Expeditious microwave-assisted thionation with the system PSCl 3/H2O/Et3N under solvent-free condition

Article abstract of DOI:10.1021/jo7022069

(Chemical Equation Presented) A novel thionation protocol for carbonyl compounds, with the system PSCl₃/H₂O/Et₃N has been discovered. Clean, rapid, and efficient synthesis of a variety of thiocarbonyl compounds such as thioamides, thiolactams, thioketones, thioxanthones, and thioacridone can be achieved through this simple and convenient method under solventless condition with microwave irradiation.

Full text of DOI:10.1021/jo7022069

TMS2S,9 elemental sulfur,10 aq ammonium sulfide,11 SiS2,12
HMDST,13 etc. have also been reported. The described methods
are in general solvent-mediated, where the nature of the solvent
often constitutes a crucial factor. Reactions are usually per-
formed in boiling toluene, xylene, chloroform, acetonitrile, or
pyridine for long periods, and therefore, extensive workup and
chromatographic purification become inevitable, which is
another serious drawback. In consequence of the foregoing
considerations, the development of novel synthetic strategies
for thionation which have advantages with respect to short
reaction time, mild reaction conditions, cleaner reactions, and
simple isolation of the product are of paramount interest. In
this note, we report a very convenient and efficient, solvent-
free thionation of amides, lactams, ketones, xanthones, acridone
with PSCl3/H2O/Et3N. To our knowledge this represents the first
general application of PSCl3 as a thionating agent.
Expeditious Microwave-Assisted Thionation with
the System PSCl3/H2O/Et3N under Solvent-Free
Condition
Uma Pathak,* Lokesh Kumar Pandey, and Rekha Tank
Synthetic Chemistry DiVision, Defence Research & DeVelopment
Establishment, Gwalior- 474002, India
sc_drde@rediffmail.com; scdrde@gmail.com
ReceiVed October 11, 2007
Due to the high nucleophilicity of sulfur and oxophilicity of
phosphorus, PSCl3 is an attractive candidate for an oxygen/sulfur
exchange reaction and may reasonably be expected to convert
carbonyl groups into their thiocarbonyl analogues. A survey of
the literature revealed that thionation by PSCl3 has scarcely been
reported14 and no attempt has been made so far to investigate
the general applicability of this potential thionating agent. Hence,
we set out to explore the ability of PSCl3 for thionation. In order
to ascertain the feasibility of this transformation N,N-diethyl-
m-toluamide was selected as a model substrate, and conversion
to its thio analogue was studied under a variety of conditions.
In the first place, on the basis of literature precedence a solvent-
mediated reaction of amide and PSCl3 was attempted. A very
slow reaction was found to occur in toluene under reflux. The
conversion was modest even after long hours of reflux, and an
increase in concentration of PSCl3 also did not noticeably affect
the outcome.
One interesting observation was that when the reaction is
carried out under strictly anhydrous conditions, almost no
conversion was found to occur. We assumed that, probably in
the presence of water, PSCl3 was getting hydrolyzed to
thiophosphoric acid which may be responsible for thionation.
Curiously, addition of water in the reaction mixture did indeed
increase the rate of reaction. Although with PSCl3/H2O thion-
ation was improved, complete conversion could not be achieved.
A novel thionation protocol for carbonyl compounds, with
the system PSCl3/H2O/Et3N has been discovered. Clean,
rapid, and efficient synthesis of a variety of thiocarbonyl
compounds such as thioamides, thiolactams, thioketones,
thioxanthones, and thioacridone can be achieved through this
simple and convenient method under solventless condition
with microwave irradiation.
