Transition-Metal-Free One-Step Synthesis of Ynamides

Article abstract of DOI:10.1021/acs.joc.8b03192

A robust transition-metal-free one-step strategy for the synthesis of ynamides from sulfonamides and (Z)-1,2-dichloroalkenes or alkynyl chlorides is presented. This method is not only effective for internal ynamides but also amenable for terminal ynamides. Various functional groups, even the vinyl moiety, are compatible, and thus, this strategy offers the opportunity for further functionalization.

Full text of DOI:10.1021/acs.joc.8b03192

Subscriber access provided by WEBSTER UNIV
Note
Transition-Metal-Free One-Step Synthesis of Ynamides
Xianzhu Zeng, Yongliang Tu, Zhenming Zhang, Changming You, Jiao Wu, Zhiying Ye, and Junfeng Zhao
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 07 Mar 2019
Downloaded from http://pubs.acs.org on March 7, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 9
The Journal of Organic Chemistry
Transition-Metal-Free One-Step Synthesis of Ynamides
1
2
3
4
5
6
7
Xianzhu Zeng,† Yongliang Tu,† Zhenming Zhang, Changming You, Jiao Wu, Zhiying Ye, Junfeng
Zhao*
Key Laboratory of Chemical Biology of Jiangxi Province, College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang, 330022, P. R. China
8
9
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
ABSTRACT: A robust transition-metal-free one-step strategy for the
synthesis of ynamides from sulfonamides and (Z)-1,2-dichloroalkenes or
alkynyl chlorides is presented. This method is not only effective for internal
ynamides but also amenable for terminal ynamides. Various functional
groups, even the vinyl moiety, are compatible, and thus, this strategy offers
the opportunity for further functionalization.
Cl
TM
EWG
Cl
EWG
R2
N
R2
N
R1
H
+
or
R1
R2 = H, Aryl
base
R2
Cl
Ynamides have evolved into versatile building blocks and
precursors for a broad range of organic transformations
including addition reactions,1 tandem ring-closing metathesis,2
Pauson-Khand reactions,3 and coupling reactions4 because of
their unique reactivities.5 As a consequence, a plethora of
complementary study on a base-promoted transition-metal-free
one-step strategy for the synthesis of internal and terminal
ynamides from secondary amides and (Z)-1,2-dichloroalkenes
or alkynyl chlorides.
With this proposal in mind, we initiated our studies by
methods have been developed for the synthesis of ynamides.6
Among them, the coupling of amides with various halides
represents a straightforward approach to these molecules. The
pioneering work involving nucleophilic substitution of alkynyl
chlorides with amines was reported by Reinstein’s group in
1964.7 The application of this strategy for ynamide synthesis is
attractive but more challenging owing to the low nucleophilicity
of amides.8 To overcome the inherently low reactivity, the use
of a transition metal catalyst such as a copper catalyst is
critical.9 For example, Hsung’s group10 and Danheiser’s group11
independently developed a general method to prepare ynamides
via a copper-catalyzed cross-coupling reaction between alkynyl
bromides and amides in 2003.12 However, this strategy suffered
from some disadvantages such as limited substrate scope, harsh
reaction conditions, and competition from the homocoupling
side reaction of the alkyne component. Recently, Evano
reported the Cu-catalyzed coupling of vinyl dibromides with
amides for the synthesis of internal ynamides via oxidative
cleavage of the trans C−Br bonds.13 Despite their contributions,
these methods still needed a copper catalyst to increase the
reactivity of amides and were limited to internal ynamides.
Therefore, a novel and convenient synthetic strategy for the
construction of ynamides without a transition metal catalyst
remains highly desirable, but is elusive.14
examining
the
reaction
of
4-methyl-N-
propylbenzenesulfonamide (1a) with (Z)-1,2-dichloroethylene
(2a) under basic reaction conditions. Fortunately, the desired
product,
N-ethynyl-4-methyl-N-propylbenzenesulfonamide
(3a), was obtained in good yield (79%) with 5 equiv of NaH in
dimethylformamide (DMF) (Table 1, entry 1). Base screening
revealed that NaH was the best base; other organic bases such
as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) resulted in no
reaction at all (Table 1, entries 2–6). Compared to DMF, other
solvents were less effective (Table 1, entries 7–11). The yield
of 3a was increased to 95% by increasing the reaction temper
ature slightly to 80 °C (Table 1, entry 13). In addition, the
amount of base had a very significant effect in this reaction, and
5 equiv of NaH gave the best yield (Table 1, entries 14–16).
Table 1. Optimization of the Reaction Conditionsa
n-Pr
base
H
N
Cl
Cl
+
N
Ts
n-Pr
Ts
solvent
1a
2a
3a
Base
Temp
(°C)
70
70
70
70
70
70
70
70
70
70
70
50
80
80
80
Time
(h)
6
6
6
6
6
6
6
6
6
6
6
6
1
1
1
Yield
(%)b
79
32
0
63
0
54
trace
0
40
49
59
70
95
20
34
89
Entry
Solvent
(equiv)
NaH (5)
NaOH (5)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
DMF
DMF
DMF
DMF
DMF
DMF
PhMe
THF
CH3CN
NMP
DMSO
DMF
DMF
DMF
DMF
DMF
DBU (5)
t-BuONa (5)
Na2CO3 (5)
Cs2CO3 (5)
NaH (5)
Recently, our group became interested in ynamide synthesis
because we have disclosed that ynamides can be used as
racemization-free coupling reagents for amide and peptide
synthesis under extremely simple reaction conditions.15 To
make ynamides competitive coupling reagents, a simple,
practical, and step-economic synthetic strategy to produce them
at a reasonably low cost is highly desirable. Very recently, our
group reported a robust transition-metal-free one-step approach
to internal and terminal ynamides using 1,1-dichloro-1-alkenes
as alkyne surrogates.16 A mechanistic study revealed that an
alkynyl chloride intermediate formed in situ from a 1,1-
dichloro-1-alkene was involved in this transformation. Inspired
by this, we envisioned that alkynyl chlorides and 1,2-dichloro-
1-alkenes, which can transform into alkynyl chlorides in situ
under basic reaction conditions, could also be valid starting
materials for the synthesis of ynamides. Herein, we report our
NaH (5)
NaH (5)
NaH (5)
NaH (5)
NaH (5)
NaH (5)
NaH (2)
NaH (3)
NaH (4)
80
1
aReaction conditions: Unless otherwise specified, the reaction was
carried out with 1a (0.2 mmol), 2a (0.4 mmol), and base in solvent (1.0
mL). bIsolated yield.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 9
Scheme 1. Substrate Scope of Secondary Amides for
Scheme 2. Substrate Scope of Secondary Amides for
Internal Ynamidesa
Terminal Ynamidesa
1
R2
N
R2
2
3
4
Cl
Cl
H
NaH, DMF
80 °C
H
N
Cl
Cl
A
conditions
N
+
N
R1
+
or
R1
R1
R2
Cl
R1
R2
Ph
Ph
B
or conditions
Ph
n-Bu
1
2a
3
1
4a
5a
6
5
6
7
8
Me
N
Et
N
n-Pr
n-Pr
Me
Et
n-Bu
N
N
N
N
N
N
Ts
Ts
6b
Ts
Ts
Ts
Ts
3b
Ts
Ts
3d
Ph
Ph
Ph
, 1 h, 93%
, 1 h, 85%
Ph
b
3a
3c
, 1 h, 95%
, 1 h, 98%
, 1 h, 96%
, 1 h, 95%
A
B
6a
6a
6c
6c
6d
6d
:
:
, 1 h, 91% (82%)
, 1 h, 96%
, 5 h, 94%
, 1 h, 86%
, 5 h, 90%
, 1 h, 75%
O
6b
OMe
9
Bn
N
OTBS
Ph
N
n-Oct
N
N
N
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
Ts
Ts
3f
Ts
Ts
N
N
N
Ts
Ts
Ts
Ts
3e
3g
3h
, 1 h, 79%
, 0.5 h, 75%
, 4 h, 72%
, 0.5 h, 75%
Ph
, 3 h, 93%
, 1 h, 75%
Ph
Ph
Ph
6e
6e
6f
6f
6g
6g
6h
6h
, 23 h, 85%
, 1 h, 90%
p-tBuPh
, 1 h, 78%
, 1 h, 75%
, 21 h, 81%
, 1 h, 67%
n-Pr
n-Pr
Me
Me
O
O
S
O
o-MePh
p-FPh
p-ClPh
N
N
S
O
S
N
O
O
S
N
O
O
S
N
O
O
S
N
O
N
N
O
Ts
Ts
Me
Me
Me
Me
Me
Me
3l
, 1 h, 74%
Ph
Ph
Ph
Ph
3i
3j
, 5 h, 69%
3k
, 1 h, 83%
, 4 h, 76%
n-Pr
O
S
6i
6i
6j
6j
6k
6k
6l
6l
, 3 h, 88%
, 1 h, 90%
, 1 h, 96%
, 1 h, 87%
, 1 h, 66%
, 1 h, 72%
, 1 h, 92%
, 1 h, 87%
n-Pr
n-Pr
n-Pr
O
S
O
N
O
S
N
N
N
S
O
O
O
O
O
O
O
O
O2N
N
N
N
N
F
Cl
N
3m
, 1 h, 92%
3n
, 1.5 h, 93%
3o
3p
, 1 h, 61%
, 1 h, 80%
Ph
Ph
Ph
Ph
Ph
, 1 h, 89%
, 1 h, 70%
6m
, 24 h, 70%
6m
, 1 h, 45%
6n
6n
6o
6o
6p
6p
, 23 h, 83%
, 1 h, 42%
, 9 h, 85%
, 1 h, 67%
Ts
Ts
Me
N
N
N
N
Ts
Ts
N
N
N
N
3q
, 1 h, 91%
3r
3s
, 1 h, 68%
, 1 h, 89%
aReaction conditions: 1 (0.2 mmol), 2a (2.0 equiv) and NaH (5.0 equiv)
Ph
Ph
Ph
Ph
6q
6q
6r
6r
6s
6s
, 1 h, 92%
, 1 h, 76%
, 1 h, 92%
, 1 h, 72%
, 13 h, 73%
, 2 h, 60%
in DMF (1.0 mL) at 80 oC.
aReaction conditions A: 1 (0.2 mmol), 4a (0.4 mmol), and Cs2CO3 (5.0
equiv., 1.0 mmol) in DMSO (1.0 mL) at 80 oC. Reaction conditions B:
1 (0.2 mmol), 5a (0.4 mmol), and Cs2CO3 (4.0 equiv., 0.8 mmol) in
DMSO (1.0 mL) at 70 oC. b10 mmol scale of 1a in parentheses.
