Iron-catalyzed thioesterification of methylarenes with thiols in water

Article abstract of DOI:10.1016/j.tetlet.2014.10.155

An iron-catalyzed coupling reaction of methylarenes with thiols leading to thioesters has been developed. The reactions were carried out in water with tert-butyl hydroperoxide (TBHP) as the oxidant and polyoxyethanyl α-tocopheryl sebacate (PTS) as the sur

Full text of DOI:10.1016/j.tetlet.2014.10.155

Tetrahedron Letters 55 (2014) 7190–7193
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iron-catalyzed thioesterification of methylarenes with thiols in water
⇑
⇑
Liang Wang , Jing Cao, Qun Chen, Ming-yang He
School of Petrochemical Engineering, Changzhou University, Changzhou 213164, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An iron-catalyzed coupling reaction of methylarenes with thiols leading to thioesters has been developed.
Received 18 September 2014
Revised 21 October 2014
Accepted 31 October 2014
Available online 6 November 2014
The reactions were carried out in water with tert-butyl hydroperoxide (TBHP) as the oxidant and
polyoxyethanyl
a-tocopheryl sebacate (PTS) as the surfactant. The reaction medium is compatible with
a series of functional groups and can be reused.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Thioester
Cross-dehydrogenative coupling
Iron catalysis
Micellar catalysis
Thioesters are important building blocks since they are ubiqui-
tous in natural products.1 Generally, thioesters are prepared via the
following pathway: (i) thioesterification of carboxylic acids or their
derivatives;2–4 (ii) palladium-catalyzed thiocarbonylation of aryl
halides with thiols and carbon monoxide;5 (iii) cross-dehydrogena-
tive coupling (CDC) of aldehydes with thiols or disulfides in the
presence of radical initiator, with the combination of N-Heterocy-
clic carbene (NHC) catalyst, Dess–Martin periodinane, and metal
catalyst such as CuCl and FeBr2.6–10 Among the reported methodol-
ogies, the CDC strategy is the most powerful since no prefunction-
alization step is required, thereby making the reactions more atom
economic. However, some problems still existed in these reported
procedures. For example, diaryl and dialkyl sulfides were not com-
patible with Kita’s procedure;6 the NHC catalyst was much more
expensive and could not be recycled;7 and much more amount of
Dess–Martin periodinane was required.8 Alternatively, Lee devel-
oped a copper-catalyzed direct coupling of aldehydes with thiols
in water assisted by TBHP. However, heterocyclo-containing alde-
hydes were not suitable for the system.9 A modified procedure was
then reported by the same group by using a cheap and nontoxic
iron catalyst.10 Just recently, Patel reported a copper-catalyzed
CDC reaction between alkylbenzenes and thiols, where alkylben-
zenes were utilized as aroyl surrogates.11 However, the activities
of heterocyclo-containing arenes were not reported.
an efficient way to solve the ‘bottle-neck’. Recently, much effort
has been made by Lipshutz in the micellar catalysis by using a non-
ionic amphiphile, polyoxyethanyl
a-tocopheryl sebacate (PTS), as
the surfactant. Micelles with diameter at ca. 25 nm were formed
in PTS/water system, in which, a series of CAC coupling reactions
were realized under mild conditions.12 Notably, the PTS/water sys-
tem could be recovered and reused. In continuation of our interest
in CAS bond formation13 as well as micellar catalysis,13b herein, we
report a S-aroylation of thiols using methylarenes as aroyl surro-
gates in the presence of FeBr2/TBHP in water (Scheme 1).
Initially, toluene 1a and 4-methoxybenzenethiol 2a were
selected as the substrates to optimize the reaction conditions
(Table 1). A series of iron salts and copper salts were investigated
by using TBHP as the oxidant in PTS/H2O system. The results sug-
gested that FeBr2 was the best choice, giving the desired product
3a in 85% yield (Table 1, entry 5). No product was observed in
the absence of either FeBr2 or TBHP. Screening other surfactants
O
R2
FeBr2 (5 mol%)
S
R2 SH
+
TBHP, 100 oC
R1
R1
2%PTS/H2O
O
Water has received wide interest as a solvent since it is inex-
pensive, nontoxic, and safe. The problem in this field is the solubil-
ity of organic substrates. In this context, micellar catalysis provides
O
O
O
4
n
H
O
O
⇑
Corresponding authors. Tel.: +86 519 86330263; fax: +86 519 86330251.
E-mail addresses: lwcczu@126.com (L. Wang), hemingyangjpu@yahoo.com
PTS (n = ca. 13)
(M.-y. He).
Scheme 1. Iron-catalyzed thioesterification of alkylbenzenes with thiols.
http://dx.doi.org/10.1016/j.tetlet.2014.10.155
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