Thionation of carbonyl compounds is an important organic
transformation.1 In view of their synthetic importance, several
routes have been developed to gain access to thiocarbonyl
compounds, and among them, CdO f CdS is the most
exploited route. The mechanistic principle for majority of the
methods employed is the nucleophilic attack of some suitable
sulfur-containing agent on the carbon atom of a polar CdO
bond leading to the substitution of oxygen by the sulfur. To
effect this transformation, Lawesson’s reagent2 and P4S10, either
alone or with additives,3 are the reagents of choice. Many other
useful reagents such as H2S,4 CS2,5 R2PSX,6 (Et2Al)2S,7 NaSH,8
(1) (a) Bernardi, F., Csizmadia, I. G., Mangini, A., Eds. Organic Sulfur
Chemistry; Elsevier: New York, 1985. (b) Damani, L. A. Sulfur-containing
Drugs and Related Organic Compounds-Chemistry, Biochemistry and
Toxicology; Ellis Harwood: Chichester, 1989. (c) Block, E. Reactions of
organosulfur compounds; Academic Press: New York, 1978. (d) Cremlyn,
R. J. An Introduction to Organosulfur Chemistry; John Wiley & Sons: New
York, 1996. (e) Shaumann, E. Synthesis of Thioamides and Thiolactams.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Winterfeldt,
E., Eds.; Pergamon Press: New York, 1991; Vol. 6, pp 419-434. (f) Duus,
F. Thiocarbonyl Compounds. In ComprehensiVe Organic Chemistry; Jones,
D. N., Ed.; (g) Brillion, D. Sulfur Rep. 1992, 1, 297. (h) Polshettiwar, V.;
Kaushik, M. P. J. Sulfur Chem. 2006, 27, 353-386.
(2) (a) Jesberger, M.; Davis, T. P.; Barner, L. Synthesis 2003, 1929-
1958. (b) Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061-5087.
(c) Scheibye, S.; Pedersen, B. S.; Lawesson, S. O. Bull. Soc. Chim. Belg.
1978, 87, 229-238. (d) Kaleta, Z.; Makowski, B.T.; Soos, T.; Dembinski,
R. Org. Lett. 2006, 8, 1625-1628.
(5) Zong, Z.-M.; Peng, Y.-L.; Liu, Z.-G.; Zhou, S.-L.; Wu, L.; Wang,
X.-H.; Wei, X.-Y.; Lee, C. W. Korean J. Chem. Eng. 2003, 20(2), 235-
238.
(6) (a) Oae, S.; Nakanishi, A.; Tsujimoto, N. Chem. Ind. 1972, 575. (b)
Pedersen, B. S.; Lawesson, S. O.; Bull. Soc. Chim. Belg. 1977, 86, 693.
(7) Ishii, Y.; Hirabayashi, T.; Imaeda, H.; Ito, Jpn, K. Patent 40441, 1974;
Chem. Abstr. 1975, 82, 156074f.
(8) Bodine, J. J.; Kaloustian, M. K. Synth. Commun. 1982, 12, 787.
(9) Smith, D. C.; Lee, S. W.; Fuchs, P. L. J. Org. Chem. 1994, 59, 348-
354.
(10) (a) Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S. O.
Bull. Soc. Chim. Belg. 1978, 87, 223-228. (b) Yang C. O-; Rotstein, D.
M.; Labadie, S.S.; Walker K. A. M. Synlett, 1995, 655.
(11) Charette, A. B.; Grenon, M. J. Org. Chem. 2003, 68, 5792-5794.
(12) (a) Dean, F. M.; Goodchild, J.; Hill, A. W. J. Chem. Soc. (c), 1969,
2192-2195. (b) Dean, F. M.; Goodchild, J.; Hill, A. W.; Moore, S.; Zahman,
A. J. Chem. Soc., Perkin Trans. 1 1975, 1335.
(3) (a) Hurd, R. N.; DeLaMater, G. Chem. ReV. 1961, 61, 45. (b)
Wakabayashi, T.; Kato, Y.; Watanabe, K. Jpn. Kokai Tokkyo Koho 1978,
78, 56, 662; Chem. Abstr. 1979, 90, 22818h. (c) Brillon, D. Sulfur Rep.
1992, 12, 297-338. (d) Curphey, T. J. J. Org. Chem. 2002, 67, 6461-
6473.
(13) Degl’Innocenti, A.; Capperucci A.; Castagnoli G.; Malesci. I. Synlett
1965 (2005).
