Product selectivity in the electroreduction of thioesters

Article abstract of DOI:10.1016/j.tet.2004.12.050

The electroreduction of differently substituted aromatic and aliphatic thioesters (RCOSR′) led to regioselective reactions depending on the nature of the substituents. Thus, the cleavage between the carbonyl group and the SR′ group afforded α-diketones an

Full text of DOI:10.1016/j.tet.2004.12.050

Tetrahedron 61 (2005) 1709–1714
Product selectivity in the electroreduction of thioesters
a
M. Weıwer, S. Olivero and E. Dun˜ach
a
a,b,
*
¨
a
ˆ ` ´
Laboratoire Aromes, Syntheses et Interactions, Universite de Nice-Sophia Antipolis, Parc Valrose, 06108 Nice cedex 2, France
´
Laboratoire de Chimie Bio-organique, UMR CNRS 6001, Universite de Nice-Sophia Antipolis, Parc Valrose, 06108 Nice cedex 2, France
b
Received 25 October 2004; revised 17 December 2004; accepted 21 December 2004
Abstract—The electroreduction of differently substituted aromatic and aliphatic thioesters (RCOSR0) led to regioselective reactions
depending on the nature of the substituents. Thus, the cleavage between the carbonyl group and the SR0 group afforded a-diketones and the
cleavage between the RCOS group and the alkyl R0 group afforded thiocarboxylic acids selectively.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
easily reduced and can be considered as a good alternative
to examine the reductive coupling of such carboxylic acid
derivatives. A few studies report on the electroreduction
of thioesters with a carbonyl-sulfur cleavage reaction of
the RCOSR0 group to afford a thiolate anion and an acyl
radical.7–10 The aromatic acyl radical could be further
trapped intramolecularly by a reaction on a double bond in a
nickel-catalysed reaction,8 or couple to afford diarylacetyl-
ene11 or rearranged compounds.12 To our knowledge, no
study involving the electroreductive homocoupling of
thioesters has yet been reported. We present here our results
on the electrochemical reduction of a series of aliphatic and
aromatic thioesters and on the influence of the thioester
substitution on the observed reactivity and on the product
selectivity.
Reductive coupling of carboxylic acid derivatives consti-
tutes a powerful method of C–C bond formation. In this
context, the chemical reductive coupling of acid chlorides
and acid cyanides (RCOCl, RCOCN) mediated by SmI2 has
been reported to selectively promote a-diketone formation
in good yields.1,2 For less activated esters, the use of alkali
metals for their reductive coupling is well known and leads
mainly to the acyloin condensation.3
Electrochemistry has been reported as an interesting
alternative for the synthesis of a-diketones in good yields
from the samarium-catalysed reductive coupling involving
aromatic esters.4 This methodology avoids the use of
dangerous alkali metals and of other stoichiometric
reducing agents. However, aliphatic esters remain very
difficult to reduce either by chemical or by electrochemical
methods because of their low reduction potentials (around
K3.0 V vs SCE).5 Their reduction generally affords an
unselective reaction providing a variety of products such as
carboxylic acids, aldehydes, alcohols or ethers.5 An
electrochemical system based on the use of magnesium as
anode and cathode in THF with lithium perchlorate as the
supporting electrolyte has been reported to promote
aliphatic a-diketone formation from aliphatic esters in
moderate to good yields but with low faradic efficiencies
(!40%).6
2. Results and discussion
2.1. Cyclic voltammetry studies
Different aliphatic and aromatic thioesters 1a–1k were
prepared in 74–86% yields from the corresponding
carboxylic acids and the thiols using the Steglich method
(DCC/DMAP).13 The different thioesters were chosen in
order to get all the possible combinations of alkyl and aryl
substituents (ArCOSAlk, ArCOSAr0, AlkCOSAr,
AlkCOSAlk0). Two bis-thioesters 1d and 1k were also
considered in order to better examine the possibilities of an
intramolecular reductive cyclisation.
The thioester functionality, as compared to esters, is more
The reduction potentials of four selected thioesters 1b, 1g,
1h and 1i are summarised in Table 1. Irreversible reduction
peaks were obtained by cyclic voltammetry, as presented in
Figure 1. Important variations in the reduction potentials,
Keywords: Thioesters; Electroreductive homocoupling; a-Diketone;
Thioacids.
* Corresponding author. Tel.: C33 492076142; fax: C33 492076141;
e-mail: dunach@unice.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.050

