Development of a solvent-reagent selection guide for the formation of thioesters

Article abstract of DOI:10.1039/c9gc00355j

For the first time a solvent-reagent guide has been developed with a view to providing greener synthetic conditions for the preparation of thioesters. A number of solvents and reagents were evaluated and optimum conditions were applied to the synthesis of pharmaceutically relevant building block-like molecules.

Full text of DOI:10.1039/c9gc00355j

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. Jordan and H.
F. Sneddon, Green Chem., 2019, DOI: 10.1039/C9GC00355J.
This is an Accepted Manuscript, which has been through the
Volume 18 Number
7 7 April 2016 Pages 1821–2242
Royal Society of Chemistry peer review process and has been
accepted for publication.
Green
Chemistry
Accepted Manuscripts are published online shortly after
Cutting-edge research for a greener sustainable future
www.rsc.org/greenchem
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1463-9262
CRITICAL REVIEW
G. Chatel et al.
Heterogeneous catalytic oxidation for lignin valorization into valuable
chemicals: what results? What limitations? What trends?
rsc.li/green-chem

Please do not adjust margins
Page 1 of 8
Green Chemistry
View Article Online
DOI: 10.1039/C9GC00355J
Journal Name
COMMUNICATION
Development of a Solvent-Reagent Selection
Guide for the Formation of Thioesters
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Andrew Jordan,*a and Helen Sneddon *b
www.rsc.org/
For the first time a solvent-reagent guide has been developed with commonly used.10 Alternative methodology has recently been
view to providing greener synthetic conditions for the explored by Nanda et al. who have demonstrated that
a
preparation of thioesters. A number of solvents and reagents were thioesters can be formed from acid chlorides using thermally
evaluated and optimum conditions were applied to the synthesis of activated silica gel as a catalyst under solvent free conditions,
pharmaceutically relevant building block-like molecules.
however carboxylic acids proved unreactive in this system.11
Inspired by recently developed solvent and reagent selection
guides produced in collaboration with GSK,12-15 the authors
have undertaken a solvent-reagent screening investigation with
the aim of providing greener conditions for the synthesis of
thioesters from carboxylic acids.
Thioesters make up a small but not insignificant proportion of
ester containing organic molecules reported in the literature.
This functional group is most commonly encountered in
biological processes where the S-acylation of amino acid
residues and peptides is common, or, in the case of biomolecule
acetyl-CoA, S-acylation of β-mercaptoethylamine groups.1,2
Thioesters have been investigated for their therapeutic uses
and there are currently 18 thioester containing drugs on the
market with a further number undergoing investigation (Fig. 1).3
As synthetic intermediates, thioesters have found themselves
employed in natural product synthesis as reactive substrates for
the Fukuyama reduction to furnish aldehydes, or the related
Fukuyama palladium coupling with an organozinc halide to form
a ketone.4, 5 Methods employed for the formation of thioesters
from carboxylic acids include reagent combinations of
O
O
O
F
S
HO
O
H
HN
F
F
H
O
O
S
Dalcetrapib
Fluticasone Propionate
dicyclohexylcarbodiimide
(DCC)/4-
dimethylaminopyridine(DMAP),6 N-(3-dimethylaminopropyl)-
N′-ethylcarbodiimide (EDC)/DMAP,7 or formation of an acyl
chloride via a reagent such as oxalyl chloride8. Anhydrides are
also commonly employed in the synthesis of S-acylated
molecules.9 As part of an ongoing collaboration between The
University of Nottingham and GSK, we have identified a need to
evaluate the synthesis of thioesters from a green chemistry
perspective. A survey of the current literature shows that ~65%
of all thioester forming reactions employ either
dichloromethane (DCM) or N,N-dimethylformamide (DMF) as
solvent with tetrahydrofuran (THF) following as the next most
O
O
H
N
S
N
S
OH
S
O
O
O
O
OH
Pivalopril
Stepronin
Fig. 1 Thioester containing drugs and investigational drug molecules.16-19
Results and Discussion
Methods
For the evaluation of thioester formation a number of typical
coupling reagents commonly used in amide bond formation
a.
GlaxoSmithKline Carbon Neutral Laboratory for Sustainable Chemistry,
Jubilee Campus, University of Nottingham, 6 Triumph Rd, Nottingham
NG7 2GA. E-mail:andrew.jordan@nottingham.ac.uk.
