Microwave-assisted Synthesis of Thioesters from Aldehydes and Thiols in Water

Article abstract of DOI:10.1002/jccs.201700045

We describe the synthesis of thioesters via copper- or iron-catalyzed coupling of thiols with aldehydes on application of microwave irradiation. In this protocol, a variety of aliphatic and aromatic aldehydes and thiols were used, and the products were ob

Full text of DOI:10.1002/jccs.201700045

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Communication
Microwave-assisted Synthesis of Thioesters from Aldehydes and Thiols in Water
Huei-Shu Jhuang,a Yi-Wei Liu,a Daggula Mallikarjuna Reddy,a Yong-Ze Tzeng,b Wei-Yu Linb
*
a
*
and Chin-Fa Lee
aDepartment of Chemistry, National Chung Hsing University, Taichung 402, Taiwan
bDepartment of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
(Received: February 10, 2017; Accepted: April 25, 2017; DOI: 10.1002/jccs.201700045)
We describe the synthesis of thioesters via copper- or iron-catalyzed coupling of thiols with alde-
hydes on application of microwave irradiation. In this protocol, a variety of aliphatic and aro-
matic aldehydes and thiols were used, and the products were obtained in good to excellent yields.
Keywords: Aldehydes; Thiols; Microwave irradiation; Aqueous medium; Thioesters.
Wei-Yu Lin received the B.S. degree from the Cheng-Kung University, Taiwan, in 1998, and the Ph.D. degree
from the National Taiwan University, Taiwan, in 2006, working with Professor T.–Y. Luh. He conducted his
postdoctoral studies with Prof. H. -R. Tseng and Prof. C. K.-F Shen at the University of California, Los
Angeles, USA, before joining Kaohsiung Medical University, Taiwan, as an Assistant Professor, in 2011. His
current research interests include organic chemistry, flow microreactor synthesis, and biorthogonal chemistry.
Chin-Fa Lee was born in 1975. He obtained the B.S. degree from Tamkang University, Taiwan, in 1997, and
the Ph.D. degree from the National Taiwan University, Taiwan, in 2002, working with Prof. T.-Y. Luh. He
spent 1 year of postdoctoral research with Prof. T.-Y. Luh at NTU, 1 year with Prof. J. F. Hartwig at Yale
University, USA, and 3 years with Prof. D. A. Leigh at Edinburgh University, UK. He joined National Chung
Hsing University as an Assistant Professor in 2008 and promoted to Associate Professor in 2011 and Professor
in 2014. His research interests include organic chemistry, transition-metal-catalyzed C–S bond formation and
related cross-coupling reactions, and materials chemistry.
INTRODUCTION
Recently, many research and pharmaceutical
the solubility of reactants during chemical reactions, reac-
tions in aqueous media are termed “in-water” or “on-
water” reactions,2 and these problems can be easily over-
come by employing reactions under MW irradiation.
Because of the presence of higher pressure and tempera-
ture in MW-assisted processes, the rate of reactions will
increase via efficient and homogeneous mixing of the reac-
tants and the hydrophobic effects will be lower. In spite of
these perceived limitations of reactions in water, it has
great promise in MW-assisted organic synthesis.
laboratories are employing nonclassical forms of heating
routinely, undoubtedly in the form of microwave irradia-
tion. The use of microwave (MW) irradiation in organic
synthesis has become popular because of its shorter reac-
tion time, wide range of reactions, minimum exposure of
hazardous chemicals, and maximum utilization of
energy.1 Generally, organic reactants show poor solubility
in aqueous media due to the formation of immiscible or
biphasic reaction mixtures, and this is a major drawback
to conducting organic reactions in water. On the basis of
Development of new methods for the constuction
of the thioester functionality has received prime interest
*Corresponding authors. Email: wylin@kmu.edu.tw; cfalee@dragon.nchu.edu.tw
J. Chin. Chem. Soc. 2017
© 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Communication
Jhuang et al.
in synthetic chemistry because these frameworks have
been used as acyl transfer reagents in organic synthesis3
and chemical biology.4 In general, the synthesis of
thioesters can be achieved from carboxylic acid deriva-
tives. Carboxylic acid derivatives such as acyl chlorides
are sensitive to moisture and will produce an equal
amount of halide anions in the reaction. Moreover, this
method when used in the preparation of thioesters also
suffers from significant drawbacks.5 Therefore, the
direct coupling of aldehydes with thiols or thiol equiva-
lents to afford thioesters can serve as an alternative and
ideal pathway.
RESULTS AND DISCUSSION
We initially selected
benzaldehyde
and
1-dodecanethiol as coupling partners to examine the reac-
tion conditions. The results are summarized in Table 1.
