Tetraethylammonium bromide-catalyzed oxidative thioesterification of aldehydes and alcohols

Article abstract of DOI:10.1002/adsc.201300584

A metal-free, tetraethylammonium bromide-catalyzed oxidative coupling of aldehydes or alcohols with thiophenols or disulfides has been developed. This protocol affords an efficient and inexpensive approach to the synthesis of a wide range of thioesters in high yields. Copyright

Full text of DOI:10.1002/adsc.201300584

COMMUNICATIONS
DOI: 10.1002/adsc.201300584
Tetraethylammonium Bromide-Catalyzed Oxidative
Thioesterification of Aldehydes and Alcohols
Xuebin Zhu,a Yan Shi,a Haibin Mao,a Yixiang Cheng,a and Chengjian Zhua,b,*
a
School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093,Peopleꢀs Republic of China
E-mail: cjzhu@nju.edu.cn
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, Peopleꢀs
Republic of China
Received: July 2, 2013; Revised: September 5, 2013; Published online: November 27, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300584.
Abstract: A metal-free, tetraethylammonium bro-
mide-catalyzed oxidative coupling of aldehydes or
alcohols with thiophenols or disulfides has been de-
veloped. This protocol affords an efficient and inex-
pensive approach to the synthesis of a wide range
of thioesters in high yields.
thetic biology. Not only do they play important roles
in various biological processes,[1] but they are also ver-
satile building blocks for the construction of various
natural products.[2] Inspired by these important scaf-
folds, in the past few years, some significant methods
for producing thioesters have been subsequently de-
veloped. Among these approaches, the thioesterifica-
tions of carboxylic acid derivatives with sulfocom-
pounds are the most common.[3] However, the direct
oxidative thioesterification of aldehydes or alcohols is
still largely elusive. To the best of our knowledge,[4]
the available thioesterifications with aldehydes usual-
ly require the use of azide intermediates,[5] azo-type
radical initiators[6] and carbene catalysts[7] (Scheme 1).
Keywords: metal-free conditions; oxidative cou-
pling; tetraalkylammonium bromides; thioesterifi-
cation
As a category of activated carboxylic acid derivatives, These methods often suffer from limitations, such as
thioesters are very useful in organic synthesis and syn- low scope of the substrates, complex systems, expen-
Scheme 1. Thioesterifications of aldehydes or alcohols.
3558
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3558 – 3562

