Alumina encapsulated phosphorus pentasulfide (P4S10/Al2O3) mediated efficient thionation of long chain amides

Article abstract of DOI:10.1016/j.tetlet.2006.02.021

Alumina encapsulated phosphorus pentasulfide (P₄S₁₀/Al₂O₃) was found to be an efficient solid supported reagent for the thionation of long chain amides. This method is advantageous in terms of use of inexpensive reagent, simple reaction processing, and clean product in good to excellent yield.

Full text of DOI:10.1016/j.tetlet.2006.02.021

Tetrahedron Letters 47 (2006) 2315–2317
Alumina encapsulated phosphorus pentasulfide
(P4S10/Al2O3) mediated efficient thionation of long chain amides
Vivek Polshettiwar*, and M. P. Kaushik*
Process Technology Development Division, Defence R&D Establishment, Jhansi Road, Gwalior 474 002, MP, India
Received 5 December 2005; revised 1 February 2006; accepted 3 February 2006
Available online 20 February 2006
Abstract—Alumina encapsulated phosphorus pentasulfide (P4S10/Al2O3) was found to be an efficient solid supported reagent for the
thionation of long chain amides. This method is advantageous in terms of use of inexpensive reagent, simple reaction processing,
and clean product in good to excellent yield.
Ó 2006 Elsevier Ltd. All rights reserved.
The amides and their thio analogues are an important
constituent of many biologically active compounds and
reactions of thioamides are important to the future
development in polypeptides and protein chemistry.1
The thioamide functional group is a relatively conserva-
tive replacement for the amide, differing in its electronic
properties, hydrogen-bonding capacity, and photoreacti-
vity.1 A variety of reagents such as P2S5,2 R3OBF4/
reagent was therefore a particularly desirable target. A
reagent that is anchored to a solid support may easily
be removed from any solution by simple filtration. It
is thus the facile purification method, which makes
supported technology ideal, not only for single reaction
synthesis, but also for robotic manipulation in high
throughput multi-step syntheses.10 The greatest advan-
tages of reaction mediated by solid-supported reagents
are that they can be optimized and scaled-up readily.
Their flexibility in allowing both linear and convergent
strategies to be selected is of considerable advantage
to synthetic chemists building complex molecules.11
Furthermore, handling supported-bound analogues of
toxic, explosive, or malodorous reagents is often found
to be safer and more convenient than handling the solu-
tion phase equivalents. Our aim in undertaking this
work was to overcome the limitations and drawbacks
of the reported methods. In our earlier letter,12 we
showed the efficiency of P4S10/Al2O3 for the thionation
of ketones to thioketones. We were interested to synthe-
size and study thio-analogues of biologically active long
chain amides13 and in continuation of our work on solid
supported reagents,14 we decided to explore the utility of
the reagent P4S10/Al2O3 for the synthesis of these long
chain thioamides and herein, we report a simple,
efficient, and economic method for the effective transfor-
mation of amides to thioamides using P4S10/Al2O3 in
acetonitrile (Scheme 1).
NaSH,3 R2PSX,4 (Et2Al)2S,5 and P2S5/Na2CO3 have
6
been utilized for thionation of carbonyl compounds. In
recent years, Lawesson’s reagent7 (LR) and a combina-
tion of P4S10/HMDO (hexamethyl disiloxane)8 have
replaced P4S10 as the reagent of choice for many
thionations. However, besides its high cost, LR results
in the formation of by-products derived from the reagent
itself, which cannot be easily removed by an extractive
procedure and require chromatography, making the
method more expensive. The combination of P4S10/
HMDO is good in terms of reactivity but the use of
HMDO makes the method expensive and the by-prod-
ucts formed need to be removed by column chromato-
graphy. There is still scope for improvement, as the
existing methods require prolonged reaction times,
aqueous work-up, high temperatures, or inconvenient
reaction conditions for their execution.
Solid supported reagents have also been used in organic
chemistry for many years.9 A solid supported thionating
Keywords: Thionation; Thioamide; Phosphorus pentasulfide; Alumina.
P4S10/Al2O3
CH3CN
O
S
*
Corresponding authors. E-mail addresses: vivekpol@yahoo.com;
mpkaushik@rediffmail.com
R1 NHR2
R1 NHR2
Present address: UMR CNRS-5076, Ecole Nationale Superieure de
Chimie de Montpellier Cedex 05, France.
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.021