L. Wang et al. / Tetrahedron Letters 55 (2014) 7190–7193
7191
Table 1
Optimized reaction conditionsa
OCH3
O
HS
catalyst
S
+
oxidant, additive
OCH3
1a
3a
2a
Entry
Catalyst (mol %)
Oxidant (equiv)
Additive
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
FeCl2 (5)
Fe(OAc)2 (5)
FeCl3 (5)
Fe(NO3)3.9H2O (5)
FeBr2 (5)
Cu(OAc)2 (5)
CuBr2 (5)
Cu2O (5)
CuCl (5)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
—
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
DTBP (4)
BPO (4)
H2O2 (4)
K2S2O8 (4)
O2
PTS
PTS
PTS
PTS
PTS
PTS
PTS
PTS
PTS
PTS
PTS
—
Trion X-100
SDS
TBAB
PTS
PTS
PTS
74
29
54
37
85
59
18
25
30
0
—
FeBr2 (5)
FeBr2 (5)
FeBr2 (5)
FeBr2 (5)
FeBr2 (5)
FeBr2 (5)
FeBr2 (5)
FeBr2 (5)
FeBr2 (5)
FeBr2 (5)
FeBr2 (2.5)
FeBr2 (10)
FeBr2 (5)
FeBr2 (5)
0
21
15
70
31
0
0
0
0
0
57
76
53
80
PTS
PTS
PTS
PTS
PTS
PTS
TBHP (4)
TBHP (4)
TBHP (3)
TBHP (5)
The bold value specifies the best reaction condition.
a
Reaction conditions: 1a (2.5 mmol), 2a (0.5 mmol), 2 wt % additive/H2O (1.5 mL), oxidant (2 mmol, 4 equiv), 100 °C, 12 h.
Isolated yields.
b
including Trion X-100, sodium dodecyl sulfate (SDS), and tetrabu-
tylammonium bromide (TBAB) revealed that they were less effec-
tive than PTS (Table 1, entries 12–15). Reaction in pure water or
solvent-free conditions dramatically decreased the yield. Other
oxidants such as di-tert-butyl peroxide (DTBP), benzoyl peroxide
(BPO), H2O2, K2S2O8, and O2 were also evaluated. However, no
products were obtained in these conditions (Table 1, entries 17–
20). Finally, study on the amount of catalyst and oxidant clearly
showed that 5 mol % of FeBr2 and 4 equiv of TBHP were the best.
With the optimized yields in hand, the scope of different meth-
ylarenes and thiols was explored.14 The results are summarized in
Table 2. Aryl thiols with different functional groups including
methyl, methoxyl, chloro, and fluoro reacted smoothly to give
the thioesters in good yields (3a–3d, 69–85%), albeit a moderate
yield was obtained for o-xylene (3e, 52%). Alkyl thiols such as ben-
zylic thiols and cyclohexylmethanethiol also showed good reactiv-
ities, affording the corresponding products in good yields (3f–3i).
Other thiols containing ester and alkenyl groups survived the reac-
tion conditions (3j, 42%; 3k, 56%). Di-thioester could be obtained
by using ethylene mercaptan as the substrate (3l, 48%).
Next, various methylarenes were evaluated. As shown in
Table 2, this reaction system showed good compatibility. Once
again, methylarenes with functional groups such as methyl, meth-
oxyl, chloro, bromo, and nitro were all tolerated under the reaction
conditions (3m–3r, 55–82%). The electron-withdrawing groups
dramatically decreased the yields (3p, 55%; 3q, trace). 2-Methyl-
naphthalene also proceeded smoothly to give 3s in 77% yield. Nota-
bly, pyridine-, furan-, and thiophene-containing methylarenes also
coupled with thiols to deliver thiol esters in acceptable to good
yields (3t–3v).
toluene with benzoic acid under the standard conditions failed to
afford the thioester product, thereby ruling out this reaction path-
way [Scheme 2 (i)]. Next, oxidation of dibenzylsulfane under this
system gave only the corresponding sulfide as the product
[Scheme 2 (ii)]. A radical scavenger (TEMPO) was also introduced
to the reaction system, and only trace amount of product was
observed, indicating a radical pathway may be involved. Moreover,
when a mixture of benzaldehyde and 4-chlorotoluene (1:1) was
coupled with 4-methoxylbenzenethiol, product 3a was obtained
exclusively, suggesting the coupling of benzoyl radical with thiol
may be involved in this reaction.
Based on the above results and the similar study that was pre-
viously reported,10,11
a possible mechanism was proposed
(Scheme 3). Initially, FeBr2 reacted with TBHP to form iron complex
A Fe(III)Br2(OH) and t-BuOOÅ radical. Then complex A reacted with
thiols to give intermediate B. Meanwhile, under the FeBr2/TBHP
system methylarene was oxidized to benzaldehyde. Subsequently,
the t-BuOOÅ radical abstracted a hydrogen atom from the aromatic
aldehyde to give a benzoyl radical. The complex B trapped the ben-
zoyl radical to provide the thioester and a complex C. The complex
C was further reacted with HBr to release the FeBr2, thereby finish-
ing the catalytic cycle.
Another advantage of this protocol is the recyclability of the
micellar aqueous medium due to the preferred solubility of PTS
in water. When the reaction is finished, the reaction mixture was
extracted with minimal amount of ethyl acetate. After that, the
starting materials, iron catalyst as well as the oxidant were added
to the aqueous medium. Using the synthesis of 3a as example,
almost the same isolated yields were obtained after 6 runs.
In summary, a direct synthesis of thioesters through coupling
reaction of methylarenes with thiols has been realized with mod-
erate to good yields in water. The FeBr2/TBHP system shows good
To gain insight into the reaction mechanism, a series of control
experiments were performed (Scheme 2). Initially, replacement of