With the optimized reaction conditions in hand, the scope of
amides 1 was examined with (Z)-1,2-dichloroethylene 2a as the
model substrate to afford terminal ynamides (Scheme 1). The
reaction was performed using a series of sulfonamides with
linear groups and the corresponding products were afforded in
good to excellent yields (3a–f). Notably, in the case of 3g, the
A). Furthermore, a 10-mmol-scale synthesis of 6a was
achieved in 82% yield under these reaction conditions. Next,
the coupling reactions of (Z)-(1,2-dichlorovinyl)benzene 4a or
phenylethynyl chloride 5a with various amides were
investigated using our optimized conditions (Scheme 2). Using
(Z)-(1,2-dichlorovinyl)benzene 4a, a broad range of ynamides
(6a–e) was prepared in good to excellent yields without a
transition metal catalyst. It appears that the steric hindrance of
the alkyl group has little effect on the reaction efficiency (6f–
h). The o-Me-, p-t-Bu-, p-F-, and p-Cl-substituted N-
methylbenzenesulfonamides turned out to be compatible and
afforded the corresponding ynamides (6i–l) in excellent yields.
Moreover, cyclic carbonates could also be tolerated to furnish
ynamides (6m and 6n) in good yields by prolonging the reaction
time to one day. Aromatic azacycles were also compatible
under these reaction conditions, giving the internal ynamines
(6o–r) in 85–92% yields. In addition, biynamide 6s was
obtained in moderate yield using these reaction conditions.
When phenylethynyl chloride 5a was employed as the substrate
vinyl
moiety
remained
intact.
bearing
When
4-
methylbenzenesulfonamide
a
γ-O-tert-
butyldimethylsilyl (γ-OTBS) group was selected as the
substrate, corresponding product 3h was obtained in 75% yield.
Notably, sulfonamides containing cyclic groups were tolerated,
giving the products in good yields (3i and 3j). Hindered N-
propylbenzenesulfonamides bearing o-methyl and o, m, p-
trimethyl groups were compatible (3k and 3l). Moreover,
moderate to excellent yields were achieved for N-
propylbenzenesulfonamides with electron-withdrawing groups
on the phenyl ring such as p-F, p-Cl, and even p-NO2
substituents (3m–o). N-Propylnaphthalene-2-sulfonamide
afforded target product 3p in 80% yield in this reaction.
Aromatic azacycles such as indole and carbazole were also well
suitable in this reaction system, furnishing ynamines 3q and 3r
in 91% and 89% yields, respectively. Terminal biynamide 3s
was obtained in 68% yield using this method.
These encouraging results prompted us to extend the reaction
to the synthesis of internal ynamides. Unfortunately, only
moderate yields of internal ynamides were obtained under the
aforementioned reaction conditions. However, to our delight,
we found that internal ynamide 6a could be obtained in up to 91%
yield by using Cs2CO3 as the base and dimethyl sulfoxide
(DMSO) as the solvent at 80 °C (Scheme 3, reaction conditions
o
and only 4.0 equiv of Cs2CO3 were used at 70 C (Scheme 3,
reaction conditions B), this transformation also proceeded
smoothly with various amides to afford the corresponding
ynamide products in slightly lower yields than those with (Z)-
(1,2-dichlorovinyl)benzene (Scheme 2, red part).
Next, a broad range of (Z)-1,2-dichloroalkenes 4 or alkynyl
chlorides 5 were subjected to this reaction (Scheme 3). It is
noteworthy to mention that (Z)-1,2-dichloroalkenes with the
ACS Paragon Plus Environment

Page 3 of 9
The Journal of Organic Chemistry
Scheme 3. Substrate Scope of (Z)-1,2-Dichloroalkenes or
Alkynyl Chlorides for Internal Ynamidesa
contrast, when R2 is an alkyl group, a β-chloroenamide is
generated.
1
2
3
4
Me
N
Cl
Cl
Ts
■ CONCLUSIONS
Cl
A
conditions
H
N
+
R
R
or
Ts
Me
R
B
or conditions
In conclusion, we have developed a robust transition-metal-
free strategy for the synthesis of ynamides in moderate to
excellent yields from (Z)-1,2-dichloroalkenes as masked
alkynes or alkynyl chlorides. A variety of functional groups and
substituents are tolerated. Both internal and terminal ynamides
can be obtained efficiently via one simple operation.
Additionally, aliphatic (Z)-1,2-dichloroalkenes or aliphatic
alkynyl chlorides employed as substrates can afford β-
chloroenamides via β-addition of alkynyl chlorides. It is
foreseeable that this method will spur the further study of
ynamide chemistry.
5
6
7
8
1a
4
5
7
Me
Me
N
Me
Me
N
N
Me
N
Ts
Ts
Ts
Ts
Me
OMe
9
A
:
B
:
7a
7a
7b
7b
7c
7c
7d
, 1 h, 84%
, 1.5 h, 90%
, 1 h, 87%
, 2 h, 80%
, 1 h, 90%
, 2 h, 79%
, 1 h, 85%
, 2 h, 73%
7d
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
Me
N
Me
N
Me
N
Me
N
Ts
Ts
Ts
Ts
t-Bu
F
Cl
Br
7e
7e
7f
7f
7g
7g
7h
7h
, 1 h, 87%
, 2 h, 80%
, 1.5 h, 76%
, 2 h, 80%
, 1 h, 79%
, 2 h, 78%
, 2 h, 74%
, 1.5 h, 82%
Me
N
Me
■ EXPERIMENTAL SECTION
Me Cl
N
Ts
Ts
N
S
Ts
H
Ph
All reactions were carried out in oven-dried glassware and
monitored by thin-layer chromatography (TLC). Product
purification was done using silica gel column chromatography. All
reagents and solvents were purchased from commercial vendors
and used without further purification. Starting material secondary
amides 1 were either purchased or synthesized. All other starting
materials (Z)-1,2-dichloroalkenes 4, and alkynyl chloride 5 were
synthesized following literature procedures.
7i
7i
7j
7k
7k
, 1 h, 80%
, 2 h, 80%
, 1 h, 80%
7j
, 2 h, 82%
, 1 h, 68%
, 3 h, 75%
aReaction conditions A: 1a (0.2 mmol), 4 (0.4 mmol), and Cs2CO3 (5.0
equiv., 1.0 mmol) in DMSO (1.0 mL) at 80 oC. Reaction conditions B:
1a (0.2 mmol), 5 (0.4 mmol), and Cs2CO3 (4.0 equiv., 0.8 mmol) in
DMSO (1.0 mL) at 70 oC..
1H/13C NMR spectra were recorded on Bruker Avance 400 MHz
and Bruker AMX 400 MHz spectrometer at 400/100 MHz,
respectively, in CDCl3 unless otherwise stated, 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 DMSO-d6 as an internal standard. High resolution mass
spectra (HRMS) were obtained by the electrospray ionization time-
of-flight (ESI-TOF) mass spectrometry. Low resolution mass
(LRMS) spectra were obtained on a Thermo Scientific LCQFLEET
(ESI) unit or SHIMADZU AOC-20i (GC-MS) mass spectrometer.
IR spectra were recorded on a Nicolet-6700 spectrophotometer.
Flash column chromatography purification of compounds was
carried out by gradient elution using ethyl acetate (EA) in light
petroleum ether (PE).
benzene ring of electron-donating and electron-withdrawing
groups all reacted smoothly and afforded the ynamides in good
to excellent yields (7a-h). Heterocyclic aryl group and
polycyclic aromatic group such as thiophene and naphthalene
were also converted to the corresponding ynamides (7i and 7j)
in high yields. Similar with that of 2-alkyl-vinyl dichloride,16
the conversion of substrate (4-chlorobut-3-yn-1-yl)benzene
failed to furnish the target ynamide but β-chloroenamide 7k in
68% yield. Likewise, corresponding products (7a-k) were
obtained in good to excellent yields when alkynyl chlorides 5
were used (Scheme 3, red part).
Scheme 4. Proposed Reaction Mechanism
Procedure for the synthesis of sulfonamide 1. To a solution of
NEt3 (10 mmol) and primary amine (5 mmol) in 4 mL of DCM was
added sulfonyl chloride (5 mmol) step by step. Upon the reaction
completion (monitored by TLC), the reaction mixture was
quenched with 5 mL of water, extracted with ethyl acetate for three
times, washed with brine, dried over anhydrous Na2SO4 and
concentrated. The crude material was purified by column
chromatography to provide sulfonamides 1. Among them, starting
materials 1-3b, 1-3q, 1-3r, 1-3s, 1-6m, 1-6n, 1-6o, and 1-6r were
purchased from commercial vendors and used without further
purification.
R1
Ts
N
R1
II
R2
I
Ts
R1
N
Cl
N
Ts
path II
path I
Cl
a
b
R2 = Alkyl
R2 = Aryl, H
R2
Cl
R2
B
A
5
H+
- Cl-
- HCl Base
Ts
Ts
R1
R1
N
Cl
Cl
R2
Cl
H
N
R2
R2
H
1
Ethyl-4-methylbenzenesulfonamide (1-3c).17a 0.89 g, 90%, H
D
4
C
NMR (400 MHz, CDCl3) δ 7.88–7.71 (m, 2H), 7.29 (d, J = 5.8 Hz,
2H), 5.57 (t, J = 5.0 Hz, 1H), 2.96 (ddd, J = 14.2, 8.6, 5.0 Hz, 2H),
2.40 (d, J = 2.8 Hz, 3H), 1.07 (td, J = 7.2, 3.2 Hz, 3H).
N-Butyl-4-methylbenzenesulfonamide(1-3d).17b 1.00 g, 88%, 1H
NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.0 Hz, 2H), 7.14 (d, J =
8.0 Hz, 2H), 5.62 (t, J = 6.0 Hz, 1H), 2.75 (dd, J = 13.4, 6.6 Hz,
2H), 2.24 (s, 3H), 1.35–1.23 (m, 2H), 1.12 (dq, J = 14.4, 7.2 Hz,
2H), 0.66 (t, J = 7.2 Hz, 3H).