GSK, Medicines Research Centre, Gunnels Wood Road, Stevenage,
b.
Herts., UK,SG1 2NY. E-mail: helen.f.sneddon@gsk.com; Fax: +44
(0)1438 768302;Tel: +44 (0)1438 763645
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 2 of 8
COMMUNICATION
Journal Name
were employed. These included 1-propanephosphonic chromophore and a low odour profile (4-terVti-ebwuAtryticlbleeOnnzlinyel
anhydride solution, (T3P), 1-[bis(dimethylamino)methylene]- mercaptan and 4-tert-butylbenzenethiolDbOoIt:h10.1039/C9GC00355J
1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
Reaction 1: Aryl Thiol - Alkyl Acid
(HATU),
dimethylaminopropyl)-N′-ethylcarbodiimide
(EDC-HCl). (1-Cyano-2-ethoxy-2-
oxoethylidenaminooxy)dimethylamino-morpholino-carbenium
hexafluorophosphate (COMU) and (benzotriazol-1-
yloxy)tripyrrolidinophosphonium hexafluorophosphate
1,1'-carbonyldiimidazole
(CDI)
and
N-(3-
OH
hydrochloride
SH
S
O
O
Coupling Reagent, Solvent
1
Reaction 2: Aryl Thiol - Aryl Acid
O
(PyBOP) were excluded from this assessment as recently
published data by Pfizer has categorised both reagents as “Red”
in their process safety guide for amide coupling reagents based
on calorimetry data.20 A less widely employed reagent,
Bis(trimethylaluminium)–1,4-diazabicyclo[2.2.2]-octane
(DABAL-Me3), was also evaluated as Woodward et al. have
reported its applications in amide bond formation from both
carboxylic acids and esters.21 The heterogeneous reagents silica
gel, silica-sulphuric acid (SSA), montmorillonite K-10 and KF-
alumina were additionally investigated.
OH
SH
S
O
Coupling Reagent, Solvent
2
Reaction 3: Alkyl Thiol - Alkyl Acid
OH
O
O
SH
S
Coupling Reagent, Solvent
3
Reaction 4: Alkyl Thiol - Aryl Acid
O
Solvents encompassing a range of functional groups and
polarities were chosen based on their sustainability profile as
assessed in GSK’s most recent solvent selection guide.13 DCM
and DMF were chosen as “benchmark” solvents that have
traditionally been employed in amide bond formation.14
Alcohols were avoided to negate the possibility of side reactions
such as ester formation. A water surfactant mixture (2 wt.%
TPGS 750M) was also investigated as the Lipschutz group have
reported the successful formation of amide bonds at room
temperature using this system.22 To evaluate the chosen
reagents and solvents, representative examples of aryl/alkyl
thiols and acids were chosen to allow alkyl–alkyl, aryl–aryl, and
alkyl–aryl couplings to be explored. To this end, a combination
of acids and thiols were chosen to give four sets of test reactions
(Scheme 1). Choice of thiol was based on the presence of a UV
OH
O
SH
S
Coupling Reagent, Solvent
4
Scheme 1. Representative thioester reactions
scored 1 out of a possible 5 for perceived odour profile).23, 24
Control experiments were conducted using samples containing
no coupling reagent and showed no conversion to product after
24 h stirring at room temperature. Reaction progress was
analysed by HPLC-UV over a range of time points (1 h, 2 h, 4 h,
8 h and 24 h) and conversion curves were prepared to compare
percentage conversions across the range of solvents and
coupling reagents (Fig. 2 and 3). See ESI for further details.
Reaction 1: Aryl Thiol –
Alkyl Acid
Reaction 2: Aryl Thiol – Aryl
Acid
Reaction 3: Alkyl Thiol –
Alkyl Acid
Reaction 4: Alkyl Thiol – Aryl
Acid
T3P HATU CDI EDC- T3P
HCl
HATU CDI EDC- T3P
HATU CDI EDC- T3P
HCl
HATU CDI EDC-
HCl
HCl
Solvent
DMC
CycP†
**
**
**
**
*
*
**
*
**
**
**
**
EtOAc
**
*
Water††
CPME
N/A
**
N/A
N/A N/A
N/A
N/A
N/A N/A
*
**
2-
MeTHF
**
**
**
*
*
CH3CN
**
*
*
**
DMF
DCM
**
**
**
*
**
**
**
*
*
**
Table 1. Thioester formation by solvent and coupling reagent type depicted using a traffic light system
Key: Red = <50% conv., orange = 50–70% conv., green = >70% conv.; * Indicates >90% conv. within 4 h. ** Indicates >90% conv. within 1 h. †Cyclopentanone (CycP).† † 1 mL water
with 2 wt. % TPGS 750 M surfactant.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 8
Green Chemistry
View Article Online
DOI: 10.1039/C9GC00355J
Journal Name
COMMUNICATION
conversion within 1 hour with the remaining alkyl thiol
reactions (reactions 3 and 4) reaching >90% conversion within
4 hours. HATU showed poor compatibility with solvent
cyclopentyl methyl ether (CPME) where oily precipitates were
observed in all reactions (although conversion was still good for
reaction 2). LCMS analysis of the precipitate showed that it did
not contain any product.
