Desulfurization of Thioamides into Amides with H2O 2/ZrCl4 Reagent System

Article abstract of DOI:10.1055/s-0028-1083314

The hydrogen peroxide/zirconium(IV) chloride reagent system has been used as a new and efficient reagent for the deprotection/desulfurization of thioamides to amides. This system is reasonably general and can be applied to the conversion of several thioamides to the corresponding amides. The salient features of this protocol are short reaction times, good chemoselectivity, cleaner reaction profiles, and simple workup that precludes the use of toxic solvents. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083314

SHORT PAPER
369
Desulfurization of Thioamides into Amides with H O /ZrCl Reagent System
2
2
4
D
K
esulfurizationof
i
Thioam
u
idesintoA
m
m
ides ars Bahrami,*a,b Mohammad Mehdi Khodaei,*a,b Yeganeh Tirandaza
a
Department of Chemistry, Razi University, Kermanshah 67149, Iran
Nanoscience and Nanotechnology Research Center (NNRC), Razi University, Kermanshah 67149, Iran
Fax +98(831)4274559; E-mail: kbahrami2@hotmail.com; E-mail: mmkhoda@razi.ac.ir
b
Received 22 August 2008; revised 6 October 2008
To evaluate the solvent effect, the desulfurization of N-
phenylthiobenzamide (1a) was carried out under similar
reaction conditions using various organic solvents such as
chloroform, toluene, acetonitrile, and ethanol. As shown
Abstract: The hydrogen peroxide/zirconium(IV) chloride reagent
system has been used as a new and efficient reagent for the depro-
tection/desulfurization of thioamides to amides. This system is rea-
sonably general and can be applied to the conversion of several
thioamides to the corresponding amides. The salient features of this in Table 1, acetonitrile and ethanol resulted in excellent
protocol are short reaction times, good chemoselectivity, cleaner re- yields of the corresponding amide 2a, whereas chloroform
action profiles, and simple workup that precludes the use of toxic
and toluene furnished the amide in low yields.
solvents.
Key words: deprotection, thioamides, amides, desulfurization, hy-
Table 1 Solvent Effect on the Desulfurization Reaction
drogen peroxide
S
C
O
C
H
N
H
N
Ph
Ph
Ph
Ph
1
a
2a
Amides are important commercial and biological com-
pounds, because amides constitute the backbone of pro- Solventa
Isolated yield (%)
tein molecules, their chemistry is of extreme importance.
The conversion of thioamides into their oxygen analogues
CHCl3
15
18
98
97
has received considerable attention. This transformation
toluene
MeCN
1
–15
has been accomplished in a variety of ways.
in spite of their potential utility, many of these reported
However,
methods suffer from drawbacks, such as harsh reaction EtOH
conditions, unsatisfactory yields, prolonged reaction
times, cumbersome product isolation procedures, and of-
ten expensive catalysts.
a
Conditions: ratio 1a/H O /ZrCl = 1:2:1, 25 °C, 2 min.
2
2
4
Optimization of the reaction conditions was carried out on
N-phenylthiobenzamide (1a) as a model substrate using
Aqueous hydrogen peroxide (30%) is an ideal oxidant in
view of its high effective oxygen content, its ecofriendly
byproduct (water), its relative safety in storage and oper-
ation, and its comparatively low cost of production and
3
0% aqueous hydrogen peroxide in the presence of differ-
ent amounts of zirconium(IV) chloride in ethanol at room
temperature. The results are demonstrated in Table 2.
1
6
transportation.
In continuation of our ongoing program to develop benign Table 2 Effect of Increasing Amount of Zirconium(IV) Chloride on
and expeditious methods for organic transformations1
and an interest in a green chemistry theme with growing
emphasis on pollution prevention, in this study, we report
an environmentally friendly, simple, and efficient method
that enables desulfurization of thioamides 1 to their oxo
analogues 2 with the hydrogen peroxide/zirconium(IV)
chloride reagent system in excellent yields (Scheme 1).
7–19
the Oxidation of N-Phenylthiobenzamide (1a) Using Hydrogen Per-
oxidea
ZrCl (mmol)a
Isolated yield (%)
4
0
0
70
80
90
98
0
0
0
.4
.6
.9
S
C
O
C
H2O2, ZrCl4
EtOH, 25 °C
R1
NR R
2
3
R1
2 3
NR R
1
2
1
a
Scheme 1
Reaction conditions: 1a (1 mmol), H O (2 mmol), EtOH, 25 °C, 2
2 2
min.
As shown, the use of zirconium(IV) chloride is essential
for the success of the reaction because hydrogen peroxide
oxidizes thioamides rather slowly. The ratio of 1:2:1 thio-
SYNTHESIS 2009, No. 3, pp 0369–0371
x
x
.
x
x
.2
0
0
9
Advanced online publication: 09.01.2009
DOI: 10.1055/s-0028-1083314; Art ID: Z19708SS
Georg Thieme Verlag Stuttgart · New York
amide 1/H O /ZrCl was found to be optimum for com-
2 2 4
©