On the basis of our experimental results, a plausible reaction
mechanism was proposed and shown in Scheme 4. Under the
basic reaction conditions, alkynyl chloride intermediate 5
would form in situ via elimination from (Z)-1,2-dichloroalkenes
4. The direct α-attack of the nitrogen nucleophile on alkynyl
chloride 5 would give ynamide C (path I). In contrast, β-attack
of the nitrogen nucleophile followed by protonation would
generate β-chloroenamide D (path II). The R2 substituent
determines the selectivity between path I and path II. When R2
is an aryl group, which can stabilize the negative charge of
alkenyl chloride intermediate A, an ynamide is produced. In
N-Cyclopropyl-4-methylbenzenesulfonamide (1-3i).17a 0.95 g,
90%, 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.2 Hz, 2H), 7.31
(d, J = 8.0 Hz, 2H), 5.67 (s, 1H), 2.42 (s, 3H), 2.26–2.15 (m, 1H),
0.63–0.46 (m, 4H).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 9
2,4,6-Trimethyl-N-propylbenzenesulfonamide (1-3l).17b 0.96 g,
(Z)-1-(1,2-Dichlorovinyl)-4-fluorobenzene (4g).18a 0.49 g, 52%,
1H NMR (400 MHz, CDCl3) δ 7.55–7.46 (m, 2H), 7.06 (t, J = 8.6
Hz, 2H), 6.63 (s, 1H).
1
2
3
4
5
6
7
8
80%, 1H NMR (400 MHz, CDCl3) δ 6.96 (s, 2H), 4.88 (d, J = 4.8
Hz, 1H), 2.95–2.81 (m, 2H), 2.65 (d, J = 1.4 Hz, 6H), 2.30 (s, 3H),
1.47 (dq, J = 7.1, 5.4 Hz, 2H), 0.85 (td, J = 7.3, 2.0 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 142.1, 139.1, 133.8, 131.9, 44.3, 23.0,
22.9, 20.9, 11.2.
(Z)-1-Chloro-4-(1,2-dichlorovinyl)benzene (4h).18a 0.70 g, 68%,
1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.6 Hz, 2H), 7.34 (d, J
= 8.6 Hz, 2H), 6.69 (s, 1H).
4-Chloro-N-propylbenzenesulfonamide (1-3n).17c 0.99 g, 85%,
1H NMR (400 MHz, CDCl3) δ 7.60–7.51 (m, 2H), 7.27–7.10 (m,
2H), 5.27 (t, J = 5.4 Hz, 1H), 2.61 (dd, J = 12.6, 6.0 Hz, 2H), 1.31–
1.11 (m, 2H), 0.74–0.47 (m, 3H).
(Z)-1-Bromo-4-(1,2-dichlorovinyl)benzene (4i).18a 0.70 g, 56%,
1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.6 Hz, 2H), 7.38 (d, J
= 8.6 Hz, 2H), 6.70 (s, 1H).
(Z)-2-(1,2-Dichlorovinyl)thiophene (4j).18a 0.53 g, 60%, 1H
NMR (400 MHz, CDCl3) δ 7.49 (dd, J = 3.0, 1.2 Hz, 1H), 7.32 (dd,
J = 5.1, 3.1 Hz, 1H), 7.19 (dd, J = 5.1, 1.2 Hz, 1H), 6.73 (s, 1H).
4-Nitro-N-propylbenzenesulfonamide (1-3o).17d 0.90 g, 74%, 1H
NMR (400 MHz, DMSO) δ 8.42 (d, J = 8.8 Hz, 2H), 8.04 (d, J =
8.8 Hz, 2H), 7.97 (t, J = 5.6 Hz, 1H), 2.76 (dd, J = 13.0, 6.8 Hz,
2H), 1.39 (h, J = 7.2 Hz, 2H), 0.79 (t, J = 7.4 Hz, 3H).
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
1
(Z)-2-(1,2-Dichlorovinyl)naphthalene (4k).18a 0.70 g, 63%, H
NMR (400 MHz, CDCl3) δ 8.01 (d, J = 1.4 Hz, 1H), 7.90–7.77 (m,
3H), 7.58 (dd, J = 8.7, 1.9 Hz, 1H), 7.54–7.48 (m, 2H), 6.82 (s, 1H).
(Z)-(3,4-Dichlorobut-3-en-1-yl)benzene (4l).18b 0.62 g, 62%, 1H
NMR (400 MHz, CDCl3) δ 7.29 (t, J = 7.4 Hz, 2H), 7.24–7.11 (m,
3H), 6.28–5.49 (m, 1H), 2.88 (t, J = 7.6 Hz, 2H), 2.65 (t, J = 7.6
Hz, 2H).
4-Methyl-N-((tetrahydrofuran-2-yl)methyl)benzenesulfonamide
(1-6h).17e 0.89 g, 70%, 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J =
7.2 Hz, 2H), 7.33–7.27 (m, 2H), 5.08–4.96 (m, 1H), 3.99–3.88 (m,
1H), 3.79–3.64 (m, 2H), 3.08–3.06 (m, 1H), 2.90–2.87 (m, 1H),
2.42 (s, 3H), 1.88–1.83 (m, 3H), 1.62–1.57 (m, 1H).
4-Methyl-N-octylbenzenesulfonamide (1-6e).17f 1.06 g, 75%, 1H
NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.1 Hz, 2H), 7.17 (d, J =
7.2 Hz, 2H), 5.60 (s, 1H), 2.78 (t, J = 8.2 Hz, 2H), 2.28 (s, 3H),
1.34–1.32 (m, 2H), 1.05–10.8 (m, 10H), 0.73–0.75 (m, 3H).
N,2-Dimethylbenzenesulfonamide (1-6i).17g 0.85 g, 92%, 1H
NMR (400 MHz, CDCl3) δ 7.94 (dd, J = 5.2, 3.0 Hz, 1H), 7.45 (t,
J = 7.0 Hz, 1H), 7.34–7.27 (m, 2H), 5.02 (s, 1H), 2.62 (dd, J = 7.1,
4.2 Hz, 6H).
Procedure for the synthesis of 5. To the mixture of terminal
alkyne (10 mmol), TBAF·3H2O (1 mmol) and K2CO3 (10 mmol),
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.
1
(Chloroethynyl)benzene (5a).19a 1.16 g, 85%, H NMR (400
MHz, CDCl3) δ 7.46–7.40 (m, 2H), 7.34–7.27 (m, 3H).
1
4-(Tert-butyl)-N-methylbenzenesulfonamide (1-6j).17a 1.01 g,
89%, 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.6 Hz, 2H), 7.53
(d, J = 8.5 Hz, 2H), 4.84 (d, J = 4.2 Hz, 1H), 2.65 (d, J = 5.2 Hz,
3H), 1.35 (s, 9H).
1-(Chloroethynyl)-2-methylbenzene (5b).19b 1.05 g, 70%, H
NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 7.6, 0.9 Hz, 1H), 7.25–
7.16 (m, 2H), 7.14–7.09 (m, 1H), 2.42 (s, 3H).
1-(Chloroethynyl)-3-methylbenzene (5c).19a 1.20 g, 80%, 1H
NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.3 Hz, 2H), 7.16 (t, J = 7.4
Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 2.29 (s, 3H).
4-Fluoro-N-methylbenzenesulfonamide (1-6k).17a 0.85 g, 90%,
1H NMR (400 MHz, CDCl3) δ 7.86–7.73 (m, 2H), 7.10 (t, J = 8.6
Hz, 2H), 5.24 (d, J = 5.0 Hz, 1H), 2.53 (d, J = 5.2 Hz, 3H).
4-Chloro-N-methylbenzenesulfonamide (1-6l).17a 0.95 g, 93%,
1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.6 Hz, 2H), 7.50 (d, J
= 8.6 Hz, 2H), 4.76 (s, 1H), 2.66 (d, J = 5.2 Hz, 3H).
1-(Chloroethynyl)-4-methylbenzene (5d).19a 1.08 g, 72%, 1H
NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.2 Hz, 2H), 7.09 (d, J =
7.8 Hz, 2H), 2.32 (s, 3H).
1
1-(Chloroethynyl)-4-methoxybenzene (5e).19a 1.24 g, 74%, H
Procedure for the synthesis of 4. To a solution of LiCl (425
mg, 10 mmol) and [(allyl)PdCl]2 (46 mg, 0.125 mmol) in 4 mL of
HOAc was added cis,cis-1,5-cyclooctadiene (54 mg, 0.5 mmol)
and alkynyl chloride (5 mmol). After stirring for 6 h at 80 oC, the
reaction mixture was quenched with 5 mL of water, extracted with
ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and
concentrated. The crude material was purified by column
chromatography to provide (Z)-1,2-dichloroalkenes.
NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.8 Hz, 2H), 6.80 (d, J =
8.8 Hz, 2H), 3.77 (s, 3H).
1
1-(tert-Butyl)-4-(chloroethynyl)benzene (5f).19c 1.42 g, 74%, H
NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.6 Hz, 2H), 7.32 (d, J =
7.8 Hz, 2H), 1.30 (d, J = 1.2 Hz, 9H).
1-(Chloroethynyl)-4-fluorobenzene (5g).19a 1.15 g, 75%, 1H
NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 8.8, 5.4 Hz, 2H), 6.99 (t,
J = 8.6 Hz, 2H).
(Z)-(1,2-Dichlorovinyl)benzene (4a).18a 0.60 g, 70%, H NMR
1-Chloro-4-(chloroethynyl)benzene (5h).18a 1.46 g, 86%, 1H
NMR (400 MHz, CDCl3) δ 7.38–7.34 (m, 2H), 7.30–7.26 (m, 2H).
1-Bromo-4-(chloroethynyl)benzene (5i).19a 1.67 g, 78%, 1H
NMR (400 MHz, CDCl3) δ 7.46–7.41 (m, 2H), 7.31–7.27 (m, 2H).
2-(Chloroethynyl)thiophene (5j).18a 1.15 g, 81%, 1H NMR (400
MHz, CDCl3) δ 7.24 (dd, J = 9.0, 4.0 Hz, 2H), 6.95 (dd, J = 5.0,
3.8 Hz, 1H).
1
(400 MHz, CDCl3) δ 7.56–7.50 (m, 2H), 7.37 (dd, J = 4.1, 2.5 Hz,
3H), 6.68 (s, 1H).
(Z)-1-(1,2-Dichlorovinyl)-2-methylbenzene (4b).18a 0.61 g, 66%,
1H NMR (400 MHz, CDCl3) δ 7.32–7.24 (m, 1H), 7.19 (dt, J = 14.8,
7.4 Hz, 3H), 6.33 (s, 1H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 136.9, 136.2, 134.8, 130.6, 129.7, 125.9, 117.8, 19.7.
