Copper-Catalyzed Annulative Coupling of S,S-Disubstituted Enones with Diazo Compounds to Access Highly Functionalized Thiophene Derivatives

Article abstract of DOI:10.1021/acs.joc.9b02982

An efficient protocol toward fully substituted thiophenes and thieno[2,3-b]thiophenes has been developed through CuCl₂-catalyzed annulative coupling of S,S-disubstituted enones with diazo compounds under mild conditions. Tetrasubstituted thiophenes and thieno[2,3-b]thiophenes were efficiently accessed by variation of the feed ratio of the reactants in good to excellent yields, respectively. The synthetic methodology has demonstrated the potential for the construction of diverse thiophene derivatives.

Full text of DOI:10.1021/acs.joc.9b02982

Subscriber access provided by BIU Pharmacie | Faculté de Pharmacie, Université Paris V
Article
Copper-Catalyzed Annulative Coupling of S,S-Disubstituted Enones with
Diazo Compounds to Access Highly Functionalized Thiophene Derivatives
Yuan He, Jiang Lou, Ping Wu, Yong-Gui Zhou, and Zhengkun Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02982 • Publication Date (Web): 20 Dec 2019
Downloaded from pubs.acs.org on December 22, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 42
The Journal of Organic Chemistry
1
2
3
4
Copper-Catalyzed Annulative Coupling of S,S-Disubstituted Enones with Diazo
5
6
Compounds to Access Highly Functionalized Thiophene Derivatives
7
8
9
Yuan He,†,‡ Jiang Lou,†,‡ Ping Wu,† ,‡ Yong-Gui Zhou,*,† and Zhengkun Yu*,†,§
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
† Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023,
People’s Republic of China
‡ University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
§ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Road, Shanghai 200032, People’s Republic of China
E-mail: zkyu@dicp.ac.cn; ygzhou@dicp.ac.cn
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
_____________________________________________________________________
ABSTRACT: An efficient protocol toward fully substituted thiophenes and
thieno[2,3-b]thiophenes has been developed through CuCl2-catalyzed annulative
coupling of S,S-disubstituted enones with diazo compounds under mild conditions.
Tetrasubstituted thiophenes and thieno[2,3-b]thiophenes were efficiently accessed by
variation of the feed ratio of the reactants in good to excellent yields, respectively.
The synthetic methodology has been demonstrated the potential for the construction
of diverse thiophene derivatives.
_____________________________________________________________________
INTRODUCTION
Synthesis of thiophenes has been paid much attention because they represent an
important class of sulfur-containing heterocycles, which are ubiquitous core structural
motifs in many pharmaceutical,1,2 functional materials,3 and transition-metal
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 42
1
2
3
4
5
6
7
8
9
complexes.4 For example, thiophene derivatives have been medically considered as
the potent inhibitors of p38 kinase,5a IKK ,5b and PTP1B,5c (Figure 1).
Thieno[2,3-b]thiophenes are pharmaceutically used for inhibiting the growth of
bacterial pathogens and treatment of bacterial infections.5d The general synthetic
approaches to access such S-heterocycles involve either functionalization of the α-
and β-positions of the preconstructed thiophene skeleton,5e,6 or construction of the
thiophene ring from appropriately substituted open chain precursors.7 The latter
approach is obviously more versatile and attractive but has been less developed. In
_____________________________________________________________________
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Selected bioactive thiophene derivatives.
_____________________________________________________________________
this regard, Fiesselmann,8 Gewald,9 Paal,10 and Hinsberg11 reactions can be applied
for the direct establishment of a thiophene ring in specific thiophene derivatives.
Ketene S,S-acetals12a are
known
for the same purpose through
transition-metal-catalyzed C S bond cleavage and reconstruction.12b The traditional
synthetic strategies for thieno[2,3-b]thiophenes are usually based on the cyclization of
prefunctionalized organosulfur compounds.13 Although considerable advance has
been achieved toward the synthesis of thiophene derivatives, concise and efficient
methods are still highly desirable for the construction of functionalized thiophenes in
2
ACS Paragon Plus Environment

Page 3 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
order to overcome the limitations of the present synthetic protocols in terms of harsh
conditions, low yields, expensive catalysts, and/or difficult purification.
8
9
Transition-metal-catalyzed reactions using diazo compounds14 as the carbene
precursors allow for the rapid assembly of useful complex molecules which cannot be
readily accessed by other methods.15 As versatile C1 synthons, diazo compounds are
potentially used for the direct construction of cyclic architectures through
cycloaddition or annulative coupling reactions.16,17 Diazo compounds are amphiphilic
and the negatively polarized diazo carbon atom is nucleophilic, while the metal
carbene species generated from a diazo compound has an electron-deficient carbene
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
center.18 Thus, diazo compounds can exhibit diverse reactivities.
_____________________________________________________________________
Scheme 1. The Synthetic Strategies to Access Functionalized Thiophenes
_____________________________________________________________________
During the ongoing investigation of the reactivities of alkylthio-functionalized
internal alkenes,19 we found that  -oxo and thioxo-fuctionalized, N,S-substituted
internal alkenes could efficiently react with the carbene precursor compounds, that is,
ketone N-tosylhydrazones, under copper catalysis, affording five-membered 2-imino
O- and S-heterocycles via carbene insertion into the olefinic C=C bond,19c whereas
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 42
1
2
3
4
5
6
7
8
9
they underwent annulative coupling with aldehyde N-tosylhydrazones to give
thiophene products under transition-metal-free conditions19d (Scheme 1a). We
conceived that the nucleophilicity/electrophilicity of the reaction intermediates
generated in situ from N-tosylhydrazones, that is, the copper carbene species in the
presence of a copper catalyst, and the diazo species under the transition-metal-free
conditions, might be dramatically altered upon variation of the reactants and reaction
conditions.20 Nucleophilic attack of the thiocarbonyl sulfur at the diazo carbon atom
may form a thiocarbonyl ylide, that is, a sulfur-centered 1,3-dipole, which can readily
undergo 1,5-dipolar electrocyclization.21 Thus, the sulfur atoms of a S,S-disubstituted
enone were envisioned to interact with diazo compounds to form sulfur ylide
intermediates which then cyclize to give S-heterocyclic compounds. Herein, we
disclose the copper-catalyzed annulative coupling of S,S-disubstituted enones with
diazo compounds for the chemoselective synthesis of highly functionatized
thiophenes and thieno[2,3-b]thiophenes (Scheme 1b).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RESULTS AND DISCUSSION
Initially,
the
reaction
of
S,S-disubstituted
enone,
that
is,
3-(bis(methylthio)methylene)pentane-2,4-dione (1a) with ethyl diazoacetate (2a) was
conducted to screen the reaction conditions (Table 1). In the presence of 10 mol %
Rh2(OAc)4 as the catalyst, the reaction of 1a and 2a in a 1:2 molar ratio underwent in
toluene at 80 ℃ for 12 h under a nitrogen atmosphere, forming the target thiophene
4
ACS Paragon Plus Environment

