Cascade Annulation of 2-Alkynylthioanisoles with Unsaturated α-Bromocarbonyls Leading to Thio-Benzobicyclic Skeletons

Article abstract of DOI:10.1021/acs.joc.8b02001

A protocol of Cu-catalyzed annulation of phenylethynylsulfanes with unsaturated α-bromocarbonyls for the construction of thio-benzobicyclic skeletons is described. In this single reaction, three new bonds and two new rings can be established, highlighting the step-economics and high efficiency of this protocol.

Full text of DOI:10.1021/acs.joc.8b02001

Subscriber access provided by University of Sunderland
Article
Cascade Annulation of 2-Alkynylthioanisoles with Unsaturated
#-Bromocarbonyls Leading to Thio-Benzobicyclic Skeletons
Yuzhen Gao, Pengbo Zhang, Gang Li, and Yufen Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02001 • Publication Date (Web): 22 Oct 2018
Downloaded from http://pubs.acs.org on October 25, 2018
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 15
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Cascade Annulation of 2-Alkynylthioanisoles with Unsaturated
α-Bromocarbonyls Leading to Thio-Benzobicyclic Skeletons
Yuzhen Gao,*a Pengbo Zhang,b Gang Li, *a Yufen Zhaoc
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
aKey Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the
Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China
bSchool of Public Health, Xinxiang Medical University, Xinxiang 453003, China
cDepartment of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry
and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian, China.
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
R4
R
Cu(OTf)2 (10 mol%)
bpy (20 mol%)
R4
X
n
R2
R3
R2
R3
Br
X
R1
+
R1
n
K2CO3 (1 equiv)
CH3CN, 80 o
C
X = S, Se, NMe
R = Me, Et, Bn
n = 1, 2
ABSTRACT: A protocol of Cu-catalyzed annulation of phenylethynylsulfanes with unsaturated α-bromocarbonyls for
the construction of thio-benzobicyclic skeletons is described. In this single reaction, three new bonds and two new
rings can be established, highlighting the step-economics and high efficiency of this protocol.
INTRODUCTION
In recent years, thioanisole derivatives have been applied for the construction of benzothiophenes via radical cascade
reactions.1, 2 In these transformations, the radical cyclization process was terminated by the addition of a radical to a
sulfur atom along with the release of a methyl group. In elegant works, Zanardi’s, Schiesser’s, König’s, Maulide’s,
McDonald’s and Zhang’s groups revealed the synthesis of benzothiophenes via tandem radical annulations between
o-methylthioarenediazonium salts/anilines and alkynes (Scheme 1a).1 Subsequently, Song’s group developed a tandem
radical addition−cyclization reaction between 2-alkynylthioanisoles and sulfinic acids/sulfonyl chlorides for the
formation of 3-(arylsulfonyl)benzothiophenes (Scheme 1b).2 Very recently, Wu’s group disclosed a radical cascade
reaction between (2-isocyanophenyl)(methyl)sulfanes and radical precursors, providing a method for the construction
of benzothiazole derivatives (Scheme 1c).3
Meanwhile, readily available α-bromocarbonyls are important organic building blocks in synthesis and chemical
industries.4 Generally, alkyl radicals are provided by α-bromocarbonyls to react with unsaturated hydrocarbons for the
construction of diverse polycyclic compounds in concise process with highly atom economic and simple operation.5, 6
However, monocyclic compounds were formed through this strategy in most cases, probably because such approaches
were terminated by halogen atoms which is known as atom transfer radical cyclization (ATRC) process.7 Thus, it still
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 15
1
2
3
4
5
6
7
8
9
remains great challenge to employ α-bromocarbonyls for the synthesis of polycyclic compounds.
Herein, we considered that α-bromocarbonyls containing unsaturated functional groups could react with
2-alkynylthioanisoles via a radical addition to the sulfur atom, leading to the construction of thio-benzobicyclic
skeletons (Scheme 1d). In this one-pot reaction, three new bonds can be formed, as well as polycyclic rings can be
constructed, highlighting the step-economics and high efficiency of this 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
Scheme 1. Studies on Intermolecular Radical Cascade Reactions of Thioanisole Derivatives
Previous works:
N2BF4/NH2
via
(a)
+
Ph
aryl radical
S
S
S
Ph
SO2Ar
Ph
ArSO2H
or
via
+
(b)
(c)
sulfonyl radical
S
ArSO2Cl
C
N
S
R'
radical
precursors
N
via
+
R'
imidoyl radical
S
This work:
S
S
CO2Et
CO2Et
Br
CO2Et
via
(d)
+
CO2Et
alkyl radical
RESULTS AND DISCUSSION
To test this hypothesis, (2-ethynylphenyl)(methyl)sulfane (1a) and diethyl 2-allyl-2-bromomalonate (2a) were
chosen as reaction partners (Table 1). Thus far, copper-based catalysts have been the common agents to induced the
cascade radical reactions.8 Hence, copper salts were first employed as the catalyst. Pleasingly, when using 10 mol% of
Cu(OAc)2·5H2O as the catalyst, 20 mol% bipy (L1) as the ligand, and 1 equiv of K2CO3 as the base, 3a was isolated in
o
22% yield, after being heated at 80 C for 8 h (entry 1). Subsequently, various copper salts were further checked and
showed that Cu(OTf)2 was the most effective and gave 3a in 71% yield (entries 1–10). Screening a few other ligands,
such as TMEDA (L2), 1,10-phenanthroline (L3) and pentamethyldiethylenetriamine (L4), revealed that L1 was the
most efficient one (entries 11–13). The influence of base was also investigated and K2CO3 was found to be the most
suitable base (entries 14−17). The reaction was inhibited in the absence of copper salt, base or ligand (entries 18–20).
Moreover, the yield of 3a decreased when the loading of Cu(OTf)2 was reduced (entry 21) or the temperature was
changed (entries 22−23). Under the optimal reaction conditions, 3a’ was found as the major byproduct.
Table 1. Optimization of Reaction Conditionsa
ACS Paragon Plus Environment

Page 3 of 15
The Journal of Organic Chemistry
1
2
3
4
5
6
Me
S
S
CO2Et
CO2Et
SMe
Br
[Cu], ligand
Base (1.0 equiv)
CH3CN, T, Ar
CO2Et
CO2Et
+
2a
1a
3a
3a'
MeS
7
8
9
N
N
N
N
N
N
N
N
N
L3
L2
L4
L1
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
entry
1
[Cu]
ligand
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
L1
L1
L1
-
base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CsF
yield (%)
22
Cu(OAc)2·5H2O
Cu(OTf)2
Cu(acac)2
CuCl
2
71
3
50
4
24
5
CuI
54
6
Cu(NO3)2·6H2O
CuBr
62
7
32
8
Cu(SO4)2·5H2O
CuCl2·2H2O
Cu(CH3CN)4PF6
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
-
66
9
24
10
11
12
13
14
15
16
17
18
19
20
21
22
23
52
trace
56
46
18
t-BuOK
Et3N
32
24
Cs2CO3
K2CO3
-
60
0
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
8
K2CO3
K2CO3
K2CO3
K2CO3
trace
51b
44c
33d
L1
L1
L1
aReaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), [Cu] (10 mol%),
ligand (20 mol%) and base (0.3 mmol) in CH3CN (2 mL) stirring under
argon in 80 oC for 8 h. Oil bath temperature. Yield of the isolated
product. b Cu(OTf)2 (5 mol%), L1 (10 mol%). c100 °C. d60 °C.
Table 2. Substrates Scopea
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 15
1
2
3
4
5
6
7
8
R4
Me
S
R2
R3
Cu(OTf)2 (10 mol%)
R4
S
n
R2
Br
bpy (20 mol%)
R3
R1
+
R1
n
K2CO3 (1 equiv)
CH3CN, 80 o
C
n = 1, 2
3
1
2
9
S
CO2Et
CO2Et
S
CO2Et
CO2Et
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
S
CO2Et
CO2Et
Me
S
Cl
S
3a
, 71%
3c
, 32%
3b
, 54%
CO2Et
CO2Et
S
CO2Et
CO2Et
CO2Et
CO2Et
CF3
S
Br
S
F
S
b
3e
, 40%
3f
, 43%
3d
, 38%
Me
Ac
Ac
CO2Et
CO2Et
CO2Me
CO2Me
3g
3h
, R = H, 66%
3j
, 64%
3i
, 63%
R
S
, R = Me, 54%
S
S
CO2Et
CO2Et
CO2Et
Ac
CO2Et
CO2Et
R
3l
, 20%
3m
3n
3k
, 61% (dr = 1:0.7)
, R = Ph, 0%
, R = n-Bu, 0%
aReaction conditions: 1 (0.3 mmol), 2 (0.45 mmol), Cu(OTf)2 (10 mol %), bpy (20 mol %), and K2CO3 (0.3 mmol) in CH3CN (2 mL),
with stirring under argon at 80 °C for 8 h. b12 h.