First, we took 1-dodecanethiol 2a (0.5 mmol), benzalde-
hyde 1a (2.5 mmol, 5.0 equiv), 70% TBHP aq. solution
(1.0 mmol, 2.0 equiv), and CuCl (2.5 mol%) in water
(1.5 mL) in an MW vial. The vial was sealed and heated
at 100ꢀC for 2.5 min under 150 W MW irradiation
(ramp time: 5 min). After purification of crude reaction
mixture by column chromatography, the desired product
was isolated in 68% yield (Table 1, entry 1). Interestingly,
when we increased the reaction time to 5.0 min, the prod-
uct was obtained in 92% isolated yield (Table 1, entry 2).
Further increase of the reaction time to 10.0 min did not
improve yield of the product (Table 1, entry 3). Notably,
when we changed the temperature higher or lower than
100ꢀC, no further improvement of product yield was
observed (Table 1, entry 4 and 5).
In 1976, Matsuda and coworkers developed a syn-
thesis route of thioesters via coupling of aldehydes with
disulfides through photoirradiation. However, this
method required the use of aldehydes as solvent, and
only benzaldehyde was used as the aryl aldehyde.6
Recently, an N-heterocyclic carbine (NHC)-catalyzed
coupling reaction of thiols with aldehydes to produce
thioesters was developed by Takemoto and coworkers.
This method has some drawbacks such as the use of
expensive carbenes and the requirement of stoichiomet-
ric amount of phenazine as oxidant in the reaction.7
The C–S bond formation between pentafluorophenyl
disulfide and aldehydes was successfully accomplished
by Kita et al.; however, diaryl and dialkyl disulfides are
not suitable as coupling partners in this system.8 Band-
gar and coworkers reported the synthesis of thioesters
from aryl thiols and aldehydes in the presence of Dess–
Martin periodinane and NaN3. Use of 6 equiv of Dess–
Martin periodinane and 6 equiv of NaN3 in this cou-
pling was a severe limitation. In addition, aryl thiols
failed to couple with thiol under these reaction condi-
tions.9 Recently, our research group reported the copper-
and iron-catalyzed coupling of aldehydes with thiols
in water by using tert-Butyl hydroperoxide (TBHP) as
an oxidant.10 Very recently, we have also reported a
metal- and solvent-free direct C–H thiolation of alde-
hydes promoted by Di-tert-Butyl peroxide (DTBP).11
This system showed good functional group compatibil-
ity with electron-donating and electron-withdrawing
groups and also with halo groups, as they are all tol-
erated by the reaction conditions employed. As part
of our ongoing progress toward C–S bond coupling
reactions,12 we here describe the synthesis of thioesters
via copper- or iron-catalyzed coupling of thiols with
aldehydes under MW irradiation.
With the optimized reaction conditions in hand, we
explored the scope of different aryl aldehydes (1) with
various alkanethiols (2) to give thioesters (3a–l) in the
presence of CuCl and TBHP under MW irradiation.
The results are summarized in Table 2. For example, the
reaction was tolerated with substituents such as chloro
(3i and 3j), bromo (3k and 3l), and methoxy (3c and 3d)
on the aryl system. Ortho substituents on aryl system
also did not affect the yield of thioesters significantly
Table 1. Optimization studiesa
Entry
Time (min)
Temp (ꢀC)
Yield (%)
1
2
3
4
5
2.5
5.0
10.0
5.0
100
100
100
90
68
92
75
69
66
5.0
110
a Reaction conditions: 1a (0.26 mL, 2.5 mmol), 2a (0.125 mL,
0.5 mmol), 70% TBHP aq. soln. (1.0 mmol), copper(I)
chloride (0.0125 mmol, 2.5 mol%), and H2O (1.5 mL) were
added to an MW vial with a magnetic stirrer bar. The vial
was sealed and heated at 100ꢀC for 5 min under 150 W of
MW irradiation (ramp time: 10 min).
Bold letters determines the given condition is the optimized
reaction condition.
2
www.jccs.wiley-vch.de
© 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2017

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Thioesters Can be Prepared in 5 Min
Table 2. Reaction between aryl aldehydes and alkanethiolsa
Table 4. Reaction between alkyl aldehydes and arenethiolsa
a Reaction conditions: 6 (2.5 mmol), 4 (0.5 mmol), TBHP in
H2O (1.0 mmol), copper(I) chloride (0.025 mmol, 5.0 mol%),
and H2O (1.5 mL) were added to an MW vial with a
magnetic stirrer bar. The vial was sealed and heated at 100ꢀC
for 5.0 min under 150 W of MW irradiation (ramp time:
10 min).
a Reaction conditions: Unless otherwise mentioned,
1 (2.5 mmol), 2 (0.5 mmol), TBHP in H2O (1.0 mmol),
copper(I) chloride (0.0125 mmol, 2.5 mol%), and H2O
(1.5 mL) were added to an MW vial with a magnetic stirrer
bar. The vial was sealed and heated at 100ꢀC for 5 min under
150 W of MW irradiation (ramp time: 10 min).
b CuCl (0.025 mmol, 5.0 mol%).