Page 5 of 42
The Journal of Organic Chemistry
1
2
3
4
5
product 3a in 27% yield (Table 1, entry 1). Copper(II) salts CuBr2 and CuCl2 behaved
6
7
more efficiently than the Rh(II) catalyst, and in the case of using 10 mol % CuCl2 as
8
9
_____________________________________________________________________
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimiation of Reaction Conditionsa
temp
(oC)
yieldsb (%)
entry
1
catalyst
solvent
PhMe
3a/4a
Rh2(OAc)4
80
27/-
2
3
4
5
6
7
8
9
CuBr2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
PhMe
PhMe
80
80
80
80
60
60
60
60
33/-
45/-
PhCF3
46/-
MeCN
27/-
PhMe
51/-
PhMe/MeCN (1:1)
PhMe/PhCF3 (1:1)
PhMe/MeCN (1:1)
76 (79)c/-
68/-
0/0
10d
11e
12f
CuCl2
CuCl2
CuCl2
PhMe/MeCN (1:1)
PhMe/MeCN (1:1)
PhMe/MeCN (1:1)
60
60
60
31/-
45/27
trace/(85)c
a
Conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst (10 mol %), solvent (2
b
mL), 0.1 MPa N2, 12 h.
Determined by 1H NMR analysis by using
c
1,3,5-trimethoxybenzene as the internal standard. Isolated yields given in
parentheses. d In air. e Using 2a (0.9 mmol). f Using 2a (1.2 mmol).
_____________________________________________________________________
the catalyst 3a was generated in 45-46% yields in toluene and trifluoromethylbenzene,
respectively (Table 1, entries 2-4). In acetonitrile the reaction proceeded less
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 42
1
2
3
4
5
6
7
8
9
efficiently to produce 3a in 27% yield (Table 1, entry 5). Lowering the temperature to
60 ℃ enhanced the yield of compound 3a to 51% (Table 1, entry 6). An obvious
solvent effect was demonstrated by using the mixed solvents of toluene and
acetonitrile or toluene and PhCF3 (1:1, v/v) at 60 ℃, leading to 3a in 79% isolated
yield (Table 1, entries 7 and 8). In the absence of a catalyst, the reaction did not occur
(Table 1, entry 9). An air atmosphere deteriorated the product yield to 31% from 76%
under a nitrogen atmosphere (Table 1, entries 7 and 10). It is noteworthy that in all the
above cases thieno[2,3-b]thiophene 4a could not be formed in a detectable amount.
Unexpectedly, increasing the loading of diazo compound 2a to 3 equiv led to a
mixture of 3a (45%) and 4a (27%), and further increasing the amount of 2a to 4 equiv
selectively afforded 4a in 85% isolated yield (Table 1, entries 11 and 12). It should be
noted that the molecular structure of compound 3a was confirmed by the X-ray single
crystal crystallographic analysis (Figure 2, see the Supporting Information for details).
_____________________________________________________________________
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Perspective view of 3a with thermal ellipsoids at the 30% probability level.
_____________________________________________________________________
Under the optimal conditions, the scope of S,S-disubstituted enones (1) was
explored (Table 2). Ethylthio, n-butylthio, and benzylthio-disubstituted enones (1b-1d)
reacted with 2a less efficiently than their methylthio analog 1a to give the target
6
ACS Paragon Plus Environment

Page 7 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
products 3b-3d (71%-75%). 2-Ester-functionalized di(methylthio)-substituted enones
1e-1i efficiently underwent the reaction to afford products 3e-3i in 72-77% yields,
exhibiting no obvious steric effect from the methyl, ethyl, isopropyl, and tert-butyl
groups in the 2-ester functionalities. The amido group-functionalized enone substrates
1j and 1k also reacted well with 2a to yield 3j (80%) and 3k (72%), respectively. The
short-chain alkyls such as ethyl and n-propyl, and cyclopropyl in the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
_____________________________________________________________________
Table 2. The Scope of S,S-Disubstituted Enones (1)a
a
Conditions: 1 (0.3 mmol), 2 (0.6 mmol), CuCl2 (10 mol %),
PhMe/MeCN (2 mL, v/v = 1:1), 0.1 MPa N2, 12 h.
_____________________________________________________________________
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 42
1
2
3
4
5
6
7
8
9
alkanoyl functionalities of the enone substrates did not show an electronic or steric
effect on the product yields for 3f, and 3l-3n (75-77%). However, the substituents on
the aryl groups in the aroyl functionalities of 1o-1w exhibited obvious steric and
electronic effects. The electron-donating methyl and methoxy groups facilitated the
reaction to form 3p-3s (62-81%), while the unsubstituted aryl enone 1o reacted with
2a to give 3o in 51% yield. 2-Methoxy exhibited an obvious negative steric effect on
the yield of 3q (62%) among the methoxy-substituted substrates 1r (73%) and 1s
(81%). The electron-withdrawing fluoro group diminished the yield of 3t to 45%, and
the ester group (CO2Et) on the aryl moiety almost completely inhibited the reaction.
4-Chloro and 4-bromo groups slightly improved the reaction efficiency to give 3u and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
_____________________________________________________________________
Table 3. The Scope of Diazo Compounds (2)a
a
Conditions: 1 (0.3 mmol), 2 (0.6 mmol), CuCl2 (10 mol %), PhMe/MeCN (2 mL,
v/v = 1:1), 0.1 MPa N2, 12 h.
_____________________________________________________________________
3v (54-56%). The reaction of 2-naphthyl-functionalized enone 1x produced 3x in 65%
yield. 2-Furyl and 2-thienyl-functionalized enones 1y and 1z reacted with 2a under
the same conditions, efficiently generating the corresponding heteroaryl-
8
ACS Paragon Plus Environment

