One-Pot Synthesis of 2,3,5-Trisubstituted Thiophenes through Three-Component Assembly of Arylacetaldehydes, Elemental Sulfur, and 1,3-Dicarbonyls

Article abstract of DOI:10.1002/adsc.201701332

The three-component reaction for the synthesis of 2-arylthiophenes has been developed. Easily available arylacetaldehydes, 1,3-dicarbonyls, and elemental sulfur were directly assembled through cascade condensation/ annulation under base conditions. The pr

Full text of DOI:10.1002/adsc.201701332

Title: One-Pot Synthesis of 2,3,5-Trisubstituted Thiophenes through
Three-Component Assembly of Arylacetaldehydes, Elemental
Sulfur, and 1,3-Dicarbonyls
Authors: Huawen Huang, Zilong Wang, Zhonghua Qu, Fuhong Xiao,
and Guojun Deng
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701332
Link to VoR: http://dx.doi.org/10.1002/adsc.201701332

Advanced Synthesis & Catalysis
10.1002/adsc.201701332
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
One-Pot Synthesis of 2,3,5-Trisubstituted Thiophenes through
Three-Component Assembly of Arylacetaldehydes, Elemental
Sulfur, and 1,3-Dicarbonyls
a
a
a
a
a,b
Zilong Wang, Zhonghua Qu, Fuhong Xiao, Huawen Huang, * Guo-Jun Deng *
a
Key Laboratory for Green Organic Synthesis and Application of Hunan Province, Key Laboratory of Environmentally
Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan
4
11105, China
E-mail: hwhuang@xtu.edu.cn; gjdeng@xtu.edu.cn
b
Beijing National Laboratory for Molecular Sciences and CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences (CAS) Beijing 100190 (P.R. China)
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))
materials.[5] Accordingly, intensive efforts have been
Abstract. The three-component reaction for the synthesis made to develop synthetic methods for functionalized
of 2-arylthiophenes has been developed. Easily available
arylacetaldehydes, 1,3-dicarbonyls, and elemental sulfur
were directly assembled through cascade condensation/
annulation under base conditions. The present protocol
provides a facile entry to 2,3,5-trisubstituted thiophenes
with moderate to excellent yields and good functional
group tolerance.
[6]
thiophenes. Besides the classic Paal−Knorr reaction,
typically, those methodologies catalogue into two
basic classes: late-stage modification of pre-existed
thiophenes and construction of thiophene ring from
acyclic precursors. Recently, the transition-metal-
catalyzed direct C-H arylation of thiophenes has
found to be an efficient tool for the thiophene
[7]
[8]
[7c,h]
Keywords: thiophenes; arylacetaldehydes; 1,3-dicarbonyls;
elemental sulfur; one-pot
diversification.
With respect to annulation
reactions, non-readily available starting materials
[8a]
[8b,g]
such as functional mercaptans, thioamides,
[8h-j]
[8k,l]
dialkynes,
and 1,2,3-thiadiazoles
were
frequently employed to generate substituted
thiophenes through intermolecular or intramolecular
cyclization. Also, few examples of multicomponent
From a green chemistry perspective, the direct
construction of functionalized molecules with
complex structures from simple chemicals is of great
significance and thereby has drawn much attention
among organic synthesis. In this context,
multicomponent synthesis and cascade reactions show
great potential to provide opportunities for rapid
reactions led to the construction of thiophene rings
[8m,n]
from readily available chemicals.
In the past
years, we and others programmed on the facile
synthesis of sulfur-containing heterocycles by using
[3a-d,9]
nontoxic and bench-stable elemental sulfur.
preparation of target compounds through predesigned
However, to our knowledge there are few examples to
routes.[
1-2]
To develop facile synthesis of
[10]
use it for direct thiophene formation to date. Given
functionalized heterocycles, we have contributed a
the great significance of thiophenes in chemistry,
efficient access to polysubstituted thiophenes from
simple starting materials is highly desirable.
We commenced our study by exploring the model
system of phenylacetaldehyde (1a), pentane-2,4-dione
[3]
number of examples of multicomponent reactions
including
sulfur-involved
synthesis
benzothiophenes,
of
[3a]
[3b]
phenothiazines,
thiadiazoles,[
3c,d]
and benzothiazoles. Herein, we
disclose the novel self-assembly of arylacetaldehydes,
elemental sulfur, and 1,3-dicarbonyls to access 2,3,5-
trisubstituted thiophenes under base conditions.
Thiophene represents one of the most important
sulfur-containing five-membered heterocycles, which
