Redox-Divergent Construction of (Dihydro)thiophenes with DMSO

Article abstract of DOI:10.1002/anie.202109026

Thiophene-based rings are one of the most widely used building blocks for the synthesis of sulfur-containing molecules. Inspired by the redox diversity of these features in nature, we demonstrate herein a redox-divergent construction of dihydrothiophenes, thiophenes, and bromothiophenes from the respective readily available allylic alcohols, dimethyl sulfoxide (DMSO), and HBr. The redox-divergent selectivity could be manipulated mainly by controlling the dosage of DMSO and HBr. Mechanistic studies suggest that DMSO simultaneously acts as an oxidant and a sulfur donor. The synthetic potentials of the products as platform molecules were also demonstrated by various derivatizations, including the preparation of bioactive and functional molecules.

Full text of DOI:10.1002/anie.202109026

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Redoxdivergent Construction of (Dihydro)thiophenes with DMSO
Authors: Heng Liu, Gu-Cheng He, Chao-Yang Zhao, Xiang-Xin Zhang,
Ding-Wei Ji, Yan-Cheng Hu, and Qing-An Chen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202109026
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10.1002/anie.202109026
Angewandte Chemie International Edition
COMMUNICATION
Redoxdivergent Construction of (Dihydro)thiophenes with DMSO
Heng Liu, Gu-Cheng He, Chao-Yang Zhao, Xiang-Xin Zhang, Ding-Wei Ji, Yan-Cheng Hu and Qing-
An Chen*
[a]
H. Liu, G. C. He, C. Y. Zhao, X. X. Zhang, D. W. Ji, Y. C. Hu, Prof. Dr. Q. A. Chen
Dalian Institute of Chemical Physics, Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023 (China)
E-mail: qachen@dicp.ac.cn, Homepage: http://www.lbcs.dicp.ac.cn
H. Liu, G. C. He, C. Y. Zhao, X. X. Zhang, Prof. Dr. Q. A. Chen
University of Chinese Academy of Sciences
[b]
Beijing 100049 (China)
Supporting information for this article is given via a link at the end of the document.
Abstract: Thiophene-based rings are one of the most widely used
building blocks for the synthesis of sulfur-containing molecules.
Inspired by the redox diversity of nature’s feature, we demonstrate
be employed as sulfur donor in organic reactions.[22] Herein, we
developed a redoxdivergent construction of (dihydro)thiophenes
with DMSO as both an oxidant and a sulfur donor. By simply
controlling the dosage of HBr and DMSO, allylic alcohols were
transformed to valuable thiophenes and dihydrothiophenes in
high selectivity and efficiency. Furthermore, through the further
transformation of thiophene and dihydrothiophene products,
various five-membered sulfur-containing heterocycles could be
readily accessed.
herein
a
redoxdivergent construction of dihydrothiophenes,
thiophenes and bromothiophenes respectively from readily available
allylic alcohols, dimethyl sulfoxide (DMSO) and HBr. The
redoxdivergent selectivity could be manipulated mainly through
controlling the dosage of DMSO and HBr. Mechanistic studies
suggest that DMSO simultaneously acts as an oxidant and a sulfur
donor. The synthetic potentials of the products as platform
molecules have also been demonstrated by various derivatizations,
including the preparation of bioactive and functional molecules.
(Dihydro)thiophenes are one of the most common five-
membered heterocycles that are widespread in a large number
of natural products, functional materials, and biologically active
compounds.[1] For example, duloxetine is a commercial drug that
possesses effective antihypertensive activity. Thiolactomycin is
a well-known thiolactone antibiotic that exhibits potent inhibitory
activity against dissociable FAS enzymes.[2] DuP 697 is an
effective inhibitor of cyclooxygenase-2 (COX-2) and has anti-
inflammatory, anticancer and antipyretic effects (Scheme 1a).[3]
Furthermore, its regoisomers show a similar COX-2 inhibitory
profile.[4] In addition, they can also serve as valuable and useful
building blocks for the assembly of molecular complexity.