With the optimized reaction conditions in hand, the scope of this Cu-catalyzed annulation was investigated, and the
results are summarized in Table 2. With methyl substituted on benzene, 3b and 3h were obtained both in 54% yields.
Halogen atoms such as chloro, bromo and fluoro on the aromatic ring were also suitable to the present reaction
conditions to afford the corresponding products 3c−3e in moderate yields, which giving opportunities for further
elaboration through the transition-metal-catalyzed coupling reactions. Substrate bearing electron-withdrawing (CF3)
group on the benzene was also investigated and converted into product 3f in 43% yield. The process was extended to
various unsaturated α-halogenocarbonyl compounds 2. The products 3g and 3h with a quaternary carbon center were
obtained by employing the methyl-substited analogue. Other activated organobromides were also performed well in
this Cu-catalyzed cascade annulation reaction, as exemplified by the formation of 3i–3k. Moreover, the structure of 3j
was confirmed by X-ray crystal structure analysis (details see Supporting Information).9 Gratifyingly, the
6-6-6-tricyclic product 3l was afforded when diethyl 2-bromo-2-(but-3-en-1-yl)malonate (2l) was employed instead
of 2a. Internal alkynes were also examined, unfortunately, no desired products were detected under the reaction
conditions.
Scheme 2. Scope of Alkynes
ACS Paragon Plus Environment

Page 5 of 15
The Journal of Organic Chemistry
1
2
3
R
R
4
5
6
7
Br
, R = CO2Et
2b
Se
R
R
SeMe
2a
, R = CO2Me
(a)
standard conditions
1aa
4a
, R = CO2Et, 52%
, R = CO2Me, 44%
4b
8
9
Me
N
CO2Et
CO2Et
NMe2
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
standard
conditions
(b)
2a
1ab
4c
, 25%
Br
EtO2C
X
CO2Et
CO2Et
X
R
standard
EtO2C
XR
conditions
(c)
X = O, S
not detected
2a
4d
4e
, XR = OMe, 63%
, XR = SPh, 32%
1ac
1ad
, XR = OMe
, XR = SPh
Importantly, (2-ethynylphenyl)(methyl)selane 1aa was also suitable to this reaction to deliver
tetrahydrocyclopentaselenochromene derivatives (4a, 4b) in 52-44% yields (Scheme 2a). When
2-ethynyl-N,N-dimethylaniline 1ab was used as the substrate, 4c was obtained in 25% yield, providing a optional
pathway for the synthesis of tetrahydro-2H-cyclopentaquinoline derivatives which is a useful core in bioactive natural
products and pharmaceuticals (Scheme 2b).10 Moreover, no desired products were afforded when
1-ethynyl-2-methoxybenzene 1ac or (2-ethynylphenyl)(phenyl)sulfane 1ad were employed as the substrates and ATRA
products were obtained in 63% and 32% yields, respectively (Scheme 2c).8a
To gain insights into the reaction mechanism, some control experiments were carried out (Scheme 3). The reaction
between 1a and 2a was inhibited by adding 1.5 equiv of 2,2,6,6-tetra-methylpiperidinooxy (TEMPO) or butylated
hydroxytoluene (BHT). Instead, compound 5 was obtained in 47% yield in the presence of BHT (Scheme 3b). These
results indicated that the Cu-catalyzed annulation might via a radical pathway.8a, 11 Additional, when changed the
methyl in the sulfur atom into ethyl and benzyl, 3a was also afforded in 53% and 48% yields, respectively (Scheme
3c). Remarkably, in our reaction mixtures, (bromomethyl)benzene (BnBr) was detected by GC-MS when 1af was
employed as the substrate, which provide evidence for the mechanism of this transformation.
Scheme 3. Control Experiments
S
S
standard
conditions
Me
Me
3a
, 0%
(a)
+
2a
1.5 equiv TEMPO
1a
1a
t-Bu
HO
t-Bu
EtO2C
standard
conditions
CO2Et
3a
, 0%
+
+
2a
(b)
(c)
1.5 equiv BHT
5
, 47%
S
CO2Et
CO2Et
standard
conditions
SR
2a
R = Et, 3a
, 53%
1ae,
1af,
R = Et
R = Bn
R = Bn, 3a
BnBr was detected by GC-MS
, 48%
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 15
1
2
3
4
8a
In accordance to literature reports1a, and the control experiments, a tentative pathway was proposed for this
transformation (Scheme 4). Initially, the alkyl radical A is formed by a SET process from 2a, which then adds to 1a to
give the alkenyl radical B. The resulting alkenyl radical B participates in an intramolecular radical substitution yielding
the corresponding intermediate C, which then cyclizes to give the sulphuranyl radical D. Intermediate D could be
oxidized by the Cu(II) species to the corresponding cation E with the formation of a Cu(I) species to re-enter the
catalytic cycle. Finally, desired product 3a is produced from cation E via an E2 process and bromomethane is
released as the byproduct.
5
6
7
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
Scheme 4. A Tentative Mechanistic Pathway
CO2Et
Br
EtO2C CO2Et
EtO2C CO2Et
CO2Et
Br
S
2a
A
Me
S
B
Me
1a
3a
+
CH3Br
Br
CuI
CuII
Me
Me
Me
S
CO2Et
CO2Et
S
CO2Et
CO2Et
S
CO2Et
CO2Et
D
C
E
■ SUMMARY
In summary, we have developed an efficient protocol for the construction of thio-benzobicyclic skeletons by
copper-mediated cascade annulation of 2-alkynylthioanisoles with unsaturated α-bromocarbonyls under mild
conditions. In this single reaction, three new bonds and two new rings can be established, highlighting the
step-economics and high efficiency of this protocol.
■ EXPERIMENTAL SECTION
1
All reactions were carried out under Ar. H and 13C NMR spectra were recorded on a Bruker AVANCE III
spectrometer (400 MHz and 100 MHz, respectively), and a JEOL ECZ600S (600 MHz and 150 MHz, respectively).
Chemical shifts are reported parts per million (ppm) referenced to CDCl3 (δ 7.26 ppm), tetramethylsilane (TMS, δ 0.00
ppm) for 1H NMR, CDCl3 (δ 77.23 ppm) for 13C NMR. All coupling constants (J values) were reported in Hertz (Hz).
Column chromatography was performed on silica gel 300-400 mesh. High-resolution mass spectra (HRMS) were
obtained on an Impact IIUHR-TOF mass spectrometry equipped with an ESI source from Bruker at Fujian Institute of
Research on the Structure of Matter.
General Procedures for the Synthesis of Substrates 1. Procedure A12a: To a mixture of corresponding
(2-iodophenyl)(methyl)sulfane and derivatives (3.0 mmol), PdCl2(PPh3)2 (5 mol%), CuI (5 mol%) and Et3N (1.5 equiv)
in dry THF was slowly added trimethylsilylacetylene (1.5 equiv). After the reaction mixture was stirred at room
temperature for overnight, the reaction was quenched by addition of water and the whole mixture was extracted with
Et2O. The organic layer was dried over anhydrous MgSO4 and filtered the solid off. After evaporation of the solvent,
ACS Paragon Plus Environment

Page 7 of 15
The Journal of Organic Chemistry
1
2
3
4
5
the crude was purified by silica gel column chromatography using petroleum ether as the eluent to afford the
trimethyl((2-(methylthio)phenyl)ethynyl)silane and derivatives. Procedure B12b
:
To
a
solution of
trimethyl((2-(methylthio)phenyl)ethynyl)silane or derivatives in methanol and CH2Cl2 (v/v = 2:1) was added K2CO3
(3.0 equiv) and stirred at room temperature for 12 h. Then, the mixture was extracted with CHCl3 and dried over
anhydrous MgSO4. After filtration of the solid, the organic layer was concentrated under reduced pressure. The residue
was purified by silica gel chromatography using petroleum ether as the eluent to provide substrates 1.