(4) (a) Asquith, R. S.; Hammick, D. Ll.; Williams, P. L. J. Chem. Soc.
1948, 1181 (b) Fournier, C.; Paquer, D.; Vazeux, M. Bull. Soc. Chim. Fr.
1975, 2753. (c) Sen, D. C. J. Indian Chem. Soc. 1935, 12, 647; 1937, 14,
214.
(14) (a) Perrenaard, J.; Pedersen, B. S.; Lawesson, S.-O. Acta Chem.
Scand. B31.460 (1977) (b) Pipko, S. E.; Simurova, N. V.; Shvadchak, V.
V.; Bezgubenko, L. V.; Luk’yaneko, S. N. Russ. J. Gen. Chem. 2006, 76,
1019-1021.
10.1021/jo7022069 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/05/2008
2890
J. Org. Chem. 2008, 73, 2890-2893

SCHEME 1. Thionation of Amides, Lactams, Ketones, and
Xanthones
are benzene, dichloromethane, and chloroform all at reflux but
less effective than toluene.
In recent years microwave-assisted synthesis has gained a
lot of importance. A number of publications have demonstrated16
that application of microwave energy offers several advantages
including enhanced reaction rates. Furthermore, an additional
advantage with PSCl3 was that, since most of the substrates
were either completely or partially soluble in it, there existed a
scope for solventless synthesis. Accordingly, in an attempt to
look for alternating reaction conditions/procedures efforts were
directed toward a prospective microwave-assisted reaction under
solventless condition.
SCHEME 2. Possible Mechanism for Thionation
In a typical microwave-assisted procedure water (1.0 mmol)
was added to PSCl3 (1.0 mmol), and the contents were
microwaved for a short period. To this 1 mmol of carbonyl
compound was added followed by 1.5 mmol of triethyl amine,
and the contents were microwaved further. Reaction occurred
immediately and went to completion within minutes. Having
established optimum conditions for conversion of N,N-diethyl-
m-toluamide to the corresponding thioamide (Table 1, entry 1),
we explored the scope and limitation of this new thionation
procedure.
A variety of compounds were investigated including sub-
strates which posed problems with the reported thionating
agents. The results of formation of various thionated products
are summarized in Table 1. Secondary and tertiary amides
underwent efficient thionation. In case of primary amides,
nitriles were also formed as side products (Table 1, entries 5,
6) under the reaction conditions, and no attempts were made to
optimize the reaction further. This reagent was particularly found
useful for thionation of sparingly soluble amides such as
nicotinamide, which is difficult to thionate due to its insolubility
in commonly used solvents for thionation. Smooth thionation
with PSCl3/H2O/Et3N took place, and thionicotinamide was
isolated easily in good yield.
Encouraged by the facile thionation of amides, the utility of
this method for thionation of lactams with different systems
was studied. The method was found applicable for the synthesis
of thiolactams also. Reaction with lactams occurred successfully
under mild condition (Table 1, entries 7, 8, 9). 1-Vinyl-2-
pyrrolidinone offered a noteworthy example. This compound
was investigated as it has been reported to be a difficult substrate
for thionation due to its highly sensitive nature.9 Our initial
attempts to thionate this compound following the protocol used
for other amides and lactams, were not successful. The reaction
mixture decomposed when the reaction was carried out at room
temperature with PSCl3/H2O/Et3N in 1:1:1.5 mol ratio. However,
satisfactory results were obtained with a slightly modified
procedure.17
Next, we turned our attention on utilization of promoters to
accelerate the reaction. Both acidic promoters9 such as POCl3,
SOCl2, oxalyl chloride, etc. and basic promoters15 such as
pyridine, Et3N, and NaHCO3 have been reported to assist in
this transformation. After extensive examination of various
promoters, organic basic promoters, i.e., triethyl amine and
pyridine, were found useful in circumventing the problem. Non-
nucleophilic organic bases such as diisopropyl ethyl amine were
also investigated as an alternative promoter and were found to
be effective. Acidic promoters and inorganic bases did not yield
the desired result. All three bases, triethyl amine, pyridine, and
diisopropyl ethyl amine, were found of equal utility, and any
one of them can be used depending upon the convenience and
availability. Keeping in view the less malodorous nature and
common availability we utilized triethyl amine in most of our
reactions. Further, we noted that addition of base was helpful
only after the water had been added to the reaction mixture.