Page 9 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
functionalized thiophene products 3y (71%) and 3z (75%), respectively. It is
noteworthy that 2-(bis(methylthio)methylene)cyclohexane-1,3-dione exhibited no
reactivity to 2a under the same conditions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Next, the protocol generality was investigated by carrying out the reaction of
enones 1 with various diazo compounds (2) (Table 3). Methyl diazoacetate (2b)
reacted with S,S-disubstituted enone 1a to give the target thiophene product, that is,
methyl 3-methyl-4-acetyl-5-(methylthio)thiophene-2-carboxylate (5a) in 80% yield.
n-Propyl, isopropyl, tert-butyl, and benzyl diazoacetates also efficiently reacted with
1a to form the corresponding thiophene products 5b-5e (71-78%), only demonstrating
slight electronic and steric effects. 2-Diazoacetonitrile (2g) reacted well with enones
1a and 1f to afford 2-cyano-functionalized thiophenes 5f and 5g in 72-76% yields,
respectively, while CF3 and TMS (trimethylsilyl)-functionalized diazo compounds 2h
and 2i showed no reactivity to enone 1a under the stated conditions.
_____________________________________________________________________
Table 4. Synthesis of Thieno[2,3-b]thiophenes (4)a
a
Conditions: 1 (0.3 mmol), 2 (1.2 mmol), CuCl2 (10 mol %), PhMe/MeCN (2 mL,
v/v = 1:1), 0.1 MPa N2, 12 h.
_____________________________________________________________________
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 42
1
2
3
4
5
6
7
8
9
Then, the protocol was applied for the synthesis of thieno[2,3-b]thiophene
derivatives 4 (Table 4). 3-(Bis(methylthio)methylene)pentane-2,4-dione (1a) was
reacted with 4 equiv of ethyl diazoacetate (2a) to give the target diethyl
3,4-dimethylthieno[2,3-b]thiophene-2,5-dicarbo-xylate (4a) in 85% yield under the
standard conditions. Variation of the functional groups from methyl, isopropyl,
n-butyl, cyclopropyl, to cyclobutyl in the 2-alkanoyl functionalities of the
S,S-disubstituted enone substrates 1 also efficiently led to the corresponding target
products 4b-4e (76-78%). 2-Acetyl and 2-benzoyl-substituted aryl enones reacted
with 2a to give the corresponding products 4f and 4g in high yields (80-83%). These
results have demonstrated a good substrate applicability of the present synthetic
protocol.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
_____________________________________________________________________
_____________________________________________________________________
Other types of S-substituted enones and diazo compounds were also employed in
the synthesis of highly functionalized thiophene derivatives by the present synthetic
methodology. The methylthio-monosubstituted enone (6) was treated with ethyl
diazoacetate (2a) under the standard conditions, no detectable amount of the target
10
ACS Paragon Plus Environment

Page 11 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
thiophene product 7 was formed (eq 1). This result verifies the crucial role of the
di(alkylthio) functionality at one terminus of the C=C backbone in the
S,S-disubstituted enone substrates. Unexpectedly, the aryl diazo compound, that is,
ethyl diazophenylacetic acid ester (2j), reacted with 1a to give a new enone 8 (80%)
which was generated by carbene insertion into the vinyl CS bond22 (eq 2). Neither of
the two diazo compounds 2-diazo-1-phenyl-ethanone (2k) and 1-diazopropan-2-one
(2l) could react with 2a under the stated conditions, suggesting the necessity of an
ester group in the diazo substrates (eq 3).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
_____________________________________________________________________
_____________________________________________________________________
To demonstrate the applicability of the synthetic protocol, gram-scale preparation
of the thiophene products 3a (80%) and 3f (76%) was performed by the reactions of
1a and 1f with 2a, respectively (eq 4). 2-Arylthiophene-based functional materials
have been found broad applications in materials science.5c Thus, derivatization of
thiophenes 3a and 3f was conducted by palladium-catalyzed Liebeskind−Srogl
cross-coupling with phenylboronic acid, giving 5-phenylated tetrasubstituted
thiophene derivatives 10a and 10b in 81-83% yields (eq 5). With
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 42
1
2
3
4
5
6
7
8
9
m-chloroperoxybenzoic acid (m-CPBA) as the oxidant, the methylthio group in 3a
was readily oxidized to the corresponding sulfone 11 in 90% yield (eq 6), which may
be used as a useful intermediate in organic synthesis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Control experiments were performed to probe into the reaction mechanism.
Under the standard conditions, thiophene 3a was reacted with two equivalents of
diazo compound 2a to give 4a in 58% yield with compound 3a partially recovered
(21%), which suggests that 3a is the possible intermediate to form
thieno[2,3-b]thiophene 4a (eq 7). Using 3 equiv of 2a led to 4a in 73% yield with
minor recovery of 3a (5%). It was noted that compounds of type 4 could be observed
as the minor products in some reactions to prepare compounds 3 and 5. The reaction
of 1a with 2a was conducted in the presence of two equivalents of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 2,6-di-tert-butyl-4-methyl-phenyl
(BHT) under the standard conditions. These radical scavengers did not inhibit the
annulative coupling reaction, and 3a was formed in 65-73% yields which were
comparable to that (79%) obtained under the standard conditions, excluding a radical
reaction pathway.
A plausible mechanism is proposed in Scheme 2. The initial reaction of the
copper catalyst and diazo compound 2 generates Cu(II)-carbene species A which then
forms an adduct (B) with S,S-disubstituted enone 1a. Regeneration of the catalytically
active Cu(II) species leads to sulfur ylide C/D. Subsequent intramolecular annulation
12
ACS Paragon Plus Environment

Page 13 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
produces intermediate E which rearranges to yield the target thiophene product 3a
through elimination of methanol. Under the stated conditions using large excess of the
diazo compound (4 equiv), thiophene 3a further interacts with Cu(II)-carbene species
A to generate adduct F from which the catalytically active Cu(II) species is
regenerated with the formation of sulfur ylide intermediate G/H. A similar
intramolecular annulation proceeds to yield species I, an analog of species E.
Elimination of methanol results in thieno[2,3-b]thiophene 4a. It is noteworthy that
compound 8 can be obtained through carbene insertion into the vinyl CS bond of the
S,S-disubstituted enone substrate when an aryl diazo compound is used.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
_____________________________________________________________________
Scheme 2. Proposed Mechanism
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 42
1
2
3
4
5
6
7
8
9
In conclusion, we have developed a concise and efficient copper(II)-catalyzed
annulative coupling protocol of S,S-disubstituted enones and diazo compounds toward
the synthesis of fully substituted thiophenes and thieno[2,3-b]thiophenes. Due to easy
manipulations, readily available reactants, excellent chemoselectivity, and mild
reaction conditions, this work offers a promising method to construct highly
functionatized thiophene motifs.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General Considerations
The solvents were dried and distilled prior to use by the literature methods. 1H and
13C{1H} NMR spectra were recorded on a Bruker DRX-400 spectrometer and all
chemical shift values refer to δTMS = 0.00 ppm or CDCl3 (δ(1H), 7.26 ppm and δ(13C),
77.16 ppm). The HRMS (ESI) analysis was obtained on a Waters GC-TOF CA156
mass spectrometer. X-Ray crystallographic analysis was achieved by the Analysis
Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. All the
chemical reagents were purchased from commercial sources and used as received
unless otherwise indicated. The starting substrates 1a and 1b,23a 1c and 1d,23b 1e-1j,23a
1k,23c 1l-1z,23a 1z5 and 1z6,23a and diazo compounds 2a,19d 2b,23d 2c,23e 2d-2g,19d 2h
and 2i,23f 2j,22 2k and 2l,19d were known and prepared by the literature procedures and
their spectroscopic features are in good agreement with those reported in the
literatures.
Preparation of S,S-Disubstituted Enones (1)23a
14
ACS Paragon Plus Environment