Therefore, the construction of thiophene skeletons has attracted
much attention over the last decades.[5] Traditionally, sulfide
sources such as P4S10,[6] K2S/Na2S,[7] H2S,[8] and S8 were
[9]
usually employed to prepare thiophene compounds through the
formation of two new C–S bonds (Scheme 1b). However, the
substrates employed in these examples were highly
functionalized precursors which resulted in limited scope and
functional group compatibility. Moreover, although some classic
methods have been developed to prepare substituted
thiophenes, the synthesis of dihydrothiophenes is still relatively
rare.[10] In nature, important bioactive metabolites with different
redox states are created by various redox enzymes. Given this
in mind, we wonder if it is possible to develop a strategy of
redoxdivergent construction of substituted (dihydro)thiophenes
from readily available starting materials under concise and
metal-free conditions.
Scheme 1. Thiophenes and their synthesis
During our initial efforts for the preparation of 2-substituted
diene with allyl alcohol 1a as the diene precursor,[23] a small
amount of thiophene 2a and dihydrothiophene 4a were
serendipitously obtained in the presence of 2.2 equivalent of
DMSO and HBr (Table 1, entry 1). Considering the important
applications of such skeletons in material and medicinal
chemistry, further evaluation for the formation of 2a and 4a was
DMSO is environmentally friendly aprotic polar solvent, which
has been widely used as an oxidant for alcohols,[11] alkyl
halides,[12] epoxides,[13] alkenes[14] and alkynes.[15] Meanwhile,
DMSO could also be employed as source of methyl,[16]
methine,[17] methylene,[18] methylthio,[19] methylsulfinyl,[20] and
oxygen.[21] However, there were rare reports that DMSO could
1
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10.1002/anie.202109026
Angewandte Chemie International Edition
COMMUNICATION
performed. An investigation of solvent revealed that 2a could be
delivered in 56% yield with exquisite selectivity in nitromethane
(entries 1−4). Notably, the reaction did not work when DMSO
was used as the solvent (entry 3). It probably resulted from that
the excess DMSO strongly inhibited the reactivity of bromine ion
generated from DMSO/HBr.[24] The reactivity for thiophene
product was further enhanced by raising the reaction
With the optimized conditions established, the substrate
scope for thiophenes was first evaluated (Scheme 2). In the
presence of 2.2 equivalents DMSO and HBr, various 3-
arylthiophenes 2 were obtained in moderate to good yields. For
instance, 2-phenylallyl alcohol with weak electron-donating
t
substituents, such as Me, Bu, and Cy at the para position of
phenyl ring, all reacted smoothly under the current condition and
gave 2b-2e in moderate yields (49-54%). Notably, halides,
including fluoro, chloro, bromo and iodo were well tolerated,
delivering corresponding products 2f-2i in 65-74% yields.
Substituents at meta and ortho position of the phenyl ring were
amenable to the transformation as well (2j, 2k). It is noteworthy
that naphthyl-substituted allyl alcohols could deliver the target
products 2l, 2m in satisfactory yields as well. Allylic alcohol with
polar functional group couldn’t be transformed to thiophene
effectively (2n). However, dihydrothiophene 4n was observed as
major product (35% yield). With respect to the alkyl substituted
allylic alcohol, the desired product was obtained with low yield
(2o). Only a trace amount of product 2p was observed when
methyl group was introduced onto R1 position. The alkene bears
aryl group on terminal site delivered no target product (2q).
However, the substitution on the internal site of alkene is
tolerated (2r).
o
temperature to 120 C (entry 5). Whereas a higher temperature
suppressed the reaction (See SI for more optimizations). It was
worthy to note that 63% yield of 2a was obtained when 33 wt%
HBr solution in acetic acid was used (entry 6). The concentration
examination suggested that 0.1 M was optimal for this process
(entries 6-8). Other source of hydrogen bromide, such as
triethylamine hydrobromide and pyridine hydrobromide, all failed
to produce the desired product (entries 9-10). Inspired by Chen’s
report,[25] KBr was added to avoid Kornblum oxidation and the
yield of 2a was successfully improved to 72% (entry 11).