6
7
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
Characterization Data of Products 1. (2-ethynylphenyl)(methyl)Sulfane(1a, known compound)13a Yellow oil. 337 mg,
76% total yield of Procedures A and B. 1H NMR (400 MHz, d-CDCl3): δ 7.46 (dd, J = 1.0 Hz, J = 7.6 Hz, 1H), 7.34 –
7.29 (m, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.11 – 7.07 (m, 1H), 3.48 (s, 1H), 2.49 (s, 3H).
(2-ethynyl-4-methylphenyl)(methyl)Sulfane (1b, New Compound) Yellow oil. 364 mg, 75% total yield of Procedures A
and B. 1H NMR (400 MHz, d-CDCl3): δ 7.30 (s, 1H), 7.14 – 7.08 (m, 2H), 3.43 (s, 1H), 2.48 (s, 3H), 2.29 (s, 3H). 13
C
NMR (100 MHz, d-CDCl3): δ 138.4, 134.6, 134.0, 130.5, 125.4, 120.8, 83.1, 81.5, 20.8, 15.8. Anal. Calcd for
C10H10S: C, 74.05; H, 6.22. Found: C, 73.62; H, 6.14.
(4-chloro-2-ethynylphenyl)(methyl)Sulfane (1c, New Compound) Yellow oil. 371 mg, 68% total yield of Procedures
1
A and B. H NMR (400 MHz, d-CDCl3): δ 7.43 (d, J = 2.3 Hz, 1H), 7.28 (dd, J = 2.4 Hz, J = 8.6 Hz, 1H), 7.09 (d, J
= 8.6 Hz, 1H), 3.50 (s, 1H), 2.49 (s, 3H). 13C NMR (100 MHz, d-CDCl3): δ 140.8, 132.9, 130.2, 129.7, 125.9, 121.9,
84.8, 80.0, 15.6. Anal. Calcd for C9H7ClS: C, 59.34; H, 3.88. Found: C, 58.08; H, 4.08.
(4-bromo-2-ethynylphenyl)(methyl)Sulfane (1d, New Compound) Yellow oil. 393 mg, 58% total yield of Procedures
1
A and B. H NMR (400 MHz, d-CDCl3): δ 7.57 (d, J = 1.7 Hz, 1H), 7.42 (dd, J = 1.7 Hz, J = 8.5 Hz, 1H), 7.01 (d, J
= 8.6 Hz, 1H), 3.51 (s, 1H), 2.47 (s, 3H). 13C NMR (100 MHz, d-CDCl3): δ 141.5, 135.7, 132.5, 126.0, 122.2, 117.6,
85.0, 79.9, 15.5. Anal. Calcd for C9H7BrS: C, 47.80; H, 3.12. Found: C, 47.67; H, 3.15.
(2-ethynyl-4-fluorophenyl)(methyl)Sulfane (1e, New Compound) Yellow oil. 324 mg, 65% total yield of Procedures
1
A and B. H NMR (400 MHz, d-CDCl3): δ 7.20 – 7.14 (m, 2H), 7.07 – 7.02 (m, 1H), 3.49 (s, 1H), 2.49 (s, 3H). 13
C
NMR (100 MHz, d-CDCl3): δ 160.3 (d, J = 244.9 Hz), 137.2 (d, J = 3.4 Hz), 127.4 (d, J = 8.4 Hz), 122.6 (d, J = 9.5
Hz), 120.2 (d, J = 23.6 Hz), 117.1 (d, J = 21.8 Hz), 84.4, 80.3 (d, J = 3.1 Hz), 16.3. 19F NMR (377 MHz, d-CDCl3): δ
-118.1. Anal. Calcd for C9H7FS: C, 65.05; H, 4.25. Found: C, 65.45; H, 4.33.
(2-ethynyl-4-(trifluoromethyl)phenyl)(methyl)Sulfane (1f, New Compound) Yellow oil. 460 mg, 71% total yield of
1
Procedures A and B. H NMR (400 MHz, d-CDCl3): δ 7.68 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.4 Hz,
1H), 3.54 (s, 1H), 2.52 (s, 3H). 13C NMR (100 MHz, d-CDCl3): δ 147.4, 129.9 (q, J = 3.9 Hz), 126.6 (q, J = 33.2 Hz),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 15
1
2
3
4
5
125.9 (q, J = 3.8 Hz), 124.0 (q, J = 271.7 Hz), 123.7, 119.9, 85.4, 79.8, 15.0. 19F NMR (377 MHz, d-CDCl3): δ -62.5.
Anal. Calcd for C10H7F3S: C, 55.55; H, 3.27. Found: C, 55.98; H, 3.24.
6
7
8
9
(2-ethynylphenyl)(methyl)Selane (1aa, known compound) Yellow oil. 341 mg, 58% total yield of Procedures A and B.
1H NMR (400 MHz, d-CDCl3): δ 7.45 (d, J = 7.7 Hz, 1H), 7.30 – 7.26 (m, 2H), 7.16 – 7.12 (m, 1H), 3.44 (s, 1H), 2.35
(s, 3H).
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-Ethynyl-N,N-dimethylaniline (1ab, known compound)13b Yellow oil. 226 mg, 52% total yield of Procedures A and B.
1H NMR (400 MHz, d-CDCl3): δ 7.45 (dd, J = 1.5 Hz, J = 7.6 Hz, 1H), 7.27 – 7.23 (m, 1H), 6.91 (d, J = 8.4 Hz, 1H),
6.88 – 6.84 (m, 1H), 3.40 (s, 1H), 2.92 (s, 6H).
1-Ethynyl-2-methoxybenzene (1ac, known compound)13c Yellow oil. 289 mg, 73% total yield of Procedures A and B.
1H NMR (400 MHz, d-CDCl3): δ 7.49 (dd, J = 1.2 Hz, J = 7.4 Hz, 1H), 7.36 – 7.32 (m, 1H), 6.95 – 6.90 (m, 2H), 3.92
(s, 3H), 3.33 (s, 1H).
(2-ethynylphenyl)(phenyl)Sulfane (1ad, known compound)13d Yellow solid. 391 mg, 62% total yield of Procedures A
and B. 1H NMR (400 MHz, d-CDCl3) δ 7.50 (dd, J = 1.6, 7.5 Hz, 1H), 7.47 – 7.45 (m, 2H), 7.38 – 7.32 (m, 3H), 7.19
– 7.09 (m, 2H), 6.97 (dd, J = 1.3, 8.0 Hz, 1H), 3.43 (s, 1H).
Ethyl(2-ethynylphenyl)sulfane (1ae, known compound)13e Yellow oil. 316 mg, 65% total yield of Procedures A and B.
1H NMR (600 MHz, d-CDCl3) δ7.47 (dd, J = 7.6, 1.3 Hz, 1H), 7.30 – 7.28 (m, 1H), 7.25 (dd, J = 8.4, 1.4 Hz, 1H),
7.12 – 7.09 (m, 1H), 3.45 (s, 1H), 3.00 (q, J = 7.4 Hz, 2H), 1.36 (t, J = 7.4 Hz, 3H).
Benzyl(2-ethynylphenyl)sulfane (1af, known compound)13f Yellow solid. 470 mg, 70% total yield of Procedures A and
B. 1H NMR (400 MHz, d-CDCl3) δ 7.48 (d, J = 7.5 Hz, 1H), 7.36 – 7.34 (m, 2H), 7.31 – 7.27 (m, 2H), 7.25 – 7.22 (m,
3H), 7.13 – 7.09 (m, 1H), 4.19 (s, 2H), 3.45 (s, 1H).
General Procedures for the Synthesis of Substrates 214. To a stirred solution of γ,δ-unsaturated carbonyls (3.0 mmol)
in EtOAc (50 mL) was added Lewis acid Mg(ClO4)2 (0.9 mmol) at room temperature. Then NBS (3.3 mmol) was
added to the above mixture carefully 20 min later. After the reaction was finished, the reaction mixture was extracted
with diethylether (3 x 15 mL). The organic phases were washed with brine (15 mL) and dried over MgSO4. The solvent
was evaporated in vacuo, and the residue was purified by silica gel chromatography using a petroleum ether/AcOEt
(50:1-20:1, v/v) as the eluent to afford substrates 2.
Characterization Data of Products 2. Diethyl 2-allyl-2-bromomalonate (2a, known compound)5b Colourless oil. 684
mg, 82% yield. 1H NMR (600 MHz, d-CDCl3) δ 5.85 – 5.78 (m, 1H), 5.23 – 5.21 (m, 1H), 5.20 – 5.18 (m, 1H), 4.28
(q, J = 7.1 Hz, 4H), 3.05 (dt, J = 7.0, 1.2 Hz, 2H), 1.29 (t, J = 7.1 Hz, 6H).
