Access to (Z)-1,2-Endiamides and 1,1-Endiamides via a Base-Promoted Tandem Reaction

Article abstract of DOI:10.1021/acs.joc.9b03305

An efficient base-promoted tandem reaction between vinyl 1,1-dichlorides and secondary sulfonamides with ynamide as the key intermediate is described. This method provides a facile approach to (Z)-1,2-endiamide and aryl 1,1-endiamide derivatives via the β-hydroamidation of terminal ynamides and the α-hydroamidation of internal ynamides, respectively. This reaction proceeded through double elimination of vinyl chlorides and double addition of nucleophiles to alkynes. In addition, it features readily available starting materials, mild reaction conditions, a broad substrate scope, a wide functional group tolerance, and an operational convenience.

Full text of DOI:10.1021/acs.joc.9b03305

Subscriber access provided by CARLETON UNIVERSITY
Article
Access to (Z)-1,2-Endiamides and 1,1-Endiamides
via a Base-Promoted Tandem Reaction
Zhenming Zhang, Bei Fu, Hui Wang, Han Chen, Yongliang Tu, and Junfeng Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03305 • Publication Date (Web): 24 Mar 2020
Downloaded from pubs.acs.org on March 28, 2020
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 10
The Journal of Organic Chemistry
Access to (Z)-1,2-Endiamides and 1,1-Endiamides via a Base-
Promoted Tandem Reaction
1
2
3
4
Zhenming Zhang, Bei Fu, Hui Wang, Han Chen, Yongliang Tu, Junfeng Zhao*
5
6
7
8
9
College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330022, Jiangxi, P. R. China
zhaojf@jxnu.edu.cn
Supporting Information
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
R1
Cl
EWG
EWG
N
H
N
H
H
Cs2CO3
Cs2CO3
N
H
EWG
N
EWG
+
R2
R2
EWG
R2
DMF, 80 o
R1 = H
C
Cl
DMF, 120 o
R1 = Ar
C
Ar
11
examples
31 examples
ABSTRACT: An efficient base-promoted tandem reaction between vinyl 1,1-dichlorides and secondary sulfonamides with ynamide as the
key intermediate is described. This method provides a facile approach to (Z)-1,2-endiamide and aryl 1,1-endiamide derivatives via the -
hydroamidation of terminal ynamides and the -hydroamidation of internal ynamides, respectively. Moreover, this reaction proceeded
through double elimination of vinyl chlorides and double addition of nucleophiles to alkynes. In addition, this transformation features
readily available starting materials, mild reaction conditions, a broad substrate scope, a wide functional group tolerance, and an operational
convenience.
the traditional synthetic strategy in this field,9 but these
methods are limited by complex substrates,
■ INTRODUCTION
a
low
stereoselectivity, and harsh reaction conditions.10 Accordingly,
the development of a novel strategy to achieve (Z)-1,2-
endiamide and 1,1-endiamide analogues from readily available
starting materials under simple and mild conditions is highly
desirable.
(Z)-1,2-Endiamides/1,1-endiamides are important structural
motifs in many bioactive molecules and natural products
(Figure 1).1 Well-known examples of compounds containing
the (Z)-1,2-endiamide unit include enkephalinase inhibitor
(A)2 and NK1 receptor (B)3 as well as the antitubercular
natural cyclic peptides Callyaerin (C)4 and Viomycin (D).5 In
addition, the cell-cell adhesion inhibitor dibohemamine (E)6
and insecticide (F)7 contain the 1,1-endiamide skeleton.
Over the past few decades, the transformations of ynamides
have been developed as a powerful tool for the construction of
nitrogen-containing heterocycles and complex organic
molecules.11 For example, the addition of ynamides has
attracted considerable attention due to the unique structure of
ynamides.12 However, precisely controlling of the
regioselectivity and stereoselectivity of this transformation
remains a challenge.13 Theoretically, ynamides consist of two
polar resonance structures, i.e., the keteniminium and
yniminium structures.14 The former, which undergoes α-
addition with nucleophiles under acidic conditions or in the
presence of transition metal catalysts, has been extensively
studied.15 In contrast, the “umpolung-type” β-addition of
ynamides has been less explored,16 although radical addition17
and the carbometallation of ynamides18 allow the β-addition
reaction to take place.19 Recently, Dodd20 and our group21
reported the base-promoted β-addition of ynamides for the
Furthermore,
(Z)-1,2-endiamide
and
1,1-endiamide
compounds have also been used as building blocks in organic
syntheses.8 Although the usefulness of the motifs, only a few
examples for the synthesis of (Z)-1,2-endiamide and 1,1-
endiamide derivatives are available. Substitution reaction is
O
F3C
CF3
Ph
N
N
CF3
O
N
O
O
N
O
OMe
O
(A)
N
O
(
)
B
O
OH
H2N
Ph
NH
OH
N
O
Nu-
H
HN
HN
H
H
O
O
H
Nu
O
N
N
N
H
N
H
OH
R1 = EWG
O O
EWG
R1 = H
EWG
EWG
H
EWG
NH
O
NH
R1
N
N
R2
H2N
O
N
R2
O
H
N
HN
NH
R2


H
Nu
O
N
NH2
?
HN
HN
O
O
O
H
I
II
intermediate
-addition
intermediate
N
O
N
N
O
O
O
O
O
NH2
HO
NH
-addition


N
N
NH
Scheme 1. Addition reactions of ynamides.
H
(C)
(D)
O
O
O
synthesis of disubstituted (Z)-enamide derivatives with
excellent regio- and stereoselectivities. However, these prior
studies suggested that the β-addition reaction via this strategy
is limited to terminal ynamides due to the steric hindrance and
the stability of intermediate I originated from the yniminium
resonance structure of the ynamide (Scheme 1, left). Thus,
considering the steric hindrance and stability of the
intermediate vinyl anion,22 we reasoned that the α-addition
O
O
NO2
N
N
HN
O
N
HN
NH
N
N
(E)
(F)
Figure 1. Bioactive compounds containing the (Z)-1,2-
endiamide and 1,1-endiamide moieties.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 10
might also be possible for election-withdrawing group-
2-Me, 4-tBu, and 4-OMe were also compatible, affording the
1
2
3
4
5
6
7
8
containing internal ynamides via intermediate II (Scheme 1,
right). Based on our previous studies on the preparation of
ynamides from sulfonamides and vinyl 1,1-dichlorides,23 we
herein describe a robust one-pot strategy for the synthesis of
1,2-endiamides via the -addition of terminal ynamides, in
addition to the preparation of 1,1-endiamides via the -
addition of internal ynamides.
desired products (3k–3n) in 89–97% yields. It should be noted
that the sterically hindered mesityl sulfonamide group also
exhibited a good reactivity (3o). Substrates containing halogen
atoms (i.e., -F, -Cl, and -Br) at the 4-position of the phenyl
ring were also tolerated, giving the corresponding products
(3p–3r) in good to excellent yields. Moreover, N-
methylnaphthalene-2-sulfonamide and N-methylmethane-
sulfonamide afforded the target products (3s and 3t) in
excellent yields. Interestingly, the reaction was also amenable
to nitrogen-containing heterocyclicaryl substrates such as
indoles, substituted indoles, and pyrazoles under the standard
reaction conditions. The structure of 3u was confirmed by X-
ray chromatography (See the Supporting Information for
details). However, no reaction was observed with oxazolidin-
2-one as substrate under the optimized conditions, it is could
be due to the effect of carbonyl of oxazolidin-2-one.
■ RESULTS AND DISCUSSION
9
We initially investigated the model tandem reaction
between 1,1-dichloroethylene (1a) and N,4-dimethylbenzenes-
ulfonamide (2a) to optimize the reaction conditions. The
corresponding product 1,2-endiamide (3a) was obtained in 66%
isolated yield with excellent regio- and stereoselectivities (Z:E >
99:1) using NaH (6 equiv) as the base in DMF at 80 °C (Table
1, entry 1). The screening of different bases revealed that
Cs2CO3 was the most efficient, affording the desired product
in 96% yield (Table 1, entries 2–6). No improvement was
observed when DMSO, THF, EtOH, or MeCN was used as the
solvent (Table 1, entries 7–10). Furthermore, shortening the
reaction time or altering the reaction temperature was not
beneficial to the reaction (Table 1, entries 11 and 14), and
reducing the amount of base or substrate 2a also gave poorer
results (Table 1, entries 15 and 16).
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. Scope of the Secondary Amide Substratea
R1 R1
H
N
H
H
Cl
Cl
Cs2CO3, DMF
EWG
N
N
EWG
R1
+
EWG
80 o
C
H
H
1a
2
3
Ph
Ph
N
Ph
Ts
Ph
Ts
3a
, R = Me, 96%
R
R
3b
, R = Et, 88%
Ts
N
N
Ts
Ts
Ts
N
Ts
N
N
, R = nPr, 85%
, R = nOctyl, 62%
3c
3d
3e
H
H
H
H
H
3g
H
, 80%
i
, R = Bu, 52%
3f
, 64%
Table 1. Optimization of the Reaction Conditionsa
S
S
Ts
MeMe
Ts
N
N
N
N
Ts
Ts
N
N
H
Ts
H
Cl
Base, Solvent
Me
Temp.
H
N
Ts
N
N
Ts
+
H
3h
H
, 93%
H
H
H
Ts
3i
, 50%
3j
H
Cl
, 86%
H
H
npr
npr
O
O
3k
, R = H, 97%
O
S
O
S
1a
2a
3a
Me Me
3l
Mesityl
S
N
N
S
Mesityl
, R = 2-Me, 94%
N
N
entry base (x equiv) solvent
time (h)
temp.
(°C)
80
80
80
80
80
80
80
80
80
80
80
80
100
60
80
80
yield
(%)b
66
ND
15
trace
96
67
t
R
R
R
R
3m
O
O
, R = 4- Bu, 97%
O
O
H
H
H
H
3n
, R = 4-OMe, 89%
3o
, 65%
1
2
3
4
5
6
7
8
NaH (6)
DBU (6)
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
THF
24
24
24
24
24
24
24
24
24
24
18
12
24
24
24
24
O
S
O
S
Me Me
O
S
O
S
Me Me
3p
3q
3r
, R = 4-F, 65%
, R = 4-Cl, 95%
, R = 4-Br, 85%
N
N
N
N
K2CO3 (3)
CsOH (6)
Cs2CO3 (3)
NaOH (6)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (2)
Cs2CO3 (3)
O
O
O
O
H
H
H
H
3s
, 95%
Me Me
O
S
O
Me Me
53
Me
N
N
S
Me
N
N
N
N
O
O
ND
ND
ND
92
73
72
64
78
90
H
H
H
H
H
H
9
EtOH
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
3t
, 98%
3u
, 74%
3v
, 74%
10
11
12
13
14
15
16c
Me
Me
O
O
N
N
N
H
N
H
N
N
N
H
N
H
O
O
H
H
3w
3x
, 90%
3y
, NR
, 69%
aReaction conditions: 1,1-Dichloroethylene 1a (0.2 mmol), secondary
amide 2 (0.6 mmol), and Cs2CO3 (0.6 mmol) in DMF (1.0 mL) at 80
°C for 24 h.
a
Reaction condition: 1a (0.2 mmol), 2a (0.6 mmol), and base (0.6
b
mmol) in solvent (1.0 mL) at 80 °C for 24 h. Isolated yields. Z:E >
99:1 (determined by crude H NMR spectroscopy). 2a (0.5 mmol)
1
c
We subsequently evaluated the disulfonamide substrate
scope of the tandem reaction for the synthesis of
cycloendiamides 5 under the optimized conditions. As shown
was used.
