NHC-catalyzed thioesterification of aldehydes by external redox activation

Article abstract of DOI:10.1039/c2cc17183j

The NHC-catalyzed thioesterification of aromatic or aliphatic aldehydes with a range of thiols was developed in the presence of a stoichiometric amount of an organic oxidant. Among the oxidants examined, phenazine was shown to give the best results in terms of chemical yield and compatibility with thiols.

Full text of DOI:10.1039/c2cc17183j

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COMMUNICATION
NHC-catalyzed thioesterification of aldehydes by external redox
activationwz
Takuya Uno, Tsubasa Inokuma and Yoshiji Takemoto*
Received 18th November 2011, Accepted 16th December 2011
DOI: 10.1039/c2cc17183j
The NHC-catalyzed thioesterification of aromatic or aliphatic
aldehydes with a range of thiols was developed in the presence
of a stoichiometric amount of an organic oxidant. Among
the oxidants examined, phenazine was shown to give the
best results in terms of chemical yield and compatibility with
thiols.
Thioesters are important compounds from both synthetic and
biological perspectives. They have frequently been used as
synthetic intermediates for acyl transfer reactions,1 including
native chemical ligation,2 functional group transformations3
into ketone and aldehyde, and the formation of carbon–
carbon bonds4 as in the aldol and Michael reactions. In
nature, acetyl-CoA, a biologically important thioester, plays
a pivotal role in fatty acid and polyketide biosynthesis.5 To
synthesize such versatile thioesters, various methods have been
developed: (1) condensation6 of carboxylic acid and thiol with
dehydrating reagents, (2) transthioesterification7 of active
carboxylic acid derivatives with thiol, (3) palladium-catalyzed
thiocarbonylation8 of iodoarenes and thiol with carbon
monoxide, and (4) radical-mediated coupling9 of aldehyde
with disulfide or thiol. However, the discovery of efficient
catalytic methods for thioesters remains an important synthetic
challenge in organic chemistry.
On the other hand, N-heterocyclic carbene (NHC)10-
catalyzed redox reactions have been applied to the concise
synthesis of esters11,12 and amides13,14 from aldehydes through
the use of internal or external redox protocols. In contrast,
there have been fewer studies on NHC-catalyzed thioesterifi-
cation. In fact, there have been only two previous reports to
date, in which either cyclopropyl aldehyde11c was used as a
substrate or azobenzene15 was used as an oxidant for the
internal or external redox reaction (Scheme 1). However, each
reaction has its own limitations in terms of substrate scope or
the formation of side-products. In particular, the choice of an
Scheme 1 NHC-catalyzed thioesterification of aldehydes by internal
and external redox activations.
appropriate external oxidant is the key to success in external
redox thioesterification. In this communication, we describe a
new, efficient and practical method for the one-step conversion
of aldehyde into the corresponding thioesters using phenazine
as an external oxidant.
As a model reaction for thioesterification, we examined the
reaction of benzaldehyde 1a and phenylmethanethiol 2a with
catalyst A (10 mol%) and triethylamine (10 mol%) in the
presence of several oxidants (Table 1). The use of oxidants
such as MnO2,12d,e quinone 3a12c,16 and riboflavin 3b,17 which
were used for NHC-catalyzed esterification, gave thioester 4a
in low to moderate yields due to the formation of disulfide 5
(entries 1–3). Other oxidants such as diethyl azodicarboxylate
(DEAD), o-iodoxybenzoic acid (IBX)18 and PhI(OAc)2 gave
disulfide 5 as the major product along with a trace amount of
4a (entries 4–6). We then examined heterocyclic compounds 3c
and 3d as hydrogen acceptors (entries 7 and 8). To our delight,
phenazine 3c was shown to be a sufficiently mild oxidant to
afford the desired product 4a in high yield without formation
of any disulfide.
After establishing the optimized reaction conditions, we
investigated the generality of this thioesterification (Table 2).
A wide range of aryl and heteroaryl aldehydes bearing electron-
donating and electron-withdrawing groups could be used regard-
less of their substituted position, to give the corresponding
thioesters 4b–j in good to high yields (entries 1–9). With regard
to the thiol used, both alkyl and aryl thiols were tolerated under
Graduate School of Pharmaceutical Sciences, Kyoto University,
Sakyo-ku, Kyoto, 606-8501, Japan.
E-mail: takemoto@pharm.kyoto-u.ac.jp; Fax: +81-75-753-4528;
Tel: +81-75-753-4569
w This article is part of the joint ChemCommꢀOrganic & Biomolecular
Chemistry ‘Organocatalysis’ web-theme issue.
z Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc17183j
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1901–1903 1901