7192
L. Wang et al. / Tetrahedron Letters 55 (2014) 7190–7193
Table 2
Substrate scope of methylarenes and thiolsa
O
R2
FeBr2 (5 mol%)
R2 SH
S
+
TBHP (4 equiv), 100 oC, 12 h
R1
R1
2%PTS/H2O (1.5 mL)
2
3
1
O
S
R
O
O
R
S
S
3i, 70%
R = p-OCH3, 3a, 85%
R = p-CH3, 3b, 71%
R = p-Cl, 3c, 83%
R = p-F, 3d, 69%
R = H, 3f, 72%
R = p-CH3, 3g, 75%
R = p-F, 3h, 68%
R = o-CH3, 3e, 52%
O
O
S
O
O
S
S
Cl
S
S
O
O
3k, 56%
3j, 42%
3l, 48%
Cl
Cl
O
S
O
S
N
R
O
Cl
R = p-CH3, 3m, 73%
R = p-OCH3, 3n, 82%
R = p-Cl, 3o, 80%
3s, 77%
3t, 36%
R = p-NO2, 3p, 55%
R = p-CF3, 3q, trace
R = m-Br, 3r, 74%
S
Cl
S
Cl
S
O
O
O
3u, 48%
3v, 72%
a
Reaction conditions: 1 (2.5 mmol), 2 (0.5 mmol), 2 wt % PTS/H2O (1.5 mL), TBHP (2 mmol, 4 equiv), 100 °C, 12 h, isolated yields.
OCH3
O
HS
COOH
standard conditions
S
+
(i)
OCH3
Not observed
O
S
standard conditions
S
(ii)
Formed only
OCH3
O
SH
standard conditions
TEMPO
+
(iii)
(iv)
S
H3CO
trace
OCH3
O
Cl
SH
CHO
standard conditions
S
+
+
H3CO
3a, 89%
1:1
Scheme 2. Control experiments.