CDI gave good conversions across all solvents for both alkyl acid
reactions 1 and 3 but poor conversion for aryl acids 2 and 4. Care
must be taken to pre-form the activated ester before thiol
addition to avoid thiourea formation. EDC.HCl gave very poor
conversion to the product giving at best 49% conversion in
reaction 3 when employing DMC as solvent. Overall, T3P gave
the best results in terms of percentage conversion, reaction
compatibility and sustainability and is the optimum coupling
reagent for the thioester forming reactions screened.
Reaction 2: Aryl Thiol + Aryl Acid + HATU
100
80
60
40
20
0
DMC
CPME
2MeTHF
DMF
DCM
CH3CN
Cyclopent
Ethyl Acetate
0
4
8
12
Hours
16
20
24
Alternative Reagents
Fig. 2 Conversion plot of reaction 2 across the range of solvents using HATU as
coupling reagent.
A number of alternative coupling reagents were examined for
their applicability in thioester formation based on their
reported use as ester/amide bond forming reagents. These
reagents include DABAL-Me321, silica gel11, 25, silica-sulphuric
acid26, montmorillonite K-1027, and KF-Alumina28. Test reactions
1-4 were initially conducted using the same HPLC method
described for the solvent/coupling reagent screen (vide supra).
All reactions were compared to reference reactions containing
no coupling reagent which showed no conversion to product
after 24 h. No product formation was detected using any of
these reagents at 10 wt. % loading at room temperature using
2-methyltetrahydrofuran (2-MeTHF) as solvent, or under
microwave (µwave heating conditions (130 °C for 8 minutes),
for reactions 1-4. Thermally activated silica gel was also
examined using refluxing toluene under Dean-Stark conditions
for 12 h but no product formation was observed.
DABAL-Me3 was trialled using conditions similar to those
reported by Woodward et al.21 2-MeTHF was investigated as
THF had been successfully employed by Woodward et al. during
optimisation of DABAL-Me3 as a coupling reagent for amide
bond formation under µwave conditions.21 Conversion to
desired product by conventional heating under reflux
conditions proceeded well initially for reactions 1-3, (Table 2)
Reaction 2: Aryl Thiol + Aryl Acid + Cyclopentanone
100
80
T3P
HATU
60
CDI
40
EDC-HCl
20
0
0
4
8
12
16
20
24
Hours
Fig. 3 Conversion plot of Reaction 2 across the range of coupling reagents using
cyclopentanone as solvent.
Results
Coupling Reagents
Overall, the results depicted in Table 1 shows that T3P and however, prolonged heating led to degradation and the
HATU were good choices for the formation of thioesters across formation of multiple side products in all three reactions.
all four test reactions and were compatible with a broad range Heating under µwave conditions was considered and reaction 3
of solvents. T3P gave good conversions with most solvents, with was investigated, heating at 130 °C for 8 minutes. Only 22%
the exception of ethyl acetate and in one case dimethyl conversion to product was observed with 21% unreacted thiol
carbonate (DMC) (reaction 4).
and multiple side products detected. Reaction 3 was also
HATU gave the most rapid conversions overall with the majority carried out at room temperature which gave just 4% conversion
of aryl thiol reactions (reactions 1 and 2) proceeding to >90% after 12 h, Table 2. No further work was carried out using
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 4 of 8
COMMUNICATION
Journal Name
DABAL-Me3 in acid-thiol reactions. The possibility of employing potential reactivity and, after initial scoping work,
View Article Online
methyl esters of the carboxylic acid test substrates was cyclopentanone was shown to react withDDOAIB: 1A0L.1-0M39e/3C.9ItGwC0a0s3n5o5Jt
subsequently examined instead, (vide infra). In conclusion, possible to track reaction progress by HPLC past 8 h due to
none of the alternative reagents investigated proved to be increased reaction viscosity and the formation of precipitate.
applicable for forming thioesters from carboxylic acids.