3
70
K. Bahrami et al.
SHORT PAPER
plete conversion of thioamides 1 into amides 2. To extend
the scope of the reaction and to generalize the procedure,
the above optimized reaction conditions were applied to
the desulfurization of various thioamides 1a–q (Table 3).
S
O
PhNHCPh
+
4-ClC6H4CHO
PhNHCPh + 4-ClC6H4CHO
1
a
2a 94%
100%
S
O
These results illustrate the general applicability of this
method for the preparation of amides 2a–q under mild
conditions and short reaction times. The reagent was
chemoselective, tolerating various functional groups,
such as, methoxy, nitro, and halide. Most importantly,
thioamides 1 carrying either electron-donating or elec-
tron-withdrawing substituents reacted very well to give
the corresponding amides in excellent yields with high pu-
rity. Secondary and tertiary thioamides undergo this reac-
tion with equal efficiency.
+
PhCO2Me
4-BrC6H4NHCMe + PhCO2Me
4
-BrC6H4NHCMe
1
q
2q 95%
90%
S
O
PhCNHCH2Ph
+
Ph C=NOH
H
PhCNHCH2Ph + Ph C=NOH
1
f
2f 95%
H
100%
S
O
4-MeC6H4NHCPh
+
PhCO2H
4-MeC6H4NHCPh
+
PhCO2H
100%
1b
2b 91%
We also have carried out competitive desulfurization of
Scheme 2 Reagents and conditions: molar ratio substrate 1/sub-
thioamides in the presence of aldehyde, ester, oxime, and strate/H O /ZrCl (1:1:2:1), EtOH, 25 °C.
2
2
4
acid groups (Scheme 2).
These observations clearly show that the method is appli-
cable to the selective desulfurization of thioamides 1 in
the presence of the mentioned functional groups and can
be considered as a useful practical achievement for this
transformation.
Table 3 Desulfurization of Thioamides 1 Using the Hydrogen Per-
oxide/Zirconium(IV) Chloride Reagent System
S
C
1
O
C
2
R1
2
3
R1
2
3
A comparison of the efficiency of this method with select-
ed previously methods is collected in Table 4, to demon-
strate that the present method is indeed superior to several
other methods.
NR R
NR R
Entry R1
NR R
2
3
Time Product Yielda,b
min)
(
(%)
98
94
99
98
98
99
97
95
96
95
93
98
95
96
95
94
98
Table 4 Comparison of Desulfurization of Thioamides
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
NHPh
2
1
1
3
2
1
2
2
5
5
5
4
5
5
7
3
1
2a
2b
2c
2d
2e
2f
Entry Conditions
Time
Product Yield
%)
4-MeC H NH
6
4
(
4-ClC H NH
6
4
1
2
3
4
5
6
7
8
9
0
1
3
H O , ZrCl , EtOH, r.t.
2 min
5 min
30 min
5 min
5 h
2a
2a
2a
2a
2a
2d
2d
2n
2n
2q
2q
98
2
2
4
4-BrC H NH
6
4
982
Bi(NO ) ·5 H O, MeCN, reflux
3
3
2
2-BrC H NH
6
4
953
(Ph PBu) Cr O , MeCN, reflux
3
2
2
7
NHBn
NHPh
N O , MeCN, 0 °C
707
2
4
4-MeC H4
2g
2h
2i
6
605
Caro’s acid, silica gel, MeCN, r.t.
H O , ZrCl , EtOH, r.t.
4-MeC H4
1-naphthylamino
NHPh
6
3 min
20 min
7 min
5 h
98
2
2
4
4-O NC H
2
6
4
4
4
4
4
4
a
974
CPCC , MeCN, reflux
H O , ZrCl , EtOH, r.t.
1
1
1
1
1
1
1
4-O NC H
4-MeC H NH
2j
2
6
6
4
96
2
2
4
4-O NC H
4-MeC H NMe
2k
2l
2
6
6
4
765
Caro’s acid, silica gel, MeCN, r.t.
H O , ZrCl , EtOH, r.t.
4-O NC H
2-MeOC H NH
6 4
2
6
1
1 min
2 h
98
2
2
4
4-O NC H
2-ClC H NH
2m
2n
2o
2p
2q
2
6
6
4
958
1
MCPBA, CH Cl r.t.
2 2
4-O NC H
NHBn
2
6
a
-Carboxypyridinium chlorochromate.
4-ClC H4
piperidino
NHBu
6
The proposed mechanism for the desulfurization of thio-
amides is shown in Scheme 3. It is reasonable to assume
that the nucleophilic attack of hydrogen peroxide on zir-
conium(IV) chloride makes the oxygen atom more elec-
trophilic. Thus, the mechanism proceeds probably
through a cyclic intermediate that undergoes sulfur extru-
sion.
Ph
1
Me
4-BrC H NH
6
4
a
The products were characterized by comparison of their spectro-
scopic and physical data with authentic samples synthesized by re-
4
,7
ported procedures.
Yields refer to pure isolated products.
b
Synthesis 2009, No. 3, 369–371 © Thieme Stuttgart · New York

