RhCl3·3H2O-Catalyzed Ligand-Enabled Highly Regioselective Thiolation of Acrylic Acids

Article abstract of DOI:10.1021/acscatal.9b02982

The simple inorganic rhodium salt RhCl₃·3H₂O was used as a catalyst to achieve the thiolation of acrylic acids, with a series of (Z)-alkenyl sulfides being obtained exclusively. It is noteworthy that [Cp*RhCl₂]₂ was not as efficient as RhCl₃·3H₂O in this strategy. Furthermore, the products could be transformed conveniently into biologically and pharmacologically useful thioflavones.

Full text of DOI:10.1021/acscatal.9b02982

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Article
RhCl3.3H2O-Catalyzed Ligand-Enabled Highly
Regioselective Thiolation of Acrylic Acids
Can Liu, Yi Fang, Shun-Yi Wang, and Shun-Jun Ji
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02982 • Publication Date (Web): 22 Aug 2019
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Page 1 of 6
ACS Catalysis
RhCl33H2O-Catalyzed Ligand-Enabled Highly Regioselective Thiolation of Acrylic Acids
1
2
3
Can Liu,†,‡ Yi Fang,†,‡ Shun-Yi Wang,*,†,‡ and Shun-Jun Ji*,†,‡
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† Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou, 215123, China.
‡Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123, China.
Supporting Information Placeholder
8
9
ABSTRACT: A simple inorganic rhodium salt RhCl33H2O was used as the
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R1 COOH
RhCl3 3H2O
R1 COOH
3
3SS
catalyst to achieve the thiolation of acrylic acids, with a series of (Z)-alkenyl
sulfides obtained exclusively. It is noteworthy that [Cp*RhCl2]2 was not as
efficient as RhCl33H2O in this strategy. Furthermore, the product could be
transferred to biological and pharmacological thioflavone conveniently.
R
R
R2
R2
R
3
H
S
* Higher catalytic efficiency than [Cp*RhCl2]2
* Easier derivative carboxyl group as DG
KEYWORDS: RhCl33H2O, carboxylate-directed, alkenyl sulfide, C-H
activation, regioselectivity