1
Diethyl 2-bromo-2-(2-methylallyl)malonate (2b, known compound)5b Light yellow oil. 675 mg, 77% yield. H NMR
(400 MHz, d-CDCl3): δ 4.96 (s, 1H), 4.86 (s, 1H), 4.31 – 4.26 (m, 4H), 3.10 (s, 2H), 1.79 (s, 3H), 1.31 (t, J = 7.0 Hz,
6H).
3-Allyl-3-bromopentane-2,4-dione (2c, known compound)5b Light yellow oil. 536 mg, 82% yield. 1H NMR (400 MHz,
d-CDCl3): δ 5.79 – 5.69 (m, 1H), 5.17 (s, 1H), 5.14 – 5.13 (m, 1H), 2.94 (d, J = 7.1 Hz, 2H), 2.37 (s, 6H).
ACS Paragon Plus Environment

Page 9 of 15
The Journal of Organic Chemistry
1
2
3
4
5
6
1
Dimethyl 2-allyl-2-bromomalonate (2d, known compound)8a Colourless oil. 375 mg, 80% yield. H NMR (600 MHz,
d-CDCl3) δ 5.84 – 5.77 (m, 1H), 5.22 (t, J = 1.2 Hz, 1H), 5.21 – 5.18 (m, 1H), 3.82 (s, 6H), 3.05 (dt, J = 7.1, 1.2 Hz,
2H).
7
8
9
Ethyl 2-acetyl-2-bromopent-4-enoate (2e, known compound)5b Light yellow oil. 580 mg, 78% yield. 1H NMR (400
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
MHz, d-CDCl3): δ 5.85 – 5.74 (m, 1H), 5.20 (s, 1H), 5.17 (d, J = 3.4 Hz, 1H), 4.28 (q, J = 7.0 Hz, 2H), 3.05 – 2.92 (m,
2H), 2.41 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).
1
Diethyl 2-bromo-2-(but-3-en-1-yl)malonate (2f, known compound)5b Light yellow oil. 702 mg, 81% yield. H NMR
(400 MHz, d-CDCl3): δ 5.86 – 5.76 (m, 1H), 5.10 (dd, J = 1.0 Hz, J = 17.1 Hz, 1H), 5.03 (d, J = 10.1 Hz, 1H), 4.29 (q,
J = 7.1 Hz, 4H), 2.40 – 2.36 (m, 2H), 2.24 – 2.19 (m, 2H), 1.31 (t, J = 7.2 Hz, 6H).
Experimental Procedure for the Synthesis of Products 3 and 4. A Schlenk tube containing Cu(OTf)2 (0.03 mmol,
10 mol%), bpy (0.06 mmol, 20 mol%) and K2CO3 (0.30 mmol, 1.0 eq) were evacuated and purged with argon three
times. 1 (0.3 mmol, 1.0 eq), 2 (0.45 mmol, 1.5 eq) and CH3CN (2.0 mL) were sequentially added to the system at room
temperature. The reaction mixture was heated with stirring at 80 oC for 8 hours. Upon completion, the reaction mixture
was concentrated under vacuum. The residue was purified by silica gel column chromatography using a petroleum
ether/AcOEt (40:1-10:1, v/v) as the eluent to give the corresponding products.
Characterization Data of Products 3 and 4. Diethyl 3a, 4-dihydrocyclopenta[c]thiochromene-2, 2(3H)-dicarboxylate
(3a, New Compound) 70.7 mg, 71% yield, yellow oil. 1H NMR (400 MHz, d-CDCl3): δ 7.65 (d, J = 7.6 Hz, 1H), 7.18
– 7.11 (m, 2H), 7.07 – 7.03 (m, 1H), 6.29 (d, J = 2.2 Hz, 1H), 4.27 – 4.16 (m, 4H), 3.42 – 3.34 (m, 1H), 3.06 (dd, J =
7.4 Hz, J = 13.3 Hz, 1H), 3.01 – 2.89 (m, 2H), 2.04 (dd, J = 8.3 Hz, J = 13.3 Hz, 1H), 1.32 – 1.26 (m, 6H). 13C NMR
(100 MHz, d-CDCl3): δ 171.2, 170.5, 143.8, 133.8, 128.7, 128.5, 127.1, 127.0, 124.6, 121.6, 65.2, 61.9, 61.8, 43.0,
39.4, 32.7, 14.2. HRMS Calcd for C18H20NaO4S+ [M+Na]+ 355.0975, found 355.0982.
1,4-Bis(2-(methylthio)phenyl)buta-1,3-diyne (3a’, known compound)13e Light yellow solid. 1H NMR (600 MHz,
d-CDCl3): δ 7.50 (dd, J = 7.6, 1.4 Hz, 2H), 7.32 (ddd, J = 8.1, 7.4, 1.5 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.10 (td, J =
7.5, 1.1 Hz, 2H), 2.51 (s, 6H).
Diethyl 8-methyl-3a, 4-dihydrocyclopenta[c]thiochromene-2, 2(3H)-dicarboxylate (3b, New Compound) 56.1 mg, 54%
yield, yellow solid, melt point: 74.7 – 76.3 oC. 1H NMR (400 MHz, d-CDCl3): δ 7.49 (s, 1H), 7.07 (d, J = 8.1 Hz, 1H),
6.97 (dd, J = 1.1 Hz, J = 8.0 Hz, 1H), 6.28 (d, J = 2.2 Hz, 1H), 4.27 – 4.17 (m, 4H), 3.40 – 3.33 (m, 1H), 3.06 (dd, J =
7.5 Hz, J = 13.3 Hz, 1H), 2.97 (dd, J = 4.3 Hz, J = 12.2 Hz, 1H), 2.90 (t, J = 12.3 Hz, 1H), 2.30 (s, 3H), 2.03 (dd, J =
8.4 Hz, J = 13.2 Hz, 1H), 1.32 – 1.27 (m, 6H). 13C NMR (100 MHz, d-CDCl3): δ 171.2, 170.5, 144.0, 134.2, 130.3,
129.8, 128.2, 127.4, 127.0, 121.3, 65.2, 61.9, 61.8, 43.1, 39.5, 32.7, 21.0, 14.23, 14.22. HRMS Calcd for
C19H22NaO4S+ [M+Na]+ 369.1131, found 369.1161.
Diethyl 8-chloro-3a,4-dihydrocyclopenta[c]thiochromene-2,2(3H)-dicarboxylate (3c, New Compound) 35.1 mg, 32%
o
1
yield, yellow solid, melt point: 99.2 – 101.1 C. H NMR (400 MHz, d-CDCl3): δ 7.61 (s, 1H), 7.08 (d, J = 0.9 Hz,
2H), 6.28 (d, J = 2.2 Hz, 1H), 4.27 – 4.15 (m, 4H), 3.37 – 3.29 (m, 1H), 3.05 (dd, J = 7.5 Hz, J = 13.4 Hz, 1H), 2.98
(dd, J = 4.3 Hz, J = 12.4 Hz, 1H), 2.88 (t, J = 12.3 Hz, 1H), 2.02 (dd, J = 8.3 Hz, J = 13.3 Hz, 1H), 1.28 (q, J = 7.1 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 15
1
2
3
4
5
6H). 13C NMR (100 MHz, d-CDCl3): δ 171.0, 170.3, 142.9, 132.3, 130.3, 129.9, 128.7, 128.4, 126.7, 123.0, 65.2,
62.1, 62.0, 42.7, 39.4, 32.5, 14.3. HRMS Calcd for C18H19ClNaO4S+ [M+Na]+ 389.0585, found 389.0583.
6
7
8
9
Diethyl 8-bromo-3a,4-dihydrocyclopenta[c]thiochromene-2,2(3H)-dicarboxylate (3d, New Compound) 46.9 mg, 38%
yield, yellow solid, melt point: 101.4 – 102.6 oC. 1H NMR (400 MHz, d-CDCl3): δ 7.75 (d, J = 2.1 Hz, 1H), 7.22 (dd,
J = 2.1 Hz, J = 8.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.27 (d, J = 2.3 Hz, 1H), 4.27 – 4.15 (m, 4H), 3.37 – 3.28 (m,
1H), 3.05 (dd, J = 7.5 Hz, J = 13.3 Hz, 1H), 2.98 (dd, J = 4.3 Hz, J = 12.4 Hz, 1H), 2.88 (t, J = 12.4 Hz, 1H), 2.02 (dd,
J = 8.3 Hz, J = 13.4 Hz, 1H), 1.28 (dd, J = 7.0 Hz, J = 13.4 Hz, 6H). 13C NMR (100 MHz, d-CDCl3): δ 171.0, 170.3,
142.8, 133.0, 131.5, 130.3, 129.7, 128.6, 123.1, 118.0, 65.2, 62.1, 62.0, 42.6, 39.4, 32.5, 14.3. HRMS Calcd for
C18H19BrNaO4S+ [M+Na]+ 433.0080, found 433.0076.
