Synthesis of thiol esters by the reaction of ricinoleic acid with thiols under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2010.516053

The synthesis of several ricinoleic acid thiol esters starting from cis-(R)-12-hydroxyoctadec-9-enoic acid and thiols in the presence of N,N'-dicyclohexylcarbodiimide (DCC) is described. The method is efficient for aromatic and aliphatic thiols, selective

Full text of DOI:10.1080/00397911.2010.516053

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Synthesis of Thiol Esters by the Reaction
of Ricinoleic Acid with Thiols Under
Solvent-Free Conditions
Renata G. Lara a , Dielson C. Rodrigues a , Samuel R. Mendes a
,
Rodrigo B. Panatieri a , Raquel G. Jacob a , Diego Alves a , Eder J.
Lenardão a & Gelson Perin a
a Institute of Chemistry and Geosciences, Laboratory of Clean
Organic Synthesis (LASOL), Federal University of Pelotas, Pelotas,
RS, Brazil
Published online: 11 Jul 2011.
To cite this article: Renata G. Lara , Dielson C. Rodrigues , Samuel R. Mendes , Rodrigo B. Panatieri ,
Raquel G. Jacob , Diego Alves , Eder J. Lenardo & Gelson Perin (2011) Synthesis of Thiol Esters by the
Reaction of Ricinoleic Acid with Thiols Under Solvent-Free Conditions, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:20, 2974-2984,
DOI: 10.1080/00397911.2010.516053
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Synthetic Communications1, 41: 2974–2984, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.516053
SYNTHESIS OF THIOL ESTERS BY THE REACTION OF
RICINOLEIC ACID WITH THIOLS UNDER
SOLVENT-FREE CONDITIONS
Renata G. Lara, Dielson C. Rodrigues, Samuel R. Mendes,
Rodrigo B. Panatieri, Raquel G. Jacob, Diego Alves,
˜
Eder J. Lenardao, and Gelson Perin
Institute of Chemistry and Geosciences, Laboratory of Clean Organic
Synthesis (LASOL), Federal University of Pelotas, Pelotas, RS, Brazil
GRAPHICAL ABSTRACT
Abstract The synthesis of several ricinoleic acid thiol esters starting from cis-(R)-12-
hydroxyoctadec-9-enoic acid and thiols in the presence of N,N0-dicyclohexylcarbodiimide
(DCC) is described. The method is efficient for aromatic and aliphatic thiols, selectively
affording the respective fat acid thiol esters in good yields under mild, neutral, and
solvent-free conditions. The protocol is general and was extended to other carboxylic acids,
furnishing the desired products in satisfactory yields. The (R,Z)-12-hydroxy-octadec-
9-enylic acid benzylthiol ester 3a was successfully reduced to (R,Z)-12-hydroxyoctadec-9-
enal 4.
Keywords Green chemistry; ricinoleic acid; solvent-free reaction; thiol esters
INTRODUCTION
Ricinoleic acid, (R,Z)-12-hydroxyoctadec-9-enoic acid, is an important
commodity in the chemical and pharmaceutical industry in view of its high function-
ality.[1] This renewable raw material is easily available from castor bean oil and is
used in processes for preparation of several compounds of interest for fine chemistry.
Ricinoleic acid presents some peculiar chemical properties, making it an attractive,
enantiomerically pure building block for the development of new, simple, and
efficient strategies for the synthesis of complex molecules.[1g,h] Thiol esters play
important roles in acyl group transfer in biological systems,[2] such as coenzyme A
Received June 14, 2010.
Address correspondence to Gelson Perin, Institute of Chemistry and Geosciences, Laboratory of
Clean Organic Synthesis (LASOL), Federal University of Pelotas, P. O. Box 354, Pelotas 96010-900,
RS, Brazil. E-mail: gelson_perin@ufpel.edu.br
2974