Tetraethylammonium Bromide-Catalyzed Oxidative Thioesterification of Aldehydes and Alcohols
sive or hazardous reagents. The search for direct oxi- 28% yield was also obtained in the absence of the cat-
dative thioesterifications of aldehydes or alcohols alyst (Table 1, entry 6). Subsequently, we examined
with regard to a simple, practical and general method- the efficiency of a number of oxidants under the cat-
ology is of great importance. As part of our continu- alysis of TBAB as shown in Table 1. It was found that
ing interest in metal-free, organocatalyzed oxidative K2S2O8 was optimal to give the product 3a in 72%
coupling reactions,[8] we wished to develop a simple yield (Table 1, entry 9). The reaction afforded the
and practical protocol to accomplish the thioesterifi- highest yield when performed at 908C. Temperatures
cation with aldehydes or alcohols. The developed lower or higher than that were deleterious to the re-
method has a broad substrate scope, simple reaction action (Table 1, entries 12 and 13).
conditions and gives high yields.
The effect of solvents was also investigated, and
Our initial attempt started with the reaction of 4- DCE was proved to be the optimal solvent. Other sol-
chlorobenzaldehyde 1a and thiophenol 2a in the pres- vents furnished the product in poor yields (see the
ence of T-HYDRO at 908C under an argon atmos- Supporting Information). We further examined sever-
phere (Table 1). To our delight, the reaction could al different tetraalkylammonium salts. It was found
take place under the catalysis of several commonly that TEAB showed the best activity (Table 1,
used metal catalysts, in spite of the low yields entry 17). The use of iodine as catalyst delivered the
(Table 1, entries 1–4). Then, it was found that the re- product with moderate yield (Table 1, entry 16). Fi-
action could be improved by using a tetraalkylammo- nally, the optimal reaction conditions were estab-
nium salt, TBAB, as the catalyst (Table 1, entry 5). A lished: TEAB (10 mol%) and K2S2O8 (2.2 equiv.)
under argon in DCE at 908C for 40 h. The reaction
was scalable, and nearly the same yield was obtained
on a larger scale (Table 1, entry 19).
Table 1. The oxdative thioesterification of 4-chlorobenzalde-
hyde with thiophenol.[a]
With the optimized conditions in hand, the sub-
strate scope of the reaction with aldehydes and thiols
was examined as shown in Table 2. It was found that
a wide range of aromatic aldehydes bearing both elec-
Table 2. Scope of the reaction with aldehydes and thiols.[a]
Entry Catalyst
Oxidant
Time [h] Yield[b] [%]
1
2
3
4
5
6
7
8
CuI
CuCl2
T-HYDRO 12
T-HYDRO 12
21
18
23
21
36
28
58
0
72
0
0
48
70
60
56
44
92
0
FeCl3·6H2O T-HYDRO 12
ZnBr2
TBAB
none
T-HYDRO 12
T-HYDRO 12
T-HYDRO 20
Entry R1
R2
Product Yield[b] [%]
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAI
TBAC
I2
TBHP
H2O2
K2S2O8
Oxzone
12
12
40
40
40
80
30
40
40
40
40
40
40
1
2
3
4
5
6
7
8
4-ClC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
92
90
85
82
90
92
80
78
75
68
86
94
84
80
0
2-ClC6H4
3-ClC6H4
3-BrC6H4
C6H5
4-MeC6H4
2-naphthyl
4-FC6H4
3-O2NC6H4
4-NCC6H4
2-MeOC6H4
4-MeOC6H4
2-furyl
2-thienyl
3-pyridyl
n-Bu
9
10
11
12[c]
13[d]
14
15
16
17
18
19[e]
PhI
N
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
9
10
11
12
13
14
15
16
17
18
19
TEAB
none
TEAB
91
[a]
Reaction conditions: 1a (0.2 mmol), 2a (1.1 equiv.), cata-
lyst (10 mol%), oxidant (2.2 equiv.), DCE (1 mL), under
argon, 908C. TBAB=(n-Bu)4NBr; TBAI=(n-Bu)4NI;
TBAC=(n-Bu)4NCl; TEAB=Et4NBr; T-HYDRO: tert-
butyl hydroperoxide solution 70 wt% in H2O; TBHP=
tert-butyl hydroperoxide solution 5.5M in decane.
Isolated yields.
82
80
88
78
C6H5CH2CH2 C6H5
4-ClC6H4
4-ClC6H4
4-ClC6H4 3r
Bn
3s
[b]
[c]
[d]
[e]
[a]
Reaction conditions: 1 (0.2 mmol), 2 (1.1 equiv.), TEAB
(10 mol%), K2S2O8 (2.2 equiv.), DCE (1 mL), under
argon, 908C, 40 h.
At 708C.
At 1108C.
[b]
The scale of the reaction was increased to 10 mmol (1a).
Isolated yields.
Adv. Synth. Catal. 2013, 355, 3558 – 3562
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3559