INTRODUCTION
(Scheme 1).3 Nevertheless, limited research has been conducted
on non-aromatic C(sp2)-H activation, and aromatic reaction still
predominates in current research. Therefore, developing
carboxylate-directed non-aromatic C(sp2)-H activation has
important practical significance.
C-H activation has attracted much attention in recent years
due to its high atom economy and diversity of reaction, and has
become one of the important strategies of organic synthesis.
However, in order to ensure regioselectivity, directing group (DG)
is usually indispensable. Strong directing groups such as pyridine,
pyrimidine and 8-aminoquinoline were first used in C-H
activation reactions.1 Soon after, weak guiding groups such as
oxime ether, ketone and amide have also been reported.2 Since
2007, carboxyl group has been initially used as directing group of
C-H activation reaction because of its non-toxicity, easy removal,
widespread existence in nature and abundant derivative reactions.
During the past decade, carboxyl group show extraordinary talents
in this field. Palladium-, rhodium-, ruthenium- and iridium-
catalyzed systems have been developed successfully to achieve
arylation, alkylation, alkenylation, thiolation and selenation
[Cp*RhCl2]2 (Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl)
is the most used catalyst in existing rhodium-catalyzed C-H
activation reactions. The Cp* ligand is believed to be helpful in
stabilizing rhodium intermediates, as well as promoting
eliminating processes due to the steric hindrance effect. Indeed, a
large number of reported facts prove that the catalyst has high
efficiency, regioselectivity and excellent functional group
tolerance.4 [Cp*RhCl2]2 is generally prepared from the
coordination reaction of RhCl33H2O with excess 1,2,3,4,5-
pentamethylcyclopentadiene in methanol under an inert
atmosphere. However, as the precursor of [Cp*RhCl2]2,
COOH
R
Ar
ref 3m
2015, Gooßen,
COOH
COOH
COOH
R
R
R
R
[IrCp*Cl2]2
R
XR'
Ar
Ar
HOOC
2018, Baidya,
X = S or Se
ref 3b
2011, Larrosa,
ref 3a
2007, Daugulis,
ref 3h
ref 3i
2017, Baidya,
COOH
[Ru(p-cymene)Cl2]2
Pd(OAc)2
R
O
O
COOH
R
COOH
R
R
nBu
ref 3c
R
CH2OBn
O
O
[RhCp*Cl2]2
[Rh(nbd)Cl2]2
ref 3d
2015, Yu,
2013, Yu,
N
R'
O
R'
ref 3l
2017, Ackermann & Baidya
ref 3j ref 3k
2018, Gooßen,
R
&
Het
COOH
ref 3f
2015, Su,
R
O
R
HOOC
R
ref 3e
2015, Li,
HOOC
2019, Gooßen,
ref 3g
Scheme 1. Carboxylate-directed C-H activation of benzoic acids under Pd, Rh, Ru and Ir catalysis
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ACS Catalysis
Page 2 of 6
RhCl33H2O was used to be the catalyst of C-H activation rarely.5
the yield up to 75% further (Table 1, entry 16). By the following
investigation, reaction time and temperature were determined to 6
h and 120 C, respectively. Under this condition, the ligand was
replaced by cheaper tris(2,6-dimethoxyphenyl)phosphane (L37),
and the yield could still maintain at 79% (Table 1, entry 20). In
addition, when [Cp*RhCl2]2 was employed in this reaction, the
yield decreased to 69% (Table 1, entry 21).
In 1990, the RhCl(PPh3)3/Cu2+ redox couple was used in
carboxylation of aromatic rings. Inspired by this work, Witulski
and cooperators used RhCl33H2O and Cu(II) salts to achieve
intramolecular C-H/C-H Coupling.6 Since then, there are only a
few articles which have reported RhCl33H2O-catalyzed C-H
activation and relevant research.7
1
2
3
4
5
6
o
Alkenyl sulfides are a class of important sulfur-containing
compounds, which are widely used in organic synthesis, material
science and biopharmaceuticals.8 With the development of related
research, its synthesis is becoming more simple and efficient.
Initial synthetic strategies required unfriendly sulfur sources, low
atomic economy, poor selectivity and harsh reaction conditions
(Scheme 2, A & B),9 but now these shortcomings have been
overcome. In 2018, we reported an N-tosylamide-assisted
synthesis of (Z)--alkenyl sulfides through [Cp*RhCl2]2-catalyzed
thiolation of alkenes with high efficiency and good substrate
tolerance (Scheme 2, C).10 However, we failed to remove the
directing group, which hinders the subsequent application.
Therefore, we hope to develop a system with directing group
which is easier to remove or derive. Meanwhile, we also desire to
apply RhCl33H2O to this system with the help of ligand. Herein,
7
8
9
Table 1. Optimization of the Rh-catalyzed thiolation of 1a
with 2aa
S
Ph
RhCl3 3H2O (5 mol %)
Cu(OAc)2
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60
H
Ligand
COOH
SS
Ph Ph
COOH
solvent, T, 6 h
1a
2a
4a
Entry
Cu(OAc)2
(mol %)
/
ligand
T (oC)
Time(h)
LC-Yield(%)b
1
2
/
120
120
120
120
120
120
120
120
120
120
120
120
120
80
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
6
0
17
10
/
3
20
/
27
4
50
/
40
5
100
150
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
/
49
.
we demonstrated a RhCl3 3H2O-catalyzed ligand-enabled highly
regioselective thiolation of acrylic acids to afford (Z)--alkenyl
sulfides(Scheme 2, D).
6
/
38
7
L2
L8
L19
L33
L34
L35
L36
L36
L36
L36
L36
L36
L36
L37
L37
25
8
25
9
52
Scheme 2. Synthesis of alkenyl sulfides through different
processes.
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16c
17 c
18 c
19 c
20 c
21 c,e
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59
A.
Nucleophilic addition of thiols to alkynes
37
smelly and toxic thiol
poor regioselectivity
R2
R1SH
R2
R1S
71
R1S
R2
Trace
73
B.
-
Cross coupling of thiols and vinyl halides
100
120
140
120
120
120
120
R1S
X
R2
R2
75
[M]
R1SH
or
harsh conditions
low atom economy
or
72
X
R2
R1S
R2
80
18
6
75
79(77 d)
C.
Our previous work: regioselective synthesis of (Z)--alkenyl sulfides
O
O
R1
R2
Ts
R1
R2
Ts
[Cp*RhCl2]2
difficult-removed DG
complicated catalyst
3
6
69
3XX
R
R
N
N
H
3
H
X = S, Se
H
X
R
PPh2
O
O
NHAc
PPh2
P
O
N
D.
This work
COOH
N
R1 COOH
R1 COOH
RhCl3 3H2O
3
3XX
simple DG
simple catalyst
R
R
L2
L8
L19
L33
X = S, Se
R2
R2
R
3
H
X
O
O
O
O
O
O
O
O
O
O
O
P