Having established the optimal reaction conditions, the
reaction scope and limitations with respect to the secondary
amides (2) were examined. As illustrated in Scheme 2, our
results demonstrate that the tandem reaction exhibits good
functional group tolerance with a broad substrate scope.
Indeed, secondary sulfonamides 2 bearing linear alkyl,
branched alkyl, and some unsaturated bond-containing groups
afforded the corresponding products (3a–3j) in moderate to
excellent yields. In addition, the presence of phenyl rings on
the sulfonyl moiety bearing electron-donating groups such as
in
methylbenzenesulfonamide) underwent the tandem reaction
with 1,1-dichloroethylene to give the 1,2,3,4-
Scheme
3,
N,Nʹ-(ethane-1,2-diyl)bis(4-
tetrahydropyrazine derivative 5a in 88% yield. Products 5b
and 5c bearing a seven-membered ring could also be
synthesized in a high efficiency under this reaction system.
Furthermore, the reaction of 1,4-butanedisulfonamide
proceeded smoothly, delivering the desired eight-membered
ring product 5d in a good yield. The structure of 5d was
confirmed by X-ray chromatography (See the Supporting
ACS Paragon Plus Environment

Page 3 of 10
The Journal of Organic Chemistry
Scheme 3. Scope of the Disulfonamide Substratea
ylbenzenesulfonamide (2a) provided a complex mixture.
1
2
3
4
5
6
7
8
Pleasingly, after a number of attempts, the -addition product
1,1-endiamide (6a) instead of -addition product 1,2-
endiamide was obtained in 40% yield by using N-
methylmethanesulfonamide (2t) as the substrate under the
standard reaction conditions. The structure of 6a was
confirmed by X-ray chromatography (See the Supporting
Information for details). It was also found that the yield of 6a
could be increased to 85% with a high regioselectivity (-
O
S
O
S
O
O
S
H
H
Cl
Cl
n
Cs2CO3, DMF
R
R
R1
N
H
N
H
R1
S
+
NH HN
80 o
C
O
O
O
O
1a
4
5
Me Me
Ts
N
N Ts
N
N
N
Ts
N
Ts
N
N
Ts
Ts
Ts
Ts
1
6a/-6a > 10/1, determined by crude H NMR measurements)
9
H
H
H
H
H
H
H
H
by increasing the amount of 2t to 5.0 equiv and increasing the
reaction temperature to 120 °C.
5a
, 88%
5b
, 88%
5c
, 75%
5d
, 82%
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
The substrate scope was then investigated with respect to
the aryl 1,1-dichloroethylenes, and the results are summarized
in Scheme 4. The substrates bearing weak electron-donating
Ts
N
N
Ts Ts
N
N
Ts Ts
N
N
Ts
t
groups such as Me and Bu on the phenyl ring were smoothly
H
H
H
H
Ph
5g
H
b
converted to the desired -addition products (6b and 6c) in
good yields and high regioselectivities. However, when the
strongly electron-donating OMe group (6d) was installed on
the phenyl ring, the yield of the -addition product 1,2-
endiamide increased to 38% and a mixture of products was
obtained in a total yield of 85%. A similar result was observed
for the electron-rich substrate thiophenyl 1,1-dichloroethylene,
which gave a mixture of products (6e) in a 90% total yield (-
6e/-6e = 7/2). Furthermore, substrates bearing halogen atoms
such as 4-F, 4-Cl, 4-Br, and 3-Cl-5-F on the phenyl ring
delivered the corresponding 1,1-endiamide products (6f and
6i) in high yields and high regioselectivities. For the electron-
withdrawing groups 4-CN, the reactions could afford the
corresponding products (6j) in high yields and excellent
regioselectivities. Moreover, as expected, substrates bearing
alkyl groups afforded vinyl chloride products (6k and 6l)
instead of the 1,2-endiamide or 1,1-endiamide products.
5e
5f
, 48%
, 32%
, 30%
aReaction conditions: 1,1-Dichloroethene 1a (0.2 mmol),
disulfonamide 4 (0.3 mmol), and Cs2CO3 (0.6 mmol, 3.0 equiv) in
DMF (1.0 mL) at 80 °C for 24 h. b5 mL DMF was used.
Information for details). In addition, the synthesis of nine- and
ten-membered ring products (5e and 5f) was achieved in 48%
and 32% yields, respectively. Importantly, aryl 1,1-
dichloroethylene was found to be compatible with N,Nʹ-
(ethane-1,2-diyl)bis(4-methylbenzenesulfonamide) under the
standard reaction conditions to give the desired cyclization
product 5g albeit in 30% yield.
Subsequently, we examined the substrate scope of the aryl
1,1-dichloroethylenes under the optimized conditions. The
reaction between (2,2-dichlorovinyl)benzene and N,4-dimeth-
Scheme 4. Scope of the 1,1-Dichloroethylene Substrate for
the Synthesis of 1,1-Endiamidesa
Scheme 5. Large-scale Synthesis and Application of the
Method
Me
H
R
Cl
Cl
H
R
N
N
Ms
Me
Cs2CO3, DMF
120 oC, 12 h
H
N
MeMe
H
N
+
Cl
Cs2CO3
Ms
Me
Ts
N
N
Ts
(1)
Me
Ts
Ms
6a-k
DMF, 80 o
C
Cl
1
2t
H
H
3a
5 mmol
15 mmol
Ts
, 1.75g, 89%
Me
Ms
Me
Me
Me
Ms
MeMe
MeMe
N
N
Ms
Me
N
Ms
Me
N
N
Ms
Me
N
N
Ms
Me
H2, Pd/C
MeOH, rt, 12 h
Ts
N
N
Ts
N
N
Ts
Me
(2)
(3)
N
Ms
Ms
H
H
H
H
3a
MeMe
7a
, 95%
tBu
MeO
6d
6b
6c
, 82% (<5%)
Me
, 72% (<5%)
Me
, 47% (38%)
Me
6a
, 85% (8%)
Me
MeMe
N
1) HBr, AcOH
Ts
N
N
Ts
PhCO
N
COPh
2) NEt3, PhCOCl, DCM
N
Ms
N
Ms
N
Ms
N
Ms
H
H
H
H
7a
8a
, 75%
N
Me
N
Me
N
Me
N
Me
S
Ms
Ms
Ms
Ms
F
Cl
Br
6e
6f
6g
6h
, 90%
, 70% (20%)
Me
, 88% (3%)
Me
, 92% (3%)
Finally, we turned our attention to the scalability and
potential application of this method (Scheme 5). First, a gram-
scale operation was performed on 5 mmol of 1a, affording 1,2-
endiamide product 3a in 89% yield (Scheme 5, eq 1). The
subsequent hydrogenation of 3a was then carried out in the
presence of Pd/C to afford the desired 1,2-diamide 7a in 95%
yield (Scheme 5, eq 2). A one-pot two-step combined removal
of the Ts group and subsequent acylation provided 8a in a
total yield of 75% (Scheme 5, eq 3),24 thereby indicating the
potential application of this reaction.
N
Ms
N
Ms
Me
Me
N
N
Me
N
Me
Ms
N
Cl
H
Ts
Cl
Cl
Ms
Ms
H
F
CN
Ph
Ph
6i
6j
6k
6l
, 80%
, 89%
, 93%
, 67%
aReaction condition: 1 (0.2 mmol), 2a (1.0 mmol), and base (0.6
mmol) in DMF (1.0 mL) at 120 °C for 12 h. Yields of the -
addition product are shown in parentheses, and were determined
by crude 1H NMR measurements.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Scheme 7. Plausible Reaction Mechanism
Page 4 of 10
Scheme 6. Control Experiments
1
2
3
4
5
6
7
8
R2
N
R1 R2
MeMe
N
H
R1
Ts
H
H
Cs2CO3 (3.0 equiv)
DMF, 80 oC, 24 h
Cl
H
Ts
N
N
Ts
H
N
(1)
Base
alkyl
Me
Cl
Cl
H
3a
H
, 70%
V
3.0 equiv
S-1
S-2
R1 R2
-
N
R2
R
MeMe
R1
N
Base
- HCl
Cl
Cl
H
-addition
Ts
Cl
H
Cs2CO3 (3.0 equiv)
DMF, 80 oC, 24 h
Ts
Ts
N
N
Ts
Ts
R
Cl


H
N
Cl
(2)
(3)
H
1
I
Me
H
Cl
III
H
3a
H
, trace
3.0 equiv
Base
- HCl
MeMe
-addition
R1
9
R2 R2
N
Ts
N
Ts
Cs2CO3 (3.0 equiv)
DMF, 80 oC, 24 h
N
N
R1
N
R1
R = H
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
H
N
R1 R2
N
-
Me
Me
3.0 equiv
-addition
R1
H
H
H
3a
H
, 96%
N
R1
R2
In-1
3
product
-
N
H/Ar
- Cl-
H/Ar
Cl

R1
N

MeMe
Me
N
R2
R2
II
IV
Ts
Cs2CO3 (3.0 equiv)
DMF, 80 oC, 24 h
-addition
Ts
N
N
Ts
Ts
Cl
(4)
(5)
H
N
R = Ar
N
Ar
Me
3.0 equiv
R1
H
3a
H
, 93%
H
H
6
product
In-2
Me
Ts
Cs2CO3 (3.0 equiv)
DMF, 80 oC, 24 h
Ts
N
Cl
H
N
Me
In-1
-addition of nucleophile R1R2N− to chloroalkyne I when the
R group of the 1,1-dichloroethylene is H. Subsequently, the
second addition of nucleophile R1R2N− to ynamide IV affords
the corresponding tandem product 3 or 6. When the R group is
H, the -addition product 3 is obtained due to steric factors,
while -addition product 6 is obtained when the R group is Ar
due to electronic factors. In contrast, when the 1,1-
dichloroethylenes bear an alkyl R group, the -addition of
nucleophile R1R2N− to intermediate chloroalkyne I takes place
to directly afford the tri-substituted vinyl chloride product V
that cannot undergo a second elimination.
