Synthesis of thioesters from carboxylic acids via acyloxyphosphonium intermediates with benzyltriethylammonium tetrathiomolybdate as the sulfur transfer reagent

Article abstract of DOI:10.1021/jo9009694

(Chemical Equation Presented) An efficient protocol is reported for the synthesis of thioesters from carboxylic acids with use of acyloxy phosphonium salts as intermediates and benzyltriethyl-ammonium tetrathiomolybdate as the sulfur transfer reagent.

Full text of DOI:10.1021/jo9009694

pubs.acs.org/joc
Traditional methods for the formation of thioesters in-
Synthesis of Thioesters from Carboxylic Acids via
Acyloxyphosphonium Intermediates with
Benzyltriethylammonium Tetrathiomolybdate as the
Sulfur Transfer Reagent
clude the direct coupling of a thiol with the parent carboxylic
acid and an activating agent,8 the coupling of a thiol with
an acid chloride,9 or reaction of thiols with an acid anhy-
dride.10 Other syntheses of thioesters include the coupling
of thiocarboxylates with arenediazonium salts11 and alkyl
halides.12 These methodologies, however, suffer from limita-
tions such as difficulties encountered in handling thiols and
thioacids and also the availability of starting materials.
However, given the prevalence of the thioester moiety in a
wide range of pharmaceutically active compounds it is
desirable to find novel procedures that provide an efficient
access to such highly useful organic products. In this regard,
we envisaged a novel methodology for the synthesis of highly
functionalized thioesters from readily available carboxylic
acids as starting materials.
Purushothaman Gopinath, Ravindran Sasitha Vidyarini,
and Srinivasan Chandrasekaran*
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560012, India
scn@orgchem.iisc.ernet.in
Received May 9, 2009
An efficient protocol is reported for the synthesis of
thioesters from carboxylic acids with use of acyloxy
phosphonium salts as intermediates and benzyltriethyl-
ammonium tetrathiomolybdate as the sulfur transfer
reagent
FIGURE 1. Structures of pharmacologically important thioesters.
Herein, we present the synthesis of various substituted
thioesters directly from carboxylic acids using benzyltriethyl-
ammonium tetrathiomolybdate13 ([BnEt3N]2MoS4, 1)
as an efficient sulfur transfer reagent. Aryl carboxylic acids
are first activated by using PPh3 and NBS to form the
corresponding acyloxy phosphonium salts,14 2, which then
on reaction with reagent (1) generate thioaroylate ions
in situ. These thioaroylates on further reaction with various
electrophiles such as alkyl halides/dihalides in the same pot
will lead to the corresponding functionalized thioesters
(Scheme 1).
While attempting the synthesis of dibenzoyl disulfide,
benzoic acid (1 equiv) was treated with PPh3 (1.1 equiv)
and NBS (1.1 equiv) in the presence of benzyltriethylammo-
nium tetrathiomolybdate ([BnEt3N]2MoS4, 1; 1.5 equiv) in
CH2Cl2 as solvent (28 °C, 2 h); we obtained two interes-
ting products, namely methanedithiol dibenzoate 3a and
Thioesters are important synthetic intermediates in org-
anic synthesis and are used for peptide coupling,1 acyl
transfer,2 protecting groups for thiols,3 and also as coupling
partners in organometallic reactions.4 They are also key
intermediates in various biological systems5 and find broad
application in medicinal chemistry6 (Figure 1). From a
synthetic perspective thioesters could be readily transformed
into a more versatile SH group under mild reaction condit-
ions.7
(1) (a) Ficht, S.; Payne, R. J.; Guy, R. T.; Wong, C. H. Eur. J. Org. Chem.
2008, 14, 3620. (b) Hojo, H.; Aimoto, S. Bull. Chem. Soc. Jpn. 1991, 64, 111.
(c) Ozawa, C.; Katayama, H.; Hojo, H.; Yuko, N.; Yoshiaki, N. Org. Lett.
2008, 10, 3531. (d) Dawson, P. E.; Muir, T. W.; Lewis, C. I.; Kent, S. B. H.
Science 1994, 266, 776. (e) Dawson, P. E.; Kent, S. B. H. Annu. Rev. Biochem.
2000, 69, 923.
(2) (a) Mukaiyama, T.; Araki, M.; Takei, H. J. Am. Chem. Soc. 1973, 95,
4763. (b) Anderson, R.; Henrick, C. A.; Rosenblum, L. D. J. Am. Chem. Soc.
1974, 96, 3654. (c) Sviridov, A. F.; Ermolenko, M. S.; Yashunsky, D. V.;
Kochetkov, N. K. Tetrahedron Lett. 1983, 24, 4355.
(8) (a) McGarvey, G. J.; Williams, M. J.; Hiner, R. N.; Matsubra, Y.; Oh,
T. J. Am. Chem. Soc. 1986, 108, 4943. (b) McCoy, J. G.; Johnson, H. D.;
Singh, S.; Bingman, C. A.; Lei, I. K.; Thorson, J. S.; Phillips, G. N. Protein
Struct. Funct. Biol. 2009, 74, 50.
(9) Zeiba, A.; Suwinska, K. Heterocycles 2008, 75, 2649.
(10) Peterson, M. J.; Marchal, C.; Loughlin, W. A.; Jenkins, I. D.; Healy,
P. C.; Almesaker, A. Tetrahedron 2006, 63, 1395.
(11) Petrillo, G.; Novi, M.; Garbarino, G.; Filiberti, M. Tetrahedron
1989, 45, 7411.
(12) Yamamoto, H.; Fukazu, N.; Tanaka, M.; Kobayashi, S. Jpn. Kokai
Tokkyo Koho 2004, 9 pp.
(13) Prabhu, K. R.; Devan, N.; Chandrasekaran, S. Synlett 2002, 1762.
(14) (a) Froyen, P. Phosphorus, Sulfur Silicon 1994, 89, 57. (b) Froyen, P.
Phosphorus, Sulfur Silicon 1994, 91, 145. (c) Froyen, P. Synth. Commun. 1995,
25, 959. (d) Sucheta, K.; Reddy, G. S. R.; Ravi, D.; Rama Rao, N.
Tetrahedron Lett. 1994, 25, 4415.
(3) Christian, F.; Bjorn, S.; Andreas, T. Eur. J. Org. Chem. 2007, 6, 1013.
(4) (a) Villalobos, J. M.; Srogl, J.; Liebeskind, L. S. J. Am. Chem. Soc.
2007, 129, 15734. (b) Prokopcova, H.; Pisani, L.; Kappe, C. O. Synlett 2007,
43. (c) Morita, A.; Kuwahara, S. Org. Lett. 2004, 8, 1613. (d) Lengar, A.;
Kappe, C. O. Org. Lett. 2004, 6, 771. (e) Alphonse, F. A.; Suzenet, F.;
Keromnes, A.; Lebert, B.; Guillaumet, G. Synlett 2002, 3, 447.
(5) Bjorn, H. T.; Ben, F. L.; Adriaan, M. J. Chem. Commun. 2007, 5, 489.
(6) (a) Metzner, P.; Thuillier, A. Sulfur Reagents in Organic Synthesis;
Academic Press: New York, 1994. (b) Nudelman, A. The Chemistry of Optically
Active Sulfur Compounds; Gordon and Breach: New York, 1984. (c) Chatgilialoglu,
C.; Asmus, K. D. Sulfur-Centered Reactive Intermediates in Chemistry and
Biology; Springer: New York, 1991
(7) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis;
John Wiley & Sons: New York, 1999; p 454.
DOI: 10.1021/jo9009694
r
Published on Web 07/20/2009
J. Org. Chem. 2009, 74, 6291–6294 6291
2009 American Chemical Society