Xuebin Zhu et al.
COMMUNICATIONS
Table 4. Scope of the reaction with alcohols and thiophenol/
tron-donating and electron-withdrawing groups could
be used regardless of their substituent positions to
give the corresponding thioesters 3a–3l in moderate
to excellent yields (Table 2, entries 1–12), and obvi-
ously aromatic aldehydes bearing strong electron-
withdrawing substituents on the aromatic ring gave
lower yields (Table 2, entries 8–10). Heteroaryl alde-
hydes such as furfural and 2-thienaldehyde could also
be used to afford the thioesters 3m and 3n in good
yields (Table 2, entries 13 and 14) while 3-pyridinecar-
boxaldehyde gave no product (Table 2, entry 15). Ali-
phatic aldehydes were also compatible in the reaction
to give products 3p and 3q in good yields. With
regard to the thiols used, we found that both aryl
thiols 2a and 2b and the alkyl thiol 2c were compati-
ble (Table 2, entries 1, 18, and 19).
As disulfides hold the advantages of easy operation,
less odour and high stability in comparison to thiols,
we conceived to further extend the reaction to disul-
fides. To our delight, the reaction could also proceed
easily to give even better results (Table 3).
Considering the stability and the availability of al-
cohols, we next studied the thioesterifications of alco-
hols with sulfur compounds. Several different substi-
tuted aryl alcohols were allowed to react with thio-
phenol 2a and disulfide 4a, affording the correspond-
ing products in good yields (Table 4, entries 1–11, and
13). However, when the aliphatic alcohol 5p was
used, only a trace of product was obtained (Table 4,
entry 12).
disulfide.[a]
Entry
R1
2a/4a
Product
Yield[b] [%]
1
2
3
4
5
6
7
8
4-ClC6H4
2-ClC6H4
C6H5
4-MeC6H4
2-naphthyl
4-FC6H4
3-O2NC6H4
4-NCC6H4
4-MeOC6H4
2-furyl
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
4a
3a
3b
3e
3f
3g
3h
3i
3j
3l
3m
3n
3p
3a
90
89
87
88
80
70
68
65
90
84
77
trace
91
9
10
11
12
13[c]
2-thienyl
n-Bu
4-ClC6H4
[a]
Reaction conditions: 5 (0.2 mmol), 2a (1.1 equiv.), TEAB
(10 mol%), K2S2O8 (4.4 equiv.), DCE (1 mL), under
argon, 908C, 40 h.
Isolated yields.
4a (0.55 equiv.) and K2S2O8 (3.3 equiv.) were used.
[b]
[c]
Control experiments for the mechanistic studies
were carried out as shown in Scheme 2. When a mix-
ture of 4-chlorobenzaldehyde (1a) and thiophenol
(2a) was subjected to the standard reaction conditions
in the presence of the radical scavenger TEMPO
(Scheme 2, conditions 1), no reaction was observed,
indicating that this reaction involves radical inter-
mediates. Performing the reaction with the catalyst
KBr in place of TEAB failed to produce any product
Scheme 2. Control experiments.
Table 3. Scope of the reaction with aldehydes and disul-
ACHTUNGTRENNUNG
fide.[a]
(Scheme 2, conditions 2). Additionally, the reaction
could be carried out smoothly using the bis(tetraeth-
ACHUTNGRENyNUG lACTHNGUTRENNUG
ammonium) peroxydisulfate (Et4N)2S2O8,[9] and this
gave the product 3a in 76% yield (Scheme 2, condi-
tions 3). These results reveal that the quaternary am-
monium cationic group is a critical part of the catalyst
system.
A plausible mechanistic scenario that is consistent
with experimental data and literature precedents[10] is
summarized in Scheme 3. The peroxydisulfate was re-
acted with tetraethylammonium bromide, generating
the bis(tetraethylammonium) peroxydisulfate which is
readily convertible to the tetraethylammonium sulfate
Entry
R1
R2
Product
Yield[b] [%]
1
2
3
4
4-ClC6H4
4-MeOC6H4
4-FC6H4
n-Bu
C6H5
C6H5
C6H5
C6H5
3a
3l
3h
3p
92
96
80
84
[a]
Reaction conditions:
1 (0.2 mmol), 4a (0.55 equiv.),
TEAB (10 mol%), K2S2O8 (1.2 equiv.), DCE (1 mL),
under argon, 908C, 40 h.
Isolated yields.
[b]
3560
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3558 – 3562

Tetraethylammonium Bromide-Catalyzed Oxidative Thioesterification of Aldehydes and Alcohols
Scheme 3. Plausible mechanism of reaction.
13C NMR (100 MHz, CDCl3): d=189.0, 140.1, 135.1, 135.0,
radical anions. Alcohol 5a was transformed into alde-
hyde 1a in the oxidizing environment, then the tetra-
129.7, 129.1, 128.8, 126.9; MS (ESI): m/z=249 [M+H]+.
ACHTUNGTRENNUNGethylammonium sulfate radical reacted with the alde-
hyde 1a and the thiol 2a to form an acyl radical A
and a sulfur radical B. Cross-coupling of the radicals
A with B leads to the formation of the corresponding
thioester 3a. Disulfide 4a could easily trap an acyl
radical A to generate a target thioester 3a and
a sulfur radical B.
In summary, we have developed an efficient
method for the synthesis of thioesters by the oxidative
coupling of easily available aldehydes or alcohols with
thiols or disulfides. Wide scope of the substrates, tran-
sition metal-free system, and extreme inexpensiveness
of the reagents outline the notable features of the re-
action. Exploration of novel oxidative coupling reac-
tions with this catalytic system is under way in our
laboratory.
Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (21172106, 21074054), the National
Basic Research Program of China (2010CB923303) and the
Research Fund for the Doctoral Program of Higher Educa-
tion of China (20120091110010) for their financial support.
References
[1] a) H. T. Bjorn, F. L. Ben, M. J. Adriaan, Chem.
Commun. 2007, 489–491; b) J. Staunton, K. J. Weiss-
man, Nat. Prod. Rep. 2001, 18, 380–416.
[2] a) K. S. A. Kumar, S. N. Bavikar, L. Spasser, T. Moyal,
S. Ohayon, A. Brik, Angew. Chem. 2011, 123, 6261–
6265; Angew. Chem. Int. Ed. 2011, 50, 6137–6141;
b) B. L. Wilkinson, R. S. Stone, C. J. Capicciotti, M. T.
Andersen, J. M. Matthews, N. H. Packer, R. N. Ben,
R. J. Payne, Angew. Chem. 2012, 124, 3666–3670;
Angew. Chem. Int. Ed. 2012, 51, 3606–3610; c) H.
Fuwa, M. Nakajima, J. Shi, Y. Takeda, T. Saito, M.
Sasaki, Org. Lett. 2011, 13, 1106–1109; d) B. Wang,
P. H. Huang, C. S. Chen, C. J. Forsyth, J. Org. Chem.
2011, 76, 1140–1150; e) Z. Geng, B. Chen, P. Chiu,
Angew. Chem. 2006, 118, 6343–6347; Angew. Chem. Int.
Ed. 2006, 45, 6197–6201.
[3] a) S. Ahmad, J. Iqbal, Tetrahedron Lett. 1986, 27, 3791–
3794; b) S. limura, K. Manabe, S. Kobayashi, Chem.
Commun. 2002, 94–95; c) A. R. Katritzky, A. A. Shes-
topalov, K. Suzuki, Synthesis 2004, 1806–1813; d) S.
Magens, B. Plietker, Chem. Eur. J. 2011, 17, 8807–8809;
e) M. H. Kim, D. V. Patel, Tetrahedron Lett. 1994, 35,
5603–5606; f) S. Ahmad, J. Iqbal, Tetrahedron Lett.
Experimental Section
Typical Procedure for the Thioesterification of
Aldehyde 1a with Thiophenol 2a
To a screw-capped test tube equipped with a magnetic stir
bar was added aldehyde 1a (0.2 mmol), thiophenol 2a
(0.22 mmol), TEAB (0.02 mmol) and K2S2O8 (0.44 mmol).
Then DCE (anhydrous, 1 mL) was added. After being
stirred at 908C for 40 h under an argon atmosphere, the re-
action mixture was filtered and the filtrate was concentrated
under vacuum. The resulting residue was purified by silica
gel column chromatography (petroleum ether:ethyl ace-
tate=20:1 to 15:1) to give 3a as a white solid; yield: 45.7 mg
1
(92%); mp 59–618C; H NMR (400 MHz, CDCl3): d=7.96–
7.98 (m, 2H), 7.50–7.52 (m, 2H), 7.45–7.48 (m, 5H);
Adv. Synth. Catal. 2013, 355, 3558 – 3562
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3561

