Phosphorus pentasulfide: A mild and versatile catalyst/reagent for the preparation of dithiocarboxylic esters

Article abstract of DOI:10.1021/ol006407q

(matrix presented) 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 (20-40 mol %) proceeded effectively to afford the corresponding dithiocarboxylic esters (2) in high yields.

Full text of DOI:10.1021/ol006407q

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3213-3216
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
ABSTRACT
The reaction of carboxylic acids (1) with a variety of thiols or alcohols in the presence of phosphorus pentasulfide (P S ) as a catalyst and
4
10
reagent (20−40 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 ef-
ficient 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
or thioamide precursors,6 (iii) thionation of thioesters using
Lawesson’s 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
(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.
(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.; Georg-
Thieme-Verlag: Stuttgart, 1985; Vol. E5, Chapter 2.5, p 891. (e) Schei-
thauer, 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.
(5) Meijer, J.; Vermeer, P.; Brandsma, L. Recueil 1973, 92, 601.
10.1021/ol006407q CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/09/2000

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 car-
boxylic 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.
carboxylic acid, R1
mercaptan R2
dithioester (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
C6H5
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
n-C3H7
n-C4H9
t-C4H9
C6H5
96
82
91
77
9112
76
85
84
87
91
79
78
67
8013
75
81
78
45
55
68
66
91
88
60
o-MeC6H4
p-MeC6H4
p-Me3CC6H4
p-MeOC6H4
Table 1. Reaction of Benzoic Acid and Benzyl Mercaptan
with P4S10: Effect of Temperaturea
c
(X)3-C6H2
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
product distribution (%)b
temp time benzoic
benzyl
dithio
no.
(°C)
(h)
acid
mercaptan esterc unknownd
1
2
3
3
25
60
110
110
24
12
1
19
- -
- -
- -
25
27
16
- -
27
24
74
99
48
49
10
3
<1
a Benzoic acid, benzyl mercaptan, and P4S10 (each 5 mmol), toluene (30
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.
o-MeOC6H4
p-ClC6H4
2-thienyl
benzyl
benzyl
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).
C6H5
2-thiophene
n-C3H7
a Carboxylic acid (5 mmol), mercaptan (5 mmol), and P4S10 (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.
3214
Org. Lett., Vol. 2, No. 20, 2000

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. Remark-
ably, 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.
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
1
analysis and by isolating and characterizing it (IR, H, and
13C NMR) when 15 mol % of P4S10 was employed. However,
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. Other-
wise, thiocarboxylic O-esters would be formed which are
difficult to convert to dithioesters under the reaction condi-
tions. 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 litera-
ture.15
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
carboxylic
acid, R1
alcohol,
R2
temp
dithio
no.
solvent
benzene
chlorobenzene 110
(°C) ester(%)b
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
benzyl
benzyl
benzyl
benzyl
tert-butyl
1-phenethyl CCl4
80
70
52
30c
71
70
75
61
72
66
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
toluene
ClCH2CH2Cl
CCl4
110
80
70
70
80
80
80
p-MeOC6H4 benzyl
p-FC6H4 benzyl
p-NO2C6H4 benzyl
ClCH2CH2Cl
benzene
benzene
a Carboxylic acid, alcohol, and P4S10 (each 5 mmol), 8 h. b Isolated yield
after chromatographic purification over neutral alumina. c The major product
(52%) is a mixture of o- and p-benzyltoluenes (Friedel-Crafts alkylated
products).
(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 red-
colored oil, benzyl 4-methoxydithiobenzoate (2.49 g, 91%). IR (neat): ν
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 dehy-
dration. Chlorinated solvents seemed to work well for this
system whereas aromatic hydrocarbon solvents such as
toluene undergo Friedel-Crafts benzylation to afford ben-
zyltoluenes (52%).
3028, 2837, 1595, 1501, 1453, 1417, 1309, 1243, 1170, 1045, 886 cm-1
;
1H NMR: (500 MHz, CDCl3): δ 3.85 (s, 3H), 4.70 (s, 2H), 6.92 (d, J )
8.0 Hz, 2H), 7.30-7.50 (m, 5H), 8.25 (d, J ) 8.0 Hz, 2H); 13C NMR:
(125 MHz, CDCl3): δ 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).
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 nucleo-
philic attack of thiols with the species A generates the species
(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-nitro-
dithiobenzoate (2.31 g, 80%). IR (neat): ν 3060, 3027, 2920, 1665, 1600,
1522, 1493, 1452, 1403, 1343, 1243, 1199, 1109, 1057, 1028, 1012, 916,
1
890, 844, 764, 697 cm-1; H NMR: (500 MHz, CDCl3): δ 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): δ 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.
(11) Enclyclopedia of Reagents for Organic Synthesis; Paquette, L. A.,
Ed.; J. Wiley & Sons: New York, 1995; Vol. 6, p 4138.
Org. Lett., Vol. 2, No. 20, 2000
3215

in the presence of P4S10 thereby producing dithioesters in
moderate yields.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures and spectral data for other dithiocarboxylic esters.
OL006407Q
3216
Org. Lett., Vol. 2, No. 20, 2000