ORGANIC LETTERS

Phosphorus Pentasulfide: A Mild and Versatile Catalyst/Reagent for the Preparation of Dithiocarboxylic Esters
Arumugam Sudalai, Subbareddy Kanagasabapathy, and Brian C. Benicewicz*
NYS Center for Polymer Synthesis and Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180 benice@rpi.edu
Received August 2, 2000

2000 Vol. 2, No. 20 3213-3216

ABSTRACT

The reaction of carboxylic acids (1) with a variety of thiols or alcohols in the presence of phosphorus pentasulfide (P4S10) as a catalyst and reagent (2040 mol %) proceeded effectively to afford the corresponding dithiocarboxylic esters (2) in high yields.

Esters of dithiocarboxylic acids are versatile synthons in organic synthesis,1 valuable sensitizers in the manufacture of dyes and photographic materials,2 potent agents in bactericidal, fungicidal, and antitumor activities,3 and efficient reversible addition-fragmentation chain transfer agents for living radical polymerization.4 They are generally prepared by the following methods: (i) alkylation of dithio acid salts,5 prepared by the reaction of carbon disulfide either with organometallic reagents and nucleophile carbanions or with aromatic compounds under Friedel-Crafts conditions, (ii) thiohydrolysis of imidothiolates, prepared from nitrile
(1) (a) Metzer, P. Synthesis 1992, 1185. (b) Meyers, A. I.; Tait, T. A.; Comins, D. L. Tetrahedron Lett. 1978, 4657. (c) Jansons, E. Russ. Chem. ReV. 1976, 45, 1035. (2) (a) Edward, H. D.; Kendall, J. D. U.S. Patent 2,535,276, 1950. Chem. Abstr. 1951, 45, 4052. (b) Gevaert, N. V. BP 623,990, 1949; Chem. Abstr. 1950, 44, 7681. (3) (a) Glaxo Group Ltd. Neth. Pat. 6,408,066, 1965; Chem. Abstr. 1965, 63. 614. (b) Neth. Pat. 6,408,067, 1965; Chem. Abstr. 1966, 65, 8928. (c) Christensen, B. G.; Ratcliffe, R. W. Ger. Offen. 2,318,829, 1973; Chem. Abstr. 1974, 80, 37128. (d) Christensen, B. G.; Ratcliffe, R. W. Ger. Offen. 2,365,456, 1975; Chem. Abstr. 1975, 83, 28249. (e) Nase, B. Z. Chem. 1968, 8, 96. (f) Thorn G. D.; Ludwig R. A. The Dithiocarbamates and Related Compounds; Elsevier Publ. Co.: Amsterdam; New York, 1962. (4) (a) Le, T. P. T.; Moad, G.; Rizzardo, E.; Thang, S. H. PCT Int. Appl. WO 9801478 A1 980115, 1998. (b) Chiefary, J.; Chong, Y. K.; Ercole, F.; Krstina, J.; Jeffery, J.; Le, T. P. T.; Mayadunne, R.; Meijs, G. F.; Moad, C. L.; Moad, G.; Rizzardo, E.; Thang, S. H. Macromolecules 1998, 31, 5559. (c) Chong, Y. K.; Le, T. P. T.; Moad, G.; Rizzardo, E.; Thang, S. H. Macromolecules 1999, 32, 2071. (5) Meijer, J.; Vermeer, P.; Brandsma, L. Recueil 1973, 92, 601. 10.1021/ol006407q CCC: $19.00 Published on Web 09/09/2000 2000 American Chemica l Socie ty