Interestingly, 3a could be obtained in 63% yield by adding
another portion of hydrogen bromide (1.1 equiv.) and DMSO
(1.1 equiv.) after 12-hours' reaction (entry 12). To our surprise,
the decrease of the loading of HBr and DMSO could switch the
product selectivity from thiophene 2a to dihydrothiophene 4a,
which is difficult to be obtained via conventional methods (entry
13).
R2
R3
HBr (2.2 equiv.)
KBr (2.0 equiv.)
R2
R3
O
S
HO
R4
R1
R4
Me
Me
CH3NO2, 120 °C, 12 h
Table 1. Optimization of reaction conditions.[a]
S
R1
1
2
Ph
Ph
Br
Ph
Ph
HO
Me
O
S
HBr
+
+
+
R
Me
Me
R
I
Me
Me
S
S
S
2a
3a
4a
1a
Yield (%)[b]
S
S
S
S
Entry
[Br]
Solvents
T (oC)
Con. (M)
R = F, 2f, 74%
= Cl, 2g, 65%
= Br, 2h, 72%
= I, 2i, 68%
2a
8
3a
-
4a
8
20
-
R = Me, 2b, 54%
= tBu, 2c, 52%
= Cy, 2d, 49%
2e, 53%
2j, 48%
1
2
HBr
HBr
toluene
dioxane
DMSO
100
100
100
100
120
120
120
120
120
120
120
120
120
0.20
0.20
0.20
0.20
0.20
0.20
0.10
0.05
0.10
0.10
0.10
0.10
0.10
15
-
-
NC
Br
3
HBr
-
4
HBr
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
DCE
56
60
63
68
55
-
-
-
S
S
S
S
2n, trace
(4n, 35% yield)
5
HBr
-
-
2k, 38%
2l, 62%
2m, 67%
6
HBr[c]
HBr[c]
HBr[c]
Py•HBr
-
-
nHex
7
-
-
Me
8
-
-
S
S
Me
S
S
9
-
-
2o, 3%[a]
2p, trace
2q, N.D.
2r, 28%
10
11[d]
12[e]
13[f]
Et3N•HBr
HBr[c]
-
-
-
Scheme 2. Synthesis of 3-arylthiophenes. Conditions: 1 (0.20 mmol), DMSO
(0.44 mmol), HBr (33%, 0.44 mmol), KBr (0.40 mmol), CH3NO2 (2.0 mL), 120
oC, 12 h. Isolated yields were given. [a]Determined by 1H NMR with mesitylene
as the internal standard.
72
2
-
-
HBr[c]
63
-
-
HBr[c]
14
43
Next, we shifted our attention to explore the substrate scope
of brominated thiophenes (Scheme 3). The reaction could be
carried out with a series of allylic alcohols with different
substituents on the aryl ring. It was observed that electron-
donating substrates (3b-3e) gave slightly decreased yields in
this case. However, substrates bearing halides, such as F, Cl, Br
and I, were readily converted to the corresponding 2-bromo
[a]Conditions: 1a (0.20 mmol), DMSO (0.44 mmol), HBr (40%, 0.44 mmol),
solvent, T oC, 12 h. [b]Determined by GC-FID with mesitylene as the internal
standard. [c]33 wt% in acetic acid. [d]KBr (0.40 mmol) was added as additive.
[e]After 12 h, additional DMSO (0.22 mmol) and HBr (33%, 0.22 mmol) was
added. The reaction mixture was then heated at 60 oC for 6 h. [f]DMSO (0.20
mmol), HBr (33%, 0.40 mmol).
