Metal-Free [2 + 2 + 2] Cycloaddition of Ynamide-Nitriles with Ynamides: A Highly Regio- and Chemoselective Synthesis of δ-Carboline Derivatives

Article abstract of DOI:10.1021/acs.joc.8b02112

A metal-free formal [2 + 2 + 2] cycloaddition of functionalized ynamide-nitriles with ynamides is disclosed which offers highly efficient access to polysubstituted δ-carboline derivatives under the mediation of TfOH. This strategy is highly regioselective and chemoselective and displays mild conditions, high yields, and efficiency (within 1 min) in addition to substrates scopes (56 examples).

Full text of DOI:10.1021/acs.joc.8b02112

Subscriber access provided by UNIV TEXAS SW MEDICAL CENTER
Article
Metal-Free [2+2+2] Cycloaddition of Ynamide-Nitriles with Ynamides: A
Highly Regio- and Chemoselective Synthesis of #-Carboline Derivatives
Hao Wen, Wei Cao, Yu Liu, Liang Wang, Ping Chen, and Yu Tang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02112 • Publication Date (Web): 12 Oct 2018
Downloaded from http://pubs.acs.org on October 13, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Metal-Free [2+2+2] Cycloaddition of Ynamide-Nitriles with
Ynamides: A Highly Regio- and Chemoselective Synthesis of
δ-Carboline Derivatives
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
†
†
†
§
†
†, ‡
Hao Wen, Wei Cao, Yu Liu, Liang Wang, Ping Chen* and Yu Tang*
†Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy,
Ocean University of China, Yushan Road, Qingdao, 266003, P. R. China.
‡
Laboratory for Marine Drugs and Bioproducts Qingdao National Laboratory for Marine Science and
Technology Qingdao, 266237, P. R. China
§
2
College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao
66109, P. R. China
Supporting Information Placeholder
Abstract
A metal-free formal [2+2+2] cycloaddition of functionalized ynamide-nitriles with ynamides
is disclosed which offers highly efficient access to polysubstituted δ-carboline derivatives
under the mediation of TfOH. This strategy is highly regioselective and chemoselective, and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
displays mild conditons, high yields and efficiency (within 1 min) in addition to substrates
scopes (56 examples).
Introduction
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Pyrido[x,y
-
b
]indoles, commonly known as carbolines, serve as unique structural units in
1
numerous natural alkaloids, pharmaceutical molecules and functional materials. Among
the class of carbolines,
δ
-carbolines have attracted considerable attention, because of
2
which represent a rather broad spectrum of biological activities. For examples,
benzo-carbolinium and N5
-
ω
-cyclohexylpentyl-N1-methyl-
δ
-carbolinium represent antifu-
2
a
2b
ngal and antibacterial activities, and SYUIQ-5 is a potential cancer therapeutic. In
addition,
δ-carboline derivatives (e.g., CzBPDCb) can be commonly used as electron
transport unit bipolar host materials for blue phosphorescent organic light-emitting
2
c
didoes (Figure 1).
Figure 1. Biologically Active Molecules and Functional Materials Containing δ-Carbolines.
ACS Paragon Plus Environment