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 8-fluoro-3a, 4-dihydrocyclopenta[c]thiochromene-2,2 (3H)-dicarboxylate (3e, New Compound) 42.0 mg, 40%
o
1
yield, yellow solid, melt point: 75.2 – 76.6 C. H NMR (400 MHz, d-CDCl3): δ 7.35 (dd, J = 2.7 Hz, J = 10.0 Hz,
1H), 7.13 (dd, J = 5.5 Hz, J = 8.8 Hz, 1H), 6.91 – 6.86 (m, 1H), 6.28 (d, J = 2.2 Hz, 1H), 4.27 – 4.16 (m, 4H), 3.40 –
3.32 (m, 1H), 3.07 (dd, J = 7.4 Hz, J = 13.3 Hz, 1H), 2.99 (dd, J = 4.3 Hz, J = 12.3 Hz, 1H), 2.89 (t, J = 12.3 Hz, 1H),
2.04 (dd, J = 8.4 Hz, J = 13.3 Hz, 1H), 1.32 – 1.26 (m, 6H). 13C NMR (100 MHz, d-CDCl3): δ 171.0, 170.3, 160.4 (d,
J = 243.7 Hz), 143.32 (d, J = 2.3 Hz), 129.94 (d, J = 7.2 Hz), 128.93 (d, J = 2.7 Hz), 128.55 (d, J = 7.6 Hz), 123.1,
116.44 (d, J = 22.8 Hz), 113.25 (d, J = 22.5 Hz), 65.2, 62.0, 61.9, 42.8, 39.5, 32.5, 14.2. 19F NMR (377 MHz,
d-CDCl3): δ -133.6. HRMS Calcd for C18H20FO4S+ [M+H]+ 351.1061, found 351.1053.
Diethyl 8-(trifluoromethyl)-3a, 4-dihydrocyclopenta[c]thiochromene-2, 2(3H)-dicarboxylate (3f, New Compound) 51.6
o
1
mg, 43% yield, yellow solid, melt point: 76.4 – 78.5 C. H NMR (400 MHz, d-CDCl3): δ 7.87 (s, 1H), 7.35 (d, J =
8.3 Hz, 1H), 7.29 – 7.27 (m, 1H), 6.37 (d, J = 2.1 Hz, 1H), 4.29 – 4.18 (m, 4H), 3.42 – 3.34 (m, 1H), 3.12 – 3.03 (m,
2H), 2.95 (t, J = 12.3 Hz, 1H), 2.08 (dd, J = 8.1 Hz, J = 13.4 Hz, 1H), 1.33 – 1.28 (m, 6H). 13C NMR (100 MHz,
d-CDCl3): δ 170.9, 170.3, 142.8, 138.7, 128.8 127.5 127.0 (d, J = 32.7 Hz), 125.6 (q, J = 271.7 Hz), 124.82 (d, J = 3.7
Hz), 128.91 (d, J = 3.8 Hz), 123.5, 65.3, 62.2, 62.1, 42.5, 39.4, 32.6, 14.28, 14.27. 19F NMR (377 MHz, d-CDCl3): δ
-78.0. HRMS Calcd for C19H19F3NaO4S+ [M+Na]+ 423.0848, found 423.0849.
Diethyl 3a-methyl-3a, 4-dihydrocyclopenta[c]thiochromene-2, 2(3H)-dicarboxylate (3g, New Compound) 68.5 mg,
66% yield, yellow oil. 1H NMR (400 MHz, d-CDCl3): δ 7.61 (d, J = 7.6 Hz, 1H), 7.17 – 7.12 (m, 2H), 7.07 – 7.03 (m,
1H), 6.11 (s, 1H), 4.31 – 4.20 (m, 4H), 3.20 (d, J = 12.3 Hz, 1H), 2.81 (dd, J = 5.7 Hz, J = 13.7 Hz, 2H), 3.37 (d, J =
13.7 Hz, 1H), 1.33 – 1.27 (m, 9H). 13C NMR (100 MHz, d-CDCl3): δ 171.3, 171.2, 147.5, 132.9, 128.6, 128.1, 127.9,
126.5, 124.4, 120.8, 64.7, 61.99, 61.96, 46.6, 43.2, 39.9, 23.9, 14.3. HRMS Calcd for C19H22NaO4S+ [M+Na]+
369.1131, found 369.1137.
Diethyl 3a,8-dimethyl-3a,4-dihydrocyclopenta[c]thiochromene-2,2(3H)-dicarboxylate (3h, New Compound) 58.3 mg,
54% yield, yellow solid, melt point: 59.3 – 61.6 oC. 1H NMR (400 MHz, d-CDCl3): δ 7.43 (s, 1H), 7.05 (d, J = 8.2 Hz,
1H), 6.98 (dd, J = 1.3 Hz, J = 8.1 Hz, 1H), 6.10 (s, 1H), 4.31 – 4.20 (m, 4H), 3.18 (d, J = 12.4 Hz, 1H), 2.79 (dd, J =
6.4 Hz, J = 13.7 Hz, 2H), 2.39 – 2.32 (m, 1H), 2.30 (s, 3H), 1.31 – 1.27 (m, 9H). 13C NMR (100 MHz, d-CDCl3): δ
171.33, 171.25, 147.6, 133.9, 129.8, 129.4, 128.2, 127.8, 126.4, 120.5, 64.6, 62.0, 61.9, 46.6, 43.3, 39.8, 23.9, 21.0,
14.3. HRMS Calcd for C20H24NaO4S+ [M+Na]+ 383.1288, found 383.1288.
1, 1'-(2, 3, 3a, 4-tetrahydrocyclopenta[c]thiochromene-2, 2-diyl) Diethanone (3i, New Compound) 51.4 mg, 63% yield,
o
1
yellow solid, melt point: 105.1 – 107.2 C. H NMR (400 MHz, d-CDCl3): δ 7.66 (dd, J = 1.0 Hz, J = 7.8 Hz, 1H),
ACS Paragon Plus Environment

Page 11 of 15
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
7.20 – 7.14 (m, 2H), 7.09 – 7.06 (m, 1H), 6.44 (d, J = 2.3 Hz, 1H), 3.32 – 3.25 (m, 1H), 3.09 (dd, J = 7.4 Hz, J = 13.1
Hz, 1H), 3.01 (dd, J = 4.3 Hz, J = 12.3 Hz, 1H), 2.90 (t, J = 12.3 Hz, 1H), 2.21 (s, 3H), 2.20 (s, 3H), 1.89 (dd, J = 8.4
Hz, J = 13.1 Hz, 1H). 13C NMR (100 MHz, d-CDCl3): δ 205.6, 203.7, 144.8, 134.0, 129.0, 128.4, 127.3, 126.9, 124.8,
121.0, 79.4, 43.0, 37.3, 32.8, 27.3, 27.1. HRMS Calcd for C16H16NaO2S+ [M+Na]+ 295.0763, found 295.0751.
9
Dimethyl 3a, 4-dihydrocyclopenta[c]thiochromene-2, 2(3H)-dicarboxylate (3j, New Compound) 58.3 mg, 64% 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
o
1
yellow solid, melt point: 122.3 – 124.1 C. H NMR (400 MHz, d-CDCl3): δ 7.66 (dd, J = 0.7 Hz, J = 7.9 Hz, 1H),
7.19 – 7.13 (m, 2H), 7.08 – 7.05 (m, 1H), 6.28 (d, J = 2.2 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.43 – 3.36 (m, 1H), 3.08
(dd, J = 7.5 Hz, J = 13.3 Hz, 1H), 2.99 (dd, J = 4.4 Hz, J = 12.2 Hz, 1H), 2.93 (t, J = 12.3 Hz, 1H), 2.05 (dd, J = 8.4
Hz, J = 13.3 Hz, 1H). 13C NMR (100 MHz, d-CDCl3): δ 171.7, 171.0, 144.0, 133.9, 128.8, 128.4, 127.2, 127.1, 124.7,
121.4, 65.0, 53.12, 53.06, 43.0, 39.6, 32.6. HRMS Calcd for C16H16NaO4S+ [M+Na]+ 327.0662, found 327.0672.