(Z)-1-(1,2-Dichlorovinyl)-3-methylbenzene (4c).18a 0.64 g, 69%,
1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 10.6 Hz, 2H), 7.24 (t, J
= 7.5 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.64 (s, 1H), 2.35 (s, 3H);
13C{1H} (100 MHz, CDCl3) δ 138.4, 135.8, 135.8, 130.3, 128.6,
127.3, 123.8, 115.8. 21.4.
1
2-(Chloroethynyl)naphthalene (5k).19d 1.41 g, 76%, H NMR
(400 MHz, CDCl3) δ 7.92 (s, 1H), 7.79–7.67 (m, 3H), 7.48–7.42
(m, 3H).
General experimental procedure for the synthesis of
terminal ynamides in Scheme 1: To an oven-dried Schlenk tube
equipped with a magnetic stir bar was added secondary amides (0.2
mmol, 1.0 equiv), (Z)-1,2-dichloroethylene (0.4 mmol, 2.0 equiv),
(Z)-1-(1,2-Dichlorovinyl)-4-methylbenzene (4d).18a 0.60 g, 65%,
1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.2 Hz, 2H), 7.15 (d, J
= 8.0 Hz, 2H), 6.61 (s, 1H), 2.34 (s, 3H).
o
NaH (1.0 mmol, 5.0 equiv) in DMF (1.0 mL) at 80 C. Upon the
(Z)-1-(1,2-Dichlorovinyl)-4-methoxybenzene (4e).18a 0.60 g,
60%, 1H NMR (400 MHz, CDCl3) δ 7.50–7.38 (m, 2H), 6.94–6.81
(m, 2H), 6.57 (s, 1H), 3.81 (s, 3H).
reaction completion (monitored by TLC), the residue was purified
by silica gel chromatography to afford the desired products.
N-Ethynyl-4-methyl-N-propylbenzenesulfonamide
(3a).16
(Z)-1-(tert-Butyl)-4-(1,2-dichlorovinyl)benzene (4f).18b 0.70 g,
62%, 1H NMR (400 MHz, CDCl3) δ 7.49–7.42 (m, 2H), 7.42–7.35
(m, 2H), 6.65 (s, 1H), 1.32 (s, 9H).
Purification by chromatography (petroleum ether/EtOAc = 10:1)
1
afforded 3a as a White solid (45 mg, 95%). H NMR (400 MHz,
CDCl3) δ 7.79 (d, J = 7.3 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 3.26 (t,
J = 7.2 Hz, 2H), 2.72 (d, J = 1.2 Hz, 1H), 2.44 (s, 3H), 1.71-1.63
ACS Paragon Plus Environment

Page 5 of 9
The Journal of Organic Chemistry
(m, 2H), 0.90 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
7.2 Hz, 2H), 2.73 (d, J = 2.0 Hz, 2H), 2.46 (s, 3H), 0.86 (s, 2H),
0.77 (d, J = 5.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.9,
1
2
3
4
δ 144.8, 134.6, 129.8, 127.6, 76.0, 59.0, 52.8, 21.8, 21.1, 10.8; MS
(EI) m/z 237, 195, 155, 130, 116, 91, 65.
133.9, 129.8, 128.0, 75.6, 58.8, 32.5, 21.7, 6.6; IR (KBr) ν̃ 3279,
N-Ethynyl-N,4-dimethylbenzenesulfonamide (3b).16 Purification
by chromatography (petroleum ether/EtOAc = 10:1) afforded 3b as
3095, 2122, 1595, 1494, 1369, 988, 866 cm-1; HRMS (ESI-TOF)
calcd for C12H14NO2S [M + H]+: 236.0745; found: 236.0749.
1
a White solid (41 mg, 98%). H NMR (400 MHz, CDCl3) δ 7.80
N-Cycloheptyl-N-ethynyl-4-methylbenzenesulfonamide
(3j).
5
6
7
8
(d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 3.06 (s, 3H), 2.69 (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; MS (EI) m/z 209, 155, 130, 91,
65.
Purification by chromatography (petroleum ether/EtOAc = 10:1)
afforded 3j as a colorless liquid (40 mg, 69%). 1H NMR (400 MHz,
CDCl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 3.86–
3.73 (m, 1H), 2.69 (s, 1H), 2.37 (s, 3H), 1.67–1.54 (m, 6H), 1.46-
1.31 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.4, 136.1,
N-Ethyl-N-ethynyl-4-methylbenzenesulfonamide
(3c).16
9
Purification by chromatography (petroleum ether/EtOAc = 10:1)
129.8, 127.4, 74.3, 61.3, 60.6, 33.3, 27.7, 24.2, 21.6; IR (KBr) ν̃
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
afforded 3c as a White solid (43 mg, 96%). H NMR (400 MHz,
3306, 32928, 2130, 1601, 1494, 1369, 976, 812 cm-1; HRMS (ESI-
TOF) calcd for C16H21NNaO2S [M + Na]+: 314.1191; found:
314.1197.
1
CDCl3) δ 7.81 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 3.39
(q, J = 7.2 Hz, 2H), 2.74 (s, 1H), 2.45 (s, 3H), 1.22 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.7, 134.8, 129.8,
127.6, 75.7, 59.2, 46.4, 21.7, 13.0; MS (EI) m/z 223, 195, 155, 130,
116, 91, 65.
N-Ethynyl-2-methyl-N-propylbenzenesulfonamide
(3k).
Purification by chromatography (petroleum ether/EtOAc = 10:1)
afforded 3k as a colorless liquid (36 mg, 76%). 1H NMR (400 MHz,
CDCl3) δ 7.98 (d, J = 8.2 Hz, 1H), 7.54–7.46 (m, 1H), 7.34 (t, J =
7.6 Hz, 2H), 3.37–3.30 (m, 2H), 2.76 (s, 1H), 2.70 (s, 3H), 1.72 (m,
2H), 0.90 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
138.3, 136.3, 133.6, 132.9, 130.4, 126.2, 75.6, 59.8, 52.4, 21.2, 20.9,
N-Butyl-N-ethynyl-4-methylbenzenesulfonamide
(3d).20
Purification by chromatography (petroleum ether/EtOAc = 10:1)
1
afforded 3d as a Light yellow solid (48 mg, 95%). H NMR (400
MHz, CDCl3) δ 7.80 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H),
3.30 (t, J = 7.2 Hz, 2H), 2.73 (s, 1H), 2.45 (s, 3H), 1.64-1.61 (m,
2H), 1.34 (dd, J = 15.0, 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 144.7, 134.6, 129.8, 127.6, 76.1, 59.0,
50.9, 29.7, 21.7, 19.4, 13.5; MS (EI) m/z 251, 186, 155, 131, 105,
91, 65.
10.7; IR (KBr) ν̃ 3297, 3065, 2139, 1595, 1455, 1354, 982, 809
cm-1; HRMS (ESI-TOF) calcd for C12H16NO2S [M + H]+
238.0902; found: 238.0899.
:
N-Ethynyl-2,4,5-trimethyl-N-propylbenzenesulfonamide
(3l).
Purification by chromatography (petroleum ether/EtOAc = 10:1)
afforded 3l as a Light yellow solid (39 mg, 74%), mp 67–68 oC. 1H
NMR (400 MHz, CDCl3) δ 6.97 (s, 2H), 3.41–3.30 (m, 2H), 2.73
(s, 1H), 2.64 (s, 6H), 2.31 (s, 3H), 1.79-1.70 (m, 2H), 0.93 (t, J =
7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.5, 140.8,
N-Benzyl-N-ethynyl-4-methylbenzenesulfonamide
(3e).20
Purification by chromatography (petroleum ether/EtOAc = 10:1)
1
afforded 3e as a White solid. H NMR (400 MHz, CDCl3) δ 7.75
(d, J = 8.4 Hz, 2H), 7.33–7.27 (m, 7H), 4.49 (s, 2H), 2.67 (s, 1H),
2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.7, 134.8,
134.3, 129.7, 128.9, 128.5, 128.4, 127.7, 76.3, 59.7, 55.3, 21.6; MS
(EI) m/z 285, 253, 220, 155, 130, 123, 91, 65.
132.0, 131.8, 75.7, 60.1, 51.7, 23.0, 21.2, 21.0, 10.9; IR (KBr) ν
̃
3270, 2964, 2128, 1601, 1568, 1384, 976, 863 cm-1; HRMS (ESI-
TOF) calcd for C14H20NO2S [M + H]+: 266.1215; found: 266.1217.
N-Ethynyl-N-(3-methoxypropyl)-4-methylbenzenesulfonamide
(3f). Purification by chromatography (petroleum ether/EtOAc =
10:1) afforded 3f as a colorless liquid (40 mg, 75%). 1H NMR (400
MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H),
3.33 (dd, J = 10.8, 6.4 Hz, 4H), 3.22 (s, 3H), 2.66 (s, 1H), 2.37 (s,
3H), 1.88–1.79 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.7,
134.6, 129.8, 127.7, 76.1, 69.0, 59.1, 58.6, 48.5, 28.1, 21.6; IR
N-Ethynyl-4-fluoro-N-propylbenzenesulfonamide
(3m).
Purification by chromatography (petroleum ether/EtOAc = 10:1)
afforded 3m as a Light yellow solid (44 mg, 92%), mp 44–45 oC.
1H NMR (400 MHz, CDCl3) δ 8.01–7.92 (m, 2H), 7.26 (d, J = 8.6
Hz, 2H), 3.29 (t, J = 7.2 Hz, 2H), 2.75 (s, 1H), 1.71-1.66 (m, 2H),
0.92 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.7
(J C-F = 254.8 Hz), 133.7 (J C-F = 2.8 Hz), 130.4 (J C-F = 9.4 Hz),
(KBr) ν
̃
3300, 2877, 2136, 1595, 1452, 1363, 976, 815 cm-1; HRMS
116.5 (J
= 22.6 Hz), 75.7, 59.3, 53.0, 21.1, 10.7; IR (KBr) ν̃
C-F
(ESI-TOF) calcd for C13H18NO3S [M+H]+: 268.1007; found:
268.1001.
3282, 3106, 2139, 1592, 1497, 1357, 991, 836 cm-1; HRMS (ESI-
TOF) calcd for C11H13FNO2S [M + H]+:242.0651; found: 242.0658.
N-Ethynyl-4-fluoro-N-propylbenzenesulfonamide (3n).
N-(But-3-en-1-yl)-N-ethynyl-4-methylbenzenesulfonamide (3g).
Purification by chromatography (petroleum ether/EtOAc = 10:1)
Purification by chromatography (petroleum ether/EtOAc = 10:1)
o
o
afforded 3g as a Light yellow solid (36 mg, 72%), mp 77–78 C.
afforded 3n as a Light yellow solid (48 mg, 93%), mp 91–92 C.