Page 3 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Due to the potential application of δ-carbolines in both medicinal chemistry and materials
3
chemistry, a multitude of protocols for synthesizing δ-carbolines have been established, which
3
b
3c
3d
include Fischer reaction, Graebe-Ullmann reaction, photochemical cyclization, Pd-catalyzed
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3e
amination and intramolecular cross-coupling reactions. Recently, although some innovative
4
methods have been reported for the construction of δ-carbolines, they still suffer from certain
salient drawbacks, e. g., low step-economy, harsh conditions and indispensability of noble
transition metallic catalysts.
Scheme 1. Cycloaddition of Ynamides with Nitriles.
Ynamides bearing an electron-withdrawing group on the nitrogen atom have been well
5
demonstrated as versatile building blocks due to their combined stability and peculiar reactivity.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Cycloaddition reactions of ynamides with various precursors provide an efficient method for
6
constructing complex frameworks. In particular, [2+2+2] cycloaddition of ynamides and nitriles
represents one of the most convenient and straightforward strategies to construct various
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
nitrogen-containing heterocycles (Scheme 1). For examples, Liu and co-workers described an
elegant gold-catalyzed [2+2+2] cycloaddition of ynamides and nitriles for the synthesis
7a,7b
pyrimidines and pyridines. In comparison with the important advances in gold catalysis,
7c,7d
metal-free catalytic cycloaddition of ynamides were developed, Maulide et al, Wang and Chang
7e
7f
7g
et al, Zhang and Sun et al and our group developed the similar cycloaddition of ynamides and
nitriles toward pyrimidines, pyridines and isoquinolines in the presence of acid catalysts. Besides,
Liu et al reported an efficient synthesis of δ-carbolines via NiCl (DME)/dppp/Zn catalyzed
2
[2+2+2] cycloaddition of alkyne-nitriles with alkynes, which has two innegligible disadvantages,
including
the employment of transition metallic catalysts and comparatively low
4b
regioselectivity when the unsymmetrical alkynes, particularly ynamides, were used as reactants.
Herein, we developed a concise and highly efficient metal-free approach to furnish
multi-substituted δ-carboline derivatives via TfOH-mediated regio- and chemoselective [2+2+2]
cycloaddition of diverse ynamide-nitriles with ynamides under extremely mild reaction
conditions.
Results and Discussion
ACS Paragon Plus Environment

Page 5 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Initially, ynamide-nitrile 1a and 3-(phenylethynyl)oxazolidin-2-one 2a were selected as the
model substrates to investigate the feasibility of [2+2+2] cycloaddition. To our delight, the
desired product δ-carboline 3a could be obtained in 65% yield in the presence of 1.0 equiv of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TfOH with CH
2
Cl as a solvent, the reaction completed within 0.5 hour (Table1, entry 1). Then,
2
various Brфnsted acid catalysts such as HBF
4
·OEt
2
, NHTf and Lewis acid catalysts including
2
TMSOTf, BF
3
·Et
2
O, Sc(OTf)
3
and FeCl were screened, however, only inferior results could be
3
obtained under the mediation of these acids (entries 2–7). Next, a number of solvents were
examined. Notably, the employment of nonpolar solvent afforded the desired product in low to
moderate yields (entries 8 and 9), with CH
2
Cl shown to be the solvent of choice. In contrast, no
2
conversion was observed with polar solvents, such as THF, DMF and dioxane (entries 10–12),
which might be rationalized that the polar solvent can serve as strong proton acceptor to compete
for the acidic catalysts. Further investigation showed that there appears to be an obvious
stoichiometric effect associated with 2a: when the proportion of 2a increased from 1.0 equiv to
1.5 equiv, the yield improved to 71% (entries 13 and 14). Subsequently, the influence of catalyst
loading on the reaction was also investigated, and the yield increased to 78% when the catalyst
loading of TfOH was increased to 1.2 equiv (entry 15). However, further increase in the catalyst
o
loading decreased the yield (entry 16). In addition, lowering the reaction temperature to 0 C
resulted in a drop in the yield from 78% to 67%, even after prolonging the reaction time (entry
17).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
With the optimal conditions in hand, the generality of this protocol was investigated
(
Scheme 2). The scope of ynamides 2 was first examined using ynamide-nitrile 1a as its
reaction partner. When a variety of ynamides with oxazolidin-2-one were subjected to the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
optimal condition, the desired
δ-carbolines 3a–3h were furnished in moderate to good yields
a,b
Table 1. Condition Optimization of the Cycloaddition
entry
additive (equiv)
TfOH (1.0)
2a (equiv)
solvent
time(h)
yield (%)
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.5
1.5
1.5
1.5
CH
CH
CH
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
2
2
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
4.0
65
26
21
45
35
13
9
HBF
NHTf
TMSOTf (1.0)
Sc(OTf) (1.0)
4
·OEt
2
(1.0)
2
(1.0)
3
BF
3
·Et
2
O (1.0)
(1.0)
FeCl
3
TfOH (1.0)
TfOH (1.0)
TfOH (1.0)
TfOH (1.0)
TfOH (1.0)
TfOH (1.0)
TfOH (1.0)
TfOH (1.2)
TfOH (1.5)
TfOH (1.2)
DCE
53
19
NR
NR
trace
67
71
78
76
67
toluene
THF
1
1
1
1
0
1
2
3
DMF
dioxane
CH
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
14
15
16
c
1
7
a
Unless otherwise specified, reactions were conducted with 1a (0.1 mmol), 2a, additive and 20 mg 4Å MS in 1.0 ml of solvent at room
b
c
o
2
temperature under N atmosphere. Isolated yield. Temperature was 0 C.
within 0.5 hour. Afterwards, the ynamides incorporating sulfonyl groups were examined.
Remarkably, these substrates were better reactants, yielding the corresponding products at
higher levels within a shorter reaction time (1 min) compared with those of 2a–2h, which
might be ascribed to the higher reactivity of sulfonyl ynamides. When aryl ynamides were
employed as reactants, the electronic nature of the substituents (R1 group) had a trivial
ACS Paragon Plus Environment

