Copper(II)-catalyzed Domino Reaction of the Acyclic Ketene-(S,S)-Acetals with Diazo Compounds: Convenient Synthesis of Poly-substituted Thiophenes

Article abstract of DOI:10.1002/adsc.201901089

Copper(II)-catalyzed domino reaction between the acyclic ketene-(S,S)-acetals and diazo compounds has been successfully developed. This reaction proceeds through a sequential formation of electrophilic copper carbenoid, sulfur ylide and subsequent C?S bon

Full text of DOI:10.1002/adsc.201901089

Title: Copper(II)-catalyzed Domino Reaction of the Acyclic Ketene-(S,
S)-Acetals with Diazo Compounds: Convenient Synthesis of Poly-
substituted Thiophenes
Authors: Ran Sun, Yang Du, Cui Tian, Lei Li, He Wang, and Yu-Long
Zhao
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901089
Link to VoR: http://dx.doi.org/10.1002/adsc.201901089

10.1002/adsc.201901089
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper(II)-catalyzed Domino Reaction of the Acyclic Ketene-
(S,S)-Acetals with Diazo Compounds: Convenient Synthesis of
Poly-substituted Thiophenes
Ran Sun,a Yang Du,a Cui Tian,c Lei Li, a He Wang,a,* and Yu-Long Zhao b,*
a
School of Chemistry and Materials Science, Liaoning Shihua University, Dandong Road 1, Fushun 113001, P. R.
China. e-mail: heliwang123@126.com.
Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Faculty of Chemistry, Northeast
b
Normal University, Changchun 130024, P. R. China. e-mail: zhaoyl351@nenu.edu.cn.
Luzhou Agricultural Bureau, Jiangyang West Road 4, Luzhou 646000, P. R. China.
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
thiophenes from easily available acyclic starting
materials in a single step is highly desirable.
Abstract. Copper(II)-catalyzed domino reaction
between the acyclic ketene-(S,S)-acetals and diazo
compounds has been successfully developed. This
reaction proceeds through a sequential formation of
electrophilic copper carbenoid, sulfur ylide and
subsequent C-S bond coupling and cleavage. Notably,
the domino reaction features broad the readily available
acyclic ketene-(S,S)-acetals scope and provides a new
strategy for the synthesis of poly-substituted
thiophenes.
Keywords: Acyclic ketene-(S,S)-acetals; Diazo
compounds; Poly-substituted thiophenes; Domino
reaction; Copper catalyst
Poly-substituted thiophenes and analogues are
valuable building blocks widely existed in
pharmaceuticals and natural products,[1] and they
have explicitly displayed a broad spectrum of
biological activities including antibacterial,[2a]
antifungal,[2b] antioxidant,[3] antithrombotic,[4] and
antitumor.[5] Moreover, they also have found
applications in functional material[6] and organic
Figure 1. Representative biologically active
tetrasubstituted thiophene derivatives.
synthesis.[7]
Among
various
poly-substituted
Diazo compounds are versatile synthons and have
been extensively studied for numerous challenging
and intriguing syntheses due to their adequate
reactivity and high energy.[9] In particular, transition-
metal-catalyzed reactions of diazo compounds have
been highly successful.[10] Pioneered by Doyle and
Hu, the applications of electrophilic trapping in situ-
generated ylides from metal carbene have become a
versatile and useful synthetic strategy for the rapid
construction of complex molecules in recent
decade.[11, 12] In addition, the situ-generation of sulfur
ylides from diazo compounds and sulfide has been
thiophenes, tetrasubstituted thiophene derivatives
possess potential pharmacologically activities, such
as tinoridine, strontium ranelate, modulators of the
adenosine A1 receptor 2A3BTs and PD81,723 (Fig.
8]
1).[1c,
Given these fascinating activities and
applications, the development of facile and
convenient synthetic route to thiophenes is of great
significance. Although a variety of protocols have
been reported for synthesis poly-substituted
thiophenes in recent years, these strategies often rely
on the functionalization of simpler thiophenes,
whereas the utility of acyclic precursors as substrate
by a tandem method are scarce. Therefore, the direct
and convenient synthesis of poly-substituted
well documented for the construction of C-S and C-C
14]
bond[13,
via the Doyle-Kirmse[15] or Stevens[16]
rearrangement reaction. In stark contrast, little
1
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10.1002/adsc.201901089
Advanced Synthesis & Catalysis
attention has been paid to cleavage C-S bond[17] via