1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.2 Hz, 2H), 7.35 (d, J
= 8.0 Hz, 2H), 5.74-5.66 (m, 1H), 5.26–4.94 (m, 2H), 3.51–3.29
(m, 2H), 2.76 (s, 1H), 2.45 (s, 3H), 2.42–2.35 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 144.8, 134.7, 133.5, 129.8, 127.7, 117.8,
1H NMR (400 MHz, CDCl3) δ 7.90–7.84 (m, 2H), 7.56–7.52 (m,
2H), 3.29 (t, J = 7.2 Hz, 2H), 2.74 (s, 1H), 1.73-1.64 (m, 2H), 0.92
(t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 140.4,
136.1, 129.5 129.0, 75.6, 59.3, 53.0, 21.1, 10.8; IR (KBr) ν̃ 3276,
75.9, 59.4, 50.6, 32.0, 21.6; IR (KBr) ν
̃
3265, 3089, 2922, 2130,
3095, 2136, 1586, 1473, 1363, 991, 833 cm-1; HRMS (ESI-TOF)
1592, 1437, 1357, 955, 821; HRMS (ESI-TOF) calcd for
calcd for C11H13ClNO2S [M + H]+: 258.0356; found: 258.0358 .
C13H16NO2S [M + H]+: 250.0902; found: 250.0905.
N-Ethynyl-4-nitro-N-propylbenzenesulfonamide
(3o).
N-(2-((Tert-butyldimethylsilyl)oxy)ethyl)-N-ethynyl-4-methyl-
benzenesulfonamide (3h).21 Purification by chromatography
(petroleum ether/EtOAc = 10:1) afforded 3h as a white solid (53
mg, 75%). 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H),
7.30 (d, J = 7.8 Hz, 2H), 3.76 (t, J = 6.0 Hz, 2H), 3.40 (t, J = 6.0
Hz, 2H), 2.68 (s, 1H), 2.40 (s, 3H), 0.82 (s, 9H), -0.00 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 144.7, 134.9, 129.8, 127.7,
76.3, 60.3, 58.8, 53.1, 25.8, 21.6, 18.3, -5.5; MS (EI) m/z 353, 246,
189, 147, 117, 91, 73.
Purification by chromatography (petroleum ether/EtOAc = 10:1)
afforded 3o as a Light yellow liquid (33 mg, 61%). 1H NMR (400
MHz, CDCl3) δ 8.42 (d, J = 8.6 Hz, 2H), 8.12 (d, J = 8.6 Hz, 2H),
3.35 (t, J = 7.2 Hz, 2H), 2.78 (s, 1H), 1.71 (dd, J = 14.6, 7.2 Hz,
2H), 0.93 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
150.7, 143.0, 128.9, 124.4, 74.9, 59.8, 53.4, 21.1, 10.7; IR (KBr) ν
3309, 3116, 2140, 1610, 1542, 1352, 855, 745 cm-1; HRMS (ESI-
TOF) calcd for C11H13N2O4S [M+H]+: 269.0596; found: 269.0593.
̃
N-Ethynyl-N-propylnaphthalene-2-sulfonamide
(3p).
N-Cyclopropyl-N-ethynyl-4-methylbenzenesulfonamide
(3i).
Purification by chromatography (petroleum ether/EtOAc = 10:1)
Purification by chromatography (petroleum ether/EtOAc = 10:1)
afforded 3i as a Light yellow solid (39 mg, 83%), mp 58–59 oC. 1H
NMR (400 MHz, CDCl3) δ 7.85 (d, J = 6.4 Hz, 2H), 7.37 (d, J =
afforded 3p as a white solid (44 mg, 80%), mp 83–84 oC. 1H NMR
(400 MHz, CDCl3) δ 8.48 (s, 1H), 8.00 (d, J = 8.6 Hz, 2H), 7.92 (t,
J = 8.6 Hz, 2H), 7.70–7.61 (m, 2H), 3.34 (t, J = 7.2 Hz, 2H), 2.75
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 9
(s, 1H), 1.74-1.65 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 135.3, 134.7, 132.0, 129.5, 129.3, 128.0,
(t, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.81–1.66 (m, 2H), 0.94 (t, J = 7.4
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.5, 134.6, 131.2,
129.7, 128.2, 127.6, 127.6, 122.9, 82.4, 70.5, 53.2, 21.5, 21.3, 10.8;
MS (EI) m/z 313, 207, 158, 143, 116, 89, 65.
1
2
3
4
5
6
7
8
127.7, 122.5, 76.0, 59.1, 53.0, 21.2, 10.8; IR (KBr) ν̃ 3261, 3056,
2964, 1589, 1500, 1351, 913, 830 cm-1; HRMS (ESI-TOF) calcd
for C15H16NO2S [M+H]+: 274.0902; found : 274.0903.
N-Butyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (6d).16
Purification by chromatography (petroleum ether/EtOAc = 10:1)
1-Ethynyl-1H-indole (3q).16 Purification by chromatography
(petroleum ether/EtOAc = 100:1) afforded 3q as a white solid (26
mg, 91%). 1H NMR (400 MHz, CDCl3) δ 7.91–7.83 (m, 2H), 7.62
(t, J = 7.6 Hz, 1H), 7.54–7.47 (m, 2H), 6.83 (d, J = 3.2 Hz, 1H),
3.41 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.1, 128.7,
127.6, 123.7, 122.1, 121.2, 111.2, 105.5, 74.3, 58.8; MS (EI) m/z
141, 114, 89, 63, 51.
1
afforded 6d as a white solid (59 mg, 90%). H NMR (400 MHz,
CDCl3) δ 7.84 (d, J = 8.2 Hz, 2H), 7.41–7.15 (m, 7H), 3.39 (t, J =
7.2 Hz, 2H), 2.44 (s, 3H), 1.76–1.60 (m, 2H), 1.41-1.37 (m, 2H),
0.92 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.6,
134.7, 131.3, 129.8, 128.3, 127.7, 127.7, 123.0, 82.5, 70.7, 51.4,
30.0, 21.6, 19.5, 13.6; MS (EI) m/z 327, 207, 172, 144, 130, 105,
65.
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
9-Ethynyl-9H-carbazole (3r).16 Purification by chromatography
(petroleum ether/EtOAc = 100:1) afforded 3r as a Colorless liquid
(34 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.6 Hz,
2H), 7.67 (d, J = 8.0 Hz, 2H), 7.58–7.49 (m, 2H), 7.35 (dd, J = 11.0,
4.0 Hz, 2H), 3.45 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
140.4, 126.8, 123.5, 122.2, 120.4, 111.3, 72.7, 62.6; MS (EI) m/z
191, 163, 140, 113, 95, 63, 51.
N,N'-(Pentane-1,5-diyl)bis(N-ethynyl-4-methylbenzenesulfon-
amide) (3s).16 Purification by chromatography (petroleum
ether/EtOAc = 4:1) afforded 3s as a white solid (62 mg, 68%). 1H
NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.2 Hz, 4H), 7.36 (d, J =
8.2 Hz, 4H), 3.27 (t, J = 7.2 Hz, 4H), 2.73 (s, 2H), 2.45 (s, 6H),
1.67 (dd, J = 14.8, 7.5 Hz, 4H), 1.36 (dd, J = 6.8, 2.8 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 144.8, 134.5, 129.8, 127.6,
75.9, 59.2, 50.9, 27.1, 22.8, 21.6; MS (ESI) m/z [M + Na]+: 481.
General experimental procedure for the synthesis of internal
ynamides in Scheme 2 and 4: To an oven-dried Schlenk tube
equipped with a magnetic stir bar was added secondary amides (0.2
mmol, 1.0 equiv), (Z)-1,2-dichloro alkenes or alkynyl chlorides 5
(0.4 mmol, 2.0 equiv), Cs2CO3 (1.0 mmol, 5.0 equiv) or (0.8 mmol,
4.0 equiv) in DMSO (1.0 mL) at 80 oC or 70 oC. Upon the reaction
completion (monitored by TLC), the residue was purified by silica
gel chromatography to afford the desired products.
4-Methyl-N-octyl-N-(phenylethynyl)benzenesulfonamide (6e).16
Purification by chromatography (petroleum ether/EtOAc = 10:1)
1
afforded 6e as a white solid (50 mg, 93%). H NMR (400 MHz,
CDCl3) δ 7.84 (d, J = 8.2 Hz, 2H), 7.38–7.26 (m, 7H), 3.39 (t, J =
7.2 Hz, 2H), 2.44 (s, 3H), 1.74–1.63 (m, 2H), 1.34–1.20 (m, 10H),
0.87 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.6,
134.6, 131.3, 129.8, 128.3, 127.7, 127.7, 123.0, 82.5, 70.7, 51.6,
31.6, 29.1, 29.1, 27.9, 26.3, 22.6, 21.6, 14.1; MS (EI) m/z 383, 271,
228, 207, 138, 105, 91.
N-Cyclopropyl-4-methyl-N-(phenylethynyl)benzenesulfonamide
(6f).16 Purification by chromatography (petroleum ether/EtOAc =
1
10:1) afforded 6f as a white solid (53 mg, 85%). H NMR (400
MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.24-7.20 (m, 4H), 7.16–
7.11 (m, 3H), 2.73-2.68 (m, 1H), 2.29 (s, 3H), 0.80–0.73 (m, 2H),
0.68–0.60 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.7,
132.8, 130.3, 128.7, 127.2, 126.9, 126.8, 121.8, 80.9, 69.6, 31.9,
20.6, 5.4; MS (EI) m/z 311, 246, 189, 174, 128, 91.
N-Benzyl-4-methyl-N-(phenylethynyl)benzenesulfonamide
(6g).22 Purification by chromatography (petroleum ether/EtOAc =
1
10:1) afforded 6g as a white solid (56 mg, 78%). H NMR (400
MHz, CDCl3) δ 7.79 (d, J = 8.2 Hz, 2H), 7.34–7.27 (m, 7H), 7.22
(s, 5H), 4.57 (s, 2H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 144.7, 134.8, 134.5, 131.2, 129.8, 128.9, 128.6, 128.4, 128.2,
127.8, 127.7, 122.9, 82.8, 71.5, 55.8, 21. 7; MS (EI) m/z 361, 297,
206, 179, 165, 106, 91.