Page 7 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
influence on the reaction, and both the electron-withdrawing and electron-donating groups
were well-tolerated, affording the corresponding products 3i–3n in moderate to good yields,
ranging from 69% to 96%. The 3-thienyl substituted ynamide 2o was also an ideal substrate,
which resulted in the desired product 3o in 90% yield. Delightedly, this protocol was
amenable to terminally unsubstituted ynamide 2p to deliver the desired product 3p in 76%
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
yield. Remarkably, the ynamides incorporating alkyl at the alkynyl terminus, such as n-Bu
and cyclopropyl, were also well tolerated during the smooth formation of the corresponding
products in 72% and 98 % yields, respectively (3q and 3s). A considerably lower yield was
obtained when the tert-butyl-substituted substrate 2r was subjected to the optimal conditions
probably due to the steric hindrance (3r).
also tolerable to afford the corresponding
ranging from 74% to 98%. Notably, the reaction of ynamide bearing an acid-sensitive
N-alkyl and
N-phenyl substituted ynamides were
δ-carbolins 3t–3y in high to excellent yields
functional group cyano also proceeded efficiently, producing the desired δ-carboline in 82%
yield (3z).
Next, various ynamide-nitriles 1 were also examined (Scheme 3). The ynamide-nitriles
terminally substituted with alkyl, and aryl or -aryl-substituted ynamides underwent [2+2+2]
N
cycloaddition smoothly to afford the desired annulation products 4b–4j within 1 min in
excellent yields including the bulkier 1-naphthyl-substituted ynamide (4g).
Heteroaromatic-substituted ynamides, such as 1h and 1i also served as ideal reactants,
producing 4h and 4i in 87% and 52% yields, respectively. Remarkably, when the terminally
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
unsubstituted ynamide 1k was employed as the substrate, the reaction also worked well to
produce the desired δ-carboline in 63% yield. Additionally, ynamides incorporating the
electron-donating and electron-withdrawing sulfonyl groups (e.g., Ts and Ns) were
compatible with this reaction, resulting in the desired products 4l–4m in excellent yields.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ynamides substituted with a methyl and a bromine atom on
this transformation, giving the expected -carboline in 91% and 97% yields (4n and 4o). In
particular, with -2-thienyl-substituted ynamide-nitrile 1p employed as a substrate, a
N-phenyl were also amenable to
δ
N
thieno[3',2':4,5]pyrrolo-[3,2-b]-pyridine derivative 4p was produced.
a,b,c
Scheme 2. Scope of the Reaction with Ynamides.
ACS Paragon Plus Environment