Reactions were run for 24 h at room temperature before being
diluted, filtered, and analysed by HPLC.
Reaction
%
%
%
%
Conversion a
Conversion b
Conversion c
Conversion d
Solvent
% Conversion
Reaction 7
79%
58%, *51%
7%
% Conversion
Reaction 8
32%
22%, *25%
0%
1
2
3
4
36%
29%
44%
7%
17%
11%
63%
9%
n/a
n/a
22%
n/a
n/a
n/a
4%
CPME
2-MeTHF
DMF
n/a
DCM
19%
1%
Table 2. DABAL-Me3 mediated thioester formation. % Conversion to product
determined by HPLC assay. a Heated under reflux conditions for 30 mins. b Heated
under reflux conditions for 12 h. c Heated under µwave conditions in a sealed tube
at 130 °C for 8 min. d Stirred at room temperature for 24 h.
CH3CN
23%
0%
Table 3. HPLC conversion after 24 h for DABAL-Me3 ester reactions 7 and 8.
*Isolated yield after column chromatography.
DABAL-Me3 Methyl Ester Substrates
Analysis of the DABAL-Me3 reactions showed slow reaction
progress but a clean conversion to product for reaction 7, Table
3, analogous to the cleaner conversions observed for DABAL-
Me3 reaction 3, Table 2. The higher % conversions of reactions
3 and 7 may be explained by the inherent extra stability of alkyl-
alkyl thioesters over their aryl analogues.29 CPME and 2-MeTHF
outperformed DMF and DCM in terms of percentage conversion
to product. Reaction 8 did not perform as well and gave poor
conversions. DABAL-Me3 did not have general compatibility to
the reactions investigated but may provide alternative synthetic
pathways for alkyl thioester formation from a methyl ester if
further optimised.
As an aside to the main solvent-reagent investigation, a number
of experiments were conducted employing DABAL-Me3 and
methyl ester protected carboxylic acids to form thioesters
(Scheme 2).
Reaction 5: Aryl Thiol - Alkyl Acid
O
SH
S
1
O
O
0.5 eq DABAL-Me3, 2-MeTHF
RT, 12 H
Reaction 6: Aryl Thiol - Aryl Acid
O
O
SH
Solvents
S
2
O
0.5 eq DABAL-Me3, 2-MeTHF
RT, 12 H
Having analysed the performance of thioester coupling
reagents, Table 1, solvent performance was then rated in terms
of percentage conversions for each of these coupling reagents
and reaction classes. CH3CN outperformed both DMF and DCM
and both of these solvents of concern can be readily replaced
with CH3CN or other greener alternatives such as DMC or
cyclopentanone.13 Ethyl acetate gave moderate to good
conversions but performed poorly when used with T3P. CPME
Reaction 7: Alkyl Thiol - Alkyl Acid
O
O
O
SH
S
0.5 eq DABAL-Me3, 2-MeTHF
RT, 12 H
3
Reaction 8: Alkyl Thiol - Aryl Acid
O
showed
a general applicability, except when used in
O
O
conjunction with HATU which should be avoided due to poor
solubility of HATU in CPME and the formation of oily
precipitates. 2-MeTHF did not have the same solubility issues
and outperformed CPME when used with HATU.
SH
S
0.5 eq DABAL-Me3, 2-MeTHF
RT, 12 H
4
Scheme 2. Trial DABAL-Me3 reactions using methyl esters.
A water surfactant mixture (2 wt.% TPGS 750M) was trialled
using conditions reported by Lipschutz et al.22 Reactions 1 and
3 were initially examined using HATU, T3P, EDC-HCl and CDI as
coupling reagents and three equivalents of 2,6-lutidine base.
Unfortunately, none of the systems gave >10% conversion.
Increasing the system’s concentration did not improve
conversion nor did doubling the amount of coupling reagent
used. No further work was carried out using water/surfactant
mixtures.