Another important observation was that the amount of water
required for the reaction is also critical. While optimizing the
reaction with the reagent combination PSCl3/H2O/Et3N, we
noted that no conversion took place when an excess of water
was used. On further inspection, the optimum quantity was
found to be 1-1.2 mol of water/mol of PSCl3. A possible
explanation for this may be that in the first step chlorothio-
phosphoric acid was generated by the hydrolysis of PSCl3
(Scheme 2). This was further assisted by the basic promoters.
The active species then reacted with carbonyl compound to give
the thionated product. To confirm this, a mixture of amide,
water, and PSCl3 in dry toluene was refluxed followed by
addition of Et3N; the contents were refluxed further whereupon
complete thionation of the amide was observed. The inability
of the reagent to thionate in the presence of excess of water
may be explained by the fact that with excess of water more
chloride groups of the reagent were replaced by hydroxyl groups.
The greater electron-withdrawing effect of oxygen may render
sulfur of the reagent insufficiently reactive toward the nucleo-
philic attack on carbonyl carbon. With the reagent combination
PSCl3/H2O/Et3N in toluene complete thionation of N,N-diethyl-
m-toluamide was achieved in 5 h. Other solvents found useful
To further illustrate the generality of this reagent, different
ketones and xanthones were investigated. It was inspiring to
find that thio analogues of these compounds were efficiently
synthesized by this method although a slightly higher amount
(16) (a) Loupy, A., Ed. MicrowaVe in Organic Synthesis; Wiley-VCH:
Weinheim, 2002. (b) Varma, R. S.; Kumar, D. Org. Lett. 1999, 1, 697-
700.
(17) Thionation procedure for 1-vinyl-2-pyrrolidinone: equimolar amount
of PSCl3 and water (0.005 mol) was taken in a test tube. To this triethyl
amine was added dropwise at 0-5 °C with constant stirring till the contents
were basic, this is followed by slow addition of 0.005 mol 1-vinyl-2-
pyrrolidinone. Reaction mixture is then microwaved at 180 W for 3-4 min.
Work up was carried by following the reaction workup procedure, method
A.
(15) (a) Barton, D. H. R. U. S. Patent 4011316, 1977; Chem Abstr. 1977,
87, 53490n. (b) Machiguchi, T.; Hoshino, M.; Kitahara, Y. Jpn. Kokai
Tokkyo Koho 77,23,066, 1977; Chem. Abstr. 1977, 82, 102153r.
J. Org. Chem, Vol. 73, No. 7, 2008 2891

TABLE 1. Thionationf of Carbonyl Compounds Using PSCl3/H2O/Et3N
a Microwave exposure was intermittent (30 s/1 min duration) with 15 s break. b GC and HPLC conversion and identification by their MS data. c Isolated
yield. d Nitrile was formed as a side product. e Reference 17. f SF, solvent-free; TEA, triethyl amine; DIPEA, diisopropyl ethyl amine; Py, pyridine. Mole
ratio of PSCl3/H2O/base used for entries 1-9, 20-21 is 1:1:1.5, entries 11-16 is 2: 2:3, and entries 17-19 is 2.5:2.5:6 for 1 mol of carbonyl compound.
of PSCl3 was used (Table 1, entries 12-19). The thionation
potential of this system was also investigated for the preparation
of sterically hindered optically active thioketones such as (+)-
1,3,3-trimethyl-bicyclo[2.2.1]heptane-2-thione (20) and (-)-1, 7,
2892 J. Org. Chem., Vol. 73, No. 7, 2008

7-trimethyl-bicyclo[2.2.1]heptane-2-thione (21), and these com-
pounds were obtained easily although the yields obtained were
less. Since these compounds are highly volatile in nature and
the reactions were carried out in open vessels, there was a loss
of both reactant and product during the reaction.
mixture. Mixing was done gently with the help of glass
thermometer, which also indicated the reaction temperature. The
reaction was monitored by GC and TLC. On completion of the
reaction the pure compound was obtained following the workup
procedure, method A.