Page 9 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
aUnless otherwise specified, reactions were conducted with 1a (0.1 mmol), 2 (0.15 mmol), TfOH
2 2 2
(0.12 mmol) and 20 mg 4Å MS in 1.0 ml of CH Cl at room temperature under N atmosphere.
b
c
Isolated yield. These reactions were completed within 0.5 hour for ynamides (2a–2h).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The 4-azaindoline frame is a unique structural core widely existing in biologically
8
important natural alkaloid products and pharmaceutical molecules, such as
9
triazabenzo[cd]azulen-9-one PDE4 inhibitors. Despite its biological significance, only
10
sporadic examples were described concerning the synthesis of 4-azaindoline framework
and they usually suffered from multistep processes, harsh conditions and low yields. When
ynamide-nitrile 1q was subjected to this reaction with ynamide 2t as the reaction partner, the
desired product 4-azaindoline 5t was produced in 75% yield (Scheme 4). Both N-Phenyl- and
thienyl-substituted terminally ynamides were compatible with this reaction, affording the
corresponding 4-azaindoline derivatives (5v, 5w, 5x and 5o) in 52%–75% yields. Hence, this
cycloaddition provided a novel and straightforward approach to construct various substituted
4
-azaindoline derivatives with a notable degree of versatility.
a,b
Scheme 3. Scope of the Reaction with Ynamide-Nitriles.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
aUnless otherwise specified, reactions were conducted with 1 (0.1 mmol), 2t (0.15 mmol), TfOH
(
2 2 2
0.12 mmol) and 20 mg 4Å MS in 1.0 ml of CH Cl at room temperature under N atmosphere.
bIsolated yield.
a,b
Scheme 4. Scope of the Reaction with Ynamides.
aUnless otherwise specified, reactions were conducted with 1q (0.1 mmol), 2 (0.15 mmol), TfOH
2 2 2
(0.12 mmol) and 20 mg 4Å MS in 1.0 ml of CH Cl at room temperature under N atmosphere.
bIsolated yield.
ACS Paragon Plus Environment

Page 11 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Intriguingly, when ynamide-nitrile 1a was employed as the sole reactant, the
self-assembled cycloaddition product 6a was successfully obtained in 78% yield (Scheme 5)
Both electron-donating and electron-withdrawing groups on the phenyl substituted at the
alkynyl terminal were well tolerated. The desired -carboline 6b was furnished in 57% yield
by employing the substrate incorporating a methoxyl group, and the substrates carrying
electron- withdrawing groups (e.g. 4-CO Et, 4-CF , 4-F, 4-Cl), furnished the corresponding
.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
δ
2
3
products in yields 41%–75% (6c–6f). Additionally, the 2-thienyl-substituted ynamide was
also compatible with this self-assembled cycloaddition, resulting in the desired compound 6h
in moderate yield. Ynamides substituted with methyl or bromine on
N-phenyl were also
amenable to this transformation, giving the expected products (6n–6o) in 72% and 67%
yields, respectively. Instead, when
N-Ns protected ynamide was employed, the reaction
proceeded smoothly as well (6m).
a,b
Scheme 5. Scope of the Self-Reaction.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
aUnless otherwise specified, reactions were conducted with 1 (0.1 mmol), TfOH (0.12 mmol) and 20
b
mg 4Å MS in 1.0 ml of CH
2
Cl
2
at room temperature under N
2
atmosphere. Isolated yield.
To examine the scalability of this developed protocol, the synthesis of the δ-carboline 3w
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
in a gram-scale was performed under the optimal condition, and the product was furnished in
82% yield. Remarkably, the tosyl-protecting group on these products could be easily
removed using over-stoichiometric TBAF, For instance, δ-carboline 4j was transformed to
detosylated product 7 in 79% yield (Scheme 6).
Scheme 6. Gram Scale Preparation and Removal of Tosyl-Protecting Group.
To probe the competitive and mechanistic studies, control experiments were conducted as
shown in scheme 7. The propotion of 1a and 2v was 1.0 equiv, the mixtures of the desired
product 3v and self-assembled product 6a were observed in 73% and 8% yields. Probably
Due to the electron-withdrawing nature of the cyano group, the alkynyl moiety of 2v is more
electron-rich than that of 1a. Thus 2v would be more preferentially protonated by TfOH,
leading to the major product 3v.
Scheme 7. Control Experiments
ACS Paragon Plus Environment