It was demonstrated that alkyl thiols could be converted to
product overnight at room temperature using 0.5 equivalents
of DABAL-Me3 using CPME as solvent (reaction 7: 79%, reaction
8: 32%). Aryl thiols appeared to be incompatible with these
reaction conditions, giving <5% conversion to product. Heating
did not effectively increase conversion and led to product
degradation. Therefore, DABAL-Me3 appeared to be a potential
candidate for only alkyl thiol coupling reactions. Solvent
screening reactions were trialled using a reduced number of
solvents. DMC and ethyl acetate were discounted due to
Overall, CH3CN and cyclopentanone gave the best general
applicability across reactions 1-4 and cyclopentanone, scoring
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 8
Green Chemistry
Please do not adjust margins
Journal Name
COMMUNICATION
higher in terms of its green chemistry evaluation,13 is thus of integrin inhibitors.31 Reaction progress was monitored by
View Article Online
considered the optimum solvent for the thioester reactions HPLC and the majority of reactions had rDeOacI:h1e0.d10c3o9m/Cp9GleCt0io0n35b5yJ
screened.
12 h. Aqueous workups were initially considered but due to
hydrolysis concerns these were instead replaced with a simple
removal of cyclopentanone in vacuo, followed by purification of
the crude materials by silica gel chromatography. See ESI for
details.
Lastly, an alternative solvent system was investigated using
acetonitrile on a 10.0 mmol scale. Upon reaction completion
the acetonitrile was extracted with heptane in which the target
compounds were soluble. Passing the heptane through a short
plug of silica removed any polar impurities with ease (Table 4,
entry 13).
Optimum Conditions
Employing T3P as coupling reagent in cyclopentanone gave
good conversion across the four classes of reactions explored,
giving >90% conversion for both aryl thiol reactions 1 and 2 and
85% and 89% conversion for reactions 3 and 4 respectively (Fig.
4). As such, this solvent-reagent combination was explored in
more detail. Combinations of CH3CN/ethyl acetate with HATU
were also considered as they gave more rapid conversions and
in some cases better conversions than T3P (see ESI for details).
However, HATU is much less green according to the criteria
used in the GSK reagent selection guide.12 CH3CN has far fewer
issues than DCM or DMF and is one of the least problematic
dipolar aprotic solvents according the GSK solvent selection
guide criteria having an “amber” rating.13 Cyclopentanone,
whilst not a particularly common solvent, did score “green”
according to the same criteria.13 CDI, although originally
considered to be more green than T3P,12 was not chosen as the
optimum reagent. The reagent guides were always intended to
be “living documents”, and updated as additional information
became available.12 One such example of this additional
information is imidazole now having a H360D phrase.30 As such,
the score for CDI has been reassessed as “red” according to the
GSK reagent selection guide criteria for amide bond formation,
of which an up to date version is included in the ESI.
Overall, the building blocks were successfully synthesised in
moderate to excellent yields using the T3P-cyclopentanone
solvent-reagent combination and demonstrates the general
applicability of the system.
Ent
ry
Compou Product
nd
Isolat
ed
Yield
O
1
2
3
5
72%
S
76%a
80%
O
6
S
S
Cyclopentanone - T3P
100
O
O
7
N
O
80
Reaction 1: Ary
Thiol - Alkyl Ac
O
60
Cl
Reaction 2: Ary
Thiol - Aryl Acid
4
5
8
95%
92%
S
40
Reaction 3: Alky
Thiol - Alkyl Ac
Cl
20
Reaction 4: Alky
Thiol - Aryl Acid
O
0
O
N
S
9
0
2 4 6 8 10 12 14 16 18 20 22 24
Hours
O
Fig. 4 Conversion curve for cyclopentanone T3P across test reactions 1-4.
Building Blocks
S
N
N
Due to the interest of the pharmaceutical industry in the
synthesis of thioester functionalised molecules, a number of
building-block like compounds were chosen to exemplify the
T3P-cyclopentanone reagent-solvent combinations’ general
applicability (Table 4). The building blocks include compound 10
which is of importance to GSK and the University of Nottingham
for their ongoing collaborative investigation into the synthesis
6
10
61%
O
O
O
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 6 of 8
COMMUNICATION
Journal Name
Use of a water surfactant mixture as reaction soVlvieewnAtrtidcliedOnnlionet
give appreciable conversion to product DwOhI:ic1h0.1m03a9y/Cb9eGCd0u0e35t5oJ
general system incompatibility such as product hydrolysis.