Page 15 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A typical procedure for the synthesis of S,S-disubstituted enones 1  Synthesis of
3-(bis(methylthio)methylene)pentane-2,4-dione (1a): Iodomethane (1.6 g, 11 mmol)
was added dropwise to a stirred mixture of acetylacetone (0.5 g, 5 mmol), K2CO3 (1.7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
g, 12 mmol), and CS2 (0.5 g, 6 mmol) in 10 mL DMF at 0 C. The reaction was
o
continued at 25 C (oil bath) for 24 h. The resulting mixture was poured into 50 mL
water, separated, and the aqueous phase was extracted with 10 mL CH2Cl2. The
combined organic phase was washed with H2O (3×10 mL), dried over anhydrous
MgSO4, filtered, and evaporated all the volatiles under reduced pressure. The resultant
residue was purified by silica gel column chromatography (eluent: petroleum ether
(60-90 oC)/EtOAc = 20:1, v/v) to afford 1a as a yellow solid (800 mg, 81%).
3-(Bis(methylthio)methylene)-6-methylheptane-2,4-dione (1z1): Following the
general procedure, compound 1z1 was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc = 20:1, v/v). 880 mg, 72% yield,
yellow liquid. 1H NMR (400 MHz, CDCl3) δ 2.50 (d, J = 6.7 Hz, 2 H), 2.37 (s, 6 H),
2.32 (s, 3 H), 2.14 (m, 1 H), 0.90 (d, J = 6.7 Hz, 6 H). C{1H} NMR (100 MHz,
13
CDCl3) δ 200.0, 197.3, 151.4, 145.3, 51.8, 30.6, 24.3, 22.5, and 18.1. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C11H19O2S2 247.0826; Found 247.0826.
3-(Bis(methylthio)methylene)octane-2,4-dione (1z2): Following the general
procedure, compound 1z2 was obtained by column chromatography on silica gel
(eluent: petroleum ether (60−90 °C)/EtOAc = 20:1, v/v). 923 mg, 75% yield, yellow
liquid. 1H NMR (400 MHz, CDCl3) δ 2.59 (m, 2 H), 2.35 (s, 6 H), 2.29 (s, 3 H), 1.55
(m, 2 H), 1.34-1.23 (m, 2 H), 0.84 (t, J = 7.3 Hz, 3 H). C{1H} NMR (100 MHz,
13
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 42
1
2
3
4
5
6
7
CDCl3) δ 201.0, 196.8, 151.7, 144.9, 42.9, 30.4, 26.0, 22.1, 18.0, and 13.8. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C11H19O2S2 247.0826; Found 247.0824.
8
9
2-(Bis(methylthio)methylene)-1-cyclopropylbutane-1,3-dione (1z3): Following
the general procedure, compound 1z3 was obtained by column chromatography on
silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 20:1, v/v). 861 mg, 75% yield,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
yellow liquid. H NMR (400 MHz, CDCl3) δ 2.35 (s, 6 H), 2.27 (s, 3 H), 2.15 (m, 1
13
H), 1.11 (m, 2 H), 0.96 (m, 2 H). C{1H} NMR (100 MHz, CDCl3) δ 200.3, 196.5,
153.8, 144.0, 62.1, 30.4, 22.0, and 12.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C10H15O2S2 231.0513; Found 231.0513.
2-(Bis(methylthio)methylene)-1-cyclobutylbutane-1,3-dione (1z4): Following the
general procedure, compound 1z4 was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc = 20:1, v/v). 842 mg, 69% yield,
yellow liquid. 1H NMR (400 MHz, CDCl3) δ 3.53 (m, 1 H), 2.37 (m, 6 H), 2.28 (s, 3
H), 2.22 (m, 2 H), 2.04 (m, 2 H), 1.95-1.69 (m, 2 H). 13C{1H} NMR (100 MHz,
CDCl3) δ 201.6, 197.1, 152.7, 143.9, 45.6, 30.5, 25.3, 18.1, and 17.7. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C11H17O2S2 245.0670; Found 245.0671.
Synthesis of Thiophenes 3 and 5
A typical procedure for the synthesis of thiophenes 3 and 5  Synthesis of ethyl
4-acetyl-3-methyl-5-(methylthio)thiophene-2-carboxylate (3a):
A
mixture of
3-(bis(methylthio)methylene)pentane-2,4-dione (1a) (61 mg, 0.3 mmol), ethyl
diazoacetate (2a) (68 mg, 0.6 mmol), CuCl2 (4 mg, 0.03 mmol) in PhMe/MeCN (2
mL, v/v = 1:1) was stirred at 60 °C (oil bath) for 12 h under a N2 atmosphere. After 1a
16
ACS Paragon Plus Environment