solution of 2a (0.6 mmol) and solvent (1 mL) were added
over 1 h via syringe pump, after the reaction mixture was
heated to at 80 °C for 3 h under air. b) Isolated yield.
sulfur ylide to produce thiophenes. As part of our
19]
ongoing research on ketene dithioacetal[18,
and
diazo compounds,[20] we report herein a new strategy
for the direct and convenient synthesis of poly-
substituted thiophenes via a Cu(II)-catalyzed domino
reaction between the acyclic ketene-(S,S)-acetals and
diazo compounds.
good yields. Notably, substituents R1 were changed
for cyano, amide, and benzoyl (1d-1f), the tandem
reaction proceeded smoothly and the exclusive multi-
substituted thiophenes 3da-3fa were isolated in
moderate to good yields. In comparison, the non-
substituted at the α-position (R1 = H), the R3 group in
1 bearing varied from alkyl to alkenyl groups, and
afforded the desired products 3ga-3na in moderate to
good yields. To scope of the diazo compounds was
next explored. Ketene-(S,S)-acetals 1h can proceed
smoothly with various diazo compounds (such as 2b,
2c, 2d, or 2e), resulting in the formation of the
corresponding multi-substituted thiophenes in
moderate yields (3hb-3he). In comparison, no
reaction was observed for substrates 2f-2i, as a result
of the steric effects. To demonstrate the synthetic
At the outset of our studies, we investigated to the
multi-substituted thiophene synthesis from the ethyl
2-(bis(ethylthio)methylene)-3-oxobutanoate 1a with
ethyl 2-diazoacetate 2a via a tandem process. Using
CuBr (7 mol%) as a catalyst, desired multi-
substituted thiophenes 3aa and 4aa were obtained in
48% and 18% yields in DCE under air, respectively
(Table 1, entry 1). Screening of copper catalysts
revealed that Cu(OTf)2 was optimal one (entries 2-5).
When switching the copper catalyst to FeCl3,
[RhCp*Cl2]2,
[Rh(COD)Cl]2,
Rh(PPh3)3Cl,
Rh2(OAc)4, or [Ru(p-cymene)Cl2]2 catalyst, the
reaction could not be activated however (Table 1,
entries 6-11). Solvent effects have also been observed, applicability of the catalytic system, synthesis of
and the reaction proceeded well in DCE, while DMF,
THF and CH3CN are not suitable for this reaction
(Table 1, entries 12-14).
product 3ha on a gram-scale was carried out and a
36% isolated yield was obtained.
Surprisingly, under the optimized reaction
With the optimized reaction conditions in hand, the
scope and generality with respect to dithioacetal
derivatives were examined in table 2. Thus, a series
of α-EWG ketene dithioacetals 1 were conveniently
synthesized and reacted with ethyl 2-diazoacetate by
copper-catalyzed C-S bond coupling and cleavage.
When the R1 group in 1 were CO2Me, CO2Et, and 4-
OMeC6H4 (1a-1c), the multi-substituted thiophenes
3aa-3ca and 4aa-4ca were observed simultaneously
in
conditions, when substituents R1 were replaced by
Table 2. Synthesis of poly-substituted thiophenesa), b)
Table 1. Sceening of reaction conditiona), b)
Entry Solvent Catalyst
Yield of Yield of
3aa (%) 4aa (%)
1
2
3
4
5
6
7
8
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CuBr
CuI
CuBr2
CuCl2
Cu(OTf)2
FeCl3
[RhCp*Cl2]2
[Rh(COD)Cl]2
Rh(PPh3)3Cl
Rh2(OAc)4
[Ru(p-
48
40
46
45
59
0
trace
8
trace
17
18
15
16
17
24
0
0
trace
0
9
10
11
trace
0
trace
cymene)Cl2]2
Cu(OTf)2
Cu(OTf)2
12
13
14
a)
DMF
THF
0
trace
38
0
trace
10
a)
Reaction conditions: 1 (0.2 mmol) and Cu(OTf)2 (7
CH3CN Cu(OTf)2
Reaction conditions: 1a (0.2 mmol) and catalyst (7
mol%) were dissolved in solvent (1 mL), followed by a
mol%) were dissolved in DCE (1 mL), followed by a
solution of 2 (0.6 mmol) and DCE (1 mL) were added over
2
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10.1002/adsc.201901089
Advanced Synthesis & Catalysis
1 h via syringe pump, after the reaction mixture was heated
Based on the above results and previously reported
studies,[10, 17, 20] a plausible mechanism is proposed for
this reaction (Scheme 1). First, decomposition of
nucleophilic diazo compounds in the presence of
Cu(OTf)2 affords electrophilic copper carbenoid A
with the elimination of N2.[23] The intermediate A is
then attacked by the acyclic ketene-(S,S)-acetal 1 to
deliver a sulfonium ylide B, which produces
intermediate C via elimination of [CuLn].[10e]
c)
to at 80 °C for 3 h under air. b) Isolated yield. Reaction
was performed at 40 °C. d) Reaction was performed with
5.5 mmol of 1h, followed by a solution of 2a (16.5 mmol)