H
, 90%
In-2
Me
Ms
H
N
N
Ms
Me
Cs2CO3 (3.0 equiv)
DMF, 120 oC, 12 h
Ph
Ph
Cl
H N
(6)
(7)
Me
Ph
In-3
In-4
Ms
6a
5.0 equiv
, 65%
Me
Me
N
Ms
Ms
H
N
N
Ms
Me
Cs2CO3 (3.0 equiv)
DMF, 120 oC, 12 h
H N
Me
5.0 equiv
Ph
Ms
6a
, 92%
■ CONCLUSIONS
To understand the mechanistic pathway, a number of
control experiments were carried out (Scheme 6). Under the
standard reaction conditions, the tandem reaction using (Z)-
In conclusion, we successfully developed an efficient
method for the synthesis of 1,2-endiamide and 1,1-endiamide
derivatives via a base-promoted tandem reaction of vinyl 1,1-
dichlorides and secondary amides where ynamide acts as the
key intermediate. It was found that the product regioselectivity
could be switched by the introduction of different substituents
on the vinyl 1,1-dichloride substrates. In addition, the results
of control experiments showed that this unprecedented tandem
reaction takes place through the double elimination reactions
of vinyl chlorides and the double addition reactions of alkynes.
Furthermore, this process is particularly attractive due to the
absence of transition metals, the mild reaction conditions, the
broad substrate scope, a good functional group tolerance, and
its operational simplicity, thereby rendering it a useful method
for application in organic syntheses.
1,2-dichloroethylene as
a substrate resulted in smooth
conversion to the 1,2-endiamide product 3a in 70% yield
(Scheme 6, eq 1), while the reaction using (E)-1,2-
dichloroethylene failed to proceed (Scheme 6, eq 2). In
addition, when ynamide In-1 or vinyl chloride In-2 were
reacted with N,4-dimethylbenzenesulfonamide (2a) under the
standard reaction conditions (Scheme 6, eqs 3 and 4), 1,2-
endiamide product 3a was obtained in excellent yields of 96%
and 93%, respectively. Furthermore, ynamide In-1 was
obtained in 90% yield by the direct reaction of vinyl chloride
In-2 under the standard conditions (Scheme 6, eq 5).
Moreover, when (chloroethynyl)benzene In-3 and ynamide
In-4 were employed as substrates, the corresponding 1,1-
endiamide product 6a was obtained in 65% and 92% yields,
respectively (Scheme 6, eqs 6 and 7). These results suggested
that the ynamide, the vinyl chloride, and the alkynyl chloride
could all be key intermediates in this tandem reaction.
Based on the above results, a possible mechanism for this
base-promoted tandem reaction of 1,1-dichloroethylenes and
secondary amides is presented in Scheme 7. Under basic
reaction conditions, an initial elimination of the 1,1-
dichloroethylenes would generate intermediate chloroalkyne I.
Ynamide IV could then be obtained through the second
elimination of either intermediate II from the -addition of
nucleophile R1R2N− to chloroalkyne I when the R group of the
1,1-dichloroethylene is Ar or H, or intermediate III from the
■ EXPERIMENTAL SECTION
All reactions were carried out in oven-dried glassware and were
monitored by thin-layer chromatography (TLC). All reagents and
solvents were purchased from commercial vendors and used
without further purification. Starting material vinyl dichlorides
and secondary amides were either purchased from commercial
vendors or synthesized following our previous works.23a
1H/13C NMR spectra were recorded on Bruker Avance 400
MHz and Bruker AMX 400 MHz spectrometer at 400/100 MHz,
respectively, in CDCl3 or DMSO-d6, using either TMS or the
undeuterated solvent residual signal as the reference. Chemical
shifts are given in ppm and are measured relative to CDCl3 or
ACS Paragon Plus Environment

Page 5 of 10
The Journal of Organic Chemistry
1
DMSO-d6 as an internal standard. High resolution mass spectra
solid, Mp: 163–165 °C; TLC Rf = 0.7 (PE/EA = 4:1, v/v); H
NMR (400 MHz, CDCl3): δ 7.55 (d, J = 8.3 Hz, 4H), 7.22 (d, J =
8.1 Hz, 4H), 7.12–7.09 (m, 6H), 6.93 (d, J = 6.8 Hz, 4H), 5.51 (s,
2H), 4.44 (s, 4H), 2.39 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 143.9, 135.6, 135.5, 129.5, 128.3, 128.2, 127.6, 127.4,
1
2
3
4
5
6
7
8
(HRMS) were obtained by the electrospray ionization time-of-
flight (ESI-TOF) mass spectrometry. Flash column
chromatography purification of compounds was carried out by
gradient elution using ethyl acetate (EA) in light petroleum ether
(PE).
General procedure for the synthesis of 1,2-endiamides in
Scheme 1. To a mixture of secondary amide (0.6 mmol, 3.0
equiv), and Cs2CO3 (0.6 mmol, 3.0 equiv) was added a solution of
1,1-dichloroethylene (0.2 mmol, 1.0 equiv) in DMF (1.0 mL). The
mixture was stirred at 80 °C (heating mantle) for 24 h and the
reaction was cooled to room temperature. Then the reaction was
quenched by water and extracted with ethyl acetate three times.
The combined organic layers were dried over anhydrous Na2SO4
and evaporated under vacuum. The desired products were
obtained in the corresponding yields after purification by flash
chromatography on silica gel with petroleum ether/ethyl acetate.
(Z)-N,N'-(Ethene-1,2-diyl)bis(N,4-
117.1, 52.5, 21.5. IR (KBr) ν̃ 2921, 2852, 1590, 1490, 1157, 931,
674, 619, 545 cm-1. HRMS (ESI) calcd for C30H30N2NaO4S2 [M +
Na]+ 569.1539, found 569.1545.
(Z)-N,N'-(Ethene-1,2-diyl)bis(4-methyl-N-
phenethylbenzenesulfonamide) (3g). Yield 80% (91.8mg); yellow
1
solid, Mp: 104–106 °C; TLC Rf = 0.6 (PE/EA = 4:1, v/v); H
9
NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.3 Hz, 4H), 7.28–7.23
(m, 8H), 7.20–7.13 (m, 6H), 5.62 (s, 2H), 3.64–3.60 (m, 4H),
2.82–2.78 (m, 4H), 2.36 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 144.2, 138.1, 134.9, 129.8, 128.6, 127.7, 126.5, 117.8,
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
50.7, 34.7, 21.5. IR (KBr) ν̃ 3025, 2933, 1658, 1498, 1159, 757,
549 cm-1. HRMS (ESI) calcd for C32H35N2O4S2 [M + H]+
575.2033, found 575.2031.
dimethylbenzenesulfonamide) (3a). Yield 96% (75.6 mg); white
solid, Mp: 156–158 °C; TLC Rf = 0.3 (PE/EA = 5:1, v/v); H
NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.0 Hz, 4H), 7.33 (d, J =
8.0 Hz, 4H), 5.54 (s, 2H), 2.99 (s, 6H), 2.43 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3): δ 144.1, 133.7, 129.8, 127.6, 118.3,
(Z)-4-Methyl-N-(2-((4-methyl-N-(2-(thiophen-2-
yl)ethyl)phenyl)sulfonamido)vinyl)-N-(2-(thiophen-2-
yl)ethyl)benzenesulfonamide (3h). Yield 93% (109.1 mg); white
1
1
solid, Mp: 80–82 °C; TLC Rf = 0.5 (PE/EA = 4:1, v/v); H NMR
(400 MHz, CDCl3): δ 7.67 (d, J = 8.3 Hz, 4H), 7.29 (d, J = 8.1
Hz, 4H), 7.11 (dd, J = 5.1, 1.1 Hz, 2H), 6.89 (dd, J = 5.1, 3.4 Hz,
2H), 6.79 (dd, J = 3.3, 0.8 Hz, 2H), 5.58 (s, 2H), 3.67–3.63 (m,
4H), 3.04–3.00 (m, 4H), 2.39 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 144.3, 139.9, 134.7, 129.8, 127.7, 127.0, 125.5, 123.9,
36.6, 21.6. IR (KBr) ν̃ 2923, 1662, 1600, 1347, 1162, 811, 547
cm-1. HRMS (ESI) calcd for C18H22N2NaO4S2 [M + Na]+
417.0913, found 417.0907.
(Z)-N,N'-(Ethene-1,2-diyl)bis(N-ethyl-4-
methylbenzenesulfonamide) (3b). Yield 88% (74.3 mg); yellow
117.7, 50.6, 28.8, 21.6. IR (KBr) ν̃ 2927, 2854, 1658, 1353, 1087,
solid, Mp: 83–85 °C; TLC Rf = 0.5 (PE/EA = 4:1, v/v); H NMR
811, 545 cm-1. HRMS (ESI) calcd for C28H31N2O4S4 [M + H]+
587.1161, found 587.1162.
1
(400 MHz, CDCl3): δ 7.68 (d, J = 8.4 Hz, 4H), 7.31 (d, J = 8.0
Hz, 4H), 5.49 (s, 2H), 3.46 (q, J = 7.2 Hz, 4H), 2.42 (s, 6H), 1.08
(t, J = 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3):: δ 143.9,
(Z)-N,N'-(Ethene-1,2-diyl)bis(N-allyl-4-
methylbenzenesulfonamide) (3i). Yield 50% (44.6 mg); white
solid, Mp: 99–101 °C; TLC Rf = 0.4 (PE/EA = 5:1, v/v); 1H NMR
(400 MHz, CDCl3): δ 7.67 (d, J = 8.3 Hz, 4H), 7.30 (d, J = 8.1
Hz, 4H), 5.69–5.59 (m, 2H), 5.51 (s, 2H), 5.14–5.06 (m, 4H), 4.07
(d, J = 6.1 Hz, 4H), 2.42 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 144.0, 135.2, 132.3, 129.6, 127.7, 118.5, 117.0, 51.6,
135.3, 129.6, 127.6, 117.1, 43.9, 21.5, 13.7. IR (KBr) ν̃ 3029,
2931, 2869, 1656, 1351, 1159, 680 cm-1. HRMS (ESI) calcd for
C20H26N2NaO4S2 [M + Na]+ 445.1226, found 445.1221.
(Z)-N,N'-(Ethene-1,2-diyl)bis(4-methyl-N-
propylbenzenesulfonamide) (3c). Yield 85% (76.5 mg); white
solid, Mp: 73–75 °C; TLC Rf = 0.3 (PE/EA = 10:1, v/v); 1H NMR
(400 MHz, CDCl3): δ 7.65 (d, J = 8.3 Hz, 4H), 7.30 (d, J = 8.1
Hz, 4H), 5.47 (s, 2H), 3.33–3.29 (m, 4H), 2.42 (s, 6H), 1.57–1.47
(m, 4H), 0.81 (t, J = 7.4 Hz, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 143.8, 135.4, 129.5, 127.6, 117.5, 50.9, 21.6, 21.5,
21.5. IR (KBr) ν̃
3085, 2929, 1658, 1180, 937, 607, 545 cm-1.
HRMS (ESI) calcd for C22H26N2O4S2Na [M + Na]+ 469.1226,
found 469.1221.
(Z)-N,N'-(Ethene-1,2-diyl)bis(N-(2-(cyclohex-1-en-1-yl)ethyl)-
4-methylbenzenesulfonamide) (3j). Yield 86% (100.1 mg); white
1
11.1. IR (KBr) ν
̃
2927, 2852, 1351, 1662, 813, 673, 545 cm-1.
solid, Mp: 178–180 °C; TLC Rf = 0.7 (PE/EA = 5:1, v/v); H
HRMS (ESI) calcd for C22H31N2O4S2 [M + H]+ 451.1720, found
451.1717.
NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.3 Hz, 4H), 7.30 (d, J =
8.1 Hz, 4H), 5.47 (s, 2H), 5.36 (s, 2H), 3.49–3.44 (m, 4H), 2.42
(s, 6H), 2.12 (t, J = 8.0 Hz, 4H), 1.97–1.92 (m, 4H) , 1.89–1.84
(m, 4H), 1.60–1.56 (m, 4H), 1.54–1.50 (m, 4H); 13C{1H} NMR
(100 MHz, CDCl3): δ 143.8, 135.2, 134.2, 129.6, 127.7, 123.3,
(Z)-N,N'-(ethene-1,2-diyl)bis(4-methyl-N-
octylbenzenesulfonamide) (3d). Yield 62% (73.2 mg); white solid,
Mp: 108–110 °C; TLC Rf = 0.8 (PE/EA = 5:1, v/v); 1H NMR (400
MHz, CDCl3): δ 7.64 (d, J = 8.2 Hz, 4H), 7.29 (d, J = 8.0 Hz,
4H), 5.45 (s, 2H), 3.38–3.30 (m, 4H), 2.41 (s, 6H), 1.49–1.45 (m,
4H), 1.29–1.23 (m, 20H), 0.88 (t, J = 6.8 Hz, 6H); 13C{1H} NMR
(101 MHz, CDCl3): δ 143.8, 135.4, 129.6, 127.6, 117.3, 49.3,
117.3, 48.2, 36.3, 28.5, 25.2, 22.9, 22.3, 21.5. IR (KBr) ν̃ 2931,
2857, 1600, 1332, 1162, 811, 553 cm-1. HRMS (ESI) calcd for
C32H43N2O4S2 [M + H]+ 583.2659, found 583.2661.
(Z)-N,N'-(Ethene-1,2-diyl)bis(N-methylbenzenesulfonamide)
(3k). Yield 97% (71.1 mg); yellow solid, Mp: 115–117 °C; TLC
31.8, 29.3, 29.2, 28.5, 26.8, 22.6, 21.5, 14.0. IR (KBr) ν̃ 2956,
1
2854, 1698, 1600, 1353, 1159, 815, 590, 549 cm-1. HRMS (ESI)
calcd for C32H50N2NaO4S2 [M + Na]+ 613.3104, found 613.3101.
(Z)-N,N'-(Ethene-1,2-diyl)bis(N-isobutyl-4-
Rf = 0.5 (PE/EA = 2:1, v/v); H NMR (400 MHz, CDCl3): δ 7.78
(d, J = 7.3 Hz, 4H), 7.61 (t, J = 7.2 Hz, 2H), 5.54 (t, J = 7.5 Hz,
4H), 5.56 (s, 2H), 3.00 (s, 6H); 13C{1H} NMR (100 MHz,
methylbenzenesulfonamide) (3e). Yield 52% (49.7 mg); white
solid, Mp: 74–76 °C; TLC Rf = 0.6 (PE/EA = 10:1, v/v); 1H NMR
(400 MHz, CDCl3): δ 7.57 (d, J = 8.2 Hz, 4H), 7.27 (d, J = 8.0
Hz, 4H), 5.43 (s, 2H), 3.17 (d, J = 7.4 Hz, 4H), 2.40 (s, 6H), 1.83–
1.76 (m, 2H), 0.80 (d, J = 6.6 Hz, 12H); 13C{1H} NMR (100
MHz, CDCl3): δ 143.7, 135.9, 129.5, 127.6, 118.5, 57.1, 27.4,
CDCl3): δ 136.7, 133.2, 129.1, 127.5, 118.4, 36.6. IR (KBr) ν̃
3062, 2929, 1654, 1344, 1091, 838, 578 cm-1. HRMS (ESI) calcd
for C16H18N2NaO4S2 [M + Na]+ 389.0600, found 389.0592.
(Z)-N,N'-(Ethene-1,2-diyl)bis(N,2-
dimethylbenzenesulfonamide) (3l). Yield 94% (74.1 mg); yellow
1
liquid, TLC Rf = 0.8 (PE/EA = 5:1, v/v); H NMR (400 MHz,
21.5, 20.1. IR (KBr) ν
̃
2964, 2875, 1600, 1338, 1168, 811, 663
CDCl3): δ 7.87 (dd, J = 1.6 Hz, J = 8.8 Hz, 2H), 7.49–7.45 (m,
2H), 7.33 (d, J = 7.4 Hz, 4H), 5.63 (s, 2H), 3.08 (s, 6H), 2.63 (s,
6H); 13C{1H} NMR (100 MHz, CDCl3): δ 138.1, 135.7, 133.1,
cm-1. HRMS (ESI) calcd for C24H35N2O4S2 [M + H]+ 479.2033,
found 479.2032.
(Z)-N,N'-(Ethene-1,2-diyl)bis(N-benzyl-4-
methylbenzenesulfonamide) (3f). Yield 64% (70.1 mg); white
130.0, 130.0, 126.3, 117.4, 36.6, 21.0. IR (KBr) ν̃ 2931, 2859,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 10
1704, 1346, 1166, 1093, 815, 713 549 cm-1. HRMS (ESI) calcd
= 0.4 (PE/EA = 5:1, v/v); 1H NMR (400 MHz, CDCl3): δ 5.70 (d,
1
2
for C18H23N2O4S2 [M + H]+ 395.1094, found 395.1085.
(Z)-N,N'-(Ethene-1,2-diyl)bis(4-(tert-butyl)-N-
J = 2.8 Hz, 2H), 3.16 (d, J = 2.8 Hz, 6H), 2.89 (d, J = 2.7 Hz, 6H);
13C{1H} NMR (100 MHz, CDCl3): δ 119.0, 36.4, 36.2. IR (KBr) ν
3014, 2935, 1662, 1330, 1159, 759, 518 cm-1. HRMS (ESI) calcd
for C6H15N2O4S2 [M + H]+ 243.0468, found 243.0465.
̃
methylbenzenesulfonamide) (3m). Yield 97% (92.7 mg); white
3
1
solid, Mp: 180–182 °C; TLC Rf = 0.5 (PE/EA = 5:1, v/v); H
4
5
6
7
8
9
NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.6 Hz, 4H), 7.54 (d, J =
8.4 Hz, 4H), 5.57 (s, 2H), 3.01 (s, 6H), 1.34 (s, 18H); 13C{1H}
NMR (100 MHz, CDCl3): δ 157.0, 133.8, 127.5, 126.1, 118.4,
(Z)-1,2-Di(1H-indol-1-yl)ethene (3u). Yield 74% (38.2 mg);
brown solid, Mp: 141–143 °C; TLC Rf = 0.8 (PE/EA = 40:1, v/v);
1H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 7.7 Hz, 2H), 7.34 (d, J
= 8.1 Hz, 2H), 7.22 (t, J = 7.2 Hz, 2H), 7.16 (t, J = 7.2 Hz, 2H),
6.77 (s, 2H), 6.75 (d, J = 3.3 Hz, 2H), 6.49 (d, J = 3.2 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 136.2, 128.5, 126.6, 122.8,
36.7, 35.2, 31.1. IR (KBr) ν̃ 2962, 2871, 1860, 1594, 1346, 1172,
759, 659 cm-1. HRMS (ESI) calcd for C24H34N2O4S2Na [M + Na]+
501.1852, found 501.1846.
(Z)-N,N'-(Ethene-1,2-diyl)bis(4-methoxy-N-
121.1, 121.0, 115.0, 109.9, 105.0. IR (KBr) ν̃ 3102 3048, 2929,
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
methylbenzenesulfonamide) (3n). Yield 89% (75.8 mg); white
1673, 1461, 1160, 767, 736, 505 cm-1. HRMS (ESI) calcd for
solid, Mp: 115–157 °C; TLC Rf = 0.5 (PE/EA = 2:1, v/v); H
C18H15N2 [M + H]+ 259.1230, found 259.1226.
1
NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.9 Hz, 4H), 7.00 (d, J =
8.9 Hz, 4H), 5.54 (s, 2H), 3.87 (s, 6H), 2.98 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3): δ 163.3, 129.7, 128.3, 118.2, 114.3,
(Z)-1,2-Bis(3-methyl-1H-indol-1-yl)ethene (3v). Yield 79%
(45.2 mg); yellow solid, Mp: 127–129 °C; TLC Rf = 0.4 (PE/EA =
40:1, v/v); H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 7.6 Hz,
2H), 7.32 (d, J = 8.0 Hz, 2H), 7.25–7.16 (m, 4H), 6.63 (s, 2H),
6.62 (s, 2H), 2.20 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ
136.7, 129.0, 124.1, 122.7, 120.4, 119.1, 114.0, 113.9, 109.9, 9.6.
1
55.7, 36.6. IR (KBr) ν
̃
3075, 2923, 1658, 1351, 1022, 836, 557
cm-1. HRMS (ESI) calcd for C18H22N2O6S2Na [M + Na]+
449.0811, found 449.0804.
(Z)-N,N'-(Ethene-1,2-diyl)bis(2,4,6-trimethyl-N-
propylbenzenesulfonamide) (3o). Yield 65% (65.8 mg); yellow
IR (KBr) ν̃ 3048, 2921, 2852, 1675, 1459, 1095, 1018, 736, 599
cm-1. HRMS (ESI) calcd for C20H19N2 [M + H]+ 287.1543, found
287.1537.
1
solid, Mp: 75–77 °C; TLC Rf = 0.5 (PE/EA = 5:1, v/v); H NMR
(400 MHz, CDCl3): δ 6.92 (s, 4H), 5.70 (s, 2H), 3.33 (t, J = 8.0
Hz, 4H), 2.57 (s, 12H), 2.27 (s, 6H), 1.36–1.31 (m, 4H), 0.68 (t, J
= 7.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 142.7, 139.7,
(Z)-1,2-Bis(4-methyl-1H-indol-1-yl)ethene (3w). Yield 69%
(39.4 mg); yellow solid, Mp: 121–123 °C; TLC Rf = 0.5 (PE/EA =
1
40:1, v/v); H NMR (400 MHz, CDCl3): δ 7.21 (d, J = 8.4 Hz,
133.3, 132.1, 116.5, 50.1, 23.5, 21.4, 20.9, 11.1. IR (KBr) ν
̃
2969,
2H), 7.15 (t, J = 8.0 Hz, 2H), 6.97 (d, J = 6.8 Hz, 2H), 6.75 (s,
2H), 6.74 (d, J = 4.4 Hz, 2H), 6.51 (d, J = 3.9 Hz, 2H), 2.53 (s,
6H); 13C{1H} NMR (100 MHz, CDCl3): δ 136.0, 130.6, 128.2,
2940, 1604, 1332, 989, 674 cm-1. HRMS (ESI) calcd for
C26H38N2NaO4S2 [M + Na]+ 529.2165, found 529.2150.