Page 17 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
was completely consumed by TLC monitoring on silica gel, all the volatiles were
evaporated under reduced pressure. The resultant residue was purified by silica gel
column chromatography (eluent: petroleum ether (60-90 °C)/ethyl acetate = 50:1, v/v),
affording 3a (60 mg, 79%) as a pale yellow solid. M.p.: 73-74 oC. 1H NMR (400 MHz,
CDCl3) δ 4.24 (q, J = 7.1 Hz, 2 H), 2.64, 2.48, and 2.46 (s both, 3:3:3 H), 1.29 (t, J =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
7.1 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 194.8, 161.7, 156.7, 146.0, 137.6,
124.4, 60.9, 31.2, 18.5, 15.8, and 14.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C11H14O3S2 259.0463; Found 259.0463.
Ethyl 4-acetyl-5-(ethylthio)-3-methylthiophene-2-carboxylate (3b): Following the
general procedure, compound 3b was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 82 mg, 75%; yellow
solid, m.p.: 67-68 oC. 1H NMR (400 MHz, CDCl3) δ 4.31 (q, J = 7.1 Hz, 2 H), 3.00 (q,
13
J = 7.4 Hz, 2 H), 2.65 and 2.54 (s both, 3:3 H), 1.37 (m, 6 H). C{1H} NMR (100
MHz, CDCl3) δ 196.2, 161.9, 151.8, 145.6, 137.6 140.2, 125.5, 61.1, 31.6, 30.4, 15.7,
14.4, and 13.7. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H17O3S2 273.0619;
Found 273.0615.
Ethyl 4-acetyl-5-(butylthio)-3-methylthiophene-2-carboxylate (3c): Following the
general procedure, compound 3c was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 64 mg, 71%; yellow
solid, m.p.: 44-45 oC. 1H NMR (400 MHz, CDCl3) δ 4.25 (q, J = 7.1 Hz, 2 H), 2.93 (q,
J = 7.4 Hz, 2 H), 2.60 and 2.49 (s both, 3:3 H), 1.66 (dt, J = 15.1, 7.4 Hz, 2 H), 1.42
(dd, J = 14.9, 7.4 Hz, 2 H), 1.30 (t, J = 7.1 Hz, 3 H), 0.88 (t, J = 7.4 Hz, 3 H). 13C{1H}
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 42
1
2
3
4
5
6
7
8
9
NMR (100 MHz, CDCl3) δ 196.1, 161.9, 152.4, 145.7, 140.0, 125.3, 61.1, 36.0, 31.6,
30.6, 22.1, 15.7, 14.5, and 13.7. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C14H21O3S2 301.0932; Found 301.0932.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 4-acetyl-5-(benzylthio)-3-methylthiophene-2-carboxylate (3d): Following
the general procedure, compound 3d was obtained by column chromatography on
silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 75 mg, 75%;
o
yellow solid, m.p.: 46-47 C. 1H NMR (400 MHz, CDCl3) δ 7.43-7.25 (m, 5 H), 4.33
(q, J = 7.1 Hz, 2 H), 4.18 (s, 2 H), 2.66 and 2.49 (s both, 3:3 H), 1.37 (t, J = 7.1 Hz, 3
H). 13C{1H} NMR (100 MHz, CDCl3) δ 196.3, 161.9, 150.3, 145.3, 141.0, 135.4,
126.2, 129.3, 128.9, 128.0, 61.2, 41.3, 31.5, 15.7, and 14.5. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C17H19O3S2 335.0776; Found 335.0765.
2-Ethyl 4-methyl 3-methyl-5-(methylthio)thiophene-2,4-dicarboxylate (3e):
Following the general procedure, compound 3e was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
51 mg, 75%; yellow solid, m.p.: 96-97 oC. 1H NMR (400 MHz, CDCl3) δ 4.25 (q, J =
7.1 Hz, 2 H), 3.81, 2.66, and 2.51 (s both, 3:3:3 H), 1.29 (t, J = 7.1 Hz, 3 H). 13C{1H}
NMR (100 MHz, CDCl3) δ 164.2, 161.8, 158.6, 148.6, 126.8, 123.8, 61.0, 51.6, 18.0,
15.6, and 14.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C11H15O4S2 275.0412;
Found 275.0419.
Diethyl 3-methyl-5-(methylthio)thiophene-2,4-dicarboxylate (3f): Following the
general procedure, compound 3f was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 65 mg, 75%; yellow
18
ACS Paragon Plus Environment

Page 19 of 42
The Journal of Organic Chemistry
1
2
3
4
5
o
1
solid, m.p.: 88-89 C. H NMR (400 MHz, CDCl3) δ 4.27 (m, 4 H), 2.67, and 2.51 (s
6
7
13
both, 3:3 H), 1.31 (m, 6 H). C{1H} NMR (100 MHz, CDCl3) δ 163.7, 161.8, 158.3,
8
9
148.7, 127.1, 123.8, 61.0, 60.9, 18.0, 15.6, 14.4, and 14.4. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C12H17O4S2 289.0568; Found 289.0568.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Ethyl 4-isopropyl 3-methyl-5-(methylthio)thiophene-2,4-dicarboxylate (3g):
Following the general procedure, compound 3g was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
o
1
70 mg, 77%; yellow solid, m.p.: 77-78 C. H NMR (400 MHz, CDCl3) δ 5.32-5.15
(m, 1 H), 4.31 (q, J = 7.1 Hz, 2 H), 2.74, and 2.58 (s both, 3:3 H), 1.36 (m, 9 H).
13C{1H} NMR (100 MHz, CDCl3) δ 163.3, 162.0, 158.0, 148.7, 127.5, 123.9, 68.9,
61.0, 22.2, 18.1, 15.7, and 14.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C13H19O4S2 303.0725; Found 303.0725.
4-Tert-butyl 2-ethyl 3-methyl-5-(methylthio)thiophene-2,4-dicarboxylate (3h):
Following the general procedure, compound 3h was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
68 mg, 72%; yellow solid, m.p.: 86-87 oC. 1H NMR (400 MHz, CDCl3) δ 4.24 (q, J =
7.1 Hz, 2 H), 2.65 and 2.50 (s both, 3:3 H), 1.52 (s, 9 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 161.9, 157.0, 148.6, 128.7, 123.7, 82.3,
60.9, 28.5, 18.0, 15.7, and 14.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C14H21O4S2 317.0881; Found 317.0875.
4-Benzyl 2-ethyl 3-methyl-5-(methylthio)thiophene-2,4-dicarboxylate (3i):
Following the general procedure, compound 3i was obtained by column
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 42
1
2
3
4
5
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
6
7
o
1
80 mg, 76%; yellow solid, m.p.: 89-90 C. H NMR (400 MHz, CDCl3) δ 6.37 (m, 2
8
9
H), 6.33-6.21 (m, 3 H), 4.27 (s, 2 H), 3.23 (q, J = 7.1 Hz, 2 H), 1.66 and 1.48 (s both,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
3:3 H), 0.28 (t, J = 7.1 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 163.5, 161.8,
158.9, 148.7, 135.8, 126.7, 123.9, 128.7, 128.5, 128.4, 66.7, 61.0, 18.1, 15.8, and 14.4.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H19O4S2 351.0725; Found 351.0724.
Ethyl 3-methyl-5-(methylthio)-4-(phenylcarbamoyl)thiophene-2-carboxylate (3j):
Following the general procedure, compound 3j was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
81 mg, 80%; yellow solid, m.p.: 99-100 oC. 1H NMR (400 MHz, CDCl3) δ 7.92 (br, 1
H), 7.56 (m, 2 H), 7.28 (m, 2 H), 7.08 (m, 1 H), 4.24 (q, J = 7.1 Hz, 2 H), 2.52 and
2.49 (s both, 3:3 H), 1.29 (t, J = 7.1 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ
13
162.2, 161.9, 146.1, 145.9, 137.7, 136.6, 126.4, 129.2, 124.9, 120.1, 61.2, 19.2, 14.9,
and 14.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H18NO3S2 336.0728; Found
336.0728.
Ethyl 4-(diethylcarbamoyl)-3-methyl-5-(methylthio)thiophene-2-carboxylate (3k):
Following the general procedure, compound 3k was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
1
68 mg, 72%; yellow liquid. H NMR (400 MHz, CDCl3) δ 4.24 (q, J = 7.1 Hz, 2 H),
3.51 (m, 2 H), 3.21-3.00 (m, 2 H), 2.47 and 2.34 (s both, 3:3 H), 1.29 (t, J = 7.1 Hz, 3
H), 1.19 (t, J = 7.1 Hz, 3 H), 1.01 (t, J = 7.1 Hz, 3 H). C{1H} NMR (100 MHz,
13
CDCl3) δ 165.3, 161.8, 143.9, 140.4, 139.7, 127.2, 60.9, 42.8, 39.1, 19.5, 14.4, 14.4,
20
ACS Paragon Plus Environment