Gopinath et al.
SCHEME 4. Synthesis of Methanedithiol Dibenzoate 3a
JOCNote
SCHEME 1. General Reaction Scheme
SCHEME 2. Reaction of in Situ Generated Thiobenzoate with
Solvent Dichloromethane
SCHEME 5. Synthesis of Chloromethylbenzoyl Sulfide 4a
SCHEME 3. Reaction of Dibenzoyl Disulfide with Reagent 1
TABLE 1. Synthesis of Methanedithiol Diaroylates and Chloromethyl-
aroyl Sulfides
chloromethylbenzoyl sulfide 4a respectively in 2:3 ratio
(Scheme 2). We speculated that thioaroylate ion could be a
possible intermediate (formed by the reductive cleavage13,15
of dibenzoyl disulfide with excess reagent, 1), which on
reaction with the solvent molecule (CH2Cl2) leads to 3a
and 4a.
This was further proved by the reaction of 1 with dibenzoyl
disulfide16 (5) in CH2Cl2 to give the corresponding thioesters
3a and 4a thereby indicating the intermediacy of thiobenzo-
ate ion in the above reaction (Scheme 3).
To achieve selectivity in the formation of these thioesters,
the solvent was changed to chloroform as it was inert to
thioaroylate ion due to the steric crowding around the
carbon and various amounts of dihalomethane were added
to obtain the corresponding thioesters. Initially we directed
our efforts toward optimizing the conditions for the forma-
tion of product 3a. This could be achieved by taking a large
excess of acyloxyphosphonium intermediate 2 and reagent 1.
After various trials it was found that the reaction works well
with dibromomethane as the electrophilic partner
(compared to two other dihalomethanes) and with benzoic
acid (2.1 equiv) taken as the standard, PPh3, NBS, and
reagent 1 (3 equiv) to give the corresponding thioester 3a
as the major product in 80% yield (Scheme 4).
The chloromethylaroyl sulfides are known for their fungi-
cidal activity.17 To achieve selective synthesis of chloro-
methylbenzoyl sulfide 4a, bromochloromethane was used
instead of dibromomethane in the above reaction
(Scheme 5). Selective displacement of bromide by the thio-
benzoate ion gave the corresponding thioester 4a in 63%
yield. The results of this study with various carboxylic acids
and dihalomethanes are summarized in Table 1.
SCHEME 6. Synthesis of Ethanedithiol Dibenzoate 6a
Subsequently, we attempted the reaction of carboxylic
acids, via intermediate 2 with 1,2-dihaloethanes. After some
experimentation it was found that reaction of benzoic
acid (2.4 equiv), PPh3, NBS, dibromomethane (1 equiv),
and reagent 1 (3 equiv) gave the corresponding thioester,
ethanedithiol dibenzoate 6a, as the major product in 83%
yield (Scheme 6).
Chlroethylbenzoyl sulfide 7a, a fungicide, was synthesized
by using benzoic acid, PPh3, NBS, dichloroethane (15 equiv),
and reagent 1 (1.5 equiv) in 60% yield (Scheme 7). The
synthetic utility of this reaction with different dihaloethanes
is exemplified in Table 2.
(15) Pan, W. H.; Harmer, M. A.; Halbert, T. R.; Stiefel, E. I. J. Am. Chem.
Soc. 1984, 106, 459.
(16) Tamami, B.; Kiasat, A. Synth. Commun. 1998, 28, 1275.
(17) Karl, K.Ernst, P. H. Ger. Offen., 1970, p 12.
6292 J. Org. Chem. Vol. 74, No. 16, 2009