SOLVENT-FREE SYNTHESIS OF THIOL ESTERS
2975
Scheme 1. General scheme of the reaction.
and S-acetyl dihydrolipolic acid,[2a–c] and in the biosynthesis of polyketides and
nonribosomal polypeptides.[2d] More recently, it was demonstrated that 2-pyridine
thiol esters have good antitumor activity.[3]
The use of thiol esters in organic synthesis goes beyond the acylating capability
and includes their conversion to ketones,[4a,b] b-lactones,[4c–e] aldehydes,[4f,g] and
vinyl sulfides[4h] and their use in the reductive alkylation of amines.[4i] Besides,
S-thioester enolization has been extensively studied and can be carried out in a
highly stereoselective fashion under a variety of conditions.[4j–m] Because of their
biological activities, as well as their synthetic versatility, a number of methods for
the preparation of thiol esters have been described. Most of them involve the con-
densation of a thiol with carbonyl compounds, such as acyl halides,[3,5a–e] anydri-
des,[5f] aldehydes,[5g] and carboxylic acids in the presence of a coupling reagent,
base, and an organic solvent.[5h–k] Despite the vast range of described methods for
thiol esters, several of them require vigorous reaction conditions (high temperature,
long reaction time); the use of toxic, expensive, and air- and moisture-sensitive metal
catalysts and volatile organic solvents; and the necessity, in some cases, of preparing
the acylating starting material. Some of these drawbacks were partially circumvented
with the use of acyl phosphate in aqueous media[6a] and by means of the thiocarbo-
nylation of iodoarenes in the presence of ionic liquids.[6b]
In the past few years, our group has studied the use of renewable feedstocks in
organic synthesis, following green and sustainable chemistry principles.[7] As a con-
tinuation of our studies, we report herein the preparation of thiol esters directly from
ricinoleic acid and thiols under mild, neutral, and solvent-free conditions (Scheme 1).
In our solvent-free approach, easily available dicyclohexylcarbodiimide (DCC)
was used as coupling reagent in the absence of base, allowing the direct use of
carboxylic acids in the thio-esterification step.[8,9]
RESULTS AND DISCUSSION
Our initial efforts were focused on the preparation of the benzylthiol ester 3a,
derived from ricinoleic acid 1a and benzylthiol 2a. We examined the temperature, use
of solvent, base, and inert atmosphere. To the best of our knowledge, the methods
described for the preparation of thiol esters starting from carboxylic acids use basic