Page 21 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
and 12.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H22NO3S2 316.1041; Found
316.1041.
7
8
9
Diethyl 3-ethyl-5-(methylthio)thiophene-2,4-dicarboxylate (3l): Following the
general procedure, compound 3l was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 70 mg, 77%; yellow
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
1
solid, m.p.: 74-75 C. H NMR (400 MHz, CDCl3) δ 4.34 (m, 4 H), 3.28 (q, J = 7.3
13
Hz, 2 H), 2.58 (s, 3 H), 1.38 (m, 6 H), 1.18 (t, J = 7.4 Hz, 3 H). C{1H} NMR (100
MHz, CDCl3) δ 163.6, 161.5, 158.6, 155.0, 126.6, 123.6, 61.0, 61.0, 22.2, 18.1, 15.0,
14.5, and 14.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C13H19O4S2 303.0725;
Found 303.0725.
Diethyl 5-(methylthio)-3-propylthiophene-2,4-dicarboxylate (3m): Following the
general procedure, compound 3m was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 72 mg, 76%; yellow
o
1
solid, m.p.: 70-71 C. H NMR (400 MHz, CDCl3) δ 4.33 (m, 4 H), 3.34-3.17 (m, 2
13
H), 2.58 (s, 3 H), 1.57 (m, 2 H), 1.38 (m, 6 H), 0.97 (t, J = 7.3 Hz, 3 H). C{1H}
NMR (100 MHz, CDCl3) δ 163.7, 161.7, 158.6, 153.5, 126.7, 123.9, 61.0, 61.0, 30.6,
24.2, 18.1, 14.4, and 14.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H21O4S2
[M+H]+ 317.0881; Found 317.0881.
Diethyl
3-cyclopropyl-5-(methylthio)thiophene-2,4-dicarboxylate
(3n):
Following the general procedure, compound 3n was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
71 mg, 75%; yellow solid, m.p.: 104-105 oC. 1H NMR (400 MHz, CDCl3) δ 4.34 (m,
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 42
1
2
3
4
5
6
7
8
9
4 H), 2.56 (s, 3 H), 2.05 (m, 1 H), 1.37 (m, 6 H), 1.05-0.94 (m, 2 H), 0.51 (m, 2 H).
13C{1H} NMR (100 MHz, CDCl3) δ 164.0, 161.2, 154.0, 151.7, 130.5, 127.8, 61.1,
18.2, 14.4, 14.4, 11.7, and 9.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H19O4S2
315.0725; Found 315.0726.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Diethyl 5-(methylthio)-3-phenylthiophene-2,4-dicarboxylate (3o): Following the
general procedure, compound 3o was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 54 mg, 51%; yellow
o
1
solid, m.p.: 74-75 C. H NMR (400 MHz, CDCl3) δ 7.45 (m, 3 H), 7.19 (m, 2 H),
4.11 (q, J = 7.1 Hz, 2 H), 3.99 (q, J = 7.1 Hz, 2 H), 2.65 (s, 3 H), 1.09 (t, J = 7.1 Hz, 3
H), 0.86 (t, J = 7.1 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.4, 161.1, 157.7,
149.7, 136.5, 127.6, 126.0, 128.7, 127.5, 127.3, 61.1, 60.6, 18.2, 14.0, and 13.6.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H19O4S2 351.0725; Found 351.0725.
Diethyl 5-(methylthio)-3-(p-tolyl)thiophene-2,4-dicarboxylate (3p): Following
the general procedure, compound 3p was obtained by column chromatography on
silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 86 mg, 79%;
yellow solid, m.p.: 80-81 oC. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 7.9 Hz, 2 H),
7.08 (d, J = 7.9 Hz, 2 H), 4.13 (q, J = 7.1 Hz, 2 H), 4.02 (q, J = 7.1 Hz, 2 H), 2.65 and
2.38 (s both, 3:3 H), 1.14 (t, J = 7.1 Hz, 3 H), 0.92 (t, J = 7.1 Hz, 3 H). 13C{1H} NMR
(100 MHz, CDCl3) δ 163.4, 161.0, 157.2, 150.2, 137.1, 133.3, 127.8, 125.6, 128.5
128.1, 61.0, 60.7, 21.5, 18.2, 14.1, and 13.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C18H21O4S2 365.0881; Found 365.0881.
Diethyl 3-(2-methoxyphenyl)-5-(methylthio)thiophene-2,4-dicarboxylate (3q):
22
ACS Paragon Plus Environment

