Thionation of amides using a solid-supported P2S5 reagent under microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2011.07.104

In this Letter, we describe an improved method for the thionation of amides. Using a solid-supported P₂S₅ reagent, heating under microwave irradiation furnished thioamides in good to excellent yields, with a significantly reduced reaction time compared with that achieved under conventional heating. Furthermore, a change of solvent from that described in the literature enabled a simplified work-up and purification of the products.

Full text of DOI:10.1016/j.tetlet.2011.07.104

Tetrahedron Letters 52 (2011) 5131–5132
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Tetrahedron Letters
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Thionation of amides using a solid-supported P2S5 reagent under
microwave irradiation
Helen Rachel Lagiakos a, Ashley Walker a, Marie-Isabel Aguilar b, Patrick Perlmutter a,
⇑
a School of Chemistry, Monash University, Clayton VIC 3800, Australia
b Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, we describe an improved method for the thionation of amides. Using a solid-supported P2S5
reagent, heating under microwave irradiation furnished thioamides in good to excellent yields, with a
significantly reduced reaction time compared with that achieved under conventional heating. Further-
more, a change of solvent from that described in the literature enabled a simplified work-up and purifi-
cation of the products.
Received 9 June 2011
Accepted 22 July 2011
Available online 29 July 2011
Keywords:
Thionation
Ó 2011 Elsevier Ltd. All rights reserved.
Microwave irradiation
Phosphorus pentasulfide
Solid-supported reagent
The thionation of carbonyl compounds is a synthetically useful
process, as organosulfur compounds appear in many biologically
interesting compounds, as well as being versatile intermediates
in organic synthesis.1,2 The literature protocols utilize various re-
agents to perform this transformation, including H2S, P2S5, and
Lawesson’s reagent.3,4 Most of these reagents require lengthy reac-
tion times, high temperatures, and result in the formation of unde-
sirable by-products and the need for complicated purification, not
to mention the expense of some reagents.5,6 New approaches, com-
bining conventional reagents with additives or new technologies
designed to improve yields, simplify purification or reduce costs
have resulted in substantial improvements to older procedures.3,7
Kaushik and co-workers reported a cost effective and simplified
route to the synthesis of thioamides and thioketones, utilizing a
novel alumina-supported P2S5 reagent.8 Amides were thionated
in good yields, in an average reaction time of 9 h. The alumina
served several functions. First, it scavenged by-products formed
during the reaction, improving the yield. Second, upon completion
of the reaction, the supported reagent could be filtered off, avoid-
ing an aqueous work-up and thereby simplifying the process. Fi-
nally, as the majority of the reaction by-products stay bound to
the alumina, the need for and difficulty of purification are
minimized.
uses microwave irradiation to improve on Kaushik’s procedure
for the thionation of amides, by both dramatically decreasing the
reaction time and simplifying even further the work-up and puri-
fication steps.
According to the published protocol,8 amides are reacted at re-
flux in MeCN with P2S5/Al2O3 for between 6 and 10 h in order to
achieve complete conversion. We have now found that heating
the reaction under microwave irradiation significantly reduces
the reaction time. Heating 0.75 mmol of the amide with P2S5/
Al2O3 in MeCN to 60 °C in a sealed vessel, at a power of 60 W
and with air cooling, gave complete conversion in just 5 min. Fur-
thermore, we were able to scale the reaction up to 7.5 mmol using
a simple round-bottomed flask placed, open to the air, in the
microwave cavity, with the reaction being complete in the same
shortened time and with a comparable yield.
Following Kaushik’s method, after completion of the reaction,
the reagent was removed by filtration and the filtrate concentrated
in vacuo to give a viscous red oil, which was triturated repeatedly
with Et2O to recover pure products with no need for chromatogra-
phy. In our hands, however, we experienced significant difficulties
with this work-up. First, we found that the resinous oil tended to
retain substantial amounts of the product, despite extensive
extraction with Et2O. We also found that after the extraction, the
products were contaminated with a significant amount of a non-
polar impurity, easily observable by TLC, along with a highly polar
impurity which remained on the baseline. In order to overcome
these problems, we decided to change both the reaction solvent
and the work-up procedure.
Microwave-assisted reactions are well documented in the liter-
ature for their ability to accelerate reactions, and as such, the tech-
nology has been previously applied to the thionation of various
classes of compounds.9–11 Herein, we present a new method that
It seemed plausible that polymerization of the solvent (MeCN)
was contributing to the viscous oil obtained after the reaction,
⇑
Corresponding author. Tel.: +61 3 9905 4522; fax: +61 3 9905 4597.
E-mail address: patrick.perlmutter@monash.edu (P. Perlmutter).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.104