RESULTS AND DISCUSSION
Initially, atropic acid 1a and diphenyl disulfide 2a were chose
O
P
O
P
P
OO
O
O
O
OO
L36
O
to investigate the reaction conditions (Table 1, see Supporting
Information for more details). Rh catalyst could not be replaced
by other transition metals such as Pd, Co, Ni, Ru. The reaction
could not undergo in common solvents such as ether, benzene and
alcohols other than amide solvents and MeCN. The amount and
type of Cu salts are key factors of the reaction. The yield peaked
L34
L35
L37
aReaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.1 mmol, 1.0
equiv), RhCl33H2O (5 mol %), ligand (15 mol %), Cu(OAc)2(1
o
b
equiv), DMF (1 mL), 120 C, 12 h. LC yield using biphenyl as
the internal standard. cPhSSPh
2
equiv. dIsolated yield.
e[Cp*RhCl2]2 (2.5 mol %). DMF = N,N-dimethylformamide.
when
1 equiv Cu(OAc)2 was added (Table 1, entry 5).
Subsequently, different ligands were applied to the reaction.
Phosphine ligands were found to be beneficial to the reaction. The
desired product could be obtained in 68% yield when 30 mol %
tris(2,4,6-trimethoxyphenyl)phosphane (L36) was added. And the
yield would increase to 71% when the amount of ligand reduced
to 15 mol % (Table 1, entry 13). The increment of 2a also brings
With the optimal conditions in hand, we explored the substrate
scope of acrylic acids (Table 2). Ortho- and meta-substituted
substrates could undergo the reaction but the yield went down (3a
and 3b). Electron effect did not show obvious effect on this
reaction, corresponding products were obtained in 72-78% yield,
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ACS Catalysis
Table 3. Substrate scope of disulfidesa
respectively (3c-3e). Benzyl acrylic acid could also react
1
2
3
4
5
6
7
8
smoothly with 76% yield (3f). Unactivated alkyl acrylic acids
could also adapt to this system to give desired products in
moderate yield (3g and 3h). It is worth mentioning that this
strategy could also be applied to the thiolation of nonterminal
alkenes, although the yields were not so ideal (3i-3k). However,
cinnamic acid could not afford products successfully (3l). We
assume that it is due to the steric hindrance effect.
RhCl3 3H2O (5 mol %)
Cu(OAc)2 (1 equiv)
L37
S
R
(15 mol %)
COOH
SS
R
R
COOH
DMF, 120 o
C
4
1a
2
(2 equiv)
(1 equiv)
OMe
Table 2. Substrate scope of acrylic acidsa
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S
S
S
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60
Ph
COOH
RhCl3 3H2O (5 mol %)
Cu(OAc)2 (1 equiv)
Ph
4b
COOH
Ph
COOH
R1
H
(15 mol %)
R1
S
L37
S
: 77%
4c
: 73%
4a
: 77%
S
R2 COOH
(1 equiv)
DMF, 120 o
C
R2 COOH
Br
Cl
3
1
2b
(2 equiv)
F
S
S
S
S
Ph
COOH
: 75%
Ph
4g
COOH
Ph
COOH
4f
: 62%
S
S
S
S
Ph
COOH
: 73%
b
4d
4e
: 22%
COOH
COOH
COOH
COOH
MeO
Cl
3a
3b
3c
3d
: 72%
: 59%
: 56%
: 76%
S
S
S
Se
Ph
4j
COOH
Ph
4i
COOH
Ph
4h
COOH
Ph
4k
COOH
b
c
b
b
: 22%
: 31%
: 36%
: 52%
S
S
S
S
aReaction conditions: 1 (0.3 mmol), 2b (0.6 mmol), RhCl33H2O
(5 mol %), Cu(OAc)2 (1 equiv), L37 (15 mol %), DMF (3 mL),
120 oC, 6 h. b140 oC, 12 h. cRhCl33H2O (10 mol %), L37 (30 mol
%), 140 oC, 12 h.
COOH
COOH
COOH
COOH
F
3e
3f
3g
3h
: 48%
: 78%
: 76%
: 52%
Scheme 3. Scale-up synthesis.
S
S
S
S
Ph
RhCl3 3H2O (5 mol %)
S
Ph
Cu(OAc)2 (1 equiv)
L37
COOH
: 39%
COOH
: 26%
COOH
COOH
(15 mol %)
DMF, 120 oC, 24 h
COOH
SS
Ph Ph
b
3i
3k
3l
: trace
COOH
3j
: 35%
aReaction conditions: 1 (0.3 mmol), 2b (0.6 mmol), RhCl33H2O
(5 mol %), Cu(OAc)2 (1 equiv), L37 (15 mol %), DMF (3 mL),
120 oC, 6 h. b140 oC, 12 h.
1a
2a
(12 mmol)
(6 mmol)
4a
, 0.9260g
isolated yield: 60%
Thioflavone is the core moiety of various natural products
Next, we investigate the tolerance of disulfides (Table 3). For
electron-rich substrates such as methyl- (4b) and methoxy- (4c),
weak electron-deficient substrates such as F-, Cl-, Br-substituted
disulfides (4d-4f), the reaction underwent smoothly, and the
corresponding target products could be obtained in 62-77% yields,
respectively. But for strong electron-deficient nitro-substituted
disulfides, the reaction could not occur. For alkyl disulfides, the
with biopharmaceutical activities. In addition, thioflavone and its
oxide can be further derived to protect many light-unstable
functional groups11. Based on the structure of aforementioned
products, Friedel-Crafts acylation was considered to achieve the
construction of thioflavone. When 4a was stirred in 0.5 mL