Gopinath et al.
JOCNote
TABLE 2. Synthesis of Ethanedithiol Diaroylates and Chloroethylaroyl
Sulfides
SCHEME 9. Synthesis of Anomeric Thioester 12
SCHEME 10. Synthesis of Bicyclic Thiolactone 14
reagent 1 to form the corresponding thioester 12 in 73% yield
(Scheme 9).
To expand the scope of our methodology, an intramole-
cular version of the reaction was performed on a compound
containing both anomeric bromide and carboxylic acid
functionality. This was achieved by treating carboxylic acid
8 with HBr/AcOH19 to form R-D-bromoglucopyranuronic
acid 13 (Scheme 10). Compound 13 was then treated with
PPh3, NBS, and reagent 1 to give the corresponding bicyclic
thiolactone 14 in 55% yield.
In conclusion, a wide variety of functionalized thioesters
have been synthesized from carboxylic acids by using acyl-
oxyphosphonium salts as intermediates and benzyltriethyl-
ammonium tetrathiomolybdate 1 as the sulfur transfer re-
agent.
SCHEME 7. Synthesis of Chloroethylbenzoyl Sulfide 7a
Experimental Section
General Procedure for the Formation of Methanedithiol Di-
aroylate 3. To a well-stirred solution of the correspond-
ing carboxylic acid (2.1 mmol), PPh3 (2.2 mmol), and NBS
(2.2 mmol) in CHCl3 (5 mL) (stirred for 10 min) was added
benzyltriethylammonium tetrathiomolybdate 1 (3 mmol) foll-
owed by dibromomethane (1 mmol). The reaction was complete
after 12 h at room temperature (28 °C). Diethyl ether (20 mL)
was added to the reaction mixture, which was then filtered
through a Celite pad. The residue was again extracted with
CH2Cl2 (5 mL) followed by extraction with diethyl ether
(20 mL) and filtered again through a Celite pad. The combined
extract was evaporated and the residue was purified by column
chromatography on silica gel to give the corresponding thioester
derivative 3.
SCHEME 8. Synthesis of Glucuronic Acid Based Thioester 10
Carbohydrate-based thioesters are important synthetic
intermediates in various transformations and also they could
be deprotected later to form synthetically more valuable
thiols. Therefore, we took 1,2,3,4-tetra-O-acetyl-β-D-gluco-
pyranuronic acid18 8, which was synthesized from glucuronic
acid by acetylation with acetic anhydride, iodine, and metha-
nol. Carboxylic acid 8 was then treated with PPh3, NBS,
reagent 1, and 1-bromopropane 9 (CHCl3, 28 °C, 2 h) to
afford the corresponding thioester 10 in 55% yield
(Scheme 8).
Methanedithiol dibenzoate, 3a: white crystalline solid (0.23 g,
1
80%); mp 113 °C; IR (neat) 1668, 1208, 915 cm-1; H NMR
(300 MHz, CDCl3) δ 7.97-7.94 (m, 4H), 7.61-7.57 (m, 2H),
7.48-7.43 (m, 4H), 4.68 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 190.8, 136.2, 133.8, 128.7, 127.3, 28.0, 21.7; HR-MS m/z calcd
for C15H12O2S2Naþ [M þ Naþ] 311.0176, found 311.0186.
General Procedure for the Formation of Chloromethylaroyl
Sulfide 4. To a well-stirred solution of the correspond-
ing carboxylic acid (1.1 mmol), PPh3 (1.2 mmol), and NBS
(1.2 mmol) in CHCl3 (5 mL) (stirred for 10 min) was added
benzyltriethylammonium tetrathiomolybdate 1 (2.5 mmol) foll-
owed by bromochloromethane (1 mmol). The reaction was
complete after 1 h at room temperature (28 °C). Diethyl ether
It was of interest to study the reactivity of anomeric
bromides to show the generality of the present methodology.
Accordingly 2,3,4,5-tetra-O-acetyl-R-D-glucopyranosyl
bromide 11 was treated with benzoic acid, PPh3, NBS, and
(18) Malkinson, J. P.; Falconer, R. A.; Toth, I. J. Org. Chem. 2000, 65,
5249.
(19) Akin, A.; Curran, T. T. Synth. Commun. 2005, 35, 1649.
J. Org. Chem. Vol. 74, No. 16, 2009 6293