Ethyl 2-acetyl-2, 3, 3a, 4-tetrahydrocyclopenta[c]thiochromene-2-carboxylate (3k, New Compound) 55.3 mg, 61%
yield, yellow solid, melt point: 53.8 – 55.7 oC. dr = 1:0.7; data of the mixture. 1H NMR (400 MHz, d-CDCl3): δ 7.67 –
7.64 (m, 1H), 7.19 – 7.13 (m, 2H), 7.08 – 7.05 (m, 1H), 6.34 – 6.31 (m, 1H), 4.28 – 4.18 (m, 2H), 3.43 – 3.24 (m, 1H),
3.07 – 2.88 (m, 3H), 2.26 (s, 3H), 2.06 – 1.89 (m, 1H), 1.33 – 1.27 (m, 3H). 13C NMR (100 MHz, d-CDCl3): δ 204.0,
202.2, 171.7, 171.0, 144.6, 144.2, 134.0, 133.9, 128.9, 128.8, 128.44, 128.36, 127.3, 127.2, 127.00, 126.97, 124.7,
121.4, 121.3, 72.1, 71.9, 62.02, 61.95, 43.01, 42.94, 38.2, 38.1, 32.8, 32.7, 26.8, 14.29, 14.27. HRMS Calcd for
C17H18NaO3S+ [M+Na]+ 325.0869, found 325.0842.
Diethyl 7, 8-dihydro-6H-benzo[c]thiochromene-9, 9(6aH)-dicarboxylate (3l, New Compound) 20.8 mg, 20% yield,
o
1
yellow solid, melt point: 70.8 – 72.1 C. H NMR (400 MHz, d-CDCl3): δ 7.61 (d, J = 7.8 Hz, 1H), 7.14 – 7.10 (m,
2H), 7.08 – 7.05 (m, 1H), 6.48 (s, 1H), 4.28 – 4.17 (m, 4H), 2.96 (t, J = 12.1 Hz, 1H), 2.83 (dd, J = 3.5 Hz, J = 12.3 Hz,
1H), 2.73 – 2.68 (m, 1H), 2.43 – 2.37 (m, 1H), 2.16 – 2.08 (m, 1H), 2.03 – 1.96 (m, 1H), 1.62 – 1.60 (m, 1H), 1.32 –
1.26 (m, 6H). 13C NMR (100 MHz, d-CDCl3): δ 171.1, 170.6, 138.1, 133.4, 132.4, 128.3, 127.0, 126.9, 124.6, 119.5,
61.95, 61.92, 56.0, 34.3, 32.6, 27.4, 27.3, 14.31, 14.28. HRMS Calcd for C19H22NaO4S+ [M+Na]+ 369.1131, found
369.1132.
Diethyl 3a,4-dihydrocyclopenta[c]selenochromene-2, 2(3H)-dicarboxylate (4a, New Compound) 59.3 mg, 52% yield,
yellow solid, melt point: 35.9 – 37.8 oC. 1H NMR (400 MHz, d-CDCl3): δ 7.67 – 7.64 (m, 1H), 7.30 – 7.28 (m, 1H),
7.12 – 7.07 (m, 2H), 6.29 (d, J = 1.9 Hz, 1H), 4.27 – 4.17 (m, 4H), 3.53 – 3.45 (m, 1H), 3.10 – 3.03 (m, 2H), 2.94 (dd,
J = 4.2 Hz, J = 11.1 Hz, 1H), 2.12 (dd, J = 7.3 Hz, J = 13.5 Hz, 1H), 1.32 – 1.27 (m, 6H). 13C NMR (100 MHz,
d-CDCl3): δ 171.2, 170.6, 145.1, 131.1, 129.5, 128.84, 128.76, 127.7, 125.4, 122.7, 65.2, 61.9, 61.8, 43.5, 40.1, 25.3,
14.2. HRMS Calcd for C18H20NaO4Se+ [M+Na]+ 403.0419, found 403.0448.
Dimethyl 3a,4-dihydrocyclopenta[c]selenochromene-2,2(3H)-dicarboxylate (4b, New Compound) 46.5 mg, 44% yield,
yellow solid, melt point: 107.0 – 109.2 oC. 1H NMR (400 MHz, d-CDCl3): δ 7.65 – 7.63 (m, 1H), 7.30 – 7.26 (m, 1H),
7.11 – 7.06 (m, 2H), 6.27 (d, J = 2.1 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.52 – 3.44 (m, 1H), 3.08 – 3.02 (m, 2H), 2.92
(dd, J = 4.2 Hz, J = 11.0 Hz, 1H), 2.10 (dd, J = 7.4 Hz, J = 13.5 Hz, 1H). 13C NMR (100 MHz, d-CDCl3): δ 171.6,
171.1, 145.3, 131.0, 129.6, 128.91, 128.89, 127.7, 125.5, 122.5, 65.0, 53.12, 53.08, 43.5, 40.3, 25.2. HRMS Calcd for
C16H16NaO4Se+ [M+Na]+ 375.0106, found 375.0105.
Diethyl 5-methyl-3,3a,4,5-tetrahydro-2H-cyclopenta[c]quinoline-2,2-dicarboxylate (4c, New Compound) 24.7 mg,
25% yield, yellow solid, melt point: 43.3 – 45.2 oC. 1H NMR (400 MHz, d-CDCl3): δ 7.49 (dd, J = 1.5 Hz, J = 7.7 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 15
1
2
3
4
5
6
7
8
1H), 7.19 – 7.15 (m, 1H), 6.70 – 6.64 (m, 2H), 6.00 (d, J = 2.4 Hz, 1H), 4.26 – 4.14 (m, 4H), 3.40 (dd, J = 5.4 Hz, J =
10.7 Hz, 1H), 3.31 – 3.22 (m, 1H), 2.97 – 2.90 (m, 5H), 1.89 (dd, J = 8.9 Hz, J = 13.0 Hz, 1H), 1.29 – 1.24 (m, 6H).
13C NMR (100 MHz, d-CDCl3): δ 171.7, 171.0, 146.4, 144.3, 130.2, 126.1, 117.5, 117.1, 116.4, 112.5, 65.8, 61.72,
61.66, 57.7, 41.3, 39.9, 37.6, 17.29, 17.27. HRMS Calcd for C19H23NNaO4+ [M+Na]+ 352.1519, found 352.1519.
9
Diethyl 4-(bromomethyl)-3-(2-methoxyphenyl)cyclopent-2-ene-1, 1-dicarboxylate (4d, New Compound) 77.5 mg,
63% yield, yellow oil. 1H NMR (400 MHz, d-CDCl3): δ 7.30 – 7.26 (m, 2H), 6.95 – 6.88 (m, 2H), 6.14 (d, J = 1.7 Hz,
1H), 4.28 – 4.14 (m, 4H), 4.01 – 3.95 (m, 1H), 3.82 (s, 3H), 3.46 (dd, J = 3.1 Hz, J = 10.0 Hz, 1H), 3.23 (t, J = 8.9 Hz,
1H), 2.92 (dd, J = 8.2 Hz, J = 13.9 Hz, 1H), 2.45 (dd, J = 5.7 Hz, J = 13.9 Hz, 1H), 1.32 – 1.23 (m, 6H). 13C NMR
(100 MHz, d-CDCl3): δ 171.3, 170.9, 157.1, 146.9, 130.4, 129.7, 128.4, 123.8, 121.0, 111.2, 65.3, 61.80, 61.77, 55.6,
48.4, 37.4, 36.9, 14.3, 14.2. HRMS Calcd for C19H23BrNaO5+ [M+Na]+ 433.0621, found 433.0647.