o
trifluoromethanesulfonic acid for 3 hours under 120 C heating,
the derivative thioflavone could be obtained in 88% yield.
Meanwhile, 4a was successfully reduced to corresponding alcohol
in 50% yield (Scheme 4).
o
reaction temperature should be increased to 140 C, and the yield
decreased in varying degrees (4g-4j). We also tried to apply
diselenides to this system, but the result was not ideal. The target
product (4k) was merely obtained in 22% yield.
Scheme 4. Derivative reaction.
Meanwhile, we attempted to amplify the template reaction to
gram level. With reaction time prolonged to 24 h, 4a could be
obtained in 60% isolated yield (scheme 3), which implies the
possibility of large-scale industrial production.
S
TfOH (0.5 ml)
120 oC, 3 h
LiAlH4 (3 equiv)
THF, reflux, 1 h
S
S
Ph
O
Ph
COOH
Ph
CH2OH
der1
4a
der2
, 88%
, 50%
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Page 4 of 6
To explore the plausible mechanism, a series controlled
Scheme 6. XPS & AES spectra of yellow precipitate.
1
2
3
4
5
6
7
8
experiments were conducted. Under standard condition, atropic
acid 1a was replaced by ethyl 2-phenylacrylate to undergo the
reaction (Scheme 5, A). However, corresponding product was not
obtained, which reveals the direction of carboxyl group is
indispensable. At the same time, the path of Michael addition-
elimination was ruled out. Next, we investigated Kinetic Isotope
Effect (KIE) of the system (Scheme 5, B). Through a competitive
experiment between 1a and 1a-d2, the KIE value was calculated
as 3.0, which suggested a concerted metalation deprotonation
(CMD) process. In addition, it was found that a large amount of
precipitate was produced after the reaction. The yellow precipitate
is poorly soluble in organic solvents, but it can dissolve in
concentrated acids to generate diphenyl disulfide. Therefore, we
speculate that the solid may be a low valent copper species bound
to disulfide. By X-ray photoelectron spectroscopy (XPS)
characterization, from the survey spectrum (Scheme 6, a), we
could confirm the existence of copper. From the high resolution
XPS spectrum (Scheme 6, b), characteristic satellite peaks of
Cu(II) (standard spectra see Scheme 6, c) did not appear, which
indicated the precipitate did not contain Cu(II). By Auger
Electron Spectroscopy (AES) characterization (Scheme 6, d), two
groups of peaks were found, which reveals the existence of Cu(0)
and Cu(I). That is to say, the precipitate is the mixture of low
valence copper species.
Cu2p Scan
LC1 Survey
3.00E+05
2.00E+05
1.00E+05
1.00E+06
9.00E+05
8.00E+05
7.00E+05
6.00E+05
5.00E+05
4.00E+05
3.00E+05
2.00E+05
1.00E+05
0.00E+00
9
0.00E+00
0
1200
1000
800
600
400
200
960
950
940
930
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45
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48
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50
51
52
53
54
55
56
57
58
59
60
Binding Energy (eV)
Binding Energy (eV)
a. XPS survey spectrum of yellow precipitate
b. XPS sprectra of yellow precipitate
CuLM2 Scan
6.00E+04
5.00E+04
4.00E+04
3.00E+04
2.00E+04
1.00E+04
582 580 578 576 574 572 570 568 566 564 562 560 558
Binding Energy (eV)
Scheme 5. Controlled experiments.
A. Replaced by ethyl 2-phenylacrylate
c. Standard XPS spectra of different kinds of Cu
d. AES sprectra of yellow precipitate
RhCl3 3H2O (5 mol %)
Cu(OAc)2 (1 equiv)
L37
S
Ph
(15 mol %)
Scheme 7. Plausible mechanism.
Ph
COOEt
SS
Ph Ph
Ph
COOEt
DMF, 120 oC, 6 h
RhCl3 3H2O
Ligand
Cu(OAc)2
B. Competitive experiment between 1a and 1a-d2
OMe
OMe
RhCl3 3H2O (5 mol %)
Cu(OAc)2 (1 equiv)
Ph
COOH
H
LRhIII(OAc)2
PhSCu0, I
1a
L37
(15 mol %)
A
Ph
COOH
S
D/H
S
DMF, 120 oC, 1.5 h
S
1a
D
D
Ph
COOH
CuII
kH/kD = 3.0
HOAc
Ph
COOH
4c
4c
and -d
OMe
1a
-d2
[LRhIIISPh]OAc
2AcOH
Based on above experimental results and related literatures,
C
we proposed a plausible mechanism (Scheme 7). Ligand and
Cu(OAc)2 enabled RhCl33H2O to form the active RhIII species A.
A reacts with substrate 1a to generate five-membered rhodacycle
B through a CMD process. Then, product 4a and intermediate C
are obtained by the nucleophilic substitution of B and disulfide.
At last, the active species A is regenerated through oxidation of
inactive intermediate C by Cu(OAc)2, and the low valence Cu
species is formed simultaneously.
L
RhIII
SPh
O
Ph
COOH
Ph
O
PhSSPh
HOAc
4a
B