The general applicability of the T3P-cyclopentanone reagent-
solvent combination was further demonstrated by successfully
applying these conditions to the synthesis of a number of
pharmaceutically relevant building block-like molecules where
the target molecules were produced in moderate to excellent
yields.
Alternative reagent DABAL-Me3 showed limited applicability in
this study when used directly with carboxylic acids and none of
the heterogeneous reagents examined demonstrated
successful conversions to product. DABAL-Me3 showed some
limited application in the conversion of alkyl thiols to thioesters
when using methyl esters as starting materials and may be of
interest when protection/deprotection strategies are being
considered.
O
7
11
9%b
N
S
N
O
S
8
9
12
13
66%
77%
S
Br
O
Br
N
S
O
O
Overall, T3P and cyclopentanone appear to be a practical
reagent-solvent combination for the synthesis of thioesters.
S
N
O
10
11
14
15
43%
71%
Conflicts of interest
There are no conflicts to declare.
O
Cl
S
Acknowledgements
Cl
The authors would like to thank GSK for postdoctoral funding for this
study and Dr. Nicholas Bennett for his helpful discussions during
manuscript preparation. We would also like to thank the Licence
Group for the kind use of their tube furnace.
O
12
13
16
1
55%
96%
S
O
N
H
O
S
Notes and references
O
1.
2.
A. Parthasarathy, W. Buckel and D. M. Smith, The FEBS
Journal, 2010, 277, 1738-1746.
Z. Li, J. M. Dilger, V. Pejaver, D. Smiley, R. J. Arnold, S. D.
Mooney, S. Mukhopadhyay, P. Radivojac and D. E.
Clemmer, Int. J. Mass Spectrom., 2014, 368, 6-14.
X.-L. Liu, Y. Shi, J. S. Kang, P. Oelschlaeger and K.-W. Yang,
ACS Med. Chem. Lett., 2015, 6, 660-664.
H. Tokuyama, S. Yokoshima, T. Yamashita, L. Shao-Cheng,
L. Leping and T. Fukuyama, J. Braz. Chem. Soc., 1998, 9,
381-387.
H. Tokuyama, S. Yokoshima, S.-C. Lin, L. Li and T.
Fukuyama, Synthesis, 2002, 2002, 1121-1123.
E. L. Myers and R. T. Raines, Angew. Chem., Int. Ed., 2009,
48, 2359-2363.
A. M. Royer, M. Salomone-Stagni, T. B. Rauchfuss and W.
Meyer-Klaucke, J. Am. Chem. Soc., 2010, 132, 16997-
17003.
T. Chatterji, M. Kizil, K. Keerthi, G. Chowdhury, T. Pospísil
and K. S. Gates, J. Am. Chem. Soc., 2003, 125, 4996-4997.
C.-T. Chen, J.-H. Kuo, V. D. Pawar, Y. S. Munot, S.-S. Weng,
C.-H. Ku and C.-Y. Liu, J. Org. Chem., 2005, 70, 1188-1197.
Reaxys Search as of 03/12/2018).
Table 4. Building Blocks synthesised using optimised thioester formation
conditions. a Yield by 1H-NMR using mesitylene as internal standard. b Conversion
to product by HPLC.
3.
4.
Conclusions
In conclusion, a number of solvents and coupling reagents for
the formation of thioester bonds were evaluated and a general
guide for the selection of solvent/reagent combinations for
their formation has been created.
A combination of T3P and cyclopentanone provided the best
balance of sustainability and general applicability across four
thioester reaction classes and outperformed CDI in terms of
compatibility
DCM and DMF can effectively be replaced with greener
alternatives, and greener coupling reagents such as T3P can be
used to replace DCC-DMAP. HATU was shown to be a good
reagent choice for the synthesis of thioesters giving the most
rapid conversion to product, but it is considered to be less green
than T3P.
5.
6.
7.
8.
9.
10.
11.
B. Basu, S. Paul and A. K. Nanda, Green Chem., 2010, 12,
767-771.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 8
Green Chemistry
Please do not adjust margins
Journal Name
COMMUNICATION
12.
J. P. Adams, C. M. Alder, I. Andrews, A. M. Bullion, M.
View Article Online
DOI: 10.1039/C9GC00355J
Campbell-Crawford, M. G. Darcy, J. D. Hayler, R. K.
Henderson, C. A. Oare, I. Pendrak, A. M. Redman, L. E.
Shuster, H. F. Sneddon and M. D. Walker, Green Chem.,
2013, 15, 1542-1549.