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 4-(bromomethyl)-3-(2-(phenylthio)phenyl)cyclopent-2-ene-1,1-dicarboxylate (4e, New Compound) 46.8 mg,
32% yield, yellow oil. 1H NMR (600 MHz, d-CDCl3): 7.30 – 7.26 (m, 3H), 7.26 – 7.19 (m, 6H), 5.98 (d, J = 2.1 Hz,
1H), 4.27 – 4.22 (m, 2H), 4.18 – 4.08 (m, 2H), 4.03 – 3.99 (m, 1H), 3.39 (dd, J = 10.1, 3.4 Hz, 1H), 3.25 (dd, J = 10.2,
8.0 Hz, 1H), 2.93 (dd, J = 13.9, 8.2 Hz, 1H), 2.44 (dd, J = 13.9, 5.8 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz,
3H). 13C NMR (150 MHz, d-CDCl3): δ 171.0, 170.4, 147.9, 136.8, 135.6, 134.7, 132.3, 131.3, 130.7, 130.4, 129.4,
128.9, 127.3, 65.5, 61.9, 49.1, 36.8, 14.3, 14.2. HRMS Calcd for C24H25BrNaO4S+ [M+Na]+ 511.0549, found
511.0549.
Radical trapping experiments for the synthesis of 5. A Schlenk tube containing BHT (0.45 mmol, 1.5 eq), Cu(OTf)2
(0.03 mmol, 10 mol%), bpy (0.06 mmol, 20 mol%) and K2CO3 (0.30 mmol, 1.0 eq) were evacuated and purged with
argon three times. 1a (0.3 mmol, 1.0 eq), 2a (0.45 mmol, 1.5 eq) and CH3CN (2.0 mL) were sequentially added to the
system at room temperature. The reaction mixture was heated with stirring at 80 oC for 8 hours. Upon completion, the
reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography using
a petroleum ether/AcOEt to afford the corresponding compound 5 (yield were determined by 2a).
Characterization Data of Product 5. Diethyl 2-allyl-2-(3,5-di-tert-butyl-4-hydroxybenzyl)malonate (5, known
1
compound)8a 88.4 mg, 47% yield, yellow soild. H NMR (400 MHz, d-CDCl3): δ 6.89 (s, 2H), 5.81 – 5.71 (m, 1H),
5.16 (s, 1H), 5.14 – 5.13 (m, 1H), 5.09 (s, 1H), 4.24 – 4.11 (m, 4H), 3.16 (s, 2H), 2.55 (d, J = 7.2 Hz, 2H), 1.40 (s,
18H), 1.24 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, d-CDCl3): δ 171.1, 152.9, 135.7, 133.2, 126.74, 126.70, 119.1,
61.3, 59.1, 38.1, 36.5, 34.4, 30.5, 14.2.
■ ASSOCIATED CONTENT
Supporting Information Available: Copies of NMR spectrum detail are available free of charge via the Internet at
http://pubs.acs.org.
NMR spectra for all compounds. (PDF)
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: gyz@fjirsm.ac.cn
*E-mail: gangli@fjirsm.ac.cn
Notes The authors declare no competing financial interest.
ACS Paragon Plus Environment

Page 13 of 15
The Journal of Organic Chemistry
1
2
3
4
5
■ ACKNOWLEDGMENTS
We gratefully thank the financial supports from NSFC (Grant No. 21702206, 21402198), the Natural Science
Foundation of Fujian Province (2017J06007, 2017J05038), the Strategic Priority Research Program of the Chinese
Academy of Sciences (Grant No. XDB20000000). Y. Gao also thanks the National Postdoctoral Program for
Innovative Talents (BX201700244) and China Postdoctoral Science Foundation (2017M622087).
6
7
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
■ REFERENCES
(1) (a) Leardini, R.; Pedulli, G. F.; Tundo, A.; Zanardi, G. Reaction pathways for the cyclization of ortho-thioalkyl
and ortho-thioaryl substituted phenyl radicals with alkynes. Reaction of o-Methylthioarenediazonium Tetrafluoroborates with
Alkynes to Give 2-Substituted Benzo[b]thiophenes. J. Chem. Soc., Chem. Commun. 1985, 1390-1391. (b) Staples, M. K.;
Grange, R. L.; Angus, J. A.; Ziogas, J.; Tan, N. P. H.; Taylor, K. T.; Schiesser, C. H. Tandem Free-Radical
Addition/Substitution Chemistry and Its Application to the Preparation of Novel AT1 Receptor Antagonists. Org. Biomol.
Chem. 2011, 9, 473-479. (c) Hari, D. P.; Hering, T.; König, B. Visible Light Photocatalytic Synthesis of
Benzothiophenes. Org. Lett. 2012, 14, 5334-5337. (d) Zang, H.; Sun, J.-G.; Dong, X.; Li, P.; Zhang, B. Preparation of
Benzothiophenes and Benzoselenophenes from Arylamines and Alkynes via Radical Cascade Reactions. Adv. Synth.
Catal. 2016, 358, 1746-1752. (e) Shaaban, S.; Jolit, A.; Petkova, D.; Maulide, N. A Family of Low Molecular-Weight,
Organic Catalysts for Reductive C–C Bond Formation. Chem. Commun. 2015, 51, 13902-13905. (f) McDonald, F. E.;
Burova, S. A.; Huffman Jr, L. G. Sulfur-Alkyne Cyclizations for Formation of Dihydrothiophenes and Annulated
Thiophenes. Synthesis 2000, 970-974.
(2) (a) Xu, J.; Yu, X.; Yan, J.; Song, Q. Synthesis of 3-(Arylsulfonyl)benzothiophenes and Benzoselenophenes via
TBHP-Initiated Radical Cyclization of 2-Alkynylthioanisoles or -Selenoanisoles with Sulfinic Acids. Org. Lett. 2017,
19, 6292-6295. (b) Yan, J.; Xu, J.; Zhou, Y.; Chen, J.; Song, Q. Photoredox-Catalyzed Cascade Annulation of
Methyl(2-(phenylethynyl)phenyl)sulfanes and Methyl(2-(phenylethynyl)phenyl)selanes with Sulfonyl Chlorides:
Synthesis of Benzothiophenes and Benzoselenophenes. Org. Chem. Front. 2018, 5, 1483-1487.
(3) Yang, W.-C.; Wei, K.; Sun, X.; Zhu, J.; Wu, L. Cascade C(sp3)–S Bond Cleavage and Imidoyl C–S Formation:
Radical Cyclization of 2-Isocyanoaryl Thioethers toward 2-Substituted Benzothiazoles. Org. Lett. 2018, 20, 3144-3147.
(4) For a review on α-bromocarbonyls, see: Ouyang, X.-H.; Song, R.-J.; Li, J.-H. Developments in the Chemistry of
α-Carbonyl Alkyl Bromides. Chem. Asian J. 2018, 13, 2316-2332.
(5) For recent reports between the unsaturated α-bromocarbonyls and alkynes to form polycyclic compounds, see: (a)
Zhou, N.; Cheng, Y.; Xie, J.; Zhu, C. Harnessing Sunlight without A Photosensitizer for Highly Efficient Consecutive
[3+2]/[4+2] Annulation to Synthesize Fused Benzobicyclic Skeletons. Chem. Commun. 2017, 53, 10707-10710. (b) Lu,
D.; Wan, Y.; Kong, L.; Zhu, G. Copper-Catalyzed Cascade Annulation between α-Bromocarbonyls and Biaryl or
(Z)-Arylvinylacetylenes Enabling A Direct Synthesis of Dibenzocycloheptanes and Related Compounds. Chem.
Commun. 2016, 52, 13971-13974. (c) Zhou, N.; Liu, J.; Yan, Z.; Wu, Z.; Zhang, H.; Lia, W.; Zhu, C. Synthesis of
Cyclohexylidenehydrazine-Fused Polycyclics via A Photocatalytic Radical Cascade Reaction of 2-Ethynylaldehyde
Hydrazones. Chem. Commun. 2017, 53, 2036-2039. (d) Che, C.; Huang, Q.; Zheng, H.; Zhu, G. Copper-Catalyzed
Cascade Annulation of Unsaturated α-Bromocarbonyls with Enynals: A Facile Access to Ketones from Aldehydes.
Chem. Sci. 2016, 7, 4134-4139. (e) Liu, B.; Yu, J.-X.; Li, Y.; Li, J.-H.; He, D.-L. Copper-Catalyzed Annulation
Cascades of Alkyne-Tethered α-Bromocarbonyls with Alkynes: An Access to Heteropolycycles. Org. Lett. 2018, 20,
2129-2132. (f) Sun, X.; Li, J.; Ni, Y.; Ren, D.; Hu, Z.; Yu, S. Synthesis of Fused Quinoline and Quinoxaline
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 15
1
2
3
4
5
6
7
8
9
Derivatives Enabled by Domino Radical Triple Bond Insertions. Asian J. Org. Chem. 2014, 3, 1317-1325.
