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 2006Available online 20 February 2006

Abstract—Alumina encapsulated phosphorus pentasulfide (P4S10/Al2O3) was found to be an efficient solid supported reagent for thethionation 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.� 2006 Elsevier Ltd. All rights reserved.

The amides and their thio analogues are an importantconstituent of many biologically active compounds andreactions of thioamides are important to the futuredevelopment in polypeptides and protein chemistry.1

The thioamide functional group is a relatively conserva-tive replacement for the amide, differing in its electronicproperties, hydrogen-bonding capacity, and photoreacti-vity.1 A variety of reagents such as P2S5,2 R3OBF4/NaSH,3 R2PSX,4 (Et2Al)2S,5 and P2S5/Na2CO3

6 havebeen utilized for thionation of carbonyl compounds. Inrecent years, Lawesson’s reagent7 (LR) and a combina-tion of P4S10/HMDO (hexamethyl disiloxane)8 havereplaced P4S10 as the reagent of choice for manythionations. However, besides its high cost, LR resultsin the formation of by-products derived from the reagentitself, which cannot be easily removed by an extractiveprocedure and require chromatography, making themethod more expensive. The combination of P4S10/HMDO is good in terms of reactivity but the use ofHMDO 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 theexisting methods require prolonged reaction times,aqueous work-up, high temperatures, or inconvenientreaction conditions for their execution.

Solid supported reagents have also been used in organicchemistry for many years.9 A solid supported thionating

0040-4039/$ - see front matter � 2006 Elsevier Ltd. All rights reserved.doi:10.1016/j.tetlet.2006.02.021

Keywords: Thionation; Thioamide; Phosphorus pentasulfide; Alumina.* Corresponding authors. E-mail addresses: vivekpol@yahoo.com;

mpkaushik@rediffmail.com�Present address: UMR CNRS-5076, Ecole Nationale Superieure de

Chimie de Montpellier Cedex 05, France.

reagent was therefore a particularly desirable target. Areagent that is anchored to a solid support may easilybe removed from any solution by simple filtration. Itis thus the facile purification method, which makessupported technology ideal, not only for single reactionsynthesis, but also for robotic manipulation in highthroughput multi-step syntheses.10 The greatest advan-tages of reaction mediated by solid-supported reagentsare that they can be optimized and scaled-up readily.Their flexibility in allowing both linear and convergentstrategies to be selected is of considerable advantageto synthetic chemists building complex molecules.11

Furthermore, handling supported-bound analogues oftoxic, explosive, or malodorous reagents is often foundto be safer and more convenient than handling the solu-tion phase equivalents. Our aim in undertaking thiswork was to overcome the limitations and drawbacksof the reported methods. In our earlier letter,12 weshowed the efficiency of P4S10/Al2O3 for the thionationof ketones to thioketones. We were interested to synthe-size and study thio-analogues of biologically active longchain amides13 and in continuation of our work on solidsupported reagents,14 we decided to explore the utility ofthe reagent P4S10/Al2O3 for the synthesis of these longchain thioamides and herein, we report a simple,efficient, and economic method for the effective transfor-mation of amides to thioamides using P4S10/Al2O3 inacetonitrile (Scheme 1).

CH3CN

P4S10/Al2O3

R1

O

NHR2 R1

S

NHR2

Scheme 1.

2316 V. Polshettiwar, M. P. Kaushik / Tetrahedron Letters 47 (2006) 2315–2317

The reaction was carried out by refluxing a mixture ofthe amide and P4S10/Al2O3 in acetonitrile as a solvent.A series of experiments established that 0.5 mol ofP4S10/Al2O3 per mole of amide were required to obtainmaximum yield of the thioamide. Using standard condi-tions, the thionation of a series of amides was examined.Amides reacted smoothly with P4S10/Al2O3 under thesereaction conditions to produce the corresponding thio-amides in good to excellent yields. The results aresummarized in Table 1.