13.
C. M. Alder, J. D. Hayler, R. K. Henderson, A. M. Redman,
L. Shukla, L. E. Shuster and H. F. Sneddon, Green Chem.,
2016, 18, 3879-3890.
14.
15.
D. S. MacMillan, J. Murray, H. F. Sneddon, C. Jamieson
and A. J. B. Watson, Green Chem., 2013, 15, 596-600.
F. I. McGonagle, D. S. MacMillan, J. Murray, H. F.
Sneddon, C. Jamieson and A. J. B. Watson, Green Chem.,
2013, 15, 1159-1165.
16.
17.
18.
H. Shinkai, K. Maeda, T. Yamasaki, H. Okamoto and I.
Uchida, J. Med. Chem., 2000, 43, 3566-3572.
K. Yamada, M. Satoh, S. Shimura, T. Sasaki, T. Takishima
and K. Shirato, Respiration, 1994, 61, 42-47.
J. T. Suh, J. W. Skiles, B. E. Williams, R. D. Youssefyeh, H.
Jones, B. Loev, E. S. Neiss, A. Schwab and W. S. Mann, J.
Med. Chem., 1985, 28, 57-66.
19.
20.
GSK, Fluticasone propionate product information,
https://au.gsk.com/media/216393/flixonase_nasule_drop
s_pi_003_approved.pdf, (accessed 23rd January, 2019).
J. B. Sperry, C. J. Minteer, J. Tao, R. Johnson, R. Duzguner,
M. Hawksworth, S. Oke, P. F. Richardson, R. Barnhart, D.
R. Bill, R. A. Giusto and J. D. Weaver, Org. Process Res.
Dev., 2018, 22, 1262-1275.
21.
N. Dubois, D. Glynn, T. McInally, B. Rhodes, S. Woodward,
D. J. Irvine and C. Dodds, Tetrahedron, 2013, 69, 9890-
9897.
22.
23.
24.
25.
C. M. Gabriel, M. Keener, F. Gallou and B. H. Lipshutz, Org.
Lett., 2015, 17, 3968-3971.
M. Node and T. Kajimoto, Heteroat. Chem., 2007, 18, 572-
583.
M. Node, K. Kumar, K. Nishide, S.-i. Ohsugi and T.
Miyamoto, Tetrahedron Lett., 2001, 42, 9207-9210.
X.-D. Yang, X.-H. Zeng, Y.-H. Zhao, X.-Q. Wang, Z.-Q. Pan,
L. Li and H.-B. Zhang, J. Comb. Chem., 2010, 12, 307-310.
M. A. Zolfigol, Tetrahedron, 2001, 57, 9509-9511.
K. V. N. S. Srinivas and B. Das, J. Org. Chem., 2003, 68,
1165-1167.
26.
27.
28.
29.
30.
H. Márquez, A. Plutín, Y. Rodríguez, E. Perez and A. Loupy,
Synth. Commun., 2000, 30, 1067-1073.
P. J. Bracher, P. W. Snyder, B. R. Bohall and G. M.
Whitesides, Orig. Life Evol. Biospheres, 2011, 41, 399-412.
Sigma Aldrich, Imidazole SDS,
https://www.sigmaaldrich.com/MSDS/MSDS/DisplayMSD
SPage.do?country=GB&language=en&productNumber=I2
399&brand=SIAL&PageToGoToURL=https%3A%2F%2Fww
w.sigmaaldrich.com%2Fcatalog%2Fproduct%2Fsial%2Fi23
99%3Flang%3Den, (accessed 21st January, 2019).
J. Adams, E. C. Anderson, E. E. Blackham, Y. W. R. Chiu, T.
Clarke, N. Eccles, L. A. Gill, J. J. Haye, H. T. Haywood, C. R.
Hoenig, M. Kausas, J. Le, H. L. Russell, C. Smedley, W. J.
Tipping, T. Tongue, C. C. Wood, J. Yeung, J. E. Rowedder,
M. J. Fray, T. McInally and S. J. F. Macdonald, ACS Med.
Chem. Lett., 2014, 5, 1207-1212.
31.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Green Chemistry
Page 8 of 8
View Article Online
DOI: 10.1039/C9GC00355J
A table of contents entry image
4 x 8 cm image
Original Size
A solvent-reagent selection guide has been developed for the synthesis of thioesters
from more sustainable solvents and coupling reagents.