(Z)-N,N'-(Ethene-1,2-diyl)bis(4-fluoro-N-
126.0, 122.9, 121.3, 115.0, 107.5, 103.4, 18.6. IR (KBr) ν̃ 3048,
methylbenzenesulfonamide) (3p). Yield 65% (52.2 mg); white
2929, 2856, 1673, 1436, 1311, 1159, 746, 715 cm-1. HRMS (ESI)
solid, Mp: 118–120 °C; TLC Rf = 0.5 (PE/EA = 4:1, v/v); H
calcd for C20H19N2 [M + H]+ 287.1543, found 287.1539.
1
NMR (400 MHz, CDCl3): δ 7.82–7.78 (m, 4H), 7.27–7.20 (m,
4H), 5.54 (s, 2H), 3.01 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 166.7 ( JC-F = 254.2 Hz), 132.8, 130.3 (JC-F = 9.4 Hz),
(Z)-1,2-Di(1H-pyrazol-1-yl)ethene (3x). Yield 90% (28.8 mg);
1
yellow liquid, TLC Rf = 0.2 (PE/EA = 2:1, v/v); H NMR (400
MHz, CDCl3): δ 7.66 (s, 2H), 7.41 (d, J = 2.0 Hz, 2H), 6.78 (s,
118.3, 116.6 (JC-F = 22.4 Hz), 36.6. IR (KBr) ν̃ 3102, 2919, 2850,
2H), 6.34 (t, J = 2.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3):
1662, 1492, 1351, 979, 842, 649 cm-1. HRMS (ESI) calcd for
C16H17F2N2O4S2 [M + H]+ 403.0592, found 403.0586.
(Z)-N,N'-(Ethene-1,2-diyl)bis(4-chloro-N-
δ 141.1, 130.4, 118.1, 107.6. IR (KBr) ν̃ 3035, 2925, 2850, 1885,
1440, 1403, 1047, 792, 620 cm-1. HRMS (ESI) calcd for C8H9N4
[M + H]+ 161.0822, found 161.0820.
methylbenzenesulfonamide) (3q). Yield 95% (82.4 mg); white
General procedure for the synthesis of cycloendiamides in
Scheme 2: To a mixture of disulfonamide (0.3 mmol, 1.5 equiv),
and Cs2CO3 (0.6 mmol, 3.0 equiv) was added a solution of 1,1-
dichloroethylene (0.2 mmol, 1.0 equiv) in DMF (1.0 mL). The
1
solid, Mp: 145–147 °C; TLC Rf = 0.5 (PE/EA = 3:1, v/v); H
NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.3 Hz, 4H), 7.52 (d, J =
8.3 Hz, 4H), 5.54 (s, 2H), 3.01 (s, 6H); 13C{1H} NMR (100 MHz,
o
CDCl3): δ 139.9, 135.2, 129.5, 129.0, 118.3, 36.6. IR (KBr) ν
̃
mixture was stirred at 80 C (heating mantle) for 24 h and the
3091, 2925, 1662, 1355, 1168, 761, 601, 480 cm-1. HRMS (ESI)
calcd for C16H17Cl2N2O4S2 [M + H]+ 435.0001, found 434.9997.
(Z)-N,N'-(Ethene-1,2-diyl)bis(4-bromo-N-
reaction was cooled to room temperature. Then the reaction was
quenched by water and extracted with ethyl acetate three times.
The combined organic layers were dried over anhydrous Na2SO4
and evaporated under vacuum. The desired products were
obtained in the corresponding yields after purification by flash
chromatography on silica gel with petroleum ether/ethyl acetate.
1,4-Ditosyl-1,2,3,4-tetrahydropyrazine (5a). Yield 88% (69.1
mg); white solid, Mp: 191–193 °C; TLC Rf = 0.7 (PE/EA = 2:1,
methylbenzenesulfonamide) (3r). Yield 85% (88.7 mg); white
1
solid, Mp: 130–132 °C; TLC Rf = 0.6 (PE/EA = 5:1, v/v); H
NMR (400 MHz, CDCl3): δ 7.70–7.67 (m, 4H), 7.64–7.62 (m,
4H), 5.56 (s, 2H), 2.99 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 135.7, 132.5, 129.0, 128.4, 118.3, 36.6. IR (KBr) ν
̃
1
3093, 2925, 2958, 1660, 1361, 1178, 748, 592 cm-1. HRMS (ESI)
calcd for C16H16Br2N2NaO4S2 [M + Na]+ 544.8810, found
544.8828.
v/v); H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 8.2 Hz, 4H),
7.25 (d, J = 8.5 Hz, 4H), 6.20 (s, 2H), 3.07 (s, 4H), 2.43 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3): δ 144.2, 133.8, 129.9, 127.1,
(Z)-N,N'-(Ethene-1,2-diyl)bis(N-methylnaphthalene-2-
sulfonamide) (3s). Yield 95% (88.5 mg); white solid, Mp: 138–
110.7, 41.7, 21.6. IR (KBr) ν̃ 2925, 2854, 1648, 1353, 1166, 958,
727, 619 cm-1. HRMS (ESI) calcd for C18H21N2O4S2 [M + H]+
393.0937, found 393.0934.
1
140 °C; TLC Rf = 0.6 (PE/EA = 3:1, v/v); H NMR (400 MHz,
CDCl3): δ 8.28 (d, J = 1.0 Hz, 2H), 7.89–7.87 (m, 4H), 7.82 (d, J
= 7.9 Hz, 2H), 7.67 (dd, J = 1.8 Hz, J = 8.7 Hz, 2H), 7.59–7.51
(m, 4H), 5.56 (s, 2H), 2.99 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 135.0, 133.8, 132.1, 129.4, 129.3, 129.0 (2C), 128.0,
1,4-Ditosyl-4,5,6,7-tetrahydro-1H-1,4-diazepine (5b). Yield
88% (71.4 mg); white solid, Mp: 144–146 °C; TLC Rf = 0.6
1
(PE/EA = 4:1, v/v); H NMR (400 MHz, CDCl3): δ 7.65 (d, J =
8.3 Hz, 4H), 7.29 (d, J = 8.1 Hz, 4H), 5.94 (s, 2H), 3.40 (t, J = 6.3
Hz, 4H), 2.42 (s, 6H), 1.69–1.61 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3): δ 144.0, 135.8, 129.9, 126.9, 114.5, 47.9, 25.9,
127.7, 122.6, 118.4, 36.8. IR (KBr) ν̃ 3060, 2923, 1662, 1347,
1166, 674, 545, 482 cm-1. HRMS (ESI) calcd for
C24H22N2O4S2Na [M + Na]+ 489.0913, found 489.0905.
21.5. IR (KBr) ν̃ 3097, 2925, 2854, 1353, 1648, 1166, 958, 727,
(Z)-N,N'-(Ethene-1,2-diyl)bis(N-methylmethanesulfonamide)
(3t). Yield 98% (47.4 mg); white solid, Mp: 104–106 °C; TLC Rf
619 cm-1. HRMS (ESI) calcd for C19H23N2O4S2 [M + H]+
407.1094, found 407.1092.
ACS Paragon Plus Environment

Page 7 of 10
The Journal of Organic Chemistry
6,6-Dimethyl-1,4-ditosyl-4,5,6,7-tetrahydro-1H-1,4-diazepine
800, 601, 518 cm-1. HRMS (ESI) calcd for C12H18N2NaO4S2 [M +
Na]+ 341.0600, found 341.0595.
N,N'-(2-(o-Tolyl)ethene-1,1-diyl)bis(N-
1
2
3
4
5
6
(5c). Yield 75% (65.1 mg); white solid, Mp: 159–161 °C; TLC Rf
= 0.4 (PE/EA = 2:1, v/v); 1H NMR (400 MHz, CDCl3): δ 7.65 (d,
J = 8.2 Hz, 4H), 7.29 (d, J = 8.1 Hz, 4H), 5.82 (s, 2H), 3.26 (s,
4H), 2.42 (s, 6H), 1.05 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 144.1, 135.3, 130.0, 127.0, 114.1, 59.6, 34.2, 24.4,
methylmethanesulfonamide) (6b). Yield 82% (54.5 mg); yellow
1
solid, Mp: 79–81 °C; TLC Rf = 0.3 (PE/EA = 2:1, v/v); H NMR
(400 MHz, DMSO-d6): δ 7.39 (t, J = 4.0 Hz, 1H), 7.24–7.22 (m,
3H), 6.55 (s, 1H), 3.21 (s, 3H), 3.15 (s, 3H), 2.84 (s, 3H), 2.66 (s,
3H), 2.28 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 138.5,
136.8, 133.3, 130.4, 128.5, 127.9, 126.4, 121.8, 40.0, 38.6, 36.1,
21.5. IR (KBr) ν̃ 2960, 2923, 2854, 1353, 1160, 1087, 892, 671,
547 cm-1. HRMS (ESI) calcd for C21H27N2O4S2 [M + H]+
435.1407, found 435.1402.
7
8
9
(Z)-1,4-Ditosyl-1,4,5,6,7,8-hexahydro-1,4-diazocine (5d). Yield
82% (68.9 mg); white solid, Mp: 139–141 °C; TLC Rf = 0.9
(PE/EA = 1:1, v/v); H NMR (400 MHz, CDCl3): δ 7.65 (d, J =
35.6, 19.9. IR (KBr) ν̃ 3023, 2929, 1641, 1328, 1143, 1072, 960,
815, 518 cm-1. HRMS (ESI) calcd for C13H21N2O4S2 [M + H]+
333.0937, found 333.0931.
1
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
8.2 Hz, 4H), 7.30 (d, J = 8.1 Hz, 4H), 5.80 (s, 2H), 3.56 (s, 4H),
N,N'-(2-(4-(tert-Butyl)phenyl)ethene-1,1-diyl)bis(N-
methylmethanesulfonamide) (6c). Yield 72% (53.9 mg); white
solid, Mp: 109–111 °C; TLC Rf = 0.2 (PE/EA = 2:1, v/v); H
NMR (400 MHz, CDCl3): δ 7.42 (s, 4H), 6.07 (s, 1H), 3.29 (s,
3H), 3.07 (s, 3H), 3.02 (s, 3H), 2.96 (s, 3H), 1.32 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3): δ 152.1, 137.2, 129.5, 128.2, 125.9,
2.43 (s, 6H), 1.78 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ
1
144.0, 135.1, 130.0, 127.2, 115.2, 47.9, 25.7, 21.5. IR (KBr) ν
3069, 2971, 2854, 1643, 1340, 1159, 925, 549 cm-1. HRMS (ESI)
calcd for C20H24N2O4S2Na [M + Na]+ 443.1070, found 443.1076.
̃
(Z)-1,4-Ditosyl-4,5,6,7,8,9-hexahydro-1H-1,4-diazonine (5e).
Yield 48% (41.7 mg); yellow solid, Mp: 140–141 °C; TLC Rf =
0.6 (PE/EA = 2:1, v/v); 1H NMR (400 MHz, CDCl3): δ 7.69 (d, J
= 8.2 Hz, 4H), 7.32 (d, J = 8.0 Hz, 4H), 5.68 (s, 2H), 3.54–3.51
(m, 4H), 2.43 (s, 6H), 1.80–1.76 (m, 4H), 1.67–1.63 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 143.9, 135.0, 129.8, 127.3,
122.6, 40.1, 39.9, 36.4, 34.8, 34.2, 31.2. IR (KBr) ν̃ 2929, 2962,
2852, 1639, 1459, 1340, 1145, 960, 796, 771, 514 cm-1. HRMS
(ESI) calcd for C16H26N2NaO4S2 [M + Na]+ 397.1226, found
397.1221.