2976
R. G. LARA ET AL.
conditions and are conducted in the presence of an organic solvent.[4,5,8] The reaction
progress was followed by thin-layer chromatography (TLC), and we observed that
when a solution of benzylthiol 2a (1.2 mmol) and ricinoleic acid 1a (1.0 mmol) in
tetrahydrofuran (THF) (5 mL) was stirred in the presence of diisopropylethylamine
(DIPEA) (1.0 mmol) and N,N0-dicyolohexylcarbodiimide (DCC) (1.0 mmol) under
N2, the respective thiol ester 3a was obtained in 68% yield after 6 h at room
temperature.
Aiming to reduce the reaction time and to improve the yield, we tested several
other bases [KF=Al2O3, 50%; Et3N, diazabicyclo[2.2.2]octane (DABCO), and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)], as well as other different solvents, such
as benzene and dichloromethane. However, the product was not obtained in yields
superior to 60–70%, even under mild heating (60 ꢀC) or longer reaction time (24 h).
Surprisingly, the best result was obtained when the reaction was performed
under solvent- and base-free conditions. Thus, when carboxylic acid 1a and ben-
zylthiol 2a where simply mixed in the presence of DCC under an N2 atmosphere
at room temperature, the desired thiol ester 3a was obtained in 76% yield after 3 h
(Table 1, entry 1).
To demonstrate the efficiency of our protocol, ricinoleic acid 1a was treated
with other thiols 2a–f; the results are summarized in Table 1. We observed that
the reaction worked well for a variety of thiols. For example, the aliphatic dodeca-
nethiol 2b gives the respective thiol ester 3b in yield comparable to aromatic thiols
after the same reaction time (Table 1 entry 2). The aromatic benzenethiol 2c reacted
with ricinoleic acid 1a to afford, after 4 h, the benzenethiol ester 3c in 65% yield
(Table 1, entry 3). The reaction also works well with aromatic substituted thiols.
Thus, when chloro-substituted benzenethiols were used, the respective thiol esters
were obtained in slightly superior yield after 4–5 h at room temperature (Table 1,
entries 4–6). For all the tested examples, the products were obtained with the original
configuration of the double bond at C-9 in the molecule. This solvent-free protocol
was extended to other carboxylic acids and aliphatic and aromatic thiols (Table 1
entries 7–11). For all the tested examples, the desired thiol esters 3g–j were obtained
selectively and in satisfactory yields, except for the solid benzoic acid 1f, which gives
3k in only 10% yield (Table 1, entry 11).
Because our interest in the synthetic use of oils extracted from plants cultivated
in southern Brazil and their constituents as renewable raw materials for use in
organic synthesis, we tried to perform the direct synthesis of thiol ester from the cas-
tor bean oil (Ricinus communis). The major component of the castor oil was found to
be ricinoleic acid (85–90%).[1a] Unfortunately, all attempts of directly converting the
oil to the respective thiol esters using basic conditions failed. To circumvent this lack
of reactivity, castor oil (1.02 g; ꢁ 3.0 mmol of ricinoleic acid) was submitted to prior
alkaline hydrolysis (ethanolic KOH).[10] DCC (3.0 mmol) and benzylthiol 2a
(3.0 mmol) were directly added to the crude potassium ricinoleate generated, and
the mixture was stirred at room temperature for 3 h, affording (R,Z)-S-benzyl
12-hydroxyoctadec-9-enethioate 3a in 65% yield.
Aiming to explore the reactivity of the fat thiol esters obtained, we decide to
study their conversion to the respective fat aldehyde 4 by reduction with triethylsi-
lane in the presence of catalytic Pd on carbon.[4f,g] Thus, when a solution of
(R,Z)-S-benzyl 12-hydroxyoctadec-9-enethioate 3a in acetone (10 mL) reacted with

2977

2978

SOLVENT-FREE SYNTHESIS OF THIOL ESTERS
2979
Scheme 2. Synthesis of (R,Z)-12-hydroxyoctadec-9-enal.
(C2H5)3SiH (3 equiv) in the presence of 10% Pd on carbon (5 mol %), the respective
aldehyde 4 was selectively obtained in 86% yield after stirring for 5 h at room tem-
perature (Scheme 2). Similarly to the methods described in the literature for aromatic
thiol esters, (R,Z)-S-phenyl 12-hydroxyoctadec-9-enethioate 3c was inert against the
reduction with(C2H5)3SiH, even after stirring for several hours.
In conclusion, an improved, solvent- and base-free protocol to prepare thiol
esters directly from carboxylic acids, without the tedious and harmful preparation
of acyl chlorides, was developed. The minimization of the use of volatile organic sol-
vents and harmful reagents are important advantages of this improved procedure.
Besides, the obtained thiol esters can be explored as enantiomerically pure building
blocks in the synthesis of more, complex bioactive candidate molecules.
EXPERIMENTAL
General Remarks
The 1H and 13C NMR sectra of CDCl3 solutions were recorded with a
200-MHz or 400-MHz spectrometer (Bruker DPX), as noted. Chemical shifts are
expressed as parts per million (ppm) downfield from tetramethylsilane (TMS) as
an internal standard. Low-resolution mass spectra (LRMS, EI) were obtained at
70 eV with a Hewlett Packard EM=CG HP-5988A spectrometer. High-resolution
mass spectra (HRESI-MS) were performed in the positive mode (UltrOTOF-Q
system, version 1.10, Bruker Daltonics, MA, USA). Merck’s silica gel (230–
400 mesh) was used for flash chromatography.
Thiol Esters 3
General procedure. A mixture of carboxylic acid 1 (1.0 mmol) and DCC
(1.0 mmol, 0.206 g) was stirred at room temperature for 15 min. Then, thiol 2
(1.2 mmol) was added, and the resulting mixture was stirred under a nitrogen atmos-
phere. The reaction progress was followed by thin-layer chromatography (TLC), and
after 2–5 h (see Table 1) the crude product was purified on column chromatography
of silica gel using ethyl acetate–hexanes (3:7) as eluent. Spectral data of 3a–k are
listed.