(3e). Branched alkane thiols (3f and 3g) were also suc-
cessfully employed under this reaction condition. In
some cases, FeBr2 worked better than CuCl (3g)
c FeBr2 (0.0125 mmol, 2.5 mol%).
The generality of this reaction was also further
extended to couple various substituted benzaldehydes
(1) with a variety of arenethiols (4) as substrates to
afford the corresponding thioesters (5a–5l) in moderate
to high yields (Table 3). The reaction was compatible
with electron-withdrawing and halogen groups on arene
thiols. Naphthalene-2-thiol and thiophene-2-thiol were
also successfully employed in this coupling to yield the
corresponding thioesters 5k and 5l, respectively.
Table 3. Reaction between aryl aldehydes and arenethiolsa
Encouraged by these results, we further extended our
reaction strategy to couple various aliphatic aldehydes (6)
with a variety of arenethiols (4) to afford the correspond-
ing thioesters (7a–7f) in moderate to good yields (Table 4).
CONCLUSION
In summary, we have described a general method
for preparing thioesters by using CuCl as a catalyst and
TBHP as an oxidant. It is important to note that the
reactions were carried out in water without any addi-
tive, and the use of MW irradiation resulted in a drastic
enhancement of the rate of reaction. Aryl- and alkyl
aldehydes were coupled with aryl- and alkyl thiols, giv-
ing the corresponding thioesters in moderate to excel-
lent yields. This system showed good functional group
tolerance. Moreover, hindered substrates were also
shown to have good activity for catalysis.
a Reaction conditions: Unless otherwise mentioned,
1 (2.5 mmol), 4 (0.5 mmol), TBHP in H2O (1.0 mmol),
copper(I) chloride (0.0125 mmol, 2.5 mol%), and H2O
(1.5 mL) were added to an MW vial with a magnetic stirrer
bar. The vial was sealed and heated at 100ꢀC for 5 min under
150 W of MW irradiation (ramp time: 10 min).
b FeBr2 (0.0125 mmol, 2.5 mol%).
c CuCl (0.025 mmol, 5.0 mol%).
J. Chin. Chem. Soc. 2017
© 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.jccs.wiley-vch.de
3

Communication
Jhuang et al.
Lett. 1986, 27, 3791; (c) H. M. Meshram, G. S. Reddy,
K. H. Mindu, J. S. Yadav, Synlett 1998, 877;
(d) C. C. Silveira, A. L. Braga, E. L. Larghi, Organome-
tallics 1999, 18, 5183; (e) S. Limura, K. Manabe,
S. Kobayashi, Chem. Commun. 2002, 94; (f )
A. R. Katritzky, A. A. Shestopalov, K. Suzuki, Synthesis
2004, 1806; (g) S. Magens, B. Plietker, Chem. Eur. J.
2011, 17, 8807.
ACKNOWLEDGMENTS
This work was supported by the Ministry of Sci-
ence and Technology, Taiwan (MOST 105-2113-M-
005-001, MOST 104-2113-M-037-001-MY2), the
National Chung Hsing University, and the Kaohsiung
Medical University.
REFERENCES
6. (a) M. Takagi, S. Goto, T. Matsuda, J. Chem. Soc.
Chem. Commun. 1976, 92; (b) M. Takagi, S. Goto,
M. Tazaki, T. Matsuda, Bull. Chem. Soc. Jpn. 1980,
53, 1982.
7. T. Uno, T. Inokuma, Y. Takemoto, Chem. Commun.
2012, 48, 1901.
8. (a) H. Nambu, K. Hata, M. Matsugi, Y. Kita, Chem.