2
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10.1002/anie.202109026
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substituted thiophenes in 46-66% yields (3f−3j). Strong electron-
withdrawing group CF3 was also applicable under the current
reaction conditions (3k). Moreover, the naphthyl substituted
allylic alcohol was tested in this process, leading to 2-
brominated thiophene 3l in 50% yield. Substrate with a polar
functional group (cyano) provided brominated thiophene with
lower yield (3n). Alkyl substituted allylic alcohol could also be
transformed to target product (3o). The introducing of methyl
group onto R1 position caused a decrease of yield (3p). The
alkene bears aryl group on terminal site didn’t work in this
protocol (3q). Interestingly, dibrominated thiophene product was
obtained with a methyl group on the internal site of alkene (3r’).
In general, the substrate tolerance for the 2-bromo-3-aryl
thiophenes is consistent with that for 3-arylthiophene (Scheme 2
vs 3). It is worth noting that other regioisomers of brominated
thiophene were not observed. This high regioselectivity of
bromination probably resulted from the higher nucleophilicity of
C2 position on 3-arylthiophene and low concentration of Br2 that
was generated in situ.[24b]
Substrates with naphthyl group, no matter located at the α- or β-
position, were both suitable and produced the desirable product
in 38% and 41% yield, respectively (4k,4l). In general, the yields
of dihydrothiophenes are comparably lower than thiophenes,
which can be attributed to the difficulties in suppressing
oxidation of dihydrothiophene to corresponding thiophene. The
introduction of a cyano group on the aryl group of allylic alcohol
provided the corresponding product in 35% yield (4n). In
addition, alkyl substituted allylic alcohol could afford the target
product (4o). Only a small amount of dihydrothiophene was
observed through the introducing of methyl group onto R1
position (4p). Substrate with phenyl group on terminal site of
alkene couldn’t be transformed to product (4q). To our delight,
substrate with a methyl group on the internal site of alkene was
tolerated (4r). Due to the decrease of DMSO, some amount of
unreacted diene was observed after workup. Furthermore, small
amount of side product from Diels-Alder cycloaddition of diene
was also detected under this protocol.
Scheme 4. Synthesis of 2-substituted 2, 5-dihydrothiophenes. Conditions: 1
(0.20 mmol), DMSO (0.20 mmol), HBr (33%, 0.40 mmol), DCE (2.0 mL), 120
oC, 12 h, under N2. Isolated yields are given. DCE = 1,2-Dichloroethane.
[a]DMSO (0.32 mmol), HBr (33%, 0.48 mmol), CH3NO2 (2.0 mL). [b]DMSO (0.44
mmol), HBr (33%, 0.44 mmol), CH3NO2 (2.0 mL). [c]Determined by 1H NMR
with mesitylene as the internal standard.
Scheme 3. Synthesis of 2-bromo-3-arylthiophenes in one pot. Conditions: 1
(0.20 mmol), DMSO (0.44 mmol), HBr (33%, 0.44 mmol), KBr (0.40 mmol),
CH3NO2 (2.0 mL), 120 oC, 12 h, then DMSO (0.22 mmol), HBr (33%, 0.22
mmol), 60 oC, 6 h. Isolated yields were given. [a]DMSO (0.40 mmol), HBr (33%,
0.40 mmol) was used in the second step. [b]Accompanied by inseparable
thiophene product, the yield of the product has been adjusted according to 1H
NMR analysis. [c]Accompanied by inseparable monobromination product, the
yield of the product has been adjusted according to 1H NMR analysis.
To unveil the mechanistic details of this established protocol,
several control experiments were thereby performed (Scheme 5).
When subjecting 2-phenyl-1,3-butadiene (5a) rather than 2-
phenylbut-3-en-2-ol (1a) to the standard reaction conditions, 3-
phenyl-thiophene (2a) could also be obtained in 72% yield
(Scheme 5a). This suggests that diene 5a might be an
intermediate for the formation thiophene 2a. According to
previous reports,[24, 26] DMSO could react with HBr to produce
dimethyl sulfide (DMS) and Br2. To test such process whether
occurred in this protocol or not, the reaction between diene 5a
Through decreasing the equivalents of mild oxidant DMSO
and HBr, the scope generality for the redox selectivity switch
towards dihydrothiophenes was investigated (Scheme 4). The
reactions of substrates with electron-donating (4b-d) and -
withdrawing substituents (4e-i) at the para position of the
benzene ring all proceeded smoothly to give dihydrothiophene
products in decent yields. Substituents at the meta position of
phenyl ring of allylic alcohol also exerted moderate reactivity (4j).