A 10 mmol scale synthesis of 6a. In 100 mL oven-dried Schlenk
flask, a solution of N,4-dimethylbenzenesulfonamide 1a (1.85 g, 10
mmol), Cs2CO3 (16.2 g, 50 mmol), and (Z)-(1,2-
dichlorovinyl)benzene (3.44 g, 20 mmol) in DMSO (20 mL) was
stirred at 80 oC for 6 h and monitored by TLC. Upon the reaction
completion, the reaction solution was cooled to room temperature
and quenched with H2O (300 mL). The aqueous layer was extracted
three times with ethyl acetate. The combined organic layer was
dried over MgSO4. The volatile solvent was removed under
reduced pressure. The residue was purified by flash
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1)
to afford pure 6a (2.34 g, 8.2 mmol) as a white solid in 82%.
N, 4-Dimethyl-N-(phenylethynyl)benzenesulfonamide (6a).16
Purification by chromatography (petroleum ether/EtOAc = 10:1)
4-Methyl-N-(phenylethynyl)-N-((tetrahydrofuran-2-yl)methyl)
benzenesulfonamide (6h).16 Purification by chromatography
(petroleum ether/EtOAc = 10:1) afforded 6h as a white solid (58
mg, 81%). 1H NMR (400 MHz, CD2Cl2) δ 7.73 (d, J = 8.2 Hz, 2H),
7.31–7.23 (m, 4H), 7.23–7.17 (m, 3H), 4.19–4.03 (m, 1H), 3.73-
3.70 (m, 1H), 3.62 (dd, J = 14.3, 7.6 Hz, 1H), 3.44 (dd, J = 13.2,
6.8 Hz, 1H), 3.24 (dd, J = 13.2, 5.4 Hz, 1H), 2.34 (s, 3H), 1.94-1.91
(m, 1H), 1.86–1.74 (m, 2H), 1.66–1.51 (m, 1H); 13C{1H} NMR
(100 MHz, CD2Cl2) δ 144.7, 134.4, 131.0, 129.6, 128.2, 127.7,
127.6, 122.7, 82.8, 76.1, 70.1, 67.9, 55.0, 29.0, 25.4, 21.3; MS (EI)
m/z 355, 290, 200, 155, 130, 105, 71.
afforded 6a as a white solid (52 mg, 91%). H NMR (400 MHz,
N, 2-Dimethyl-N-(phenylethynyl)benzenesulfonamide (6i).16
Purification by chromatography (petroleum ether/EtOAc = 10:1)
1
CDCl3) δ 7.85 (d, J = 8.2 Hz, 2H), 7.41–7.34 (m, 4H), 7.29 (dd, J
= 5.0, 1.6 Hz, 3H), 3.15 (s, 3H), 2.46 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 144.9, 133.3, 131.4, 129.8, 128.3, 127.9, 127.9
122.7, 84.0, 69.1, 39.3, 21.9; MS (EI) m/z 285, 187, 130, 105, 89,
65.
1
afforded 6i as a white solid (50 mg, 88%). H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 7.4 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.38–
7.33 (m, 2H), 7.31–7.21 (m, 5H), 3.21 (s, 3H), 2.74 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 138.3, 135.4, 133.5, 132.8, 131.0, 130.4,
128.1, 127.6, 126.1, 122.6, 83.6, 69.7, 38.6, 20.9; MS (EI) m/z 285,
239, 224, 181, 155, 132, 118, 91.
N-Ethyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (6b).16
Purification by chromatography (petroleum ether/EtOAc = 10:1)
1
afforded 6b as a white solid (56 mg, 94%). H NMR (400 MHz,
4-(Tert-butyl)-N-methyl-N-(phenylethynyl)benzenesulfonamide
CDCl3) δ 7.84 (d, J = 8.2 Hz, 2H), 7.38-7.33 (m, 4H), 7.30–7.24
(m, 3H), 3.48 (q, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.26 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.7, 134.8, 131.4,
129.8, 128.3, 127.8, 127.7, 123.0, 82.2, 70.9, 46.8, 21.6, 13.3; MS
(EI) m/z 299, 207, 180, 165, 144, 105, 89, 65.
(6j).16 Purification by chromatography (petroleum ether/EtOAc =
1
10:1) afforded 6j as a white solid (63 mg, 96%). H NMR (400
MHz, CDCl3) δ 7.80 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H),
7.29 (dd, J = 6.4, 3.0 Hz, 2H), 7.21 (dd, J = 5.0, 1.8 Hz, 3H), 3.09
(s, 3H), 1.28 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.7,
132.4, 130.3, 127.3, 126.8, 126.7, 125.2, 121.8, 83.1, 68.1, 38.3,
34.3, 30.1; MS (EI) m/z 327, 248, 165, 130, 89.
4-Methyl-N-(phenylethynyl)-N-propylbenzenesulfonamide
(6c).16 Purification by chromatography (petroleum ether/EtOAc =
1
10:1) afforded 6c as a white solid (58 mg, 93%). H NMR (400
4-Fluoro-N-methyl-N-(phenylethynyl)benzenesulfonamide
MHz, CDCl3) δ 7.84 (d, J = 8.2 Hz, 2H), 7.37-7.26 (m, 7H), 3.36
(6k).16 Purification by chromatography (petroleum ether/EtOAc =
ACS Paragon Plus Environment

Page 7 of 9
The Journal of Organic Chemistry
1
10:1) afforded 6k as a white solid (38 mg, 66%). H NMR (400
δ 144.6, 134.4, 131.3, 129.8, 128.2, 127.7, 127.6, 122.8, 82.2, 70.7,
51.3, 27.4, 22.9, 21.6; MS (ESI) m/z [M + Na]+: 633.
1
2
3
4
5
6
7
8
MHz, CDCl3) δ 8.01–7.94 (m, 2H), 7.38–7.33 (m, 2H), 7.32–7.27
(m, 4H), 7.26 (s, 1H), 3.17 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 165.9 (JC-F = 254.8 Hz), 132.3, 131.5, 130.6 (JC-F = 9.6
Hz), 128.3, 128.1, 122.4, 116.5 (JC-F = 22.6 Hz), 83.5, 69.3, 39.4;
MS (EI) m/z 289, 276, 178, 130, 89, 63.
N, 4-Dimethyl-N-(o-tolylethynyl)benzenesulfonamide (7a).16
Purification by chromatography (petroleum ether/EtOAc = 10:1)
1
afforded 7a as a white solid (52 mg, 87%). H NMR (400 MHz,
CDCl3) δ 7.82 (d, J = 8.2 Hz, 2H), 7.36–7.26 (m, 3H), 7.13 (d, J =
4.0 Hz, 2H), 7.09–7.04 (m, 1H), 3.14 (s, 3H), 2.39 (s, 3H), 2.35 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 145.0, 139.7, 133.4,
131.4, 129.9, 129.5, 127.9, 127.8, 125.6, 122.6, 87.9, 68.1, 39.5,
21.6, 20.7; MS (EI) m/z 299, 144, 115, 103, 77, 51.
4-Chloro-N-methyl-N-(phenylethynyl)benzenesulfonamide
(6l).16 Purification by chromatography (petroleum ether/EtOAc =
1
10:1) afforded 6l as a white solid (56 mg, 92%). H NMR (400
MHz, CDCl3) δ 7.89 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H),
7.39–7.34 (m, 2H), 7.32–7.27 (m, 3H), 3.17 (s, 3H);13C{1H} NMR
(100 MHz, CDCl3) δ 140.5, 134.7, 131.5, 129.6, 129.2, 128.4,
128.1, 122.4, 83.4, 69.4, 39.4; MS (EI) m/z 305, 226, 165, 130, 105,
89, 63.
N, 4-Dimethyl-N-(m-tolylethynyl)benzenesulfonamide (7b).16
Purification by chromatography (petroleum ether/EtOAc = 10:1)
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
1
afforded 7b as a white solid (54 mg, 90%). H NMR (400 MHz,
CDCl3) δ 7.84 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.21–
7.13 (m, 3H), 7.09 (d, J = 6.2 Hz, 1H), 3.14 (s, 3H), 2.46 (s, 3H),
2.31 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.7, 137.9,
133.4, 132.0, 129.8, 128.7, 128.4, 128.1, 127.9, 122.5, 83.6, 69.2,
39.3, 21.6, 21.2; MS (EI) m/z 299, 220, 144, 119, 103, 77, 51.
N, 4-Dimethyl-N-(p-tolylethynyl)benzenesulfonamide (7c).16
Purification by chromatography (petroleum ether/EtOAc = 10:1)
3-(Phenylethynyl)oxazolidin-2-one (6m).16 Purification by
chromatography (petroleum ether/EtOAc = 10:1) afforded 6m as a
white solid (26 mg, 70%). 1H NMR (400 MHz, CDCl3) δ 7.47–7.41
(m, 2 H), 7.33–7.28 (m, 3 H), 4.49-4.45 (m, 2 H), 4.03–3.95 (m, 2
H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.0, 131.6, 128.4, 128.2,
122.2, 79.0, 71.2, 63.1, 47.1; MS (EI) m/z 187, 143, 115, 88, 77,
51.
1
afforded 7c as a white solid (51 mg, 85%). H NMR (400 MHz,
(R)-4-phenyl-3-(phenylethynyl)oxazolidin-2-one
(6n).16
CDCl3) δ 7.84 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.26
(d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 3.14 (s, 3H), 2.45 (s,
3H), 2.33 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.8, 138.1,
133.3, 131.5, 129.8, 129.1, 127.9, 119.6, 83.3, 69.1, 39.4, 21.7, 21.4;
MS (EI) m/z 299, 253, 144, 103, 77, 51.
N-((4-Methoxyphenyl)ethynyl)-N,4-dimethylbenzenesulfonam-
ide (7d).16 Purification by chromatography (petroleum ether/EtOAc
= 10:1) afforded 7d as a white solid (53 mg, 84%). 1H NMR (400
MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H),
7.31 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 3.80 (d, J = 4.3
Hz, 3H), 3.13 (s, 3H), 2.46 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 159.6, 144.7, 133.4, 129.8, 129.7, 127.9, 114.6, 113.9,
82.5, 68.7, 55.3, 39.4, 21.6; MS (EI) m/z 315, 236, 160, 119, 91,
65.
N-((4-(Tert-butyl)phenyl)ethynyl)-N,4-dimethylbenzenesulfon-
amide (7e).16 Purification by chromatography (petroleum
ether/EtOAc = 10:1) afforded 7e as a white solid (59 mg, 87%). 1H
NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.34 (d, J =
8.2 Hz, 2H), 7.30 (s, 4H), 3.12 (s, 3H), 2.43 (s, 3H), 1.29 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 151.3, 144.8, 133.3, 131.4,
129.8, 127.9, 125.3, 119.7, 83.4, 69.1, 39.4, 34.7, 31.2, 21.7; MS
(EI) m/z 341, 326, 186, 171, 145, 115, 91.