(6) For recent reports on the reaction of 2-bromo-1,3-dicarbonyls to form polycyclic compounds, see: (a) Li, Y.; Liu, B.;
Song, R.-J.; Wang, Q.-A.; Li, J.-H. Visible Light-Initiated C(sp3)–Br/C(sp3)–H Functionalization of α-Carbonyl Alkyl
Bromides through Hydride Radical Shift. Adv. Synth. Catal. 2016, 358, 1219-1228. (b) Hu, M.; Song, R.-J.; Ouyang,
X.-H.; Tan, F.-L.; Wei, W.-T.; Li, J.-H. Copper-Catalyzed Oxidative [2+2+1] Annulation of 1,n-Enynes with
α-Carbonyl Alkyl Bromides through C–Br/C–H Functionalization. Chem. Commun. 2016, 52, 3328-3331. (c) Wei,
P.-S.; Wang, M.-X.; Xu, D.-C.; Xie, J.-W. Synthesis of 2,3-Dihydrothieno(2,3-b)quinolines and
Thieno(2,3-b)-quinolines via An Unexpected Domino Aza-MBH/Alkylation/Aldol Reaction. J. Org. Chem. 2016, 81,
1216-1222.
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
(7) For selected reviews on ATRA, see: (a) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Transition Metal-Promoted
Free-Radical Reactions in Organic Synthesis: The Formation of Carbon-Carbon Bonds. Chem. Rev. 1994, 94, 519-564.
(b) Clark, A. J. Copper Catalyzed Atom Transfer Radical Cyclization Reactions. Eur. J. Org. Chem. 2016, 2231-2243.
(c) Studer, A.; Curran, D. P. Catalysis of Radical Reactions: A Radical Chemistry Perspective. Angew. Chem. Int. Ed.
2016, 55, 58-102. (d) Pintauer, T.; Matyjaszewski, K. Atom Transfer Radical Addition and Polymerization Reactions
Catalyzed by ppm Amounts of Copper Complexes. Chem. Soc. Rev. 2008, 37, 1087-1097.
(8) For selected reports, see: (a) Gao, Y.; Zhang, P.; Ji, Z.; Tang, G.; Zhao, Y. Copper-Catalyzed Cascade Radical
Addition–Cyclization Halogen Atom Transfer between Alkynes and Unsaturated α-Halogenocarbonyls. ACS Catal.
2017, 7, 186-190. (b) Bull, J. A.; Hutchings, M. G.; Quayle, P. A Remarkably Simple and Efficient Benzannulation
Reaction. Angew. Chem., Int. Ed. 2007, 46, 1869-1872. (c) Sebren, L. J.; Devery, J. J., III; Stephenson, C. R. J.
Catalytic Radical Domino Reactions in Organic Synthesis. ACS Catal. 2014, 4, 703-716. (d) Ram, R. N.; Kumar, N.;
Singh, N. Synthesis of Chlorinated Bicyclic C-Fused Tetrahydrofuro[3,2-c]azetidin-2-ones. J. Org. Chem. 2010, 75,
7408-7411. (e) Wallentin, C.-J.; Nguyen, J. D.; Finkbeiner, P.; Stephenson, C. R. J. Visible Light-Mediated Atom
Transfer Radical Addition via Oxidative and Reductive Quenching of Photocatalysts. J. Am. Chem. Soc. 2012, 134,
8875-8884. (f) Xu, T.; Hu, X. Copper-Catalyzed 1,2-Addition of α-Carbonyl Iodides to Alkynes. Angew. Chem., Int.
Ed. 2015, 54, 1307-1311.
(9) CCDC 1859515 (3j) contains the supplementary crystallographic data for this paper. See the Supporting
Information for details.
(10) (a) Bosco, E. E.; Kumar, S.; Marchioni, F.; Biesiada, J.; Kordos, M.; Szczur, K.; Meller, J.; Seibel, W.; Mizrahi,
A.; Pick, E.; Filippi, M. D.; Zheng, Y. Rational Design of Small Molecule Inhibitors Targeting the Rac
GTPase-p67phox Signaling Axis in Inflammation. Chem. Biol. 2012, 19, 228-242. (b) Neelamegam, R.; Hellenbrand, T.;
Schroeder, F. A.; Wang, C.-N.; Hooker, J. M. Imaging Evaluation of 5HT2C Agonists, [11C]WAY-163909 and
[11C]Vabicaserin, Formed by Pictet–Spengler Cyclization. J. Med. Chem. 2014, 57, 1488-1494. (c) Upadhayaya, R. S.;
Lahore, S. V.; Sayyed, A. Y.; Dixit, S. S.; Shinde, P. D.; Chattopadhyaya, J. Conformationally-Constrained
Indeno[2,1-c]quinolines – A new Class of Anti-Mycobacterial Agents. Org. Biomol. Chem. 2010, 8, 2180-2197.
(11) (a) Gao, Y.; Lu, G.; Zhang, P.; Zhang, L.; Tang, G.; Zhao, Y.
A
Cascade
Phosphinoylation/Cyclization/Desulfonylation Process for the Synthesis of 3-Phosphinoylindoles. Org. Lett. 2016, 18,
1242-1245. (b) Egami, H.; Ide, T.; Kawato, Y.; Hamashima, Y. Benzylic C–H Trifluoromethylation of Phenol
Derivatives. Chem. Commun. 2015, 51, 16675-16678.
(12) (a) Thorand, S.; Krause, N. Improved Procedures for the Palladium-Catalyzed Coupling of Terminal Alkynes with
Aryl Bromides (Sonogashira Coupling). J. Org. Chem. 1998, 63, 8551-8553. (b) Pearson, A. J.; Kim, J. B.
ACS Paragon Plus Environment

Page 15 of 15
The Journal of Organic Chemistry
1
2
3
4
5
Cyclopentadienones as Intermediates for the Synthesis of Highly Functionalized Biaryls. Tetrahedron Lett. 2003, 44,
8525-8527.
(13) (a) Chen, C.-C.; Chen, C.-M.; Wu, M.-J. Transition Metal-Catalyzed Cascade Cyclization of Aryldiynes to
Halogenated Benzo[b]naphtho[2,1-d]thiophene Derivatives. J. Org. Chem. 2014, 79, 4704-4711. (b) Chen, C.-C.;
Chin, L.-Y.; Yang, S.-C.; Wu, M.-J. Synthetic Development and Mechanistic Study on Pd(II)-Catalyzed Cyclization of
Enediynes to Benzo[a]carbazoles. Org. Lett. 2010, 12, 5652-5655. (c) Chen, C.-C.; Wu, M.-Y.; Chen, H.-Y.; Wu, M.-J.
Halogen-Mediated Cascade Cyclization Reaction of Aryldiynes to Indeno[1,2-c]chromene Derivatives. J. Org. Chem.
2017, 82, 6071-6081. (d) Wang, Y.; Zheng, Z.; Zhang, L. Ruthenium-Catalyzed Oxidative Transformations of
Terminal Alkynes to Ketenes By Using Tethered Sulfoxides: Access to β-Lactams and Cyclobutanones. Angew. Chem.,
Int. Ed. 2014, 53, 9572. (e) Takashi, M.; Chihoko, Y.; Hitomi, K.; Makoto, K.; Shuichi, O. Novel Pyrrolopyrimidine
Compound of Salt Thereof, Pharmaceutical Composition Containing Same, Especially Agent for Prevention and/or
Treatment of Tumors etc Based on Nae Inhibitory Effect. US2017/66772, 2017. (f) Lin, C.-H., Chen, C.-C., Wu, M.-J.
Mercury(II)-Catalyzed Cyclization of 2-Alkynylphenyl Alkyl Sulfoxides Provides 3-Acylbenzo[b]thiophenes. Chem.
Eur. J. 2013, 19, 2578-2581.
6
7
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
Mercury(II)-Catalyzed Cyclization of 2-Alkynylphenyl Alkyl Sulfoxides
Provides 3-Acylbenzo[b]thiophenes
Cheng-Han Lin, Chin-Chau Chen, and Ming-Jung Wu
(14) Yang, D.; Yan, Y.-L.; Lui, B. Mild α-Halogenation Reactions of 1,3-Dicarbonyl Compounds Catalyzed by Lewis
Acids. J. Org. Chem. 2002, 67, 7429-7431.
(15) Gupta, A.; Flynn, B. L. Linear and Angular Heteroacenes from Double-Electrophilic Cyclization (DEC) and
DEC-Reductive Elimination of Diynes. Org. Lett. 2017, 19, 1939-1941.
ACS Paragon Plus Environment