¨
M. Weıwer et al. / Tetrahedron 61 (2005) 1709–1714
1710
Table 1. Reduction potentials of different thioesters in DMF, n-Bu4NBF4
(0.1 M) at 25 8C
esters after in situ esterification of the crude reaction
mixtures with methyl iodide for ease of analysis. The
thiolates (RSK) present in the reaction medium were also
converted into the corresponding methyl sulfides by this
treatment.
Thioesters
E (V) versus Ag/AgCl
1b
1g
1h
1i
n-PrCOSMe
n-BuCOSPh
PhCOSEt
K2.7
K2.3
K1.9
K1.8
PhCOSTol
The amides 5 were formed as the major products in some
electrolyses. The formation of 5 can be issued from a
coupling reaction involving the solvent, DMF.
from K1.8 to K2.7 V versus Ag/AgCl were observed,
according to the nature of the substituents.
In some reactions we could also identify the presence of
carboxylic acids 6 in low ratios. The presence of carboxylic
acids from the electroreduction of aryl thioesters has already
been reported,7 the authors claiming their formation by
the presence of dioxygen. The formation of carboxylic acids
was a non-expected process in our case because the
electrolyses were run under a nitrogen atmosphere and
with a degassed DMF solution, in order to avoid the
presence of dioxygen.
In the case of thioesters 1g, 1h and 1i, an oxidation peak was
observed at around K0.5 V versus Ag/AgCl. This oxidation
peak could be attributed to the oxidation of the RSK
moieties, formed from the reductive cleavage of the
thioester groups, according to the reported thiolate oxidation
by Sawyer.14
2.2. Preparative-scale electrolyses
Table 2 summarises the results obtained in the electro-
reduction of thioesters 1a–1i.
Preparative-scale electroreductions were carried out with
compounds 1a–k (0.08 M) in freshly distilled DMF
solution, in a single-compartment cell in the presence of a
magnesium anode and a carbon fibre cathode, under a
nitrogen atmosphere. Lithium perchlorate (LiClO4, 0.04 M)
was used as the supporting electrolyte. Different C–C
coupling products such as a-diketones 2 and a-ketols 3 were
obtained, as well as cleavage compounds such as thioacids
4, amides 5 and carboxylic acids 6 (Scheme 1).
We first examined the reactivity of aliphatic thioesters
AlkCOSAlk0 such as 1a–1d. The electroreduction of ethyl
thioheptanoate 1a led after 2.2 F to a complete conversion
with the formation of the thioacid 4a as the main compound
in 78% yield (isolated as methyl thioheptanoate after
methylation with MeI), together with minor amounts of
a-diketone 2a (5%) and a-ketol 3a (4%). The S–Et cleavage
reaction leading to 4a was very selectively favoured when
compared with the CO–S cleavage leading to the C–C
coupling reaction of the acyl moiety to afford 2a or 3a. The
ratio between S–Alk0 cleavage versus C–C coupling was of
90/10.
a-Diketones 2 and a-ketols 3 are issued from the reductive
coupling of the acyl moiety of the reduced thioesters, with
loss of the thiolate groups (RSK). Since a-diketones are
more easily reduced than the starting thioesters, compounds
2 can be reduced to the corresponding a-ketols 3 in situ.
The reactivity of methyl thiobutyrate 1b and ethyl 10-thio-
undecenoate 1c was similar to that observed for 1a and
afforded also selectively the thiocarboxylic acids 4b and 4c
The 0reduction of 1 can also occur with the cleavage of the
S–R bond to afford the thioacids 4 after hydrolysis. The
thioacids were analysed as their corresponding methyl
Figure 1. Cyclic voltammograms of different thioesters (5 mM) at a glassy carbon electrode in DMF (n-Bu4NBF4 0.1 M) at 25 8C, scan rateZ100 mV sK1
.
Scheme 1.