2316
V. Polshettiwar, M. P. Kaushik / Tetrahedron Letters 47 (2006) 2315–2317
The reaction was carried out by refluxing a mixture of
the amide and P4S10/Al2O3 in acetonitrile as a solvent.
A series of experiments established that 0.5 mol of
P4S10/Al2O3 per mole of amide were required to obtain
maximum yield of the thioamide. Using standard condi-
tions, the thionation of a series of amides was examined.
Amides reacted smoothly with P4S10/Al2O3 under these
reaction conditions to produce the corresponding thio-
amides in good to excellent yields. The results are
summarized in Table 1.
expected to be potent electrophiles, in analogy with
P4O10, and therefore capable of promoting undesirable
side reactions of both the carbonyl and thiocarbonyl
derivatives. In fact, as the reaction with P4S10 proceeds,
the general reaction environment becomes increasing
electrophilic with each successive replacement of sulfur
on phosphorus by oxygen. However, the Al2O3 in the
reaction binds with these highly electrophilic species
and scavenges them thereby raising the yield of the thio-
nation product. Thus, the beneficial effect of Al2O3 is
basically due to the scavenging of yield-lowering inter-
mediates formed during the course of the reaction.
This method has allowed us to transform amides into
thioamides in reduced reaction time with quantitative
yields and with high purity. The catalytic role of
Al2O3 was also studied by carrying out the reaction in
the absence of Al2O3 using P4S10 alone. It was found
that the yield of the thioamides using the combination
of P4S10/Al2O3 were greater than those with P4S10 alone
(Table 1). Thionation by P4S10 alone produce highly
condensed polythiophosphates. These species might be
Although the yield and reaction times are comparable
with LR, the P4S10/Al2O3 combination still offers advan-
tages over LR. LR requires 2 mol of the reagent per
mole of amides and the high equivalent weight of
Lawesson’s reagent means that the substrate comprises
only a small percentage by weight of the crude reaction
mixture, whereas P4S10/Al2O3 requires only 0.5 mol/
Table 1. Synthesis of thioamides using P4S10/Al2O3
15
16
S. no.
Thioamide
R. time (h)
P4S10/Al2O3
Yield (%)
P4S10
Yield (%)
S
1
6
81
85
76
C6H5
C6H5
C
S
C
NH2
2
5
6
62
70
62
70
56
61
62
60
60
61
C H
N
H
11
6
S
3
78
79
88
80
82
79
79
81
84
H
3C
C
S
NH2
4
6
H3C C
N C6H5
H
S
5
9
H3C(H2C)6 C N C6H11
H
S
6
10
10
11
11
11
10
H3C(H2C)6 C N C6H4-Cl
H
S
7
H3C(H2C)8 C N C6H11
H
S
8
H3C(H2C)5 C N C6H11
H
S
9
H3C(H2C)8 C N C6H5
H
S
10
11
H3C(H2C)8 C N C6H4-Cl
H
S
H3C(H2C)5 C N C6H5
H

