PAPER
Highly efficient synthesis of thioesters in water†
Hassan Zali Boeini* and Maryam Eshghi Kashan
Received 17th August 2009, Accepted 25th September 2009
First published as an Advance Article on the web 27th October 2009
DOI: 10.1039/b916852d
Thioesters were efficiently prepared via the direct reaction of tertiary thioamides and alkyl halides
in water, and in the presence of catalytic amounts of NaI, hexadecyltrimethylammonium bromide
(HTAB), and 1,4-diazabicyclo[2.2.2]octane (DABCO). Hence, thioamides smoothly undergo an
S-alkylation with alkyl halides in aqueous media following by hydrolysis to afford the
corresponding thioesters in very good to excellent yields.
of thiols as starting materials, which are very unpleasant
Introduction
and noxious compounds. However, despite the efficiency of
the latter protocols, the development of less expensive and
environmentally benign reaction courses is a major goal for
organic synthesis. Therefore, we were eager to develop a single-
step and quite eco-friendly method for the synthesis of diverse
thioesters.
Undoubtedly, thioamides are very important building blocks
in organic synthesis and especially in construction of hetero-
cyclic compounds.27 Herein, we report the first development, to
our knowledge, of a straightforward and versatile method to
obtain thioesters using tertiary thioamides in aqueous media
and in the presence of catalytic amounts of NaI, DABCO, and
hexadecyltrimethylammonium bromide (HTAB).
Thioesters represent organic derivatives of wide interest due
to their wide range of biological activity and considerable
applications in drug development1–5 and industry.6-8 Thioesters
of coenzyme A (CoA) are ubiquitous in all living organisms and
play central roles in their metabolism.9 In addition, polyketide
synthases (PKSs) and nonribosomal polypeptide synthetases
(NRPKs) use thioesters of fatty acids and amino acids as key
intermediates to assemble bioactive polyketides and peptides.10-12
Also, thioesters show distinctive chemical properties compared
to oxoesters13 and their enhanced reactivity has successfully been
employed in a wide range of synthetic organic transformations.14
Hence, developing a simple and versatile method for the
preparation of thioesters is still an urgent need.
The most well known approach to the synthesis of thioesters
is the direct reaction of the corresponding thiols with a suitable
acid chloride 15 or acid anhydride.16-18 Moreover, thioesters have
been synthesized by direct reaction of carboxylic acids with
thiols and in the presence of diverse reaction conditions and
catalysts.19-21 Thioesters have also been prepared by the reaction
of esters22 or N-acylbenzotriazoles23 with thiols. Recently, tert-
butyl protected thiols have been utilized for the preparation
of thioesters.24 More recently the N–S acyl shift, mediated by
attaching a thiol auxiliary residue to the peptide backbone,
has been applied to peptide thioester syntheses.25 However,
this method employs thiols and long reaction times, and the
overall yields are not satisfactory (16–31%). The Dess–Martin
periodinane (DMP)-mediated reaction of thiols and aldehydes
represents another method for the synthesis of thioesters.26
Although most of these approaches provide efficient access
to thioesters, they suffer from the use of corrosive reagents,
harsh reaction conditions, expensive catalysts or reagents, and
unfriendly organic solvents. Nevertheless, the greatest disadvan-
tage of the previously mentioned methods is the application
Results and discussion
We started our study with examining the reaction of mor-
pholino (phenyl) methanethione 1a as a test thioamide starting
material, prepared by the Willgerodt–Kindler method,28 with
4-nitrobenzyl bromide 2a and in various reaction conditions to
produce the corresponding S-4-nitrobenzyl benzothioate 3a.
At the outset of our study, DMF was used as the solvent for
the reaction course. Therefore, the starting morpholino (phenyl)
methanethione and equimolar amounts of 4-nitrobenzyl bro-
mide were dissolved in small quantities of DMF and the reaction
mixture was heated at 95 ◦C for 40 min. Thereafter, the reaction
mixture was treated in the same temperature with catalytic
amounts of DABCO in small quantities of water for 20 min to
obtain the corresponding thioester in moderate yield (68%). In
addition to DMF, other solvents were also examined as reaction
media and the screening results indicate a notable increase of
the yields in polar solvents (Table 1). These outcomes are in
accordance with the ionic nature of the thioformamidinium
intermediate salt and the low solubility of such an intermediate
in less polar solvents. It is also worthwhile to note that increasing
the reaction times and temperatures does not lead to an increase
in the yield of thioester, and our investigations revealed that in
these conditions the reaction mixture is contaminated with some
colored or tarry materials.
Department of Chemistry, University of Isfahan, Isfahan, Iran.
E-mail: h.zali@chem.ui.ac.ir, m.eshghi@chem.ui.ac.ir;
Fax: +98-311-6689732; Tel: +98-311-7932715
† Electronic supplementary information (ESI) available: Complete ex-
perimental procedures, 1H NMR and 13C NMR spectral data (including
their copies), and elemental microanalysis for compounds. See DOI:
10.1039/b916852d
According to these results, we were intrigued to investigate the
reaction in water as a green solvent. Interestingly, it was found
This journal is
The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 1987–1991 | 1987
©
Boeini, Hassan Zali