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M. Weıwer et al. / Tetrahedron 61 (2005) 1709–1714
1711
Table 2. Electroreduction of thioesters 1a–i in DMF/LiClO4 solutionsa
Thioester
F
Diketone 2 (%)
Ketol 3 (%)
Thioacid 4 (%)
Amide 5 (%)
Carboxylic acid 6 (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
n-HexCOSEt
n-PrCOSMe
2.2
2.2
2.7
4.2
2.3
2.3
2.1
2.1
2.1
5
5
3
—
—
—
—
63
59
4
78
53
74
71
—
—
—
—
—
4
—
5
—
9
10
8
—
—
—
5
Trace
—
Trace
—
—
—
20
20
CH2:CH(CH2)8COSEt
EtSCO(CH2)3COSEt
n-HexCOSTolb
C9H19COSPhb
n-BuCOSPhb
5
32
32
28
—
—
PhCOSEt
PhCOSTolb
3
1
a Yields determined by H NMR and by the mass balance of the extracted crude mixtures.
b Quantitative formation of TolSMe or PhSMe was observed after electrolysis and methylation (K2CO3/MeI, DMF) of the reaction medium.
in 53 and 74% yields, respectively issued from the S–Alk0
cleavage process. In the case of 1c, the presence of a
terminal double bond on the aliphatic chain did not allow
the formation of any intramolecular radical cyclisation
products or intermolecular reaction indicating that an
anionic intermediate AlkCOSK was most possibly formed.
yields, respectively. The thiolate moieties that were formed
during the electrolysis of 1e, 1f and 1g (TolSKand PhSK,
respectively) were isolated as methyl aryl sulfides ArSMe
after methylation of the crude reaction mixtures in almost
quantitative yields. In contrast with the behaviour observed
for the aliphatic thioesters 1a–1d, a chemoselective CO–S
cleavage occurred with these AlkCOSAr thioesters 1e–1g.
In order to favour the possibility of an acyl C–C
homocoupling with aliphatic AlkCOSAlk0 type thioesters
by an intramolecular reaction, the electroreduction of the
bis-thioester 1d was examined. This compound was
expected to form the 5-membered ring cyclopentane-1,2-
diketone 2d or the corresponding ketol 3d. However, the
electrolysis of 1d led, after 4.2 F, mainly to the bis-thioacid
4d in 71% yield. No formation of the a-diketone or of the
a-ketol could be observed.
To increase the possibilities of C–C coupling reaction of the
acyl moieties, the electrolysis of 1e was run at a higher
concentration (0.32 M instead of 0.08 M). However, the
amide 5e was again obtained in a similar yield.
We further studied the reactivity of aromatic thioesters of
type ArCOSAlk and ArCOSAr, such as 1h and 1i,
respectively. A selective C–C reductive homocoupling of
the acyl moieties leading to a-diketones 2h and 2i occurred
in 63 and 59% yields, respectively. The corresponding
a-ketols 3h and 3i (20%) were also obtained. In these cases,
the reduction selectively involved the CO–S cleavage. No
S–Alk or S–Ar cleavage leading to the formation of
thioacids 4h or 4i was observed.
In order to evaluate if these thioacids could be isolated
in good yields as such without further methylation,
10-undecenoic thioacid 4c was extracted after the electro-
lysis of 1c using degassed diethyl ether and it could be
isolated in 61% yield. Therefore, the electrochemical
transformation of aliphatic thioesters into their correspond-
ing thioacid analogues can constitute a novel alternative
method of deprotection. In conventional chemistry, strong
acidic (fluorhydric acid, triflic acid),15 basic16 or reductive
(Na, K)17 media are usually required for this deprotection.
From a preparative point of view, we can conclude that the
products obtained in the electroreduction of thioesters
RCOSR0 strongly depend on the aromatic or aliphatic
nature of the two substituents R and R0. Upon reduction, the
all-aliphatic thioesters AlkCOSAlk0 led selectively to the
formation of thioacids involving a S–R0 cleavage reaction.
The all-aromatic thioesters ArCOSAr0 led selectively to the
formation of a-diketones and a-ketols resulting from the
cleavage of the CO–S bond with a further C–C coupling of
the acyl moieties. Thioesters of type ArCOSAlk led also to
the selective formation of a-diketones and a-ketols by the
same process. Thioesters of type AlkCOSAr led to the
We then carried out the electroreduction of aryl aliphatic
thioesters of type AlkCOSAr such as 1e, 1f and 1g, bearing
an aromatic group linked to the S atom in order to disfavour
the S–R cleavage process. The electoreduction of these
thioesters did not lead to the S–Ar cleavage compounds nor
to the coupling products of type 2 and 3. The only isolated
compounds were amides 5e, 5f and 5g, in 32, 32 and 28%
Scheme 2.