V. Polshettiwar, M. P. Kaushik / Tetrahedron Letters 47 (2006) 2315–2317
2317
6. Shalaby, M. A.; Grote, C. W.; Rapoport, H. J. Org.
Chem. 1996, 61, 9045.
7. (a) Pedersen, B. S.; Lawesson, S. O. Tetrahedron 1979, 35,
2433–2437; (b) Cava, M. P.; Levinson, M. I. Tetrahedron
1985, 41, 5061–5087.
8. (a) Curphey, T. J. Tetrahedron Lett. 2000, 41, 9963–
9966; (b) Curphey, T. J. J. Org. Chem. 2002, 67, 6461–
6473; (c) Curphey, T. J. Tetrahedron Lett. 2002, 43, 371–
373.
9. (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P.
S.; Leach, A. G.; Longbottom, D. A. J. Chem. Soc.,
Perkin Trans. 1 2000, 3815; (b) Merrifield, R. B. J. Am.
Chem. Soc. 1963, 85, 2149.
mol of amide making the method less expensive. The
combination P4S10/Al2O3 also provides cleaner products
in comparison to LR, which gives by-products, that are
difficult to remove. Also this method is economic and
practical as compared to the reported methods. The
use of a solid support for P4S10/Al2O3 is advantageous
over LR and P4S10/HMDO because this supported
reagent is removed easily by filtration, avoiding an
aqueous work-up and decreasing waste solvent.
In summary, we have developed an efficient, high yield-
ing, and simple method for thionation of amides using
P4S10/Al2O3, which offers the following advantages: (i)
simple reaction processing and clean product, (ii) effi-
ciency and economy gain through the use of readily
accessible P4S10/Al2O3 as thionating agent, and (iii)
good to excellent yield.
10. (a) Ley, S. V.; Bolli, M. H.; Hinzen, B.; Gervois, A. G.;
Hall, B. J. J. Chem. Soc., Perkin Trans. 1 1998, 2239; (b)
Gayo, L. M. Biotechnol. Bioeng. 1998, 61, 95.
11. Baxendale, I. R.; Ley, S. V. Bioorg. Med. Chem. Lett.
2000, 1.
12. Polshettiwar, V.; Kaushik, M. P. Tetrahedron Lett. 2004,
45, 6255.
13. Gannett, P. M.; Nagel, D. L.; Reilly, P. J.; Lawson, T.;
Sharpe, J.; Toth, B. J. Org. Chem. 1988, 53, 1064–1071.
14. (a) Polshettiwar, V.; Kaushik, M. P. Catal. Commun. 2004,
5, 515; (b) Polshettiwar, V.; Kaushik, M. P. Catal.
Commun. 2005, 6, 191; (c) Polshettiwar, V.; Nivsarkar,
M.; Acharya, J.; Kaushik, M. P. Tetrahedron Lett. 2003,
44, 887; (d) Polshettiwar, V.; Nivsarkar, M.; Pardashani,
D.; Kaushik, M. P. J. Chem. Res. 2004, 474.
Acknowledgments
We thank the referee for critical comments/suggestions,
which helped us to modify the presentation and the con-
tent of this letter. Thanks are also due to DRDO, New
Delhi, for financial support to V.P. during his Ph.D.
15. Experimental: The reagent was prepared as per our
reported method.12 The thionation of amide was carried
out by refluxing 1 mol equiv of amide and 0.5 mol equiv of
P4S10/Al2O3 with respect to P4S10 in acetonitrile. The
reaction mixture was refluxed for the time given in Table 1
and monitored by GC. After completion of reaction the
supported reagent was removed by filtration and solvent
was evaporated. The resultant liquid is extracted with
ether to yield thioamide, which was characterized by IR,
GC–MS, and NMR analyses.
16. The thionation of amide was carried out by refluxing
1 mol equiv of amide and 0.5 mol equiv of P4S10 without
alumina as per the above procedure. The reaction mixture
was refluxed for the same time as that required for P4S10/
Al2O3 method and yield was determined by GC and GC–
MS.
References and notes
1. (a) Beckwith, A. L. J. Synthesis of amides. In The
Chemistry of Amides; Zabicky, J., Ed.; Interscience, John
Wiley and Sons: New York, London, 1970; p 96; (b) Hurd,
R. N.; DeLamater, G. Chem. Rev. 1960, 61, 45.
2. (a) Brillon, D. Sulfur Rep. 1992, 12, 297–338; (b)
Hofmann, A. W.; Gabriel, S. Ber. 1892, 25, 1578.
3. Bodine, J. J.; Kaloustian, M. K. Synth. Commun. 1982, 12,
787.
4. Pedersen, B. S.; Lawesson, S.-O. Bull. Soc. Chim. Belg.
1977, 86, 693.
5. Ishi, Y.; Hirabayashi, T.; Imaeda, H.; Ito, K. Jpn. Patent
1974, 40, 441.