryanarayana, M. V. S. Synthesis 2012, 44, 377.
2
has a mild odor of hydrogen sulfide.
On the basis of the above experimental results and the litera-
1
0b,12,17
ture precedents,
a plausible mechanism for the conversion
of ketones and aldehydes into thioamides is depicted in Scheme
. In case of ketones the intermediate nitrilium ion 5 is possibly
2