N,N'-(2-(4-Methoxyphenyl)ethene-1,1-diyl)bis(N-
methylmethanesulfonamide) (6d). Yield 50% (34.8 mg); yellow
117.4, 49.6, 30.4, 23.8, 21.6. IR (KBr) ν̃ 2927, 2850, 1731, 1450,
1
1338, 1164, 1087, 970, 671, 620, 549 cm-1. HRMS (ESI) calcd for
solid, Mp: 150–152 °C; TLC Rf = 0.2 (PE/EA = 2:1, v/v); H
C21H27N2O4S2 [M + H]+ 435.1407, found 435.1407.
NMR (400 MHz, CDCl3): δ 7.44 (d, J = 8.8 Hz, 2H), 6.93 (d, J =
8.8 Hz, 2H), 6.04 (s, 1H), 3.83 (s, 3H), 3.29 (s, 3H), 3.09 (s, 3H),
3.02 (s, 3H), 2.95 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
159.9, 136.2, 129.8, 124.8, 122.5, 114.3, 55.3, 40.0 (double), 36.3,
(Z)-1,4-Ditosyl-1,4,5,6,7,8,9,10-octahydro-1,4-diazecine (5f).
Yield 32% (28.6 mg); yellow solid, Mp: 151–153 °C; TLC Rf =
0.8 (PE/EA = 1:1, v/v); 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J
= 8.2 Hz, 4H), 7.32 (d, J = 8.2 Hz, 4H), 5.51 (s, 2H), 3.50 (t, J =
6.2 Hz, 4H), 2.43 (s, 6H), 1.67–1.62 (m, 4H), 1.59–1.53 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3): δ 143.8, 135.2, 129.6, 127.6,
34.1. IR (KBr) ν̃ 3008, 2935, 2842, 1338, 1149, 1251, 958, 773,
514 cm-1. HRMS (ESI) calcd for C13H21N2O5S2 [M + H]+
349.0886, found 349.0882.
117.4, 47.7, 24.0, 22.7, 21.6. IR (KBr) ν
̃
2927, 2856, 1650, 1347,
N,N'-(2-(Thiophen-2-yl)ethene-1,1-diyl)bis(N-
1164, 1093, 817, 711, 545 cm-1. HRMS (ESI) calcd for
methylmethanesulfonamide) (6e). Yield 70% (45.4 mg); yellow
1
C22H29N2O4S2 [M + H]+ 449.1563, found 449.1556.
solid, Mp: 174–176 °C; TLC Rf = 0.2 (PE/EA = 2:1, v/v); H
5-Phenyl-1,4-ditosyl-1,2,3,4-tetrahydropyrazine (5g). Yield
30% (28.1 mg); yellow solid, Mp: 48–50 °C; TLC Rf = 0.5
NMR (400 MHz, DMSO-d6): δ 7.69 (d, J = 5.2 Hz, 1H), 7.29 (d, J
= 3.2 Hz, 1H), 7.12 (t, J = 4.0 Hz, 1H), 6.94 (s, 1H), 3.17 (s, 6H),
3.12 (s, 3H), 3.03 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6):
δ 135.8, 134.8, 130.5, 129.5, 127.4, 120.8, 40.3, 39.2, 37.1, 35.4
cm-1. HRMS (ESI) calcd for C10H17N2O4S3 [M + H]+ 325.0345,
found 325.0336.
1
(PE/EA = 2:1, v/v); H NMR (400 MHz, DMSO-d6): δ 7.58 (d, J
= 8.0 Hz, 2H), 7.45 (t, J = 8.7 Hz, 4H), 7.35 (t, J = 6.6 Hz, 4H),
7.29 (d, J = 7.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.63 (s, 1H),
3.57 (t, J = 4.2 Hz, 2H), 2.75 (t, J = 4.2 Hz, 2H), 2.46 (s, 3H),
2.31 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 144.8,
144.6, 137.9, 134.0, 133.7, 130.6, 130.2, 128.4, 127.8, 127.6,
N,N'-(2-(4-Fluorophenyl)ethene-1,1-diyl)bis(N-
methylmethanesulfonamide) (6f). Yield 88% (59.1 mg); yellow
1
127.2, 126.8, 121.4, 116.6, 43.8, 40.7, 21.6, 21.5. IR (KBr) ν
2919, 2854, 1635, 1349, 1166, 692, 658, 553 cm-1. HRMS (ESI)
calcd for C24H25N2O4S2 [M + H]+ 469.1250, found 469.1248.
̃
solid, Mp: 149–151 °C; TLC Rf = 0.4 (PE/EA = 2:1, v/v); H
NMR (400 MHz, DMSO-d6): δ 7.56 (q, J = 3.6 Hz, J = 8.4 Hz,
2H), 7.28 (d, J = 8.2 Hz, 2H), 6.51 (s, 1H), 3.19 (s, 3H), 3.15 (s,
3H), 3.08 (s, 3H), 2.82 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-
d6): δ 163.33 (d, J = 245 Hz), 137.62 (d, J = 2 Hz), 130.73 (d, J =
8 Hz), 130.18 (d, J = 4 Hz), 122.0, 116.24 (d, J = 21 Hz), 39.57,
General procedure for the synthesis of 1,1-endiamides in
Scheme 3. To a mixture of N-methylmethanesulfonamide (1.0
mmol, 5.0 equiv), aryl 1,1-dichloroethylene (0.2 mmol, 1.0
equiv), and Cs2CO3 (0.6 mmol, 3.0 equiv) was added to DMF (1.0
36.30, 35.29 (double). IR (KBr) ν̃ 3025, 2927, 2852, 1509, 1334,
o
mL). The mixture was stirred at 120 C (heating mantle) for 12 h
1151, 962, 779, 559, 512 cm-1. HRMS (ESI) calcd for
C12H17FN2NaO4S2 [M + Na]+ 359.0506, found 359.0500.
N,N'-(2-(4-Chlorophenyl)ethene-1,1-diyl)bis(N-
and the reaction was cooled to room temperature. Then the
reaction was quenched by water and extracted with ethyl acetate
three times. The combined organic layers were dried over
anhydrous Na2SO4 and evaporated under vacuum. The desired
products were obtained in the corresponding yields after
purification by flash chromatography on silica gel with petroleum
ether/ethyl acetate.
methylmethanesulfonamide) (6g). Yield 92% (64.8 mg); yellow
1
solid, Mp: 139–141 °C; TLC Rf = 0.4 (PE/EA = 2:1, v/v); H
NMR (400 MHz, CDCl3): δ 7.21 (d, J = 8.0 Hz, 2H), 7.14 (d, J =
8.0 Hz, 2H), 5.85 (s, 1H), 3.07 (s, 3H), 2.87 (s, 3H), 2.82 (s, 3H),
2.69 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 138.6, 134.4,
N,N'-(2-Phenylethene-1,1-diyl)bis(N-
131.1, 129.6, 129.1, 121.1, 40.1, 39.8, 36.4, 34.3. IR (KBr) ν̃
methylmethanesulfonamide) (6a). Yield 85% (54.1 mg); white
3015, 2933, 2850, 1643, 1492, 1342, 1143, 1008, 962, 800, 539,
1
solid, Mp: 89–91 °C; TLC Rf = 0.3 (PE/EA = 2:1, v/v); H NMR
518 cm-1. HRMS (ESI) calcd for C12H18ClN2O4S2 [M + H]+
353.0391, found 353.0388.
(400 MHz, CDCl3): δ 7.48 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 8.0 Hz,
2H), 7.31 (t, J = 7.2 Hz, 1H), 6.10 (s, 1H) , 3.23 (s, 3H), 3.06 (s,
3H), 3.04 (s, 3H), 2.93 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 138.0, 132.6, 128.9, 128.7, 128.3, 122.5, 40.1, 39.7,
N,N'-(2-(4-Bromophenyl)ethene-1,1-diyl)bis(N-
methylmethanesulfonamide) (6h). Yield 90% (71.2 mg); white
1
solid, Mp: 147–149 °C; TLC Rf = 0.2 (PE/EA = 2:1, v/v); H
36.4, 34.4. IR (KBr) ν
̃
3025, 2929, 2852, 1643, 1332, 1147, 962,
NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.4 Hz, 2H), 7.35 (d, J =
8.4 Hz, 2H), 6.03 (s, 1H), 3.29 (s, 3H), 3.08 (s, 3H), 3.03 (s, 3H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 10
2.91 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 138.7, 132.1,
Procedure for the removal of Ts group of 7a. To a solution
of sulfonamide 7a (38.0 mg, 0.1 mmol, 1 eq), NaH2PO4 (240.0
1
2
3
4
5
6
7
8
131.5, 129.8, 122.7, 121.1, 40.2, 39.8, 36.5, 34.3. IR (KBr) ν̃
3019, 2929, 2850, 1639, 1340, 1153, 1010, 516, 746, 615 cm-1.
HRMS (ESI) calcd for C12H17BrN2NaO4S2 [M + Na]+ 418.9705,
found 418.9699.
mg, 20 eq) and 120 mg of 20% w/w Na/Hg amalgam in THF (1
o
mL) at 0 C was added MeOH (1 mL) dropwise. The reaction
mixture was stirred for 12 hours at room temperature. The solvent
was removed under vacuum. NEt3 (0.1 mL) was added to the
residue in an ice-water bath, and then benzoyl chloride (70.0 mg,
5 eq) in DCM (1 mL) was added slowly. After stirred for 2 h, the
reaction mixture was concentrated and purified by silica gel
chromatography to afford the product 8a in 70% yield (two-step).
N,N'-(Ethane-1,2-diyl)bis(N-methylbenzamide) (8a).25 Yield
N,N'-(2-(3-Chloro-5-fluorophenyl)ethene-1,1-diyl)bis(N-
methylmethanesulfonamide) (6i). Yield 89% (65.9 mg); yellow
1
solid, Mp: 148–150 °C; TLC Rf = 0.4 (PE/EA = 2:1, v/v); H
NMR (400 MHz, CDCl3): δ 7.22 (s, 1H), 7.16 (d, J = 9.6 Hz, 1H),
7.04 (d, J = 8.0 Hz, 1H), 6.02 (s, 1H), 3.28 (s, 3H), 3.09 (s, 3H),
3.04 (s, 3H), 2.93 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
164.1 (d, J = 249 Hz), 140.2, 136.0 (d, J = 9 Hz), 135.6 (d, J = 11
Hz), 124.5 (d, J = 3 Hz), 119.7, 116.3 (d, J = 25 Hz), 113.4 (d, J =
9
1
70% (20.7 mg); H NMR (400 MHz, CDCl3) δ 7.37-7.36 (m,
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
10H), 3.90 (s, 4H), 3.09 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 172.0, 136.3, 129.5, 128.4, 126.8, 44.5, 37.9.