2980
R. G. LARA ET AL.
(R,Z)-S-Benzyl
12-hydroxyoctadec-9-enethioate
(3a). 1H
NMR
(200 MHz, CDCl3) d 7.24–7.26 (m, 5H), 5.54 (dt, J ¼ 10.2 and 7.2 Hz, 1H), 5.36
(dt, J ¼ 10.2 and 6.6 Hz, 1H), 4.11 (s, 2H), 3.58 (quint, J ¼ 6.8 Hz, 1H), 2.55 (t,
J ¼ 7.4 Hz, 2H), 2.20 (t, J ¼ 6.6 Hz, 2H), 1.28–2.12 (m, 22H), 1.78 (br s, 1H), 0.88
(t, J ¼ 6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 198.8, 137.7, 134.4, 128.8,
128.5, 127.1, 125.9, 70.9, 43.8, 40.7, 36.7, 33.1, 32.5, 31.8, 29.3, 29.2, 29.0, 28.8,
25.6, 25.5, 22.5, 14.0; IR (KBr) n (C O) 1686 cmꢂ1; MS m=z (rel. int.) 557
=
(Mþ ꢂ 1, 14.6), 295 (15.2), 91 (100.0). HRMS (ESI): m=z calcd. for C25H40O2S
[M þ Na]þ: 427.2647; found: 427.2646.
(R,Z)-S-Dodecyl 12-hydroxyoctadec-9-enethioate (3b). 1H NMR
(400 MHz, CDCl3) d 5.55 (dtt, J ¼ 10.8, 7.6 and 1.2 Hz, 1H), 5.40 (dtt, J ¼ 10.8,
6.4 and 1.2 Hz, 1H), 3.61 (quint, J ¼ 6.8 Hz, 1H), 2.86 (t, J ¼ 7.2 Hz, 2H), 2.53 (t,
J ¼ 7.6 Hz, 2H), 2.21 (t, J ¼ 6.0 Hz, 2H), 1.25–2.01 (m, 43H), 0.89 (t, J ¼ 7.2 Hz,
3H), 0.88 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 199.7, 134.4, 125.9,
70.9, 44.1, 40.7, 36.7, 32.6, 31.9, 31.8, 29.7, 29.57, 29.5, 29.4, 29.3 29.2, 29.1, 29.0,
28.9, 28.8, 28.7, 25.6, 22.7, 22.6, 14.1, 14.0; IR (KBr) n (C O) 1695 cmꢂ1; MS
=
m=z (rel. int.) 328 (Mþ ꢂ C11H24, 22.4), 282 (25.8), 166 (38.5), 55 (100.0). HRMS
(ESI): m=z calcd. for C30H58O2S [M þ Na]þ: 505.4055; found: 505.4043.
(R,Z)-S-Phenyl
12-hydroxyoctadec-9-enethioate
(3c). 1H
NMR
(400 MHz, CDCl3) d 7.37–7.41 (m, 5H), 5.54 (dtt, J ¼ 10.8, 6.8 and 1.0 Hz, 1H),
5.41 (dtt, J ¼ 10.8, 6.4 and 1.0 Hz, 1H), 3.60 (quint, J ¼ 6.8 Hz, 1H), 2.64 (t,
J ¼ 7.6 Hz, 2H), 2.20 (t, J ¼ 6.4 Hz, 2H), 2.02–2.07 (m, 2H), 1.66–1.74 (m, 2H),