Entries 13-16 indicate that this protocol has excellent
functional group compatibility, and in this context thionation
of isophorone, an R,â-unsaturated ketone, should be noted. This
compound was readily converted to its thio analogue (entry 16).
Similarly xanthione, thioxanthione, and thioacridone were also
obtained conveniently in excellent yield.
In summary, a new protocol for rapid and efficient thionation
of carbonyl compounds has been disclosed. This method has
several advantages over the reported methods: extreme precau-
tion in carrying out the reaction under completely anhydrous
condition is not required, workup is very simple, and hazards
of using solvents during reaction are minimized. Additionally,
fast reaction, low consumption of solvent, mild reaction
conditions, good to excellent yield, clean reaction, and readily
obtainable, simple reagents make this method an attractive and
useful alternative to the existing methods for thionation. The
advantages associated with this method may lead to its wider
application.
Yield 0.92 gm (89%); light yellowish crystals: mp 80-
1
81 °C; H NMR (CDCl3/TMS-400 MHz): δ 1.14 (t, J ) 7.2,
3H), 1.39 (t, J ) 7.1, 3H), 2.34 (s, 3H), 3.44 (q, J ) 7.1 Hz,
2H), 4.11 (q, 7.1 Hz, 2H), 7.11 (m, 4H); 13C NMR (CDCl3/
TMS - 100.6 MHz): δ 200.55, 143.90, 138.27, 128.87, 128.35,
125.68, 121.96, 47.90, 46.11, 21.53, 13.98, 11.39; EIMS m/z
207 (M+), 205, 192, 146, 135, 118, 91, 65, 51; Anal. Calcd for
C12H17NS. C, 69.51; H, 8.26; N, 6.76; S, 15.47. Found: C,
69.67; H, 8.15; N, 6.84, S, 15.32.
Reaction Workup Procedures. Method A. Contents were
adsorbed on silica, loaded on a column of silica gel, and eluted
with the solvent of appropriate strength. Solvent removal
afforded pure compound.
Method B. Contents were cooled, neutralized with Et3N, and
precipitated by addition of cold water. The insoluble thionated
product obtained was filtered under vacuum and dried. Further
purification, if required, can be achieved through recrystalliza-
tion from the appropriate solvent. In the case of thionicotina-
mide, additional recovery was made by extracting the aqueous
layer with ethyl acetate.
Experimental Section
Representative Experimental Procedure. To 0.51 mL (5
mmol) of PSCl3 was added 0.09 mL (5 mmol) of water, and
the mixture was microwaved (Samsung CE2977N operating at
2450 MHz) for 30 s. To this was added 0.95 mL (5 mmol) of
N,N-diethyl-m-toluamide followed by dropwise addition of 0.76
mL (7.5 mmol) of triethyl amine. The temperature of the
reaction mixture was maintained at 60-70 °C. Contents were
mixed and microwaved further at 180 W for 4-5 min.
Instantaneous reaction took place with simultaneous formation
of thionated product. Microwave exposures were intermittent
with 15 s break since it was necessary to mix the reaction
Acknowledgment. We thank A. Narasimha Rao and Avik
Mazumder for GC/MS analysis and NMR spectra respectively.
We are grateful to the reviewers for their useful suggestions.
We also thank Dr. R Vijayaraghavan, Director, DRDE, for his
keen interest and encouragement.
Supporting Information Available: Copies of mass spectra
for compounds 1-21; 1H NMR spectra of 1, 2, 4, 5, 7, 10-12, 14,
17-21; 13C NMR spectra of 1, 7, 10-12, 14, 17-21. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO7022069
J. Org. Chem, Vol. 73, No. 7, 2008 2893