23 Hz), 40.1, 39.5, 36.6, 34.7. IR (KBr) ν̃ 3081, 2938, 1639, 1432,
1155, 962, 674, 514 cm-1. HRMS (ESI) calcd for
C12H17ClFN2O4S2 [M + H]+ 371.0297, found 371.0291.
N,N'-(2-(4-Cyanophenyl)ethene-1,1-diyl)bis(N-
Procedure for the synthesis of ynamide In-1 and In-4. To an
oven-dried Schlenk tube equipped with a magnetic stir bar was
added sulfonamide (0.5 mmol, 1.0 equiv), 1,1-dichloroethene (1.0
mmol, 2.0 equiv), NaH (2.5 mmol, 5.0 equiv) in DMF (2.5 mL) at
methylmethanesulfonamide) (6j). Yield 93% (63.8 mg); white
1
o
solid, Mp: 158–160 °C; TLC Rf = 0.1 (PE/EA = 2:1, v/v); H
80 C (heating mantle). Upon the reaction completion (monitored
NMR (400 MHz, DMSO-d6): δ 7.89 (d, J = 8.4 Hz, 2H), 7.65 (d, J
= 8.0 Hz, 2H), 6.57 (s, 1H), 3.23 (s, 3H), 3.16 (s, 3H), 3.11 (s,
3H), 2.82 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 140.1,
138.8, 133.0, 129.2, 121.0, 119.2, 110.7, 40.1, 39.3, 36.5, 35.5. IR
by TLC), the residue was purified by silica gel chromatography to
afford the desired products In-1 and In-4.
N-Ethynyl-N,4-dimethylbenzenesulfonamide (In-1).23a Yield
1
95% (99.3 mg); white solid; H NMR (400 MHz, CDCl3) δ 7.80
(KBr) ν
̃
2925, 2854, 2229, 1639, 1340, 1149, 1012, 960, 612 cm-1.
(d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 3.06 (s, 3H), 2.70 (s,
1H), 2.46 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 145.0,
133.2, 129.9, 127.8, 77.6, 57.5, 38.9, 21.7.
HRMS (ESI) calcd for C13H17N3NaO4S2 [M + Na]+ 366.0553,
found 366.0551.
(Z)-N-(1-Chloro-4-phenylbut-1-en-2-yl)-N-
N-Methyl-N-(phenylethynyl)methanesulfonamide
(In-4).23a
methylmethanesulfonamide (6k). Yield 67% (36.7 mg); colorless
liquid; 1H NMR (400 MHz, DMSO-d6): δ 7.31 (t, J = 7.2 Hz, 2H),
7.25–7.20 (m, 3H), 6.24 (s, 1H), 3.09 (s, 3H), 3.01 (s, 3H), 2.78 (t,
J = 7.6 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (100
MHz, DMSO-d6): δ 142.5, 141.1, 128.8, 128.7, 126.5, 116.8,
40.0, 36.3, 36.3, 32.9. HRMS (ESI) calcd for C12H16ClNNaO2S
[M + Na]+ 296.0482, found 296.0484.
Yield 90% (94.0 mg); yellow solid; 1H NMR (400 MHz, DMSO-
d6): δ 7.42–7.40 (m, 2H), 7.38–7.35 (m, 3H), 3.30 (s, 3H), 3.24 (s,
3H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 131.6, 129.1, 128.6,
122.6, 84.8, 68.6, 39.6, 36.9.
Procedure for the synthesis of In-2. To an oven-dried Schlenk
tube equipped with a magnetic stir bar was added N,4-
dimethylbenzenesulfonamide (1.0 mmol, 1.0 equiv), 1,1-
dichloroethene (1.0 mmol, 1.0 equiv), NaH (2.0 mmol, 2.0 equiv)
(Z)-N-(1-Chloro-4-phenylbut-1-en-2-yl)-N,4-
o
dimethylbenzenesulfonamide (6l).42 Yield 80% (56.0 mg);
colorless liquid; TLC Rf = 0.3 (PE/EA = 10:1, v/v); 1H NMR (400
MHz, DMSO-d6) δ 7.74 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.4 Hz,
2H), 7.27 (t, J = 7.2 Hz, 2H), 7.18 (d, J = 7.2 Hz, 1H), 7.12 (d, J =
7.2 Hz, 2H), 6.38 (s, 1H), 2.97 (s, 3H), 2.69–2.65 (m, 2H), 2.62–
2.58 (m, 2H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6)
δ 144.0, 142.2, 140.9, 136.9, 130.3, 128.8, 128.6, 127.5, 126.5,
117.3, 36.9, 36.4, 33.0, 21.5.
in DMF (2.5 mL) at 80 C (heating mantle) for 12 h. Upon the
reaction completion (monitored by TLC), the residue was purified
by silica gel chromatography to afford the desired products In-2.
(Z)-N-(2-Chlorovinyl)-N,4-dimethylbenzenesulfonamide (In-2).
Yield 40% (98.0 mg); yellow liquid; 1H NMR (400 MHz, DMSO-
d6): δ 7.74 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 7.9 Hz, 2H), 6.66 (d, J
= 6.1, Hz, 1H), 5.91 (d, J = 6.1 Hz, 1H), 3.08 (s, 3H), 2.41 (s,
3H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 144.8, 134.3, 130.6,
128.6, 127.6, 107.2, 36.0, 21.5. HRMS (ESI) calcd for
C10H13ClNO2S [M + H]+ 246.0350, found 246.0346.
Procedure for Large Scale Reaction. To a mixture of N,4-
dimethylbenzenesulfonamide (2a) (15.0 mmol, 2.77 g, 3.0 equiv),
and Cs2CO3 (15 mmol, 4.88 g, 3.0 equiv) was added a solution of
1,1-dichloroethylene (5.0 mmol, 0.40 mL, 1.0 equiv) in DMF
Procedure for the synthesis of In-3. To the mixture of
ethynylbenzene (10 mmol), TBAF·3H2O (1 mmol), K2CO3 (10
mmol), and CCl4 (6 mL) was added and the mixture was stirred at
room temperature for two hours. After completion of the reaction,
the solution concentrated under reduced pressure. The residue was
purified by column chromatography to give alkynyl chlorides In-
3.
o
(20.0 mL). The mixture was stirred at 80 C (heating mantle) for
24 h and the reaction was cooled to room temperature. Then the
reaction was quenched by water and extracted with ethyl acetate
three times. The combined organic layers were dried over
anhydrous Na2SO4 and evaporated under vacuum. The desired
products were obtained in 89%yield after purification by flash
chromatography on silica gel with petroleum ether/ethyl acetate.
Hydrogenation of product 3a. To the solution of 3a (0.2
mmol) in MeOH was added Pd/C (0.02 mmol), and then the
reaction mixture was stirred at room temperature for 12 h under a
balloon pressure of H2. The reaction mixture was concentrated
and purified by silica gel chromatography to afford the product 7a
in 95% yield.
N,N'-(Ethane-1,2-diyl)bis(N,4-dimethylbenzenesulfonamide)
(7a).37 Yield 95% (79.4 mg); White soild, mp 173–174 °C;
purification by chromatography (petroleum ether/EtOAc = 8:1);
1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 8.0 Hz, 4H), 7.43
(d, J = 8.0 Hz, 4H), 3.08 (s, 4H), 2.67 (s, 6H), 2.40 (s, 6H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 143.8, 134.5, 130.3,
127.6, 47.9, 35.3, 21.4.
(Chloroethynyl)benzene (In-3).23b Yield 85% (1.16 g), colorless
liquid; 1H NMR (400 MHz, CDCl3) δ 7.46–7.40 (m, 2H), 7.34–
7.27 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 132.0 128.6,
128.4, 122.2, 69.4, 68.0.
■ ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at http://pubs.acs.org.
Copies of 1H and 13C NMR spectra for all compounds
Crystallographic data for 3u (CIF)
Crystallographic data for 5d (CIF)
Crystallographic data for 6a (CIF)
ACS Paragon Plus Environment

Page 9 of 10
The Journal of Organic Chemistry
Vartanian, M.; Lang, S.; Kashman, Y. Synthesis of Cyclic Endiamino
■ AUTHOR INFORMATION
Peptides. J. Am. Chem. Soc. 2005, 127, 7682–7683. (c) Kornev, A.
N.; Sushev, V. V.; Zolotareva, N. V.; Baranov, E. V.; Fukin, G. K.;
Abakumov, G. A. Interaction of Azobenzene and Benzalaniline with
Strong Amido Bases. Org. Lett. 2015, 17, 6154–6157.
1
2
3
Corresponding Author
*E-mail: zhaojf@jxnu.edu.cn
4
5
6
7
8
9
(11) (a) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.;
Zhang, Y.; Hsung, R. P. Ynamides: A Modern Functional Group for
the New Millennium. Chem. Rev. 2010, 110, 5064–5106. (b) Evano,
G.; Coste, A.; Jouvin, K. Ynamides: versatile tools in organic
synthesis. Angew. Chem., Int. Ed. 2010, 49, 2840–2859. (c) Wang,
X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski, B.
L.; Hsung, R. P. Ynamides in Ring Forming Transformations. Acc.
Chem. Res. 2014, 47, 560–578. (d) Prabagar, B.; Ghosh, N.; Sahoo,
A. K. Cyclization and Cycloisomerization of π-Tethered Ynamides:
An Expedient Synthetic Method to Construct Carbo- and
Heterocycles. Synlett 2017, 28, 2539–2555. (e) Zhou, B.; Li, L.; Zhu,
X.-Q.; Yan, J.-Z.; Guo, Y.-L.; Ye, L.-W. Yttrium-Catalyzed
Intramolecular Hydroalkoxylation/Claisen Rearrangement Sequence:
Efficient Synthesis of Medium-Sized Lactams. Angew. Chem., Int.
Ed. 2017, 56, 4015–4019. (f) Hong, F.-L.; Wang, Z.-S.; Wei, D.-D.;
Zhai, T.-Y.; Deng, G.-C.; Lu, X.; Liu, R.-S.; Ye, L.-W. Generation of
Donor/Donor Copper Carbenes through Copper-Catalyzed Diyne
Cyclization: Enantioselective and Divergent Synthesis of Chiral
Polycyclic Pyrroles. J. Am. Chem. Soc. 2019, 141, 16961–16970.
(12) (a) Cook, A. M.; Wolf, C. Terminal ynamides: synthesis,
coupling reactions, and additions to common electrophiles.
Tetrahedron Lett. 2015, 56, 2377–2392. (b) Evano, G.; Blanchard, N.;
Compain, G.; Coste, A.; Demmer, C. S.; Gati, W.; Guissart, C.;
Heimburger, J.; Henry, N.; Jouvin, K.; Karthikeyan, G.; Laouiti, A.;
Lecomte, M.; Martin-Mingot, A.; Métayer, B.; Michelet, B.; Nitelet,
A.; Theunissen, C.; Thibaudeau, S.; Wang, J.; Zarca, M.; Zhang, C. A
Journey in the Chemistry of Ynamides: From Synthesis to
Applications. Chem. Lett. 2016, 45, 574–585.