1.28–1.47 (m, 19H), 0.88 (t, J ¼ 6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3) d 197.4,
134.3, 129.2, 129.0, 127.9, 125.9, 125.2, 70.9, 43.6, 40.6, 36.7, 35.3, 32.5, 31.8, 29.3,
29.2, 29.0, 28.8, 25.6, 25.5, 22.5, 14.0; IR (KBr) n (C O) 1711 cmꢂ1; MS m=z
=
(rel. int.) 281 (Mþ ꢂ C6H5S, 9.3), 263 (49.3), 109 (53.8), 55 (100.0). HRMS (ESI):
m=z calcd. for C24H38O2S [M þ Na]þ: 413.2490; found: 413.2505.
(R,Z)-S-2-Chlorophenyl 12-hydroxyoctadec-9-enethioate (3d). 1H NMR
(400 MHz, CDCl3) d 7.20–7.50 (m, 4H), 5.54 (dt, J ¼ 10.2 and 7.0 Hz, 1H), 5.41 (dt,
J ¼ 10.2 and 6.8 Hz, 1H), 3.57–3.62 (m, 1H), 2.67 (t, J ¼ 7.2 Hz, 2H), 2.21 (t,
J ¼ 6.4 Hz, 2H), 2.01–2.06 (m, 2H), 1.14–1.76 (m, 21H), 0.88 (t, J ¼ 6.8 Hz, 3H);
13C NMR (50 MHz, CDCl3) d 195.4, 138.6, 136.9, 133.0, 130.9, 130.1, 127.3,
127.1, 125.2, 71.3, 43.6, 36.7, 35.2, 32.5, 31.7, 29.4, 29.2, 29.0, 28.9, 28.7, 25.6,
25.4, 22.5, 14.0; IR (KBr) n (C O) 1714 cmꢂ1; MS m=z (rel. int.) 281 (Mþ
=
ꢂ 2-ClC6H4S, 1.8), 167 (42.2), 109 (18.5), 55 (100.0). HRMS (ESI): m=z calcd. for
C24H37ClO2S [M þ Na]þ: 447.2100; found: 447.2105.
(R,Z)-S-3-Chlorophenyl 12-hydroxyoctadec-9-enethioate (3e). 1H NMR
(200 MHz, CDCl3) d 7.26–7.44 (m, 4H), 5.53 (dt, J ¼ 10.2 and 7.0 Hz, 1H), 5.37 (dt,
J ¼ 10.2 and 6.8 Hz, 1H), 3.58–3.62 (m, 1H), 2.65 (t, J ¼ 7.2 Hz, 2H), 2.21 (t,
J ¼ 6.4 Hz, 2H), 2.01–2.04 (m, 2H), 1.28–1.74 (m, 21H), 0.85 (t, J ¼ 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 196.5, 134.6, 134.4, 134.0, 132.5, 130.0, 129.4,
125.9, 70.9, 43.7, 40.6, 36.7, 32.5, 31.8, 29.3, 29.0, 28.8, 25.6, 25.4, 22.5, 14.0; IR
(KBr) n (C O) 1713 cmꢂ1; MS m=z (rel. int.) 281 (Mþ ꢂ 3-ClC6H4S, 1.5), 167
=
(43.5), 109 (19.2), 55 (100.0). HRMS (ESI): m=z calcd. for C24H37ClO2S [M þ Na]þ:
447.2100; found: 447.2104.