Gopinath et al.
JOCNote
(20 mL) was added to the reaction mixture, which was then
filtered through a Celite pad. The residue was again extracted
with CH2Cl2 (5 mL) followed by extraction with diethyl ether
(20 mL) and filtered again through a Celite pad. The combined
extract was evaporated and the residue was purified by column
chromatography on silica gel to give the corresponding thioester
derivative 4.
S-Chloromethyl 4-methoxybenzothioate, 4d: colorless liquid
(0.151 g, 70%); IR (neat) 1671, 1601, 1168, 908 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.94 (d, J=9.3 Hz, 2H), 6.95 (d, J=9.3 Hz,
2H), 5.12 (s, 2H), 3.88 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
186.3, 164.4, 129.9, 128.6, 55.6, 42.1; HR-MS m/z calcd for
C9H9ClO2SNaþ [M þ Naþ] 238.9909, found 238.9915.
Synthesis of 2,3,4-Tri-O-acetyl-β-D-glucopyranuronic Acid ε-
Thiolactone, 14. To a well-stirred mixture of 2,3,4-tri-O-acetyl-
1-bromo-R-D-glucopyranuronic acid (0.383 g, 1.0 mmol), PPh3
(0.576 g, 1.1 mmol), and NBS (0.392 g, 1.1 mmol) in CHCl3
(5 mL) was added benzyltriethylammonium tetrathiomolybdate
1 (1.34 g, 2.2 mmol) and stirring was continued for 2 h at room
temperature (28 °C). Diethyl ether (20 mL) was added to the
reaction mixture, which was then filtered through a Celite pad.
The residue was again extracted with CH2Cl2 (5 mL) followed
by extraction with diethyl ether (20 mL) and filtered again
through a Celite pad. The combined extract was evaporated
and the residue was purified by column chromatography on
silica gel to give the lactone 14 as a colorless liquid (0.175 g,
55%). [R]26 þ6.5 (c 0.8, CHCl3); IR (neat) 1747, 1371, 1215,
D
1047 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.09 (d, J=1.5 Hz,
1H), 4.95 (m, 1H), 4.91 (d, J=1.2 Hz, 1H), 4.88 (m, 1H), 4.55 (m,
1H), 2.20 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 199.6, 169.5, 169.2, 168.5, 84.9, 79.6, 69.5, 68.7, 67.8,
20.8; HR-MS m/z calcd for C12H14O8SNaþ [MþNaþ] 341.0307,
found 341.0308.
Acknowledgment. P.G. thanks CSIR, New Delhi for a
Senior Research Fellowship.
Supporting Information Available: Experimental proce-
1
dures, full characterization, H and 13C NMR spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
6294 J. Org. Chem. Vol. 74, No. 16, 2009