Purification by chromatography (petroleum ether/EtOAc = 10:1)
afforded 6n as a white solid (43.6 mg, 83%). 1H NMR (400 MHz,
CDCl3) δ 7.55–7.36 (m, 5H), 7.30–7.17 (m, 5H), 5.14 (dd, J = 8.5,
7.2 Hz, 1H), 4.78 (t, J = 8.8 Hz, 1H), 4.31 (dd, J = 8.9, 7.1 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 155.5, 136.1, 131.5, 129.6,
129.3, 128.1, 128.1, 126.9, 122.2, 78.0, 72.9, 70.7, 62.3; MS (EI)
m/z 263, 218, 178, 128, 89, 77.
1-(Phenylethynyl)-1H-pyrrolo[2,3-b]pyridine
(6o).16
Purification by chromatography (petroleum ether/EtOAc = 10:1)
afforded 6o as a Colorless liquid (37 mg, 85%). 1H NMR (400 MHz,
CDCl3) δ 8.46 (dd, J = 4.8, 1.4 Hz, 1H), 7.92 (dd, J = 7.8, 1.4 Hz,
1H), 7.70–7.56 (m, 2H), 7.43–7.31 (m, 4H), 7.18 (dd, J = 7.8, 4.8
Hz, 1H), 6.57 (d, J = 3.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ 149.5, 144.8, 132.0, 129.7, 129.6, 128.3, 122.4, 120.3, 118.0,
103.7, 100.0, 79.2, 71.7; MS (EI) m/z 218, 190, 163, 109, 91, 63.
9-(Phenylethynyl)-9H-carbazole (6p).16 Purification by
chromatography (petroleum ether/EtOAc = 10:1) afforded 6p as a
Colorless liquid (48 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 8.01
(d, J = 7.6 Hz, 2H), 7.71 (d, J = 8.0k Hz, 2H), 7.65–7.59 (m, 2H),
7.55–7.47 (m, 2H), 7.41–7.31 (m, 5H); 13C{1H} NMR (100 MHz,
CDCl3) δ 140.5, 131.5, 128.5, 128.0, 126.8, 123.6, 123.0, 122.1,
120.4, 111.3, 78.9, 74.7; MS (EI) m/z 267, 225, 207, 191, 155, 91,
80.
N-((4-Fluorophenyl)ethynyl)-N,4-dimethylbenzenesulfonamide
(7f).16 Purification by chromatography (petroleum ether/EtOAc =
1
1-(Phenylethynyl)-1H-indole
(6q).16
Purification
by
10:1) afforded 7f as a white solid (46 mg, 76%). H NMR (400
chromatography (petroleum ether/EtOAc = 10:1) afforded 6q as a
Colorless liquid (40 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.69–
7.51 (m, 4H), 7.45–7.30 (m, 4H), 7.29–7.18 (m, 2H), 6.67–6.54 (m,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.2, 131.5, 128.9,
128.5, 128.1, 127.9, 123.6, 122.7, 122.1, 121.3, 111.4, 105.6, 80.9,
70.7; MS (EI) m/z 217, 189, 163, 139, 108, 94.
MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.42–7.30 (m, 4H), 6.97
(dd, J = 12.0, 5.2 Hz, 2H), 3.14 (s, 3H), 2.46 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 162.3 (JC-F = 247.6 Hz), 144.8 (JC-F = 5.8 Hz),
133.5 (JC-F = 8.2 Hz), 133.3, 129.9, 127.8, 118.8, 115.5 (JC-F = 22.0
Hz), 83.6, 68.0, 39.3, 21.6; MS (EI) m/z 303, 224, 148, 107, 91, 65.
N-((4-Chlorophenyl)ethynyl)-N,4-dimethylbenzenesulfonamide
(7g).16 Purification by chromatography (petroleum ether/EtOAc =
3-Methyl-1-(phenylethynyl)-1H-indole (6r).16 Purification by
chromatography (petroleum ether/EtOAc = 10:1) afforded 6r as a
Colorless liquid (43 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.66–
7.49 (m, 4H), 7.39–7.31 (m, 4H), 7.24 (dd, J = 5.8, 2.0 Hz, 1H),
7.03 (d, J = 1.0 Hz, 1H), 2.32 (d, J = 1.0 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 138.5, 131.3, 128.7, 128.4, 127.8, 125.8,
123.5, 123.0, 121.5, 119.3, 114.9, 111.3, 81.2, 70.4, 9.6; MS (EI)
m/z 231, 202, 178, 131, 91, 51.
N,N'-(Pentane-1,5-diyl)bis(4-methyl-N-(phenylethynyl)benze-
nesulfonamide) (6s).16 Purification by chromatography (petroleum
ether/EtOAc = 10:1) afforded 6s as a white solid (89 mg, 73%). 1H
NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.2 Hz, 4H), 7.44–7.36 (m,
8H), 7.34–7.28 (m, 6H), 3.42 (t, J = 7.2 Hz, 4H), 2.47 (s, 6H), 1.82-
1.69 (m, 4H), 1.51-1.44 (m, 2H);13C{1H} NMR (100 MHz, CDCl3)
1
10:1) afforded 7g as a white solid (50 mg, 79%). H NMR (400
MHz, CDCl3) δ 7.82 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H),
7.30–7.23 (m, 4H), 3.14 (s, 3H), 2.46 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 144.9, 133.8, 133.3, 132.6, 129.7, 128.6, 127.8,
121.3, 84.9, 68.2, 39.2, 21.7; MS (EI) m/z 319, 280, 207, 167, 135,
88, 61.
N-((4-Bromophenyl)ethynyl)-N,4-dimethylbenzenesulfonamide
(7h).16 Purification by chromatography (petroleum ether/EtOAc =
1
10:1) afforded 7h as a white solid (54 mg, 74%). H NMR (400
MHz, CDCl3) δ 7.81 (d, J = 8.2 Hz, 2H), 7.46–7.33 (m, 4H), 7.20
(d, J = 8.4 Hz, 2H), 3.14 (s, 3H), 2.45 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 144.9, 133.3, 132.7, 131.5, 129.9, 127.8, 121.9,
121.8, 85.1, 68.3, 39.2, 21.7; MS (EI) m/z 363, 284, 208, 167, 114,
91, 65.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 9
Ye,
L.-W.,
Yttrium-Catalyzed
Intramolecular
N,
4-Dimethyl-N-(thiophen-2-ylethynyl)benzenesulfonamide
1
2
3
4
5
6
7
8
(7i).16 Purification by chromatography (petroleum ether/EtOAc =
Hydroalkoxylation/Claisen Rearrangement Sequence: Efficient
Synthesis of Medium-Sized Lactams. Angew. Chem., Int. Ed. 2017, 56
, 4015−4019. (e) Huang, B.; Zeng, L.; Shen, Y.; Cui, S., One-Pot
Multicomponent Synthesis of β-Amino Amides. Angew. Chem., Int.
Ed. 2017, 56 , 4565−4568.
(2) (a) Huang, J.; Xiong, H.; Hsung, R. P.; Rameshkumar, C.; Mulder,
J. A.; Grebe, T. P., The First Successful Base-Promoted Isomerization
of Propargyl Amides to Chiral Ynamides. Applications in Ring-
Closing Metathesis of Ene−Ynamides and Tandem RCM of
Diene−Ynamides. Org. Lett. 2002, 4, 2417−2420. (b) 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.
1
10:1) afforded 7i as a white solid (47 mg, 80%). H NMR (400
MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H),
7.28–7.22 (m, 1H), 7.16 (dd, J = 3.6, 1.0 Hz, 1H), 6.96 (dd, J = 5.2,
3.6 Hz, 1H), 3.14 (s, 3H), 2.47 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 144.9, 133.3, 132.9, 129.8, 127.8, 127.7, 126.9, 122.7,
87.4, 62.5, 39.3, 21.6; MS (EI) m/z 291, 245, 212, 154, 136, 111,
95, 65.
N, 4-Dimethyl-N-(naphthalen-2-ylethynyl)benzenesulfonamide
(7j).16 Purification by chromatography (petroleum ether/EtOAc =
9
1
10:1) afforded 7j as a white solid (54 mg, 80%). H 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, CDCl3) δ 7.87 (d, J = 6.2 Hz, 3H), 7.77 (dd, J = 15.8, 9.0 Hz,
3H), 7.49–7.45 (m, 2H), 7.39 (t, J = 9.2 Hz, 3H), 3.19 (s, 3H), 2.46
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.8, 133.4, 133.4,
133.0, 132.6, 130.9, 129.9, 128.3, 127.9, 127.8, 127.6, 126.5, 126.5,
120.1, 84.3, 69.6, 39.4, 21.7; MS (EI) m/z 335, 271, 229, 180, 139.
91.
(Z)-N-(1-chloro-4-phenylbut-1-en-2-yl)-N,4-dimethylbenzenes-
ulfonamide (7k).16 Purification by chromatography (petroleum
ether/EtOAc = 10:1) afforded 7k as a Colorless liquid (48 mg,
68%). 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.2 Hz, 2H), 7.28
(dd, J = 7.4, 5.8 Hz, 4H), 7.23–7.13 (m, 3H), 5.89 (s, 1H), 3.04 (s,
3H), 2.86–2.74 (m, 4H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 143.5, 142.6, 140.4, 136.5, 129.5, 128.4, 128.3, 127.5,
126.1, 116.2, 37.4, 36.8, 33.3, 21.5; MS (ESI) m/z [M + Na]+: 372.
(3) (a) Bernhard Witulski; Gößmann, M., Intermolecular Pauson-
Khand Reactions withN-Alkynylamides
- Electronically Tuned
Variants of Ynamines. Synlett 2000, 12, 1793−1797. (b) Shen, L.;
Hsung, R. P., Pauson–Khand Cycloaddition Reactions of Chiral
Ynamides. Observation of an Unusual Endo-Addition with
Norbornadiene. Tetrahedron Lett. 2003, 44, 9353−9358.
(4) Saá, C.; Rodríguez, D.; Castedo, L., New Alkynyl Amides by
Negishi Coupling. Synlett 2004, 783−786.
(5) (a) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.;
Wei, L. L., Recent Advances in the Chemistry of Ynamines and
Ynamides. Tetrahedron 2001, 57, 7575−7606. (b) 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. (c) Evano, G.; Coste, A.; Jouvin,
K., Ynamides: Versatile Tools in Organic Synthesis. Angew. Chem. Int.