This method has allowed us to transform amides intothioamides in reduced reaction time with quantitativeyields and with high purity. The catalytic role ofAl2O3 was also studied by carrying out the reaction inthe absence of Al2O3 using P4S10 alone. It was foundthat the yield of the thioamides using the combinationof P4S10/Al2O3 were greater than those with P4S10 alone(Table 1). Thionation by P4S10 alone produce highlycondensed polythiophosphates. These species might be

Table 1. Synthesis of thioamides using P4S10/Al2O3

S. no. Thioamide R. t

1C6H5 C

S

NH2

6

2C

S

NH

C6H11C6H55

3H3C

S

NH2C6

4H3C

S

NH

C6H5C6

5H3C(H2C)6 C

S

NH

C6H119

6H3C(H2C)6 C

S

NH

C6H4-Cl10

7H3C(H2C)8 C

S

NH

C6H1110

8H3C(H2C)5 C

S

NH

C6H1111

9H3C(H2C)8 C

S

NH

C6H511

10H3C(H2C)8 C

S

NH

C6H4-Cl11

11H3C(H2C)5 C

S

NH

C6H510

expected to be potent electrophiles, in analogy withP4O10, and therefore capable of promoting undesirableside reactions of both the carbonyl and thiocarbonylderivatives. In fact, as the reaction with P4S10 proceeds,the general reaction environment becomes increasingelectrophilic with each successive replacement of sulfuron phosphorus by oxygen. However, the Al2O3 in thereaction binds with these highly electrophilic speciesand scavenges them thereby raising the yield of the thio-nation product. Thus, the beneficial effect of Al2O3 isbasically due to the scavenging of yield-lowering inter-mediates formed during the course of the reaction.

Although the yield and reaction times are comparablewith LR, the P4S10/Al2O3 combination still offers advan-tages over LR. LR requires 2 mol of the reagent permole of amides and the high equivalent weight ofLawesson’s reagent means that the substrate comprisesonly a small percentage by weight of the crude reactionmixture, whereas P4S10/Al2O3 requires only 0.5 mol/

ime (h) P4S10/Al2O315 P4S10

16

Yield (%) Yield (%)

81 76

85 62

78 70

79 62

88 70

80 56

82 61

79 62

79 60

81 60

84 61

V. Polshettiwar, M. P. Kaushik / Tetrahedron Letters 47 (2006) 2315–2317 2317

mol of amide making the method less expensive. Thecombination P4S10/Al2O3 also provides cleaner productsin comparison to LR, which gives by-products, that aredifficult to remove. Also this method is economic andpractical as compared to the reported methods. Theuse of a solid support for P4S10/Al2O3 is advantageousover LR and P4S10/HMDO because this supportedreagent is removed easily by filtration, avoiding anaqueous work-up and decreasing waste solvent.

In summary, we have developed an efficient, high yield-ing, and simple method for thionation of amides usingP4S10/Al2O3, which offers the following advantages: (i)simple reaction processing and clean product, (ii) effi-ciency and economy gain through the use of readilyaccessible P4S10/Al2O3 as thionating agent, and (iii)good to excellent yield.

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, NewDelhi, for financial support to V.P. during his Ph.D.

References and notes

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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.

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13. Gannett, P. M.; Nagel, D. L.; Reilly, P. J.; Lawson, T.;Sharpe, J.; Toth, B. J. Org. Chem. 1988, 53, 1064–1071.

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15. Experimental: The reagent was prepared as per ourreported method.12 The thionation of amide was carriedout by refluxing 1 mol equiv of amide and 0.5 mol equiv ofP4S10/Al2O3 with respect to P4S10 in acetonitrile. Thereaction mixture was refluxed for the time given in Table 1and monitored by GC. After completion of reaction thesupported reagent was removed by filtration and solventwas evaporated. The resultant liquid is extracted withether to yield thioamide, which was characterized by IR,GC–MS, and NMR analyses.

16. The thionation of amide was carried out by refluxing1 mol equiv of amide and 0.5 mol equiv of P4S10 withoutalumina as per the above procedure. The reaction mixturewas refluxed for the same time as that required for P4S10/Al2O3 method and yield was determined by GC and GC–MS.