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M. Weıwer et al. / Tetrahedron 61 (2005) 1709–1714
1712
Scheme 3.
formation of amides resulting from a reaction with DMF
and involving the CO–S selective reductive cleavage.
and the treatment of the crude electrolysis mixture with MeI
yields the corresponding methyl thioesters.
To explain the formation of amides 5 obtained in particular
for RCOSAr type thioesters, the reaction with the DMF
solvent has to be considered. When R is an aliphatic group,
the acyl radicals B are highly unstable. These aliphatic acyl
radicals have been reported to have half-lifes of about
10K5–10K6 s at 298 K,19 and to decompose thermally with
loss of carbon monoxide to form an alkyl radical R%. In the
electrolytic medium, the R% radicals or the RK anion issued
from the reduction of R% could react with DMF or its
reduced species to afford, the corresponding amides 5,
according to Scheme 4. There is some literature evidence
that amides can be formed from DMF in the presence of RK
nucleophiles, in a redox process.20 Alternatively, the
reaction of RK with DMF can lead to the aldehyde and
Me2NK, which could form the corresponding amide 5 with
the starting thioester (Scheme 4).
2.3. Mechanistic considerations
The study of the reactivity of the differently substituted
thioesters RCOSR0 indicated that the first one-electron
reduction of the thioester group was followed by two
different main pathways. Both CO–S and S–R0 cleavage
processes should be considered from a first common radical
anion intermediate A (Scheme 2). Following path (a), the
cleavage between the carbonyl moiety and the SR0 group
takes place, to form an acyl radical B and a thiolate anion.
Such a process has already been described by Webster et al.
in the case of aromatic thioesters.7
Following path (b), the cleavage of the radical anion A
occurs between the RCOS moiety and the R0 group. The
generated R0 radicals can be further reduced and protonated
to R0H, or dimerised. The thionocarboxylate and the
thiocarboxylate species C are in equilibrium. After
hydrolysis, the thiocarboxylic acids 4 are formed. In order
to indirectly confirm the formation of R0 species, the
electroreduction of dodecyl thioacetate 1j (CH3COSC12-
H25) was carried out. At the end of the electrolysis,
dodecane as well as a low amounts of tetracosane
(C24H50) were obtained in 80% yield. This result confirmed
that AlkCOSAlk0 type thioesters were reduced following
path (b) in Scheme 2.
Scheme 4.
Considering the formation of the different products 2–6,
the formation of C–C coupling compounds 2 and 3 should
follow pathway (a) of Scheme 2. The formation of
a-diketones 2 can be explained from the homocoupling of
two acyl units B. If a-diketones 2 are formed in the
electrolysis medium, they should be rapidly reduced,
because of their low reduction potentials,18 and ketols 3
should be obtained after hydrolysis (Scheme 3). Alterna-
tively, the direct homocoupling of the radical anion A
should also lead to 2. In this last case, as shown in Scheme 3,
a dithio dialcoolate D can be formed and trapped as a
magnesium diolate in the presence of Mg2C ions issued
from the consumable Mg anode. In the hydrolysis step, the
a-diketones 2 and the corresponding thiols are formed.
To get some more insight into the reactivity of RCOSAr
type thioesters, the electroreduction of the bis-thioester 1k
was carried out (Scheme 5). Complete conversion of 1k was
attained after 4.3 F. The treatment of the crude reaction
mixture with MeI led to the isolation of only methyl phenyl
sulfide. No cyclic a-diketone 2j issued from intermediates E
or F was obtained. A rapid decarbonylation of F leading to a
propyl diradical G and further cyclisation, dimerisation,
reduction and/or protonation affording volatile hydro-
carbons could explain the observed results. No amide
function was identified in 1H or 13C NMR experiments and
thus the formation of hydrocarbons issued from G seems to
be favoured.
The formation of thioacids 4 can be explained by path (b) in
Scheme 2. The hydrolysis of C affords directly thioacids 4
The carboxylic acid 6 was obtained as a minor by-product in
3–10% yields in some reactions. Its formation probably