Page 23 of 42
The Journal of Organic Chemistry
1
2
3
4
5
Following the general procedure, compound 3q was obtained by column
6
7
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
8
9
o
1
71 mg, 62%; yellow solid, m.p.: 71-72 C. H NMR (400 MHz, CDCl3) δ 7.35 (m, 1
H), 7.09 (m, 1 H), 7.03-6.83 (m, 2 H), 4.14 (m, 2 H), 4.09-3.97 (m, 2 H), 3.74 and
2.68 (s both, 3:3 H), 1.12 (t, J = 7.1 Hz, 3 H), 0.91 (t, J = 7.1 Hz, 3 H). 13C{1H} NMR
(100 MHz, CDCl3) δ 163.4, 161.1, 157.3, 156.8, 146.2, 127.6, 126.1, 125.8, 130.1,
129.1, 119.9, 110.3, 60.9, 60.4, 55.6, 18.1, 14.0, and 13.6. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C18H21O5S2 381.0830; Found 381.0830.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Diethyl 3-(3-methoxyphenyl)-5-(methylthio)thiophene-2,4-dicarboxylate (3r):
Following the general procedure, compound 3r was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
o
1
83 mg, 73%; yellow solid, m.p.: 79-80 C. H NMR (400 MHz, CDCl3) δ 7.28 (m, 1
H), 691 (m, 1 H), 6.81 (m, 1 H), 6.76 (m, 1 H), 4.14 (q, J = 7.1 Hz, 2 H), 4.03 (q, J =
7.1 Hz, 2 H), 3.81 and 2.67 (s both, 3:3 H), 1.13 (t, J = 7.1 Hz, 3 H), 0.92 (t, J = 7.1
Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.4, 161.0, 158.9, 157.6, 149.3,
137.7, 127.6, 126.0, 128.3, 121.3, 114.5, 113.1, 61.1, 60.6, 55.3, 18.2, 14.0, and 13.6.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H21O5S2 381.0830; Found 381.0830.
Diethyl 3-(4-methoxyphenyl)-5-(methylthio)thiophene-2,4-dicarboxylate (3s):
Following the general procedure, compound 3s was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
o
1
92 mg, 81%; yellow solid, m.p.: 82-83 C. H NMR (400 MHz, CDCl3) δ 7.20-7.06
(m, 2 H), 6.94-6.83 (m, 2 H), 4.14 (q, J = 7.1 Hz, 2 H), 4.03 (q, J = 7.1 Hz, 2 H), 3.83
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 42
1
2
3
4
5
6
7
8
9
and 2.64 (s both, 3:3 H), 1.15 (t, J = 7.1 Hz, 3 H), 0.95 (t, J = 7.1 Hz, 3 H). 13C{1H}
NMR (100 MHz, CDCl3) δ 163.5, 161.1, 159.2, 157.1, 149.7, 128.5, 128.0, 125.8,
130.0, 112.9, 61.1, 60.7, 55.4, 18.2, 14.1, and 13.8. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C18H21O5S2 381.0830; Found 381.0832.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Diethyl
3-(4-fluorophenyl)-5-(methylthio)thiophene-2,4-dicarboxylate
(3t):
Following the general procedure, compound 3t was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
o
1
50 mg, 45%; yellow solid, m.p.: 59-60 C. H NMR (400 MHz, CDCl3) δ 7.16 (m, 2
H), 7.05 (m, 2 H), 4.12 (q, J = 7.1 Hz, 2 H), 4.02 (q, J = 7.1 Hz, 2 H), 2.65 (s, 3 H),
1.13 (t, J = 7.1 Hz, 3 H), 0.93 (t, J = 7.1 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3)
δ 163.7, 162.2 (d, J = 224.7 Hz), 161.3, 158.1, 148.6, 132.4 (d, J = 35.2 Hz), 127.4,
126.2, 130.4 (d, J = 81.4 Hz), 114.3 (d, J = 214.6 Hz), 61.2, 60.7, 18.2, 14.1, and 13.7.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H18FO4S2 369.0631; Found 369.0631.
Diethyl 3-(4-chlorophenyl)-5-(methylthio)thiophene-2,4-dicarboxylate (3u):
Following the general procedure, compound 3u was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
65 mg, 56%; yellow liquid. 1H NMR (400 MHz, CDCl3) δ 7.16 and 7.05 (m each, 2:2
H), 4.12 (q, J = 7.1 Hz, 2 H), 4.02 (q, J = 7.1 Hz, 2 H), 2.65 (s both, 3 H), 1.13 (t, J =
13
7.1 Hz, 3 H), 0.93 (t, J = 7.1 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 163.1,
160.9, 158.4, 148.4, 135.5, 135.0, 133.5, 121.6, 130.5, 130.4, 130.1, 127.6, 61.2, 60.8,
18.2, 14.0, and 13.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H18ClO4S2
385.0335; Found 385.0335.
24
ACS Paragon Plus Environment

Page 25 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Diethyl 3-(4-bromophenyl)-5-(methylthio)thiophene-2,4-dicarboxylate (3v):
Following the general procedure, compound 3v was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
70 mg, 54%; yellow liquid. H NMR (400 MHz, CDCl3) δ 7.50 (m, 1 H), 7.34 (m, 1
H), 7.19-7.03 (m, 2 H), 4.12 (q, J = 7.1 Hz, 2 H), 4.02 (q, J = 7.1 Hz, 2 H), 2.65 (s, 3
H), 1.13 (t, J = 7.1 Hz, 3 H), 0.93 (t, J = 7.1 Hz, 3 H). C{1H} NMR (100 MHz,
13
CDCl3) δ 163.1, 160.9, 159.2, 158.4, 148.3, 135.5, 135.0, 133.5, 121.6, 130.5, 130.4,
130.1, 127.6, 61.2, 60.8, 18.2, 14.0, and 13.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C17H18BrO4S2 428.9830; Found 428.9832.
Diethyl 5-(methylthio)-3-(naphthalen-2-yl)thiophene-2,4-dicarboxylate (3x):
Following the general procedure, compound 3x was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
78 mg, 65%; yellow solid, m.p.: 102-103 oC. 1H NMR (400 MHz, CDCl3) δ 7.85 (m,
3 H), 7.68 (s, 1 H), 7.58-7.44 (m, 2 H), 7.38 (m, 1 H), 4.10 (q, J = 7.1 Hz, 2 H), 3.95
(q, J = 7.1 Hz, 2 H), 2.70 (s, 3 H), 1.02 (t, J = 7.1 Hz, 3 H), 0.69 (t, J = 7.1 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3) δ 163.4, 161.1, 157.8, 149.5, 134.0, 132.9, 132.8,
127.8, 126.2, 128.1, 127.8, 127.5, 127.3, 126.6, 126.0, 125.9, 61.1, 60.6, 18.2, 14.0,
and 13.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H21O4S2 401.0881; Found
401.0886.
Diethyl
3-(furan-2-yl)-5-(methylthio)thiophene-2,4-dicarboxylate
(3y):
Following the general procedure, compound 3y was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 42
1
2
3
4
5
o
1
73 mg, 71%; yellow solid, m.p.: 78-79 C. H NMR (400 MHz, CDCl3) δ 7.49 (m, 1
6
7
H ), 6.50 (m, 2 H), 4.19 (m, 4 H), 2.62 (s, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.12 (t, J =
8
9
13
7.1 Hz, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 163.2, 160.6, 156.3, 146.1, 137.4,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
128.3, 128.2, 142.0, 110.9, 110.9, 61.4, 61.0, 18.2, 14.2, and 14.1. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C15H17O5S2 341.0517; Found 341.0517.
Diethyl 5'-(methylthio)-[2,3'-bithiophene]-2',4'-dicarboxylate (3z): Following the
general procedure, compound 3z was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 80 mg, 75%; yellow
o
1
solid, m.p.: 86-87 C. H NMR (400 MHz, CDCl3) δ 7.38 (dd, J = 5.1, 1.0 Hz, 1 H),
7.03 (dd, J = 5.0, 3.5 Hz, 1 H), 6.91 (dd, J = 3.5, 1.0 Hz, 1 H), 4.17 (q, J = 7.1 Hz, 2
H), 4.08 (q, J = 7.1 Hz, 2 H), 2.64 (s, 3 H), 1.17 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz,
13
3H). C{1H} NMR (100 MHz, CDCl3) δ 163.2, 160.7, 157.1, 141.4, 135.7, 128.5,
128.2, 127.5, 126.3, 125.8, 61.3, 60.8, 18.1, 14.1, and 13.7. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C15H17O4S3 357.0289; Found 357.0281.
Methyl 4-acetyl-3-methyl-5-(methylthio)thiophene-2-carboxylate (5a): Following
the general procedure, compound 5a was obtained by column chromatography on
silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 60 mg, 82%;
o
1
yellow solid, m.p.: 114-115 C. H NMR (400 MHz, CDCl3) δ 3.86, 2.74, 2.57, and
2.56 (s both, 3:3:3:3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 195.0, 162.2, 157.1,
146.4, 137.7, 124.0, 52.0, 31.3, 18.6, and 16.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C10H13O3S2 245.0306; Found 245.0301.
Propyl 4-acetyl-3-methyl-5-(methylthio)thiophene-2-carboxylate (5b): Following
26
ACS Paragon Plus Environment