Table 1 Screening of oxidantsa
Table 3 Screening of reaction conditions for thioesterification of
aliphaitc aldehydea
Entry
Catalyst
Base
Time/h
Yield of 7ab (%)
1
2
3
A
A
B
B
B
Et3N
DBU
Et3N
DBU
DBU
24
24
24
12
12
55
71
Trace
74
86
4
5c
Entry
Oxidant
Yield of 4ab (%)
Yield of 5b (%)
a
Conditions: 6a (0.3 mmol), 2b (1.1 equiv.), 3c (1.2 equiv.), catalyst A
b
or B (10 mol%), Base (10 mol%), THF (0.5 M), rt. Isolated yields.
c
1
MnO2
3a
21
59
67
Trace
10
Trace
94
6
70
27
23
88
82
90
Trace
33
c
1.5 equiv. of 2b and 3c were used.
2
3d
4
3b, O2
DEAD
IBXe
PhI(OAc)2
3c
5
e
We next explored the thioesterification of aliphatic aldehydes
(Table 3). When the reaction of 3-phenylpropionaldehyde 6a
with an odorless dodecanethiol 2b was carried out under the
same reaction conditions, the yield of 7a significantly decreased
(entry 1). This could probably be attributed to the sluggish
reaction due to the low reactivity of the aliphatic aldehyde.
The use of DBU instead of Et3N improved the chemical yield
from 55 to 71% (entry 2). Replacement of the NHC precatalyst
A by more nucleophilic N-mesityl triazolium salt B, along
with an increase in the amounts of the thiol and base, led to a
further increase in yield, and gave the thioester 7a in 86% yield
(entries 3–5).
6
7f
8
3d
a
Conditions: 1a (0.3 mmol), 2a (1.1 equiv.), oxidant (1.2 equiv.),
b
A (10 mol%), NEt3 (10 mol%), THF (0.5 M), Ar, rt. Isolated yields.
c
d
5.0 equiv. of MnO2 was used. Conditions: 1a (2.0 equiv.),
2a (0.3 mmol), 3b (10 mol%), A (10 mol%), NEt3 (50 mol%), CHCl3,
e
MS4A, O2, rt. 2.0 equiv. of oxidant was used. Run for 6 h.
f
Table 2 Thioesterification of aromatic aldehydesa
We finally applied the optimal reaction conditions to
a variety of aliphatic aldehydes (Table 4). Primary and
secondary alkyl aldehydes bearing functional groups such
as an isolated olefin, ether, and carbamate were converted
into the corresponding thioesters 7b–f in good yields without
any problems (entries 1–5). The reaction of chiral a-amino
aldehyde derivative 6f was accompanied by racemization to
provide the racemic thioester 7f in 79% yield. Although
a,b-unsaturated aldehyde 6g underwent a redox reaction
to give thioester 7g as a major product together with the
Michael adduct in 11% yield, b,b-disubstituted unsaturated
aldehyde 6h only gave the desired product 7h in 83% yield
(entries 6 and 7). In a similar manner, several alkyl and aryl
thiols could be introduced to 3-phenylpropionaldehyde 6a in
good yields (entries 8–12).
Entry
Ar1
R2
Yield of 4b (%)
1
2
3
4
5
6
7
8
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-NO2C6H4
4-MeOCOC6H4
2-Furyl
3-Pyridyl
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
98 (4b)
84 (4c)
90 (4d)
499 (4e)
92 (4f)
83 (4g)
91 (4h)
499 (4i)
68 (4j)
88 (4k)
82 (4l)
72 (4m)
67 (4n)
62 (4o)
57 (4p)
9
Bn
10
11
12
13c
14c
15c
(2-Furyl)methyl
c-Hexyl
tBu
Ph
4-MeOC6H4
4-FC6H4
Ph
Ph
Ph
Ph
In summary, we found that phenazine was the best oxidant
for the NHC-catalyzed direct thioesterification of aldehydes,
and did not lead to the formation of any disulfides. Further-
more, the appropriate combination of a NHC precatalyst and
base (catalyst A/Et3N, catalyst B/DBU) was shown to be
important for the efficient thioesterification of aromatic and
aliphatic aldehydes by redox activation.
Ph
a
Conditions: 1 (0.3 mmol), 2 (1.1 equiv.), 3c (1.2 equiv.), A (10 mol%),
b
c
NEt3 (10 mol%), THF (0.5 M), Ar, rt. Isolated yields. 1.5 equiv. of 2
and 3c, 24 h.
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘‘Advanced Molecular Trans-
formations by Organocatalysts’’ from The Ministry of Education,
Culture, Sports, Science and Technology, Japan.
these conditions, while products 4n–p were obtained in slightly
lower yields even with 1.5 equiv. of both thiols and 3c in the case
of aryl thiols (entries 10–15).
c
1902 Chem. Commun., 2012, 48, 1901–1903
This journal is The Royal Society of Chemistry 2012

Table 4 Thioesterification of aliphatic aldehydesa
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Entry
1
R1
R2
Yieldb (%)
C12H25
Bn
83 (7b)
2
3
71 (7c)
96 (7d)
c-hexyl
C
12H25
4
5
C12H25
80 (7e)
79 (7f)c
Bn
6
7
tBu
tBu
71 (7g)d
83 (7h)
8
9
10
11
12e
PhCH2CH2–
PhCH2CH2–
PhCH2CH2–
PhCH2CH2–
PhCH2CH2–
Bn
91 (7i)
81 (7j)
88 (7k)
63 (7l)
60 (7m)
(2-Furyl)methyl
c-Hexyl
tBu
4-MeOC6H4
a
Conditions: 6 (0.3 mmol), 2 (1.5 equiv.), 3c (1.5 equiv.), B (10 mol%),
b
DBU (10 mol%), THF (0.5 M), Ar, rt. Isolated yields. Racemic
c
d
product was obtained. S-tert-Butyl 3-(tert-butylthio)-2-methyl-
e
phenylpropanethiolate was formed in 11% yield. Run for 24 h.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1901–1903 1903