L. Wang et al. / Tetrahedron Letters 55 (2014) 7190–7193
7193
H2O
2t-BuOOH
Supplementary data
Fe(II)Br2
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
10.155.
HBr
t-BuOH
References and notes
t-BuOO
t-BuOH
1. Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18, 380.
2. Limura, S.; Manabe, K.; Kobayashi, S. Chem. Commun. 2002, 94.
3. Katritzky, A. R.; Shestopalov, A. A.; Suzuki, K. Synthesis 2004, 1806.
4. Magens, S.; Plietker, B. Chem. Eur. J. 2011, 17, 8807.
5. Cao, H.; McNamee, L.; Alper, H. J. Org. Chem. 2008, 73, 3530.
6. (a) Nambu, H.; Hata, K.; Matsugi, M.; Kita, Y. Chem. Commun. 2002, 1082; (b)
Nambu, H.; Hata, K.; Matsugi, M.; Kita, Y. Chem. Eur. J. 2005, 11, 719; (c) Zeng, J.-
W.; Liu, Y.-C.; Hsieh, P.-An.; Huang, Y.-T.; Yi, C.-L.; Badsara, S. S.; Lee, C.-F. Green
Chem. 2014, 16, 2644; (d) Zhu, X.; Shi, Y.; Mao, H.; Cheng, Y.; Zhu, C. Adv. Synth.
Catal. 2013, 355, 3558.
Fe(II)Br(OH)
Fe(III)Br2(OH)
A
C
O
Ar CHO
[O]
R2
R1SH
Ar-CH3
O
Ar
R2
S
R1S
7. Uno, T.; Inokuma, T.; Takemoto, Y. Chem. Commun. 2012, 1901.
8. Bandgar, S. B.; Bandgar, B. P.; Korbad, B. L.; Sawant, S. S. Tetrahedron Lett. 2007,
48, 1287.
Fe(III)Br(OH)
B
HBr
9. Yi, C.-L.; Huang, Y.-T.; Lee, C.-F. Green Chem. 2013, 15, 2476.
10. Huang, Y. T.; Lu, S. Y.; Yi, C. L.; Lee, C. F. J. Org. Chem. 2014, 79, 4561.
11. Ali, W.; Guin, S.; Rout, S. K.; Gogoi, A.; Patel, B. K. Adv. Synth. Catal. 2014, 356,
3099.
Scheme 3. Proposed mechanism.
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Rich, B. Adv. Synth. Catal. 2009, 351, 1717; (d) Nishikata, T.; Lipshutz, B. H. Org.
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14. Typical procedure for the synthesis of thioester 3a: A sealed tube was charged
with toluene (230 mg, 2.5 mmol), 4-methoxybenzenethiol (70 mg, 0.5 mmol),
FeBr2 (5.6 mg, 0.025 mmol), TBHP (2.0 mmol) and 2 wt % PTS/H2O (1.5 ml). The
reaction mixture was stirred at 100 °C in an oil bath for 12 h. After cooling to
room temperature, the mixture was extracted with ethyl acetate. The organic
layer was then dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by column chromatography on silica
gel (hexane/ethyl acetate = 10/1) to give the pure product 3a (103.7 mg, 85%).
1H NMR (500 MHz, CDCl3): d 7.99 (d, J = 7.5 Hz, 2H), 7.57–7.50 (m, 1H), 7.45–
7.35 (m, 4H), 6.94 (d, J = 8.7 Hz, 2H), 3.73 (d, J = 27.4 Hz, 3H). 13C NMR
(125 MHz, CDCl3): d 191.0, 160.9, 136.7, 133.7, 128.9, 127.5, 118.0, 115.1, 55.5.
MS (ESI) m/z: 244.
reactivity as well as compatibility with a series of methylarenes
and thiols. The methylarenes, as aroyl surrogates, are much
more cheap and available compared with the corresponding
aldehydes. Moreover, the micellar aqueous system can be easily
recovered and reused for several runs with a slight decrease in
its activity.
Acknowledgments
This project was financially supported by the National Natural
Science Foundation of China (No. 21302014), the Natural Science
Foundation for Colleges and Universities of Jiangsu Province
(13KJB150002), and the Jiangsu Key Laboratory of Advanced
Catalytic Materials and Technology (Grant No. BM2012110).