Commun. 2002, 1082; (b) H. Nambu, K. Hata,
M. Matsugi, Y. Kita, Chem. Eur. J. 2005, 11, 719.
9. S. B. Bandgar, B. P. Bandgar, B. L. Korbad,
S. S. Sawant, Tetrahedron Lett. 2007, 48, 1287.
10. (a) C.-L. Yi, Y.-T. Huang, C.-F. Lee, Green Chem. 2013,
15, 2476; (b) Y.-T. Huang, S.-Y. Lu, C.-L. Yi, C.-F. Lee,
J. Org. Chem. 2014, 79, 4561.
1. (a) P. Lidstrom, J. Tierney, B. Wathey, J. Westman, Tetra-
hedron 2001, 57, 9225; (b) P. Lidstrom, J. Tierney, Micro-
wave-Assisted Organic Synthesis, Blackwell Scientific,
Oxford, 2004; (c) A. de la Hoz, A. Diaz-Ortiz, A. Moreno,
Chem. Soc. Rev. 2005, 34, 164; (d) V. Polshettiwar,
M. N. Nadagouda, R. S. Varma, Aust. J. Chem. 2009, 62,
16; (e) M. B. Gawande, S. N. Shelke, R. Zboril,
R. S. Varma, Acc. Chem. Res. 2014, 47, 1338.
2. M. B. Gawande, V. D. B. Bonifacio, R. Luque,
P. S. Branco, R. S. Varma, Chem. Soc. Rev. 2013, 42, 5522.
3. (a) M. Benaglia, M. Cinquini, F. Cozzi, Eur. J. Org. Chem.
2000, 563; (b) S. Iimura, K. Manabe, S. Kobayashi, Org.
Lett. 2003, 5, 101; (c) J. M. Yost, G. Zhou, D. M. Coltart,
Org. Lett. 2006, 8, 1503; (d) H. Yang, H. Li,
R. Wittenberg, M. Egi, W. Huang, L. S. Liebeskind, J. Am.
Chem. Soc. 2007, 129, 1132; (e) A. Iida, J. Osada,
R. Nagase, T. Misaki, Y. Tanabe, Org. Lett. 2007, 9, 1859;
(f ) N. Utsumi, S. Kitagaki, C. F. Barbas III. , Org. Lett.
2008, 10, 3405; (g) D. A. Alonso, S. Kitagaki, N. Utsumi,
C. F. Barbas III. , Angew. Chem. Int. Ed. 2008, 47, 4588;
(h) H. Li, H. Yang, L. S. Liebeskind, Org. Lett. 2008, 10,
4375; (i) D. Crich, I. Sharma, Angew. Chem. Int. Ed. 2009,
48, 2355; (j) D. Crich, K. Sasaki, Org. Lett. 2009, 11, 3514;
(k) K. Matsuo, M. Sindo, Org. Lett. 2010, 12, 5346;
(l) K. Kunchithapatham, C. C. Eichman, J. P. Stambuli,
Chem. Commun. 2011, 47, 12679; (m) S. Rossi,
M. Benaglia, F. Cozzi, A. Genoni, T. Benincori, Adv.
Synth. Catal. 2011, 353, 848.
11. J.-W. Zeng, Y.-C. Liu, P.-A. Hsieh, Y.-T. Huang, C.-
L. Yi, S. S. Badsara, C.-F. Lee, Green Chem. 2014,
16, 2644.
12. (a) J.-R. Wu, C.-H. Lin, C.-F. Lee, Chem. Commun.
2009, 4450; (b) C.-K. Chen, Y.-W. Chen, C.-H. Lin, H.-
P. Lin, C.-F. Lee, Chem. Commun. 2010, 46, 282; (c) H.-
L. Kao, C.-F. Lee, Org. Lett. 2011, 13, 5204; (d) H.-
L. Kao, C.-K. Chen, Y.-J. Wang, C.-F. Lee, Eur. J. Org.
Chem. 2011, 1776; (e) C.-H. Cheng, C. Ramesh, H.-
L. Kao, Y.-J. Wang, C.-C. Chan, C.-F. Lee, J. Org.
Chem. 2012, 77, 10369; (f ) J.-H. Cheng, C.-L. Yi, T.-
J. Liu, C.-F. Lee, Chem. Commun. 2012, 48, 8440; (g) Y.-
Y. Lin, Y.-J. Wang, C.-H. Lin, J.-H. Cheng, C.-F. Lee,
J. Org. Chem. 2012, 77, 6100; (h) C.-S. Lai, H.-L. Kao,
Y.-J. Wang, C.-F. Lee, Tetrahedron Lett. 2012, 53, 4365;
(i) Y.-C. Liu, C.-F. Lee, Synlett 2013, 24, 2320; (j) C.-
L. Yi, T.-J. Liu, J.-H. Cheng, C.-F. Lee, Eur. J. Org.
Chem. 2013, 3910; (k) T.-J. Liu, C.-L. Yi, C.-C. Chan,
C.-F. Lee, Chem. Asian. J. 2013, 8, 1029.
4. J. Staunton, K. J. Weissman, Nat. Prod. Rep. 2001,
18, 380.
5. (a) G. O. Spessard, W. K. Chan, S. Masamune, Org.
Synth. 1982, 61, 134; (b) S. Ahmad, J. Iqbal, Tetrahedron
4
www.jccs.wiley-vch.de
© 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2017