Page 13 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
According to the above experimental results, a plausible mechanism leading to δ-carboline
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7c
is depicted in Scheme 8. Because of the electron-withdrawing nature of the cyano group,
the alkynyl moiety of 2v is more electron-rich than that of 1a. Thus 2v would be more
preferentially protonated by TfOH to furnish the keteniminium intermediate A in-situ, which
is then attacked by ynamide-nitrile 1a to afford the intermediate B. Subsequently, an
intramolecular cyclization of B Probably be triggered by the nucleophilicity of enamine,
furnishing the final product 3v. Similarly, ynamide-nitrile 1a is protonated to furnish the
intermediate C in the absence of another ynamide 2, followed by a nucleophilic attack by
another molecule of 1a to produce the intermediate D. Finally, an intramolecular cyclization
of D proceeds to yield the corresponding δ-carboline 6a.
Scheme 8. The Proposed Mechanism for [2+2+2] Cycloaddition
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Conclusion
In summary, we have developed a novel and highly efficient TfOH-mediated [2+2+2]
cycloaddition of ynamide-nitriles with ynamides, which provides a straightforward access to
polysubstituted δ-carboline and 4-azaindoline derivatives in excellent yields. This strategy
has the features of high regio- and chemoselectivity, metal-free condition, high yields and
efficiency (within 1 min) in addition to wide substrate scopes, offering the synthetic chemists
more flexibility for construction of the nitrogen-containing heterocycles. Further bioactivity
investigation of these δ-carboline and 4-azaindoline derivatives are currently ongoing and
will be reported in our future work.
EXPERIMENTAL SECTION
General Information. Unless otherwise mentioned, all reactions were performed in
flame-dried glassware under air. Solvents were distilled prior to use. Reagents were used as
ACS Paragon Plus Environment

Page 15 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
purchased from commercial available unless otherwise noted. Chromatographic separations
1
19
13
were performed using Kangbino 48-75 Å SiO . H, F and C NMR spectra were recorded
2
on Agilent Pro Pulse spectrometers using CDCl with TMS or residual solvent as standard
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
unless otherwise noted. Melting points were determined using a melting point apparatus and
were uncorrected/calibrated. TLC analysis was performed using Kangbino glass-backed
plates (60 Å, 250 μm) and visualized using UV and Iodine stains. Low-resolution mass
spectra were obtained using an Agilent 1100 series LS/MSD. High resolution mass spectra
for new compounds were recorded on a Thermo Fisher Exactive APCI-orbitrap spectrometer.
All spectral data obtained for new compounds are reported here.
General procedure.
11a
General Procedure 1 for the Synthesis of ynamides (2v).
To a solution of
phenylacetylene (1020.5 mg, 10.0 mmol, 1.0 equiv) in acetone (100 mL) was added NBS
1780.0 mg, 11.0 mmol, 1.1 equiv) and AgNO (169.9 mg, 1.0 mmol, 10 mol %). The
(
3
resulting solution was stirred under nitrogen at room temperature for 6 hours. After removing
excess acetone the reaction was quenched with water, and extracted with EtOAc three times,
dried over MgSO
a short silica column (petroleum ether) to obtain the bromoalkyne (1530.0 mg，85%).
To a dried flask was added -phenylmethanesulfonamide (513.0 mg, 3.0 mmol, 1.0 equiv),
CuSO ·5H O (375.0 mg, 1.5 mmol, 0.5 equiv), 1,10-phenanthroline (162.0 mg, 0.9 mmol, 30
4
, and concentrated under reduced pressure. The residue was eluted through
N
4
2
mol % equiv) and K
2
CO
3
(828.0 mg, 6.0 mol, 2.0 equiv), bromoalkyne (648.0 mg, 3.6 mol,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1.2 equiv) and this mixture was subsequently treated with anhydrous toluene (100 mL). The
o
flask was charged with nitrogen, and the solution was heated at 80 C overnight. After
completion, the crude reaction mixture was cooled to room temperature, filtered through
CeliteTM, and concentrated in vacuo. Purification of the crude residue using silica gel flash
column chromatography yielded the pure ynamide 2v (458.6 mg, 52%) as white solid.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1b
General Procedure 2 for the Synthesis of ynamides (2w). CuCl
0 mol %), 4-methyl- -phenylbenzenesulfonamide (2964.0 mg, 12.0 mmol, 4.0 equiv) and
Na CO (636.0 mg, 6.0 mmol, 2.0 equiv) were added to a three-necked round-bottomed flask.
2
(80.4 mg, 0.6 mmol,
2
N
2
3
The flask was purged with oxygen for 15 min and a solution of pyridine (474.0 mg, 6.0
mmol, 2.0 equiv) in dry toluene (0.2 M) was added. A balloon filled with oxygen was
connected to the flask and the stirred mixture was heated at 70 ºC. After 15 min, a solution of
phenylacetylene (306.2 mg, 3.0 mmol, 1.0 equiv) in anhydrous toluene (0.2 M) was added by
syringe pump over 4 h. The mixture was allowed to stir at 70 ºC for another 4 h and allowed
to cool to rt. The reaction mixture was filtered through a plug of silica gel, washed with ethyl
acetate and concentrated. The crude residue 2w (610.5 mg, 55%) was purified by flash
chromatography over silica gel.
1
1c
General Procedure 3 for the Synthesis of ynamide (1k).
-(2-cyanophenyl)methanesulfonamide (5.9 g, 30.0 mmol 1.0 equiv) in DMF (70 mL) was
added Cs CO 12.7 g, 39.0 mmol, 1.3 equiv). The solution was stirred at room temperature
To a solution of
N
2
3
(
for 30 min, then phenyl((trimethylsilyl)ethynyl)iodonium triflate (17.6 g, 39.0 mmol, 1.3
ACS Paragon Plus Environment