3
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10.1002/anie.202109026
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and DMS in the presence of Br2 was conducted (Scheme 5b).
The result showed that 69% yield of 2a could be delivered,
indicating that DMS and Br2 may be the active intermediates
enrolled in the formation of 2a. In addition, it was also found that
3-phenyl-thiophene 2a could be obtained in 72% yield from the
oxidation of dihydrothiophene 4a with the aid of DMSO and HBr,
(Scheme 5c). Notably, 34% yield of trimethylsulfonium bromide
6 was observed as a side-product under the optimal conditions
(Scheme 5d). This observation implies MeBr is the other
destination for the methyl groups on DMSO.
volcano-shaped correlation was observed between the yield of
dihydrothiophene 4a and the reaction time, while a sigmoidal
kinetic curve was found for the desired thiophene 2a. In addition,
the trend of decrease of DMSO is consistent with 5a. These
results were in accordance with the above control experiments
(Scheme 5a and 5c) which suggests that diene 5a is a probable
intermediate of the reaction and can be converted into
dihydrothiophene 4a and furthermore, thiophene 2a.
On the basis of the aforementioned observations and
previous reports,[24, 26-27] a plausible mechanism for this DMSO-
based redoxdivergent construction of (dihydro)thiophenes was
shown in Scheme 6. Initially, an acid and thermal-induced
dehydration of allylic alcohol 1a produces the diene product 5a.
Meanwhile, the Br2 and DMS are generated from the oxidation of
HBr by DMSO.[28] Next, the reaction between diene 5a and Br2
gives bromonium ion A, which then undergoes nucleophilic
attack by DMS to afford the sulfonium ion B (Path I). A
subsequent nucleophilic substitution of intermediate B with
bromide anion releases the MeBr species and generates sulfide
C. A further intramolecular nucleophilic substitution yields cyclic
sulfonium salt D. An alternative pathway for the formation of
intermediate
D includes dibromination of alkene (A') and
subsequent inter-/intramolecular nucleophilic substitutions (Path
II). A final reaction between intermediate D and bromide anion
produces the dihydrothiophene product 4a. In the presence of
excess Br2, intermediate
E can be yielded through the
bromination of 4a. Subsequent elimination of HBr from the E
gives thiophene 2a. In the end, further bromination of 2a with Br2
produces 2-bromothiophene 3a in an oxidative fashion.
Scheme 5. Control experiments
HBr (2.2 equiv.)
Ph
Ph
HO
Me
O
S
KBr (2.0 equiv.)
Me
Me
CH3NO2, 100 °C
S
1a
2a
Ph
Ph
S
5a
4a
Scheme 6. Proposed redoxdivergent mechanism for (dihydro)thiophene.
The synthetic utility of current protocol was demonstrated by
diverse derivatizations of the obtained (dihydro)thiophene
products 2a-4a (Scheme 7). As illustrated in Scheme 7a,
oxidation of 4a with m-CPBA could readily give sulfolene 7 in
93% yield. In the presence of trifluoroacetic acid and
triethylsilane, 2a could be reduced to tetrahydrothiophene 8 in
an acceptable yield.[29] A bromination of 2a with Br2 successfully
provided 2,3,5-tribromo-4-phenylthiophene 11 in 97% yield. To
our delight, the obtained polybrominated thiophene 11 could be
further functionalized through Suzuki-Miyaura cross-coupling to
Figure 1. Kinetic studies of this synthesis.