(
2a), and sulfur powder (S ) in DMSO under an
8
ambient atmosphere (Table 1). The formation of
thiophene 3a was observed in a trace amount when
o
the reaction was run at 95 C for 16 h (entry 1). Then
a series of bases were screened for this transformation.
There was a big gap upon the yield enhancement of
as a key unit widely exists in naturally occurring
4]
products,
pharmaceuticals,[
and
functional
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201701332
[
g]
h]
thiophene formation with different carbonate bases.
2
Under O .
Yield from 5 mmol scale reaction.
[
While Cs
yield, respectively, good yield (76%) was afforded
when K CO was used (entries 2–4). Other type of
potassium bases such as CH COOK, K PO , and
KOH could not lead to yield enhancement (entries 5–
). Delightedly, the combination of K CO with
KHCO , a buffer system, was found to be the best
2
CO
3
and KHCO
3
gave 3a in 10% and 30%
Under the optimized reaction conditions, the
2
3
model reaction was gram-scalable and delivered 3a in
0% yield in the 5 mmol reaction (Table 1, entry 8).
Next we explored the scope and generality of the
base-promoted three-component assembly of
3
3
4
7
7
2
3
3
thiophenes (Scheme 1). With respect to the
arylacetaldehydes, the phenylacetaldehydes bearing
electron-donating methoxy group (3b) and bromo (3f)
at the para-position decreased the yield to 57% and
promoter for the three-component assembly, affording
the desired thiophene 3a in 81% yield (entry 8). The
examination of solvents showed that those with high
polarity, such as DMSO, DMF, and NMP, were
superior to the low-polar solvents (entries 9–13). The
reaction temperature and atmosphere were also
studied (entries 14–17), which indicated that the
reaction run at 95 C gave the best yield and the yield
was very slightly affected by the argon, oxygen, and
air atmosphere.
55%, respectively. Other reactants with para- and
meta-substituent such as methyl (3c), fluoro (3d, 3g),
and chloro (3e, 3h) gave the corresponding products
in good yields. Notably, the phenylacetaldehydes
bearing ortho-substituents (3i–3k) gave higher yields
than those with para- and meta-substituents, as
exemplified by 3c (65%) versus 3i (83%) and 3f (55%)
versus 3k (73%). These results could be attributed to
the neighborhood effect to the participated benzylic
position of arylacetaldehydes. Unfortunately, other
aliphatic aldehydes such as octanal and 3,3-
dimethylbutanal did not work at all in this reaction
system.
o
Table1. Optimization of the reaction conditions.[a]
Entry Base
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
DCE
Yield (%)[b]
1
2
3
4
5
6
-
trace
76
K
2
CO
CO
KHCO
CH COOK
PO
KOH
3
Cs
2
3
10
3
30
3
26
K
3
4
trace
7
7
8[c]
81 (70)[h]
trace
trace
10
K
K
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
2
2
CO
3
/KHCO
3
/KHCO
3
/KHCO
3
/KHCO
3
/KHCO
3
/KHCO
3
/KHCO
3
/KHCO
3
/KHCO
3
/KHCO
3
3
3
3
3
3
3
3
3
3
9[c]
CO
CO
CO
CO
CO
CO
CO
CO
CO
1 [
1 [
1 [
1 [
1 [
1 [
1 [
1 [
0
c]
c]
1
PhCl
c]
2
DMF
72
c]
3
NMP
48
c,d]
c,e]
c,f]
c,g]
4
DMSO
DMSO
DMSO
DMSO
66
5
63
6
80
Scheme 1. Scope of arylacetaldehydes.
7
79
Thereafter, we studied the scope of viable 1,3-
dicarbonyls 2 (Scheme 2). Thereby, among others 1,3-
[
a]
Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), S
16 mg, 0.5 mmol), base (3.5 equiv), DMSO (1.0 mL)
under air at 95 C for 16 h.
Isolated yields were given.
8
(
diketones
were
successfully
coupled
with
o
phenylacetaldehyde 1a to afford the target thiophenes
3l–3n in moderate yields, attached as observed with
excellent regioselectivity when unsymmetrical
diketones were subjected (3m, 3n). This unique
regioselectivity may be attributed to the steric
[
[
[
[
[
b]
c]
d]
e]
f]
2 3 3
K CO (2.0 equiv) combined with KHCO (1.5 equiv).
o
8
1
5 C.
o
00 C.
Under Ar.
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201701332
handrance of the substuents since the 2-Me- low yields. The reaction of vinylic aldehyde such as
thiophenes were formed. Then various β-ketone esters acrolein 7 and 3-butenal 8 was performed with 1,3-
bearing functional groups including synthetically dicarbonyl compound under base conditions, but no
useful alkyl fluoro (3r), decorated hydroxyl (3v), and desired vinylthiophene was formed in both cases
allyl ester (3u) were all accommodated with the (Scheme 3c). To our delight, α,β-unsaturated ketone 9
present base system, generating the desired functional instead of diketones afforded a moderate yield of