or thioamide precursors,6 (iii) thionation of thioesters using Lawessons reagents,7 (iv) oxidative sulfuration of benzyl halides or benzaldehydes with elemental sulfur under alkaline conditions,8 (v) transesterification of dithioesters with thiols,9 and (vi) exchange of bis(thiocarbonyl) disulfide with azo compounds.10 Many of the published procedures suffer from the following disadvantages: expensive or scarcely available reagents, use of strongly basic conditions, use of large excess of reagents often resulting in quite variable yields, and incompatibility of certain reactive functional groups (NO2, CN, etc.) under Grignard conditions. Phosphorus pentasulfide (P4S10), a commercially available reagent, has been widely
(6) (a) Ramadas, S. R.; Srinivasan, P. S.; Ramachandran, J.; Sastry, V. V. S. K. Synthesis 1983, 605. (b) Voss, J. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 6, p 435. (c) Kota, S.; Ishida, M. Sulfur Rep. 1988, 8 (4), 155. (d) Mayer, R.; Scheithauer, S. In Houben-Weyl, 4th ed.; Falbe, J., Ed.; GeorgThieme-Verlag: Stuttgart, 1985; Vol. E5, Chapter 2.5, p 891. (e) Scheithauer, S.; Mayer, R. In Thio- and Dithiocarboxylic Acids and Their DeriVatiVes; Senning, A., Ed.; Georg Thieme Publishers: Stuttgart, 1979. (7) (a) Pedersen, B. S.; Scheibye, S.; Clausen, K.; Lawesson, S.-O. Bull. Soc. Chim. Belg. 1978, 87, 293. (b) Cava, M. P.; Levinson, M. I. Tetrahedron, 1985, 41, 5061. (c) Josse, O.; Labar, D.; Brynaert, J. M. Synthesis 1999, 404. (8) (a) Amann, A.; Koenig, H.; Thieme; P. C.; Giertz, H.; Kretzschmar, R. DOS 2,408,288, 1975; Chem. Abstr. 1975, 83, 193341. (b) Bost, R. W.; Sheally, O. L. J. Am. Chem. Soc. 1951, 73, 25. (9) Leon, N. H.; Asquith, R. S. Tetrahedron 1970, 26, 1719. (10) Thang, S. H.; Chong, Y. K.; Mayadunne, R. T. A.; Moad, G.; Rizzardo, E. Tetrahedron Lett. 1999, 40, 2435.

employed in organic synthesis for effecting the conversion of carbonyl to thiocarbonyl compounds under a variety of conditions such as use of polar solvents or base catalysts.11 We became interested in synthesizing benzyldithio esters as chain transfer agents (CTAs) for living radical polymerization of vinyl monomers. In this communication, we wish to provide an efficient and single-step procedure for the preparation of such substituted dithioesters (2) when carboxylic acids (1) are reacted either with thiols or alcohols in the presence of 20-40 mol % P4S10 (Scheme 1).

Scheme 2

Scheme 1

One of the most important features of the methodology is that P4S10 can be used in reduced amounts (20 mol %). By varying the molar proportions of P4S10, it is possible to establish the nature of the intermediate formed in the reaction from GC-MS. For example, when 4-cyanobenzoic acid was subjected to thiation with benzyl mercaptan in the presence of 15 mol % P4S10, the corresponding thiocarboxylic S-ester was formed in 86% yield. However, further addition of 5 mol % to this reaction mixture completely transformed thioester to dithioester. The conversion was generally faster in toluene and benzene compared to chlorinated and other solvents. To optimize the reaction parameters, benzoic acid and benzyl mercaptan were subjected to treatment with P4S10 in toluene at various temperatures (Table 1). The reaction

To study the scope and limitation of the reaction, various substituted carboxylic acids and thiols were subjected to treatment with P4S10 in refluxing toluene (Table 2). As

Table 2. Synthesis of Dithioesters (2) via Mercaptansa

no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 carboxylic acid, R1 C6H5 o-MeC6H4 p-MeC6H4 p-Me3CC6H4 p-MeOC6H4 (X)3-C6H2c m-FC6H4 p-FC6H4 p-ClC6H4 p-BrC6H4 p-IC6H4 p-CF3C6H4 m-NO2C6H4 p-NO2C6H4 p-CNC6H4 C6H5 C6H5 C6H5 C6H5 p-FC6H4 C6H5 C6H5 2-thiophene n-C3H7 mercaptan R2 benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl benzyl n-C3H7 n-C4H9 t-C4H9 C6H5 o-MeOC6H4 p-ClC6H4 2-thienyl benzyl benzyl dithioester (%)b 96 82 91 77 9112 76 85 84 87 91 79 78 67 8013 75 81 78 45 55 68 66 91 88 60

Table 1. Reaction of Benzoic Acid and Benzyl Mercaptan with P4S10: Effect of Temperaturea
product distribution (%)b no. 1 2 3 3 temp (C) 25 60 110 110 time (h) 24 12 1 3 benzoic acid 19 ---benzyl mercaptan 25 27 16 -dithio esterc 27 24 74 99 unknownd 48 49 10 <1

a Benzoic acid, benzyl mercaptan, and P S (each 5 mmol), toluene (30 4 10 mL). b Analyzed by GC-MS with capillary column. c (R1 ) Ph, R2 ) Bz). d The fragmented peak in GC-MS corresponds to m/z 105 (PhCO+) as base peak with no M+ ion.