ASSOCIATED CONTENT

CONCLUSION
In summary, a RhCl33H2O-Catalyzed thiolation of acrylic
Supporting Information
acids was reported. With higher efficiency than [Cp*RhCl2]2, this
strategy provides a novel way to construct C-S bond through C-H
activation. The reaction can be successfully enlarged to gram
scale, and the product can be efficiently converted into
thioflavone with potential biopharmaceutical activity, which
shows practical application in industrial production.
Detailed experimental procedures. This material is available free
of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION
Corresponding Author
shunyi@suda.edu.cn;
shunjun@suda.edu.cn
Notes
The authors declare no competing financial interests.
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ACS Catalysis
Rh(III)-Catalyzed
Acceptorless
Dehydrogenative
Coupling
of

ACKNOWLEDGMENT
(Hetero)arenes with 2-Carboxyl Allylic Alcohols. Org. Lett. 2018, 20,
1
2
3
4
5
6
7
8
740-743.
We gratefully acknowledge the National Natural Science
Foundation of China (21971174, 21772137, 21672157), the Major
Basic Research Project of the Natural Science Foundation of the
Jiangsu Higher Education Institutions (No. 16KJA150002), the
Ph.D. Programs Foundation of PAPD, the project of scientific and
technologic infrastructure of Suzhou (SZS201708), and Soochow
University for financial support. We thank Rong Zhang in this
group for reproducing the result of 3f, 3i, 4b, 4f.
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