ORCID
Zhenming Zhang: 0000-0001-8550-5398
Junfeng Zhao: 0000-0003-4843-4871
Notes
The authors declare no competing financial interests.
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
■ ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (21778025 and 21762021), and the Science
and Technology Project of Jiangxi Provincial Education
Department (GJJ150297and GJJ150324).
■ REFERENCES
(1) (a) Archer, G. A.; Sternbach, L. H. Chemistry of benzodiazepines.
Chem. Rev. 1968, 68, 747–784. (b) Arrayas, R. G.; Carretero, J. C.
Catalytic asymmetric direct Mannich reaction: a powerful tool for the
synthesis of [small alpha], [small beta]-diamino acids. Chem. Soc.
Rev. 2009, 38, 1940−1948. (c) Berer, N.; Rudi, A.; Goldberg, I.;
Benayahu, Y.; Kashman, Y. Callynormine A, a New Marine Cyclic
Peptide of a Novel Class. Org. Lett. 2004, 6, 2543–2545. d) Viso, A.;
Fernández de la Pradilla, R.; García, A.; Flores, A. α,β-Diamino
Acids:ꢀ Biological Significance and Synthetic Approaches. Chem.
Rev. 2005, 105, 3167–3196.
(2) Warshawsky, A. M.; Flynn, G. A. U.S. Patent 5428158, 1995.
(3) Xiao, D.; Palani, A.; Wang, C.; Tsui, H.-C.; Huang, X.; Shah, S.
S.; Rao, A. U.; Chen, X.; Paliwal, S.; Shih, N.-Y. PCT Int. Appl., WO
2006065654, 2006.
(4) Daletos, G.; Kalscheuer, R.; Koliwer-Brandl, H.; Hartmann, R.; de
Voogd, N. J.; Wray, V.; Lin, W.; Proksch, P. Callyaerins from the
Marine Sponge Callyspongia aerizusa: Cyclic Peptides with
Antitubercular Activity. J. Nat. Prod. 2015, 78, 1910–1925.
(5) Wang, M.; Gould, S. J. Biosynthesis of capreomycin. 2.
Incorporation of L-serine, L-alanine, and L-2,3-diaminopropionic
acid. J. Org. Chem. 1993, 58, 5176–5180.
(13) Zhou, B.; Tan, T.-D.; Zhu, X.-Q.; Shang, M.; Ye, L.-W. Reversal
of Regioselectivity in Ynamide Chemistry. ACS Catal. 2019, 9, 6393–
6406.
(14) (a) Evano, G.; Michelet, B.; Zhang, C. The anionic chemistry of
ynamides: A review. C. R. Chim. 2017, 20, 648–664. (b) Dodd, R. H.;
Cariou, K. Ketenimines Generated from Ynamides: Versatile
Building Blocks for Nitrogen-Containing Scaffolds. Chem. Eur. J.
2018, 24, 2297–2304.
(15) (a) Pan, F.; Shu, C.; Ye, L.-W. Recent progress towards gold-
catalyzed synthesis of N-containing tricyclic compounds based on
ynamides. Org. Biomol. Chem. 2016, 14, 9456–9465. (b) Hu, L.;
Zhao, J. Ynamide: A New Coupling Reagent for Amide and Peptide
Synthesis. Synlett 2017, 28, 1663–1670. (c) Hu, L.; Xu, S.; Zhao, Z.;
Yang, Y.; Peng, Z.; Yang, M.; Wang, C.; Zhao, J. Ynamides as
Racemization-Free Coupling Reagents for Amide and Peptide
Synthesis. J. Am. Chem. Soc. 2016, 138, 13135–13138. (d) Yang, J.;
Wang, C.; Xu, S.; Zhao, J. Ynamide-Mediated Thiopeptide Synthesis.
Angew. Chem., Int. Ed. 2019, 58, 1382–1386. (e) Yu, L.; Deng, Y.;
Cao, J. Synthesis of Ketenaminals via Catalyst-Free Hydroamination
of Ynamides and Diphenylsulfonimide. Synthesis 2015, 47, 783–788.
(16) Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H. Copper-catalyzed
1,2-double amination of 1-halo-1-alkynes. Concise synthesis of
protected tetrahydropyrazines and related heterocyclic compounds. J.
Am. Chem. Soc. 2008, 130, 1820–1821.
(17) Oshima, K.; Yorimitsu, H.; Sato, A. Thieme Chemistry Journal
Awardees – Where are They Now? Regio- and Stereoselective
Radical Additions of Thiols to Ynamides. Synlett 2008, 2009, 28–31.
(18) (a) Das, J. P.; Chechik, H.; Marek, I. A unique approach to aldol
products for the creation of all-carbon quaternary stereocentres. Nat.
Chem. 2009, 1, 128–132. (b) Marek, I.; Chechik-Lankin, H.; Livshin,
S. Regiocontrolled Carbometallation Reactions of Ynamides. Synlett
2005, 2098–2100.
(6) Zhang, Q.; Schrader, K. K.; ElSohly, H. N.; Takamatsu, S. New
cell-cell adhesion inhibitors from Streptomyces sp. UMA-044. J.
Antibiot. 2003, 56, 673–681.
(7) Li, Z.; Xu, X.; Xu, R.; Qian, X.; Shao, X.; Xu, Z.; Cheng, J.;
Song, G. Chinese Patent, CN 105461724 A 20160406, 2016.
(8) (a) Bennani, Y. L.; Hanessian, S. trans-1,2-Diaminocyclohexane
Derivatives as Chiral Reagents, Scaffolds, and Ligands for Catalysis:ꢀ
Applications in Asymmetric Synthesis and Molecular Recognition.
Chem. Rev. 1997, 97, 3161–3196. (b) Kizirian, J.-C. Chiral Tertiary
Diamines in Asymmetric Synthesis. Chem. Rev. 2008, 108, 140–205.
(c) Ma, Y.-L.; Wang, K.-M.; Huang, R.; Lin, J.; Yan, S.-J. An
environmentally benign double Michael addition reaction of
heterocyclic ketene aminals with quinone monoketals for
diastereoselective synthesis of highly functionalized morphan
derivatives in water. Green Chem. 2017, 19, 3574–3584.
(9) (a) Zeitler, K.; Steglich, W. A Short Diastereoselective Synthesis
of Orthogonally Protected Diaminosuccinic Acid Derivatives. J. Org.
Chem. 2004, 69, 6134–6136. (b) Jones, R. C. F.; Martin, J. N.; Smith,
P.; Gelbrich, T.; Light, M. E.; Hursthouse, M. B. Synthesis of ene-
1,1-diamines
and
pyrrolo[1,2-]imidazolediones
by
4,5-
dihydroimidazole -oxide cycloaddition and isoxazoline ring opening.
Chem. Commun. 2000, 1949–1950.
(10) (a) Zhang, S.; De Leon Rodriguez, L. M.; Leung, I. K. H.; Cook,
G. M.; Harris, P. W. R.; Brimble, M. A. Total Synthesis and
Conformational Study of Callyaerin A: Anti-Tubercular Cyclic
(19) (a) Romain, E.; Fopp, C.; Chemla, F.; Ferreira, F.; Jackowski, O.;
Oestreich, M.; Perez–Luna, A. Trans–Selective Radical Silylzincation
of Ynamides. Angew. Chem., Int. Ed. 2014, 53, 11333–11337. (b)
Hashmi, A. S. K.; Salathé, R.; Frey, W. Gold-Catalyzed Cyclization
of N-Alkynyl Carbamates. Synlett. 2007, 11, 1763–1766. (c) Istrate,
F. M.; Buzas, A. K.; Jurberg, I. D.; Odabachian, Y.; Gagosz, F.
Peptide Bearing
a Rare Rigidifying (Z)-2,3-Diaminoacrylamide
Moiety. Angew. Chem., Int. Ed. 2018, 57, 3631–3635. (b) Pappo, D.;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 10
Synthesis of Functionalized Oxazolones by a Sequence of Cu(II)- and
F.; Evano, G. Synthesis of Ketene N,N-Acetals by Copper-Catalyzed
Au(I)-Catalyzed Transformations. Org. Lett. 10, 5, 925–928. (d) Yu,
Y.; Chen, G.; Zhu, L.; Liao, Y.; Wu, Y.; Huang, X. Gold-Catalyzed β-
Regioselective Formal [3 + 2] Cycloaddition of Ynamides with
Pyrido[1,2-b]indazoles: Reaction Development and Mechanistic
Insights. J. Org. Chem. 2016, 81, 8142–8154.
(20) Hentz, A.; Retailleau, P.; Gandon, V.; Cariou, K.; Dodd, R. H.
Transition-metal-free tunable chemoselective N functionalization of
indoles with ynamides. Angew. Chem., Int. Ed. 2014, 53, 8333–8337.
(21) (a) Peng, Z.; Zhang, Z.; Tu, Y.; Zeng, X.; Zhao, J. Regio- and
Stereo-Selective Intermolecular Hydroamidation of Ynamides: An
Approach to (Z)-Ethene-1,2-Diamides. Org. Lett. 2018, 20, 5688–
5691. (b) Peng, Z.; Zhang, Z.; Zeng, X.; Tu, Y.; Zhao, J. Regio- and
Double-Amidation of 1,1-Dibromo-1-alkenes. Org. Lett. 2009, 11,
4454–4457.
1
2
3
4
5
6
7
8
(23) (a) Tu, Y.; Zeng, X.; Wang, H.; Zhao, J. A Robust One-Step
Approach to Ynamides. Org. Lett. 2018, 20, 280–283. (b) Zeng, X.;
Tu, Y.; Zhang, Z.; You, C.; Wu, J.; Ye, Z.; Zhao, J. Transition-Metal-
Free One-Step Synthesis of Ynamides. J. Org. Chem. 2019, 84, 4458–
4466.
(24) Zhang, Y.; Hsung, R. P.; Zhang, X.; Huang, J.; Slafer, B. W.;
Davis, A. Bronsted acid-catalyzed highly stereoselective arene-
ynamide cyclizations.
A
novel keteniminium Pictet-Spengler
9
cyclization in total syntheses of (+/-)-desbromoarborescidines A and
C. Org. Lett. 2005, 7, 1047–1050.
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
Stereoselective Hydrophosphorylation of Ynamides:
Approach to (Z)-β-Phosphor-Enamides. Adv. Synth. Catal. 2019, 361,
4489–4494.
(22) (a) Dooleweerdt, K.; Birkedal, H.; Ruhland, T.; Skrydstrup, T.
Irregularities in the effect of potassium phosphate in ynamide
synthesis. J. Org. Chem. 2008, 73, 9447–9450. (b) Coste, A.; Couty,
A
Facile
(25) Kaufmann, L.; Dzyuba, E. V.; Malberg, F.; Löw, N. L.;
Groschke, M.; Brusilowskij, B.; Huuskonen, J.; Rissanen, K.;
Kirchner, B.; Schalley, C. A. Substituent effects on axle binding in
amide pseudorotaxanes: comparison of NMR titration and ITC data
with DFT calculations. Org. Biomol. Chem. 2012, 10, 5954–5964.
ACS Paragon Plus Environment