SHORT PAPER
Desulfurization of Thioamides into Amides
371
HO OZrCl3
N-Benzylbenzamide (2f)
Mp 105 °C (Lit. 105–106 °C).
IR (KBr): 3312, 1638 cm–1.
H2O2
+ ZrCl4
–
Cl–
4
S
+
S
H
OH
.
.
HO O ZrCl2
Cl
.
– Cl–
– O ZrCl2
.
N
N
1
H NMR (200 MHz, CDCl ): d = 4.78 (d, J = 5.62 Hz, 2 H), 6.63 (br
+
3
H
s, 1 H, NH), 7.33–7.64 (m, 8 H), 7.91–7.95 (m, 2 H).
1
3
C NMR (50 MHz, CDCl ): d = 44.1, 126.93, 127.64, 127.92,
3
1
28.59, 128.79, 131.55, 134.36, 138.14, 167.32.
O
S
S
H
+
.
O
N
H
O
.
– H+
N
N
4-Nitro-N-phenylbenzamide (2i)
Mp 210–212 °C (Lit. 211–212 °C).
–
1/8 S8
H
H
4
–
1
Scheme 3 Proposed mechanism for the desulfurization of thio-
amides
IR (KBr): 3328, 1651 cm .
1
H NMR (200 MHz, acetone-d ): d = 7.17–7.89 (m, 5 H), 8.25 (d,
J = 9 Hz, 2 H), 8.39 (d, J = 9 Hz, 2 H), 9.86 (br s, 1 H, NH).
6
In conclusion, the mild reaction conditions, good
13
C NMR (50 MHz, acetone-d ): d = 120.18, 123.48, 124.19,
6
chemoselectivity, the excellent yields and purity of the 127.14, 128.58, 138.95, 141.03, 149.62, 163.76.
products obtained coupled with a simple experimental
procedure undoubtedly makes this method superior to
some of the known methods. This methodology also over-
Acknowledgment
comes the formation of unwanted byproducts, slow reac- We are thankful to the Razi University Research Council for partial
support of this work.
tion times, high temperatures and hazardous solvents, thus
making it a more user-friendly procedure.
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(
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(
(
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3
(
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(
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3
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Synthesis 2009, No. 3, 369–371 © Thieme Stuttgart · New York