proceeded at room temperature to produce considerable yield (27%) of dithioester. At 60 C and 110 C, benzoic acid was completely consumed. However, at 110 C after 3 h, both benzoic acid and benzyl mercaptan were quantitatively converted to the corresponding dithioester (99%). The unknown in Table 1 may be due to the formation of activated carboxylic acid derivative by P4S10 (see species A, in Scheme 2).
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a Carboxylic acid (5 mmol), mercaptan (5 mmol), and P S 4 10 (20 mol %), toluene (40 mL), 110 C, 4 h. b Isolated yield after chromatographic purification over neutral alumina. The purified products (minimum purity 95 % after 1 column pass) were characterized by IR, 1H and 13C NMR, and GC-MS. c X ) 3,4,5-(MeO)3.

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evident from Table 2, the method appears to be quite general as a variety of thiols and carboxylic acids can be employed. The yields of dithioesters were good to excellent. Remarkably, even benzoic acids with electron-withdrawing groups such as CN, NO2, CF3, etc., were efficiently transformed to the corresponding dithioesters, which otherwise may be difficult to obtain by the conventional Grignard reaction. Also heteroaryl carboxylic acid reacted smoothly to give the corresponding dithioester in high yield (entry 23). However, substrates such as p-hydroxybenzoic acid, p-acetoxybenzoic acid, and pyridinecarboxylic acid failed to produce the required dithioesters when subjected to similar treatment with P4S10 and benzyl mercaptan possibly due to the formation of highly insoluble polymeric materials. It was also of interest to replace benzyl mercaptan with benzyl alcohol in the P4S10-mediated reaction with carboxylic acids (Table 3). As seen in Table 3, the thiation reaction

Table 3. Synthesis of Dithioesters (2) via Alcoholsa

no. 1 2 3 4 5 6 7 8 9 carboxylic acid, R1 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 p-MeOC6H4 p-FC6H4 p-NO2C6H4 alcohol, R2 benzyl benzyl benzyl benzyl tert-butyl 1-phenethyl benzyl benzyl benzyl solvent benzene chlorobenzene toluene ClCH2CH2Cl CCl4 CCl4 ClCH2CH2Cl benzene benzene temp dithio (C) ester(%)b 80 110 110 80 70 70 80 80 80 70 52 30c 71 70 75 61 72 66

a Carboxylic acid, alcohol, and P S (each 5 mmol), 8 h. b Isolated yield 4 10 after chromatographic purification over neutral alumina. c The major product (52%) is a mixture of o- and p-benzyltoluenes (Friedel-Crafts alkylated products).