Ed. 2010, 49, 2840−2859. (d) 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. (e)
Cook, A. M.; Wolf, C., S3S63 Terminal Ynamides: Synthesis,
Coupling Reactions and Additions to Common Electrophiles.
Tetrahedron Lett. 2015, 56, 2377−2392. (f) Evano, G.; Michelet, B.;
Zhang, C., The Anionic Chemistry of Ynamides: A review. C. R. Chim.
2017, 20, 648−664. (g) Dodd, R. H.; Cariou, K., Ketenimines
Generated from Ynamides: Versatile Building Blocks for Nitrogen-
Containing Scaffolds. Chem. Eur. J. 2018, 24, 2297−2304.
■ 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
■ AUTHOR INFORMATION
Corresponding Author
(6) (a) Evano, G.; Jouvin, K.; Coste, A., General Amination Reactions
for the Synthesis of Ynamides. Synthesis 2013, 45, 17−26. (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. (c) Jouvin, K.; Couty,
F.; Evano, G., Copper-Catalyzed Alkynylation of Amides with
Potassium Alkynyltrifluoroborates: A Room-Temperature, Base-Free
Synthesis of Ynamides. Org. Lett. 2010, 12, 3272−3275. (d) Jouvin,
K.; Heimburger, J.; Evano, G., Click-alkynylation of N- and P-
Nucleophiles by Oxidative Cross-Coupling with Alkynylcopper
Reagents: a General Synthesis of Ynamides and Alkynylphosphonates.
Chem. Sci. 2012, 3, 756−760. (e) Jia, W.; Jiao, N., Cu-catalyzed
Oxidative Amidation of Propiolic Acids Under Air via
Decarboxylative Coupling. Org. Lett. 2010, 12, 2000−2003. (f)
Hamada, T.; Ye, X.; Stahl, S. S., Copper-Catalyzed Aerobic Oxidative
Amidation of Terminal Alkynes:ꢀ Efficient Synthesis of Ynamides. J.
Am. Chem. Soc. 2008, 130, 833−835.
(7) Viehe, H. G.; Reinstein, M., Synthesis of Alkynylamines by
Nucleophilic Substitution of Halogenoalkynes. Angew. Chem. Int. Ed.
1964, 3, 506−506.
(8) Mansfield, S. J.; Campbell, C. D.; Jones, M. W.; Anderson, E. A.,
A Robust and Modular Synthesis of Ynamides. Chem. Commun. 2015,
51, 3316−3319.
(9) (a) Jin, X.; Yamaguchi, K.; Mizuno, N., Heterogeneously Catalyzed
Selective Aerobic Oxidative Cross-Coupling of Terminal Alkynes and
Amides with Simple Copper(II) Hydroxide. Chem. Commun. 2012, 48,
4974−4976. (b) 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
*E-mail: zhaojf@jxnu.edu.cn
ORCID
Zhenming Zhang: 0000-0001-8550-5398
Junfeng Zhao: 0000-0003-4843-4871
Author Contributions
†X.Z., and Y.T contributed equally
Notes
The authors declare no competing financial interests.
■ ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (21778025, 21762021), and the Science and
Technology Project of Jiangxi Provincial Education Department
(GJJ150297, GJJ150324).
■ REFERENCES
(1) For selected examples, see: (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) 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. (c) Zeng, X.; Li, J.; Ng,
C. K.; Hammond, G. B.; Xu, B., (Radio)fluoroclick Reaction Enabled
by a Hydrogen-Bonding Cluster. Angew. Chem. Int. Ed. 2018, 57,
2924−2928. (d) Zhou, B.; Li, L.; Zhu, X.-Q.; Yan, J.-Z.; Guo, Y.-L.;
ACS Paragon Plus Environment

Page 9 of 9
The Journal of Organic Chemistry
Compounds. J. Am. Chem. Soc. 2008, 130, 1820−1821.
M.; Irving, A. J.; Nevalainen, T. J., Potent and selective N-(4-
sulfamoylphenyl)thiourea-based GPR55 agonists. Eur. J. Med. Chem.
2016, 107, 119−132. (e) Tang, X.; Huang, L.; Qi, C.; Wu, X.; Wu, W.;
Jiang, H., Copper-catalyzed sulfonamides formation from sodium
sulfinates and amines. Chem. Commun. 2013, 49, 6102−6104. (f) Zhu,
M.; Fujita, K.; Yamaguchi, R., Simple and Versatile Catalytic System
for N-Alkylation of Sulfonamides with Various Alcohols. Org. Lett.
2010, 12, 1336−1339. (g) Liang, R.; Li, S.; Wang, R.; Lu, L.; Li, F., N-
Methylation of Amines with Methanol Catalyzed by a Cp*Ir Complex
Bearing a Functional 2,2’-Bibenzimidazole Ligand. Org. Lett. 2017, 19,
5790−5793.
(18) (a) Zhu, G.; Chen, D.; Wang, Y.; Zheng, R., Highly
Stereoselective Synthesis of (Z)-1,2-Dihaloalkenes by a Pd-Catalyzed
Hydrohalogenation of Alkynyl Halides. Chem. Commun. 2012, 48,
5796−5798. (b) 10. Zeng, X.; Liu, S.; Hammond, G. B.; Xu, B.,
Hydrogen-Bonding-Assisted Brønsted Acid and Gold Catalysis:
Access to Both (E)- and (Z)-1,2-Haloalkenes via Hydrochlorination of
Haloalkynes. ACS Catal. 2018, 8, 904−909.
(19) (a). Shi, D.; Liu, Z.; Zhang, Z.; Shi, W.; Chen H., Silver-Catalyzed
Synthesis of 1-Chloroalkynes Directly from Terminal Alkynes. Chem.
Cat. Chem. 2015, 7, 1424−1426. (b). Chowdhury, R.M.; Wilden, J. D.,
An Improved Transition-Metal-Free Synthesis of Aryl Alkynyl
Sulfides via Substitution of a Halide at an sp-Centre. Org. Biomol.
Chem. 2015, 13, 5859−5861. (c). Ye, M.; Wen, Y.; Li, H.; Fu, Y.;
Wang, Q., Metal-free Hydration of Aromatic Haloalkynes to α-
Halomethyl Ketones. Tetrahedron Lett. 2016, 57, 4983−4986. (d).
Satoh, T.; Itoh, N.; Watanabe, S.; Koike, H.; Matsuno, H.; Matsuda,
K.; Yamakawa, K., Ligand Exchange Reaction of Sulfoxides in
Organic Synthesis: A Novel Method for Synthesizing Acetylenes and
Allenes from Carbonyl Compounds Through Sulfoxides Having a
Trifluoro-methanesulfonyloxy Group on the β-Carbon. Tetrahedron
1995, 51, 9327−9338.
(10) (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.;
Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J., A Copper-
Catalyzed C−N Bond Formation Involving sp-Hybridized Carbons. A
Direct Entry to Chiral Ynamides via N-Alkynylation of Amides. J. Am.
Chem. Soc. 2003, 125, 2368−2369.
(11) Dunetz, J. R.; Danheiser, R. L., Copper-Mediated N-Alkynylation
of Carbamates, Ureas, and Sulfonamides. A General Method for the
Synthesis of Ynamides. Org. Lett. 2003, 5, 4011−4014.
(12) (a) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C.; Vera, E.
L., Copper sulfate-pentahydrate-1,10-phenanthroline catalyzed
Amidations of Alkynyl Bromides. Synthesis of Heteroaromatic Amine
Substituted Ynamides. Org. Lett. 2004, 6, 1151−1154. (b) 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.
(13) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G., Copper-
Mediated Coupling of 1,1-Dibromo-1-alkenes with Nitrogen
Nucleophiles: A General Method for the Synthesis of Ynamides.
Angew. Chem. Int. Ed. 2009, 48, 4381−4385.
(14) Aubineau, T.; Cossy, J., Chemoselective Alkynylation of N-
Sulfonylamides versus Amides and Carbamates--Synthesis of
Tetrahydropyrazines. Chem. Commun. 2013, 49, 3303−3305.
(15) (a) 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. (b) Hu, L.; Zhao, J., Ynamide: A New Coupling
Reagent for Amide and Peptide Synthesis. Synlett 2017, 28, 1663−1670.
(c) Yang, J.; Wang, C.; Xu, S.; Zhao, J., Ynamide-Mediated
Thiopeptide Synthesis. Angew. Chem. Int. Ed. 2019, 58, 1382−1386.
(16) Tu, Y.; Zeng, X.; Wang, H.; Zhao, J., A Robust One-Step
Approach to Ynamides. Org. Lett. 2018, 20, 280−283.
1
2
3
4
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
(17) (a) Powell, D. A.; Fan, H., Copper-Catalyzed Amination of
Primary Benzylic C−H Bonds with Primary and Secondary
Sulfonamides. J. Org. Chem. 2010, 75, 2726−2729. (b) Zhu, M.; Wei,
W.; Yang, D.; Cui, H.; Wang, L.; Meng, G.; Wang, H., Metal-Free
I2O5-Mediated Direct Construction of Sulfonamides from Thiols and
Amines. Org. Biomol. Chem. 2017, 15, 4789−4793. (c) Sanghavi, N.
M.; Parab, V. L.; Patravale, B. S.; Patel, M. N., N-alkylation of
Sufonamides Using Anion Exchange Resin. Synth. Commun. 1989, 19,
1499−1503. (d) Yrjola, S.; Parkkari, T.; Navia-Paldanius, D.; Laitinen,
T.; Kaczor, A. A.; Kokkola, T.; Adusei-Mensah, F.; Savinainen, J. R.;
Laitinen, J. T.; Poso, A.; Alexander, A.; Penman, J.; Stott, L.; Anskat,
(20) Huang, H.; Tang, L.; Han, X.; He, G.; Xi, Y.; Zhu, H.,
Regioselective Iodoamination of Terminal Ynamides for the Synthesis
of α-Amino-β,β-diiodo-enamides. Chem. Commun. 2016, 52,
4321−4324.
(21) Yang, Y.; Liu, H.; Peng, C.; Wu, J.; Zhang, J.; Qiao, Y.; Wang,
X.-N.; Chang, J., AlCl3-Catalyzed Annulations of Ynamides Involving
a Torquoselective Process for the Simultaneous Control of Central and
Axial Chirality. Org. Lett. 2016, 18, 5022−5025.
(22) Huang, H.; Zhu, H.; Kang, J. Y., Regio- and Stereoselective
Hydrophosphorylation of Ynamides for the Synthesis of β-
Aminovinylphosphine Oxides. Org. Lett. 2018, 20, 2778−2781.
ACS Paragon Plus Environment