thiophene products in generally modest yields. We thiophene 3n (Scheme 3d). Other α,β-unsaturated
also tested cyclic 1,3-dicarbonyls such as ketones such as chalcone, however, gave very low
cyclohexane-1,3-dione. Very low conversion of the conversion of the thiophene generation, which is
corresponding thiophene formation was observed.
similar as the result observed by using 1,3-
diphenylpropane-1,3-dione as the coupling partner.
Scheme 2. Scope of 1,3-dicarbonyls.
We also tried heterocyclic acetaldehydes such as
pyridinyl, furanyl, and thiophenyl acetaldehyde.
Among them, only thiophenyl acetaldehyde afforded
the target bithiophene 3w in modest yield [Eq. (1)].
When malononitrile instead of 1,3-dicarbonyls was
used as the coupling partner, the respected 2-
aminothiophene 3x was given in 45% yield. [Eq. (2)]
Scheme 3. Control experiments.
Finally, to clarify the reaction pathway of the three-
component formation of substituted thiophenes,
several control experiments were performed. First, the
reaction of 1a and 2a within 1 h in the absence of
sulfur powder produced the β,γ-unsaturated diketone
A as the major product (Scheme 3e). This compound
could be the intermediate of thiophene formation
since it reacted with sulfur to give 3a in 95% yield
under the standard base conditions (Scheme 3f).
Moreover, the addition of a radical scavenger such as
BHT or TEMPO to the reaction system did not inhibit
the thiophene formation (Scheme 3g), which
To explore a broader generality of the three-
component thiophene formation, variants of
arylacetaldehydes such as 2-phenyloxirane 4, styrene
5, and ethynylbenzene 6 were employed instead of 1a
(
Scheme 3a-b). Among them, 5 and 6 proceeded
under the standard reaction conditions to give
promising results of thiophene formation, albeit in
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201701332
indicated that the three-component assembly would pressure. The residue was purified by column
chromatography on silica gel (petroleum ether/EtOAc =
not proceed through a radical pathway.
5
3
0:1) to yield the desired product 3a as light brown solid,
Based on the experimental results above, we
proposed a plausible reaction pathway for the three-
component formation of thiophenes (Scheme 4). The
base-promoted condensation of dicarbonyls and
acetaldehydes generates the β,γ-unsaturated diketone
A.[ The deprotonation of A delivers the anion
o
1
5 mg, yield 81%, mp 67-68 C. H NMR (400 MHz,
) δ 7.57 – 7.55 (m, 2H), 7.53 (s, 1H), 7.39 (t, J = 7.6
Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 2.76 (s, 3H), 2.55 (s, 3H);
CDCl
3
13
C NMR (100 MHz, CDCl
33.5, 129.0, 127.7, 125.6, 124.2, 29.8, 16.3; MS (EI): 216
70), 201 (100), 173 (10), 129 (40); HRMS (ESI) m/z calcd.
3
) δ 194.1, 148.4, 139.5, 136.9,
1
(
11]
+
+
intermediate B, which undergoes a nucleophilic attack for C H OS (M+H) 217.06816, found 217.06837.
13
13
to sulfur S
Kindler-type
n
to afford the intermediate C (Willgerodt–
reactions).[
12]
Subsequently, the Acknowledgements
intramolecular nucleophilic attack of sulfur moiety to
the carbonyl combined with an elimination of Sn-1
gives the dihydrothiophene D. Finally, the hydroxide
elimination of D with the base assistance forms the
target thiophene products.
This work was supported by the National Natural
Science Foundation of China (21502160, 21572194),
the Program for Innovative Research Cultivation
Team in University of Ministry of Education of China
(
1337304), the Hunan Provincial Innovative
Foundation for Postgraduate (CX2015B202) and the
Undergraduate Investigated-Study and Innovated-
Experiment Plan of Hunan Province.
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Trisubstituted Thiophenes
A 10 mL oven-dried reaction vessel was charged with
phenylacetaldehyde (1a, 47 μL, 0.4 mmol) acetylacetone
(
8
2a, 21 μL, 0.2 mmol), S (16 mg, 0.5 mmol), potassium
carbonate (55 mg, 0.4 mmol), potassium bicarbonate (30
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4
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Advanced Synthesis & Catalysis
10.1002/adsc.201701332
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Advanced Synthesis & Catalysis
10.1002/adsc.201701332
COMMUNICATION
One-Pot
Synthesis
of
2,3,5-Trisubstituted
Thiophenes through Three-Component Assembly
of Arylacetaldehydes, Elemental Sulfur, and 1,3-
Dicarbonyls
Adv. Synth. Catal. Year, Volume, Page – Page
Zilong Wang, Zhonghua Qu, Fuhong Xiao,
a
a,b
Huawen Huang, * Guo-Jun Deng *
6
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