Xuebin Zhu et al.
COMMUNICATIONS
1986, 27, 3791–3794; g) G. O. Spessard, W. K. Chan, S.
Masamune, Org. Synth. 1983, 61, 134–141.
[4] In the process of our submission, a related work on the
thioesterifications with aldehydes through copper-cata-
lyzed coupling was published: C. L. Yi, Y. T. Huang,
C. F. Lee, Green Chem. 2013, 15, 2476–2484.
Jiang, Y. X. Chen, C. J. Zhu, Chem. Commun. 2012, 48,
979–981; b) Q. C. Xue, J. Xie, P. Xu, K. D. Hu, Y. X.
Chen, C. J. Zhu, ACS Catal. 2013, 3, 1365–1368.
[9] Selected examples of the radical reactions using bis-
AHCTUNGTREG(NNUN tetraalkylammonium) peroxydisulfate as the radical
source, see: a) J. P. Whang, S. G. Yang, Y. H. Kim,
Chem. Commun. 1997, 1355–1356; b) S. G. Yang, J. P.
Hwang, M. Y. Park, K. Lee, Y. H. Kim, Tetrahedron
2007, 63, 5184–5188; c) J. C. Jung, Y. H. Kim, K. Lee,
Tetrahedron Lett. 2011, 52, 4662–4664.
[5] S. B. Bandgar, B. P. Bandgar, B. L. Korbad, S. S.
Sawant, Tetrahedron Lett. 2007, 48, 1287–1290.
[6] a) H. Nambu, K. Hata, M. Matsugi, Y. Kita, Chem.
Eur. J. 2005, 11, 719–727; b) H. Nambu, K. Hata, M.
Matsugi, Y. Kita, Chem. Commun. 2002, 1082–1083.
[7] a) T. Uno, T. Inkuma, Y. Takemoto, Chem. Commun.
2012, 48, 1901–1903; b) S. Singh, L. D. S. Yadav, Tetra-
hedron Lett. 2012, 53, 5136–5140.
[10] For recent reports on tetraalkylammonium bromide-
À
promoted catalytic C H activation reactions, see: a) B.
Tan, N. Toda, C. F. Barbas III, Angew. Chem. 2012, 124,
12706–12709; Angew. Chem. Int. Ed. 2012, 51, 12538–
12541; b) Z. Z. Shi, F. Glorius, Chem. Sci. 2013, 4, 829–
833.
[8] For our previous reports on metal-free, organocata-
lyzed oxidative coupling reactions, see: a) J. Xie, H. L.
3562
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3558 – 3562