Page 17 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
equiv) in dichloromethane (30 mL) was added to the mixture and stirred until the reaction
was completed as monitored by TLC. The reaction mixture was quenched by water and
stirred for 30 min. The resulting mixture was extracted with CH
2
Cl , washed with water and
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
brine, and dried over anhydrous MgSO . The mixture was filtered and the solvent was
4
evaporated under the reduced pressure, then the residue was purified by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 8/1 to petroleum ether/
ethyl acetate = 6/1) to afford the desired product 1k (6.63 g，60%) as a white solid.
1
1c
General Procedure 4 for the Synthesis of ynamide (1a).
N-(2-cyanophenyl)-N-ethynyl-4-methylbenzenesulfonamide (2.2 g, 10.0 mmol, 1.0 equiv) in THF
40 mL) was cooled to -40 ºC and ZnBr (2.48 g, 11.0 mol, 1.1 equiv) in THF (20 mL) was added
The solution of
(
2
dropwise. After stirring at the same temperature for 20 min, LiHMDS (15.0 ml, 15.0 mmol, 1.5
equiv, 1M in THF) was added and stirred for another 20 min at -40 ℃. Then themixture of
Pd
2
(dba)
3
(457.5 mg, 0.5 mmol, 0.05 equiv), PPh (524 mg, 2.0 mmol, 0.2 equiv) and
3
iodobenzene (3.06 g, 15 mmol, 1.5 equiv) in THF (5 mL) was added dropwise. The reaction
mixture waswarmed up to room temperature and stirred for 24 h, then quenched by brine and
stirred for 30 min. The mixture was filtered over a celite pad, and extracted with ethyl acetate.
The combined organic layers were washed with water and brine, and dried over anhydrous
MgSO . The mixture was filtered and the solvent was evaporated under the reduced pressure, and
4
the residue was purified by column chromatography on silica gel to afford the desired product 1a
2.05 g, 69%).
(
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1c
General Procedure 5 for the Synthesis of ynamide (1r)
To a solution of
N-(2-cyanophenyl)-4-methylbenzenesulfonamide (816.0 mg, 3.0 mmol 1.0 equiv) in DMF (50
mL) was added Cs
2
CO (1271.4 mg, 3.9 mmol, 1.3 equiv). The solution was stirred at room
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
temperature for 30 min, then phenyl((trimethylsilyl)ethynyl)iodoniumtriflate (1755.0 mg, 3.9
mmol, 1.3 equiv) in dichloromethane (30 mL) was added to the mixture and stirred until the
reaction was completed as monitored by TLC. The reaction mixture was quenched by water and
stirred for 30 min. The resulting mixture was extracted with CH
2
Cl , washed with water and brine,
2
and dried over anhydrous MgSO . The mixture was filtered and the solvent was evaporated under
4
the reduced pressure, then the residue was purified by column chromatography on silica gel
eluent: petroleum ether/ethyl acetate = 3/1 topetroleum ether/dichloromethane = 1/1) to afford
the desired product 1r (666.0 mg, 75%).
General Procedure for the Synthesis of ynamide (1l).
(
1
1c
6
The solution of
N-(2-cyanophenyl)-N-ethynyl-4-methylbenzenesulfonamide (592.0 mg, 2.0 mmol, 1.0 equiv) in
THF (40 mL) was cooled to -40 ℃ and LiHMDS (3.0 ml, 3.0 mmol, 1.5 equiv, 1M in THF) was
added dropwise. After stirring at the same temperature for 20 min, ZnBr (495.0 mg, 2.2 mol, 1.1
2
equiv) in THF (20 mL)was added and stirred for another 20 min at -40 ℃. Then themixture of
Pd
2
(dba)
3
(91.5 mg, 0.1 mmol, 0.05 equiv), PPh (104.8 mg, 0.4 mmol, 0.2 equiv) and
3
iodobenzene (612.0 mg, 3.0 mmol, 1.5 equiv) in THF (5 mL) was added dropwise. The reaction
mixture waswarmed up to room temperature and stirred for 24 h, then quenched by brine and
stirred for 30 min. The mixture was filtered over a celite pad, and extracted with ethyl acetate.
ACS Paragon Plus Environment