5132
H. R. Lagiakos et al. / Tetrahedron Letters 52 (2011) 5131–5132
Table 1
In order to remove the impurities observed by TLC, we chose to
Thionation of primary, secondary, and tertiary amides
pass the reaction mixture through a short plug of silica, rather than
using the extraction described in the literature. Eluting with hex-
anes readily removed the highly non-polar contaminants, after
which the product could be eluted with hexanes/EtOAc, leaving
the reagent and other highly polar impurities bound to the silica.
These conditions were applied to a range of aliphatic and aro-
matic, primary, secondary, and tertiary amides. The results are col-
lated in Table 1. All the reactions proceeded with complete
conversion, as determined by TLC and analysis of the 1H NMR spec-
tra. The thionation of benzamide (entry 1) is representative of the
general procedure:
O
S
P2S5/Al2O3, THF
R''
R''
R
N
R'
R
N
R'
µW, 60 W, 60 °C, 5 min
Entry
Product
Yield (%)
1
2
92
S
98a
Benzamide (0.75 mmol) was dissolved in THF (5 mL) in a micro-
wave vial and to this was added P2S5/Al2O3 (0.53 g, equivalent to
0.90 mmol of P2S5).12 The vial was then sealed and the suspension
was heated under microwave irradiation in a CEM Discover™
microwave reactor: 60 W at 60 °C, with stirring and air cooling.
Complete conversion (as indicated by TLC) was achieved after
5 min. The entire solution was cooled and poured onto a short plug
of silica. The material was eluted with hexanes to remove non-
polar impurities, then with hexanes/EtOAc to recover the product.
Removal of the solvent gave pure thiobenzamide in 92% yield.
Entry 2 shows the possibility for the reaction to be scaled-up,
with thiobenzamide being obtained in 98% yield on a 7.5 mmol
scale. Worthwhile to note is that this increase in scale can be
achieved in an open vessel, showing that the high pressure usually
attributed to the acceleration of microwave reactions is not
required in this case. Good to excellent yields were achieved
throughout all entries. Even the bis-amides shown in entries 10
and 11 were thionated with ease, despite the steric bulk of these
substrates – a factor that can hinder the effectiveness of other com-
mon thionating reagents.
NH2
S
N
S
3
4
5
76
86
90
NH
S
N
S
6
7
92
84
N
S
N
O
O
S
In conclusion, we have developed an improved method for the
thionation of amides in good to excellent yields, using a solid-
supported P2S5 reagent under microwave irradiation. This method
allows for substantially shortened reaction times, a more efficient
work-up procedure, and yields higher than those in previous reports.
N
8
77
O
Acknowledgments
9
NH
S
81
90
82
H.R.L. is grateful to the Australian Research Council for financial
support. A.W. thanks the Australian Government for an Australian
Postgraduate Award.
S
S
S
10
11
N
H
N
H
References and notes
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2. Metzner, P. Top. Curr. Chem. 1999, 204, 127.
3. Brillon, D. Synth. Commun. 1990, 20, 3085.
4. Yde, B.; Yousif, N. M.; Pedersen, U.; Thomsen, I.; Lawesson, S. O. Tetrahedron
1984, 40, 2047.
S
N
N
5. Brillon, D. Sulfur Rep. 1992, 12, 297.
6. Cherkasov, R. A.; Kutyrev, G. A.; Pudovik, A. N. Tetrahedron 1985, 41, 2567.
7. Curphey, T. J. Tetrahedron Lett. 2000, 41, 9963.
a
7.50 mmol amide, 50 mL THF, open vessel.
8. Polshettiwar, V.; Kaushik, M. P. Tetrahedron Lett. 2006, 47, 2315.
9. Varma, R. S.; Kumar, D. Org. Lett. 1999, 1, 697.
10. Polshettiwar, V.; Nivsarkar, M.; Paradashani, D.; Kaushik, M. P. J. Chem. Res.
2004, 474.
11. Cho, D.; Ahn, J.; De, C.; Ahn, H.; Rhee, H. Tetrahedron 2010, 66, 5583.
12. The P2S5/Al2O3 reagent was prepared by grinding P2S5 (6 g) and basic alumina
(10 g) in mortar and pestle to a fine, homogeneous powder. The reagent was
stored under nitrogen and remained effective for several months.
and thus we felt that changing the solvent would assist in simpli-
fying the work-up and in improving the yields. THF proved to be a
suitable substitute, and indeed we found that the amount of resin-
ous by-products was reduced by this change, allowing for an in-
crease in overall yields.