SOLVENT-FREE SYNTHESIS OF THIOL ESTERS
2981
(R,Z)-S-4-Chlorophenyl 12-hydroxyoctadec-9-enethioate (3f). 1H NMR
(200 MHz, CDCl3) d 7.38 (dt, J ¼ 8.8 and 2.0 Hz, 2H), 7.34 (dt, J ¼ 8.8 and 2.0 Hz,
2H), 5.54 (dt, J ¼ 10.2 and 6.8 Hz, 1H), 5.43 (dt, J ¼ 10.2 and 6.8 Hz, 1H),
3.58–3.63 (m, 1H), 2.66 (t, J ¼ 7.2 Hz, 2H), 2.22 (t, J ¼ 6.4 Hz, 2H), 2.01–2.08 (m,
2H), 1.28-1.74 (m, 21H), 0.90 (t, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
196.9, 135.6, 134.4, 129.4, 126.4, 126.0, 125.3, 70.9, 43.7, 40.7, 36.8, 36.7, 35.3,
ꢂ1
=
32.6, 31.8, 29.3, 29.0, 28.9, 28.8, 25.5, 22.6, 14.1; IR (KBr) n (C O) 1711 cm
;
MS m=z (rel. int.) 281 (Mþ ꢂ 4-ClC6H4S, 10.0), 263 (46.1), 144 (79.8), 109 (100.0).
55 (95.0). HRMS (ESI): m=z calcd. for C24H37ClO2S [M þ Na]þ: 447.2100;
found: 447.2090.
S-Phenyl hexanethioate (3g)[11] 1H NMR (200 MHz, CDCl3) d 7.33–7.40
.
(m, 5H), 2.63 (t, J ¼ 7.2 Hz, 2H), 1.67 (qui, J ¼ 7.2 Hz, 2H), 1.31–1.35 (m, 4H),
0.90 (t, J ¼ 7.0 Hz, 3H); IR (KBr) n (C O) 1708 cmꢂ1; MS m=z (rel. int.) 208
=
(Mþ, 2.2), 137 (9.1), 131 (3.2), 110 (23.2), 85 (34.0), 57 (94.7), 43 (100.0).
S-Phenyl 2,2-dimethylpropanethiolate (3h)[12]
.
1H NMR (200 MHz,
ꢂ1
=
CDCl3) d 7.39 (br s, 5H), 1.32 (s, 9H); IR (KBr) n (C O) 1710 cm
.
S-tert-Butyl propanethioate (3i)[13]. IR (KBr) n (C O) 1708 cmꢂ1; MS m=z
(rel. int.) 145 (Mþ ꢂ 1, 1.0), 129 (5.6), 126 (100.0), 117 (75), 111 (95), 91 (3.6), 57
(43.3).
=
S-tert-Butyl butanethioate (3j)[14]. IR (KBr) n (C O) 1709 cmꢂ1; MS m=z
=
(rel. int.) 159 (Mþ ꢂ 1, 1.0), 154 (25.1), 149 (65.0), 131 (54.6), 126 (100.0).
S-Phenyl benzothioate (3k)[6b] 1H NMR (200 MHz, CDCl3) d 8.12–8.16
.
(m, 2H), 7.61–7.68 (m, 2H), 7.52–7.54 (m, 6H); 13C NMR (100 MHz, CDCl3) d
=
129.3, 129.4, 130.3, 130.6, 131.0, 135.5, 136.9, 138.5, 191.1; IR (KBr) n (C O)
1707 cmꢂ1; MS m=z (rel. int.) 122 (74.0), 105 (100.0), 77 (2.7).
General Procedure for the Synthesis of (R,Z)-12-Hydroxyoctadec-9-
enal (4)[15]
(C2H5)3SiH (0.348 g, 3 mmol) was added to a stirred mixture of thiol ester 3a
(0.389 g, 1 mmol) and 10% Pd on carbon (5 mol%) in acetone (10 mL) at room tem-
perature a under nitrogen atmosphere. The stirring was continued at rt until the
reduction was completed (5 h, TLC). The catalyst was filtered off through celite
and washed with acetone (3 ꢃ 5 mL). Evaporation and separation on a silica-gel
=
column gave a colorless oil, characterized as the aldehyde 4. IR (KBr) n (C O)
1711 cmꢂ1; MS m=z (rel. int.) 246 (Mþ ꢂ 2H2O, 1.0), 217 (93.0), 189 (100.0), 161
(61.0).
ACKNOWLEDGMENTS
This work was partially supported by CNPq, FINEP, CAPES, and FAPERGS.

2982
R. G. LARA ET AL.
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