and DCE (15 mL) were added over 1.5 h via syringe pump.
propionyl and acetyl, the multi-substituted thiophenes
3oa-3qa were isolated as the minor products. The
fused-ring thienothiophenes 5oa-5pa could be
obtained in 55-59% yields as the major products.
Notably, increasing the amount of 2a to 5 equiv.
delivered 5oa-5op in high yields (Table 3). The
molecular structure of 5pa was unambiguously
confirmed by X-ray crystallography (CCDC
1949636).[21] To evaluate the practical synthesis of the
catalytic system, a large-scale (4.5 mmol) reaction
was performed, and a satisfactory isolated yield could
be obtained for 5pa (from 1q).
Table 4. Synthesis of poly-substituted thiophenesa), b)
Table 3. Synthesis of poly-substituted thiophenes and
fused-ring thienothiophenea), b)
a)
Reaction conditions: 6q (0.2 mmol) and Na2S•9H2O
(0.22 mmol) in DMF (1 mL) at 80 °C for 2 h. b) Isolated
yield.
Subsequent an intramolecular aldol cyclization
affords the five-membered intermediate D, which
undergoes elimination of HO− to give intermediate E.
Finally, the product 3 is formed via C-S bond
cleavage in the presence of HO−.[13] In the case of α-
EWG ketene dithioacetals 1a-1c, the product 3
attacked the intermediate A to furnish a sulfonium
ylide F, which undergoes elimination of [CuLn] and
C-S bond cleavage, leading to the formation of multi-
substituted thiophenes 4. In addition, the substitution
R1 are propionyl and acetyl, intermediate F further
undergoes an intramolecular aldol cyclization to
afford the fused five-membered alcohol intermediate
H. Finally, the product 5 is formed via elimination of
R2OH. Since the propionyl and acetyl group have the
stronger electron-withdrawing property than esters or
amides, intramolecular aldol cyclization reaction is
more likely to proceed.
a)
Reaction conditions: 1 (0.2 mmol) and Cu(OTf)2 (7
mol%) were dissolved in DCE (1 mL), followed by a
solution of 2a (0.6 mmol) and DCE (1 mL) were added
over 1 h via syringe pump, after the reaction mixture was
c)
heated to at 80 °C for 3 h under air. b) Isolated yield.
d)
Reaction was performed using 2a (1 mmol). Reaction
was performed with 4.5 mmol of 1q, followed by a
solution of 2a (22.5 mmol) and DCE (15 mL) were added
over 1.5 h via syringe pump.
To demonstrate the synthetic utility of the multi-
substituted thiophenes, the substrate 6q was
conveniently prepared in high yield by the reaction of
product 3qa with aldehydes. Formation of 6q was
proposed to occur the [5C+1S] annulation with Na2S•
9H2O,[22] and furnished thieno[2,3-b]thiopyran-4-ones
7q in excellent yield (Table 4).
3
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10.1002/adsc.201901089
Advanced Synthesis & Catalysis
General Procedure for the Preparation of 7q (7qa as
Example)
To a solution of 6qa (0.2 mmol) and Na2S•9H2O (0.22
mmol) in DMF (1 mL) at 80 °C for 2 h. After completion
of the reaction (monitored by TLC), the reaction mixture
was poured into water (50 mL) and extracted with CH2Cl2
(10 mL × 3). The combined organic extracts were dried
over anhydrous Na2SO4, filtered and concentrated under
reduced pressure to yield the corresponding crude product,
which was purified by chromatography (silica gel,
petroleum ether/ diethyl ether = 30/1, V/V) to give 7qa as
a white solid.
Acknowledgements
We acknowledge financial supports from the National Natural
Science Foundation of China (21702087, 21871044, and
21801105), Natural Science Foundation of Liaoning Province
(20170520353, and 20180510033), Research Project Fund of
Liaoning Provincial Department of Education (L2017LQN010
and L2017LZD001 ), Talent Scientific Research Fund of
Liaoning Shihua University (2016XJJ-078 and 2016XJJ-079), the
open project of Jilin Province Key Laboratory of Organic
Functional Molecular Design & Synthesis (No.130028836 and
130028911).
Scheme 1. Postulated Mechanism.
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In conclusion, we have developed a novel
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This reaction provides simple and convenient,
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UPDATE
Copper(II)-catalyzed Domino Reaction of the
Acyclic Ketene-(S, S)-Acetals with Diazo
Compounds: Convenient Synthesis of Poly-
substituted Thiophenes
Adv. Synth. Catal. Year, Volume, Page – Page
Ran Sun, Yang Du, Cui Tian, Lei Li, He Wang,*
and Yu-Long Zhao*
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