The kinetic studies were further carried out to interpret the
reaction process. As shown in Figure 1, the diene intermediate
5a was quickly formed at the early stage of the reaction and was
continuously consumed as the reaction ongoing. In addition, a
4
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10.1002/anie.202109026
Angewandte Chemie International Edition
COMMUNICATION
enable a rapid assembly of tetraphenylthiophene 12 (85% yield).
For the transformation of 3a, an acylative reaction with benzoyl
chloride generated trisubstituted thiophene 9. On the other hand,
the Pd-catalyzed cross-coupling reaction of 3a with
phenylboronate efficiently delivered disubstituted thiophene 10
with excellent yield (99%).
practicability of this redoxdivergent strategy, bioactive DuP 697
and its regioisomers were programmatically and concisely
synthesized from brominated thiophenes 3i and 3f. Firstly, 3i
could be easily transformed to 16a through a CuI-catalyzed
coupling reaction.[32] Then, DuP 697 (18a) could be obtained in
40% yield through Pd-catalyzed Suzuki–Miyaura cross-coupling
with arylboronic acids, followed by bromination of the
diarylthiophene 17a. Under Pd catalysis,[33] 16a was coupled
with potassium aryltrifluoroborate to give 18b in 27% yield (two
steps from 3i). Another DuP 697 regioisomer 18c could be
easily accessed (74% yield) through Pd-catalyzed C–H arylation
at the C5 position of brominated thiophenes 3f with aryl
iodide.[34] Under the condition for the direct C3 C–H arylation,
18d can be produced between the cross coupling between
thiophene 3f and potassium aryltrifluoroborate. This one step
synthesis represents the shortest synthesis for 18d. Finally, 3f
were cross-coupled with arylboronic acids in the presence of
Pd(PPh3)4 catalyst to afford 17b in excellent yied, which could
be easily brominated with bromine to gave the last DuP 697
regioisomer 18e.
Tetraarylthiophenes with four totally different aryl groups are
privileged structures and useful building blocks in material
chemistry.[30] However, the synthetic access to such skeletons is
challenging and usually requires multiple steps (5-6 steps).[30a,
30b]
With brominated arylthiophene 3a in hand, we could easily
synthesize the triarylthiophene 14 in 46% yield (for two steps)
via the continuous Suzuki-type C–H/C–Br arylation under
palladium catalysis. After a final Pd-catalyzed C–H arylation with
bromoarene, a new tetraarylthiophene 15 with four different aryl
groups could be prepared in high efficiency (3 steps, 27.1%
overall yields, Scheme 7b).
With respect to bioactive molecules, DuP 697 (18a) and
analogs were difficult to obtain via the traditional methods which
need five steps at least.[31] To further demonstrate the
a) Divergent transformation of (dihydro)thiophenes
b) Three step synthesis of tetrasubstituted thiophene bearing four different aryl groups
tBu
Ph
Ph
Br
B(OH)2
Ph
Ph
Pd(tfa)2 (10 mol%)
S
O
S
S
+
O
O
Ag2O (2.0 eq.), Cs(tfa) (1.0 eq.)
1,4-benzoquinone (0.5 eq.)
TFA in HOAc (40% v/v)
tBu
Br
7: 93% yield
8: 48% yield
9: 35% yield
S
Br
S
13
3a
m-CPBA
DCM
TFA, Et3SiH
Benzene
Yb(OTf)3
PhCOCl
MeO
CH3NO2
Pd(PPh3)4
(3 mol%)
BPin
L:
Ph
Ph
Ph
Br
PtBu2
MeO
MeO
tBu
tBu
S
4a
S
2a
S
3a
4-MeOC6H4Br (2.0 eq.)
Pd(OAc)2 (10 mol%)
L
(20 mol%)
Br2
AcOH
Pd(PPh3)4
(3 mol%)
Ph-BPin
MeO
Cs2CO3 (3.0 eq.)
o-xylene, reflux
S
S
Pd(PPh3)4
(3 mol%)
Ph
Ph
Ph
Ph
Ph
Br
Br
Ph
OMe
MeO
MeO
Ph-BPin
Br
Ph
S
S
S
15, 59% yield
14, 46% yield of two steps
12: 85% yield
11: 97% yield
10: 99% yield
(c) Programmable and concise synthesis of bioactive DuP 697 and its regioisomers
Me
F
O
Me
O
O
S
I
F
S
O
Ar
HO
Me
b) Pd cat.
a) Cu cat.