Page 27 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the general procedure, compound 5b was obtained by column chromatography on
silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 58 mg, 71%;
yellow solid, m.p.: 95-96 oC. 1H NMR (400 MHz, CDCl3) δ 4.22 (t, J = 6.6 Hz, 2 H),
2.72, 2.56, and 2.54 (s both, 3:3:3 H), 1.75 (dd, J = 14.2, 7.0 Hz, 2 H), 1.00 (t, J = 7.4
Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 195.0, 162.0, 156.7, 146.0, 137.9,
124.6, 66.6, 31.3, 22.2, 18.6, 15.9, and 10.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C12H17O3S2 273.0619; Found 273.0619.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Isopropyl
4-acetyl-3-methyl-5-(methylthio)thiophene-2-carboxylate
(5c):
Following the general procedure, compound 5c was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
o
1
61 mg, 75%; yellow solid, m.p.: 95-96 C. H NMR (400 MHz, CDCl3) δ 5.18 (m, 1
13
H), 2.72, 2.57, 2.54, 1.35, and 1.33 (s both, 3:3:3:3:3 H). C{1H} NMR (100 MHz,
CDCl3) δ 195.2, 161.6, 156.5, 145.9, 138.0, 125.2, 68.8, 31.4, 22.1, 18.7, and 16.0.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H17O3S2 273.0619; Found 273.0619.
Tert-butyl
4-acetyl-3-methyl-5-(methylthio)thiophene-2-carboxylate
(5d):
Following the general procedure, compound 5d was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
62 mg, 72%; yellow solid, m.p.: 117-118 oC. 1H NMR (400 MHz, CDCl3) δ 2.68, 2.55,
13
and 2.53 (s both, 3:3:3 H), 1.55 (s, 9 H). C{1H} NMR (100 MHz, CDCl3) δ 195.2,
161.3, 155.8, 145.2, 138.0, 126.4, 82.2, 31.4, 28.4, 18.7, and 15.9. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C13H19O3S2 287.0776; Found 287.0778.
Benzyl 4-acetyl-3-methyl-5-(methylthio)thiophene-2-carboxylate (5e): Following
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 42
1
2
3
4
5
the general procedure, compound 5e was obtained by column chromatography on
6
7
silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 75 mg, 78%;
8
9
o
1
yellow solid, m.p.: 82-83 C. H NMR (400 MHz, CDCl3) δ 7.39 (m, 5 H), 5.31 (s, 2
H), 2.74, 2.56, and 2.55 (s both, 3:3:3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 195.1,
161.7, 157.2, 146.7, 138.0, 135.9, 124.1, 128.8, 128.4, 128.2, 66.7, 31.4, 18.7, and
16.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H17O3S2 321.0619; Found
321.0610.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Acetyl-3-methyl-5-(methylthio)thiophene-2-carbonitrile (5f): Following the
general procedure, compound 5f was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 46 mg, 72%; yellow
o
1
solid, m.p.: 110-111 C. H NMR (400 MHz, CDCl3) δ 2.60, 2.58, and 2.55 (s both,
3:3:3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 193.3, 159.8, 150.0, 135.0, 113.7, 103.6,
31.1, 18.9, and 17.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C9H10NOS2 212.0204;
Found 212.0203.
Ethyl 5-cyano-4-methyl-2-(methylthio)thiophene-3-carboxylate (5g): Following
the general procedure, compound 5g was obtained by column chromatography on
silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v). 55 mg, 76%;
o
1
yellow solid, m.p.: 117-118 C. H NMR (400 MHz, CDCl3) δ 4.35 (q, J = 7.1 Hz, 2
H), 2.58, and 2.56 (s both, 3:3 H), 1.38 (t, J = 7.1 Hz, 3 H). 13C{1H} NMR (100 MHz,
CDCl3) δ 162.7, 160.4, 152.3, 125.2, 113.7, 102.5, 61.3, 18.2, 17.4, and 14.4. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C10H12NO2S2 242.0309; Found 242.0309.
Synthesis of Thieno[2,3-b]thiophenes 4
28
ACS Paragon Plus Environment

Page 29 of 42
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A typical procedure for the synthesis of thieno[2,3-b]thiophenes 4  Synthesis of
diethyl 3,4-dimethylthieno[2,3-b]thiophene-2,5-dicarboxylate (4a): A mixture of
3-(bis(methylthio)methylene)pentane-2,4-dione (1a) (61 mg, 0.3 mmol), ethyl
diazoacetate (2a) (136 mg, 1.2 mmol), CuCl2 (4 mg, 0.03 mmol) in PhMe/MeCN (2
mL, v/v = 1:1) was stirred at 60 °C (oil bath) for 12 h under a N2 atmosphere. After 1a
was completely consumed by TLC monitoring on silica gel, all the volatiles were
evaporated under reduced pressure. The resultant residue was purified by silica gel
column chromatography (eluent: petroleum ether (60-90 °C)/ethyl acetate = 50:1, v/v),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
1
affording 4a (80 mg, 85%) as a pale yellow solid. M.p.: 134-135 C. H NMR (400
MHz, CDCl3) δ 4.35 (q, J = 7.1 Hz, 4 H), 2.87 (s, 6 H), 1.39 (t, J = 7.1 Hz, 6 H).
13C{1H} NMR (100 MHz, CDCl3) δ 162.7, 147.6, 145.1, 141.0, 129.9, 61.2, 14.5, and
14.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H17O4S2 313.0568; Found
313.0575.
Diethyl
3-isobutyl-4-methylthieno[2,3-b]thiophene-2,5-dicarboxylate
(4b):
Following the general procedure, compound 4b was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc = 50:1, v/v).
83 mg, 78%; yellow solid, m.p.: 121-122 oC. 1H NMR (400 MHz, CDCl3) δ 4.31 (q, J
= 7.1 Hz, 4 H), 3.21 (d, J = 7.2 Hz, 2 H), 2.79 (s, 3 H), 1.89 (m, 1 H), 1.35 (m, 6 H),
13
0.93 (d, J = 6.7 Hz, 6 H). C{1H} NMR (100 MHz, CDCl3) δ 162.3, 162.2, 146.9,
145.3, 145.0, 140.5, 130.3, 129.9, 61.2, 60.9, 35.2, 30.8, 22.0, 14.3, 14.3, 14.1, and
14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H23O4S2 355.1038; Found
355.1040.
29
ACS Paragon Plus Environment