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M. Weıwer et al. / Tetrahedron 61 (2005) 1709–1714
1713
Scheme 5.
involves the reaction of the intermediate acyl radical B with
depending on their stability and on the reaction conditions,
affording either an amide (1e–g) or an a-diketone (1h–i).
dioxygen or with O2%K as it has already been proposed.7,21
For AlkCOSAlk0 type thioesters 1a–d and 1j, thioacids were
selectively obtained by the cleavage of the S–Alk0 bond
following path (b) of Scheme 2. AlkCOSAr type thioesters
such as 1e, 1f and 1g presented a different reactivity, which
could be explained by a first AlkCO–SAr cleavage
according to path (a) in Scheme 2 and further decarbonyla-
tion and reaction with DMF (Scheme 4). A selective CO–S
cleavage occured also with ArCOSAlk and ArCOSAr0 type
thioesters such as 1h and 1i. However, in these cases, the
aromatic acyl radical of type B is stable enough to undergo
dimerisation to 2 and/or 3. The decarbonylation and further
reaction with DMF did not occur. Table 3 summarises the
results obtained in the different electrolyses, from the point
of view of the selectivity of the CO–S versus S–R0 cleavage,
for example, path (a) or b) followed by the first formed
radical anion A in Scheme 2.
3. Conclusion
In conclusion, the electroreduction of thioesters may lead to
highly regioselective cleavages depending on the nature of
the different substituents. In the case of ArCOSAlk
substrates, their electroreduction can constitute an alterna-
tive method of C–C bond formation to provide aromatic
a-diketones and a-ketols. The electrochemical method can
also selectively afford aliphatic thioacids from aliphatic
thioesters in good yields. Finally, upon electroreduction in
DMF, thioesters of type AlkCOSAr undergo chemoselec-
tive process affording the corresponding AlkCONMe2
amides.
4. Experimental
Table 3. Cleavage between the carbonyl group and the SR0 group versus
cleavage between the RCOS group and the R0 group in the electroreduction
of different RCOSR0 thioestersa
4.1. Cyclic voltammetry
Cleavage RCO-SR0
versus RCOS-R0
Cyclic voltammetry measurements were conducted with a
potentiostat/galvanostat EG&G model 273A using a three
electrode arrangement at room temperature. The auxiliary
electrode consisted of a Pt wire and the working electrode
was a glassy carbon disc. Ag/AgCl was used as the reference
electrode. Freshly distilled DMF was used as the solvent and
tetrabutyl ammonium tetrafluoroborate n-Bu4NBF4 (0.1 M)
as the supporting electrolyte.
Thioester
Main product
type
9
1a
1b
1c
1d
1j
1e
1f
1g
1k
1h
1i
n-HexCOSEt
n-PrCOSMe
22:78
26:74
22:78
15:85
15:85
100:—
100:—
100:—
100:—
100:—
100:—
>
>
>
=
CH2:CH(CH2)8COSEt
EtSCO(CH2)3COSEt
CH3COSC12H25
n-HexCOSTol
C9H19COSPh
RCOSH
>
>
>
;
9
=
RCONMe2
RCOCOR
;
n-BuCOSPh
PhSCO(CH2)3COSPh
PhCOSEt
PhCOSTol
4.2. Typical procedure for the electroreduction of
thioesters
ꢀ
a The ratio of cleavage between the carbonyl group and the SR0 group was
obtained by adding the yields of diketone 2, ketol 3, amide 5 and
carboxylic acid 6 or by using R0SMe yields. The ratio of cleavage between
the RCOS group and the R0 group was obtained according to the yields of
thioacid 4.
In a typical procedure, a single-compartment cell containing
carbon fiber as the circular cathode and magnesium rod as
the sacrificial anode was purged with nitrogen. LiClO4
(1 mmol), freshly distilled DMF (25 mL) and the thioester
(2 mmol) were added. The mixture was then degassed with
nitrogen. The electrolysis was run at 60 mA under constant
intensity (current density of 0.3 A/dm2) and was followed
by gas chromatography. After the total conversion of the
starting thioester, usually around 2.2 F, the crude mixture
was transferred under nitrogen to a Schlenk containing
potassium carbonate (2 mmol). Methyl iodide (4 mmol) was
added and the mixture was heated at 40 8C overnight. The
reaction mixture was quenched with HCl 1 M and extracted
Table 3 clearly indicates that ‘all-aliphatic’ thioesters of
type AlkCOSAlk0 (1a–d and 1j) undergo a selective S–Alk0
cleavage reaction, with selectivities of around 80%. In
contrast, all the other thioesters possessing one or two aryl
groups such as 1e–1i and 1k react exclusively through the
cleavage of the CO–S bond, following path (a) in Scheme 2.
The intermediates formed (B, D, E or F) can then evoluate

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M. Weıwer et al. / Tetrahedron 61 (2005) 1709–1714
1714
9. Loginova, N. F.; Mairanovskii, V. G. Zhurnal Obshchei
Khimii 1974, 44, 1838.
with diethyl ether. The organic layers were washed with
water, dried with MgSO4 and the solvent was evaporated.
The products were analysed by GC, mass spectrometry and
NMR and the data were compared with authentic samples.
10. Ozaki, S.; Matsui, E.; Yoshinaga, H.; Kitagawa, S.
Tetrahedron Lett. 2000, 41, 2621.
11. Falsig, M.; Lund, H. Acta Chem. Scand. Ser. B 1980, B34, 585.
12. Praefcke, K.; Weichsel, C.; Falsig, M.; Lund, H. Acta Chem.
Scand. Ser. B 1980, B34, 403.
13. Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 46, 4475.
14. Howie, J. K.; Houts, J. J.; Sawyer, D. T. J. Am. Chem. Soc.
1977, 99(19), 6323.
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