Ar = 4-I-Ph
Ar = 4-F-Ph
f) Pd cat.
+
O
O
S
Br
Br
3f, 66% yield
S
S
Br
S
S
S
Me
S
Me
Me
F
O
17a
16a
3i, 66% yield
17b, 98% yield
Br2
c) Pd cat.
d) Pd cat.
e) Pd cat.
Br2
F
Me
F
O
Me
Me
O
S
O
O
F
S
O
S
F
O
O
O
Br
Br
S
S
Br
S
S
S
Br
Me
Me
Br
18d, 58% yield
S
F
S
O
O
DuP 697, 18a
40% yield of three steps from 3i
18b, 27% yield of two steps from 3i
18c, 74% yield
18e, 79% yield
a) CuI (10 mol%), L-proline sodium salt (20 mol%), MeSO2Na, 24 h; b) Pd(PPh3)4 (3 mol%), 4-FC6H4B(OH)2, 12 h; c) Pd(tfa)2 (10 mol%), Ag2O, BQ, Cs(tfa), 4-FC6H4BF3K, TFA, 24 h;
d) PdCl2(PPh3)2 (5 mol%), AgNO3, KF, 4-MeSO2C6H4I, 5 h; e) Pd(tfa)2 (10 mol%), Ag2O, BQ, Cs(tfa), 4-MeSO2C6H4BF3K, TFA, 24 h; f) Pd(PPh3)4 (3 mol%), 4-MeSO2C6H4B(OH)2, 12 h.
Scheme 7. Divergent and programmable synthetic transformations of (dihydro)thiophenes
5
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10.1002/anie.202109026
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Röhrig, M. Sicken, B. Knipp, A. Herrmann, M. Pohl, H. Schmickler, J.
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In conclusion, we have established a redoxdivergent
strategy for the selective construction of substituted
thiophenes or dihydrothiophenes under metal-free conditions.
This protocol employed readily available allylic alcohols as
starting materials and DMSO as mild oxidant to offer
derivatives of (dihydro)thiophenes efficiently. Manipulation of
the selectivity could be governed by the dosage of DMSO
and HBr. Mechanistic investigations were conducted to
interpret the redox selectivity and the roles of DMSO. In
addition, synthetic transformations demonstrated that this
strategy could realize programmable and concise synthesis of
tetraarylthiophenes, bioactive DuP 697 and its regioisomers.
Thus, this redoxdivergent strategy may serve as a general
platform for achieving synthetically and medicinally useful
five-numbered sulfur-containing heterocycles.
Acknowledgements
We thank Prof. Yong-Gui Zhou (DICP) and Prof. Zhi-Shi Ye
(DUT) for helpful discussions and manuscript revisions; Xiao-
Dong Liu for initial contributions for the thiophene synthesis.
Financial support from Dalian Outstanding Young Scientific
Talent (2020RJ05), and the National Natural Science
Foundation of China (22071239, 21801239) is acknowledged.
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Keywords: redoxdivergent • thiophene • dihydrothiophene •
bromothiophene • dimethyl sulfoxide
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7
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Entry for the Table of Contents
Ar
S
O
S
Ar
Me
Me
HBr
+
S
Ar
HO
Me
Ar
Br
Metal free
S
Redoxdivergent control
Easily available materials
We reported herein a redoxdivergent construction of dihydrothiophenes, thiophenes and bromothiophenes respectively from readily
available allylic alcohols, dimethyl sulfoxide (DMSO) and HBr. Synthetic transformations demonstrated that this strategy could realize
programmable and concise synthesis of bioactive and functional molecules.
8
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