B and thiocarboxylic S-ester, C. Such condensation reactions with the use of phosphorus reagents are well established in the literature.14 It is also possible that both the species A and B are in equilibrium (at different time intervals of the reaction mixture, appearance and disappearance of thiol can be seen in GC-MS). The formation of the intermediate thiocarboxylic S-ester, C was confirmed from GC-MS analysis and by isolating and characterizing it (IR, 1H, and 13C NMR) when 15 mol % of P S was employed. However, 4 10 further addition of 5 mol % of P4S10 transformed the species C completely to the corresponding dithioester 2. It is also quite likely that B might undergo dehydration to regenerate P4S10. In step 2, the intermediate C undergoes thiation of carbonyl group with P4S10 readily to yield dithioesters (2). In the case of alcohols, we believe that they are at first converted to the corresponding thiols on reaction with P4S10 before they could react with activated species A. Otherwise, thiocarboxylic O-esters would be formed which are difficult to convert to dithioesters under the reaction conditions. It is further confirmed from our observation that when methyl 4-methoxybenzoate was subjected to thiation reaction with P4S10, only the CdO of the ester group was converted to CdS (thiocarboxylic O-ester) in agreement with literature.15 In summary, we have conducted an alcohol thiation, condensation, and carbonyl thiation in one pot and in the appropriate order to obtain high to moderate yields of the desired dithioesters. The reagents are inexpensive and readily available, yields are generally high, and the method avoids the use of basic conditions or higher temperature required by many previously reported procedures. Alcohols can also be employed instead of thiols to react with carboxylic acids
(12) Benzyl 4-methoxydithiobenzoate: In a typical experiment, a mixture of 4-methoxybenzoic acid (1.52 g, 10 mmol), benzyl mercaptan (1.24 g, 10 mmol), and phosphorus pentasulfide (0.88 g, 20 mol %) in toluene (40 mL) was refluxed for 10 h. A dark red color was developed immediately after heating. The reaction was monitored by GC-MS. After the reaction was completed, it was cooled to room temperature and the product purified by column chromatography packed with neutral alumina, eluting with toluene. Removal of the solvent by distillation gave the redcolored oil, benzyl 4-methoxydithiobenzoate (2.49 g, 91%). IR (neat): 3028, 2837, 1595, 1501, 1453, 1417, 1309, 1243, 1170, 1045, 886 cm-1; 1H NMR: (500 MHz, CDCl ): 3.85 (s, 3H), 4.70 (s, 2H), 6.92 (d, J ) 3 8.0 Hz, 2H), 7.30-7.50 (m, 5H), 8.25 (d, J ) 8.0 Hz, 2H); 13C NMR: (125 MHz, CDCl3): 42.3, 55.8, 113.9, 128.0, 128.9, 129.0, 129.5, 129.7, 136.0, 138.1, 164.0, 225.1 (CdS); MS (m/z % rel intensity): 274 (M+, 25), 241(15), 183 (10), 152 (12), 151 (100), 136 (10), 108 (10), 91 (35), 77 (10) and 65 (10). (13) Benzyl 4-nitrodithiobenzoate: In a typical experiment, a mixture of 4-nitrobenzoic acid (1.67 g, 10 mmol), benzyl alcohol (1.08 g, 10 mmol), and phosphorus pentasulfide (1.78 g, 40 mol %) in benzene (40 mL) was refluxed for 12 h. A dark red color was developed immediately after heating. The reaction was monitored by GC-MS. After the reaction was complete, it was cooled to room temperature and the product purified by column chromatography packed with neutral alumina eluting with toluene. Removal of the solvent by distillation gave the red-colored oil, benzyl 4-nitrodithiobenzoate (2.31 g, 80%). IR (neat): 3060, 3027, 2920, 1665, 1600, 1522, 1493, 1452, 1403, 1343, 1243, 1199, 1109, 1057, 1028, 1012, 916, 890, 844, 764, 697 cm-1; 1H NMR: (500 MHz, CDCl3): 4.62 (s, 2H), 7.25-7.4 (m, 5H), 8.05 (d, J ) 7.2 Hz, 2H), 8.2 (d, J ) 7.2 Hz, 2H); 13C NMR: (125 MHz, CDCl3): 43.0, 123.8, 128.0, 128.4, 128.9, 129.0, 129.1, 129.6, 129.7, 134.4, 149.0, 149.8, 224.6 (CdS); MS (m/z % rel intensity): 289 (M+, 12), 120(15), 108 (10), 91(100), 69 (12), 65 (25), and 45 (22). (14) Hoffman, H.; Becke-Goehring, M. Top. Phosphorus Chem. 1976, 8, 235. (15) Trebaul, P. C. Bull. Soc. Chim. Fr. 1971, 1102. 3215

proceeded to give dithioesters in high yields. A novel feature of this system is the unexpected reactivity shown by the tertiary as well as secondary alcohols affording good yields of the corresponding dithioesters without undergoing dehydration. Chlorinated solvents seemed to work well for this system whereas aromatic hydrocarbon solvents such as toluene undergo Friedel-Crafts benzylation to afford benzyltoluenes (52%). The probable mechanism for the formation of dithioester is believed to take place in two steps as shown in Scheme 2. In step 1, P4S10 activates carboxylic acid through its electrophilic phosphorus center to give an active species A. The evidence in favor of formation of such species can be deduced from the GC-MS analysis of the reaction mixture, in which the complete conversion of carboxylic acids and the simultaneous formation of active species A (R1CO+, base peak in MS) can be seen when the reactions were done at lower temperatures (cf. unknown in Table 1). The nucleophilic attack of thiols with the species A generates the species
(11) Enclyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; J. Wiley & Sons: New York, 1995; Vol. 6, p 4138.

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in the presence of P4S10 thereby producing dithioesters in moderate yields. Supporting Information Available: Experimental procedures and spectral data for other dithiocarboxylic esters.

This material is available free of charge via the Internet at http://pubs.acs.org.

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