Page 19 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The combined organic layers were washed with water and brine, and dried over anhydrous
MgSO . The mixture was filtered and the solvent was evaporated under the reduced pressure, and
4
the residue was purified by column chromatography on silica gel to afford the desired product 1l
498.5 mg, 67 %).
General Procedure The solution of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
1
1c
7
for the Synthesis of ynamide (1j).
N-(2-cyanophenyl)-N-ethynyl-4-methylbenzenesulfonamide (592.0 mg, 2.0 mmol, 1.0 equiv) in
o
THF (10 mL) was cooled to -40 C and LiHMDS (3.0 ml, 3.0 mmol, 1.5 equiv 1M in THF) was
added dropwise. After stirring at the same temperature for 1 h, iodomethane (0.5 ml, 8 mmol, 4.0
equiv) in THF (2 mL) was added. The temperature was slowly raised to –5 °C and then the
reaction mixture was allowed to warm up to room temperature and stirred for 24 h. Thereaction
mixture was quenched by brine and stirred for 30 min, then extracted with ethylacetate. The
combined organic layers were washed with water and brine, and dried overanhydrous Na
2
SO .
4
The solvent was evaporated under the reduced pressure and the residuewas purified by column
chromatography on silica gel to afford the product 1j (551.8 mg, 89%).
1
1a,11d
General Procedure 8 for the Synthesis of ynamide (2z).
argon, solution of triphenylphosphine (10.5g, 40.0 mmol,4.0 equiv) and
tetrabromomethane (6.6 g, 20.0 mmol, 2.0 equiv) in CH Cl (0.15 M) was stirred at 0 °C for
0 minutes. The 2-formylbenzonitrile (1.3 g, 10.0 mmol, 1.0 equiv) was added over a period
of five minutes, and the mixture as stirred at 0 °C for one hour. After addition of water, the
layers were separated, and the aqueous layer was extracted with CH Cl (three times). The
Under an atmosphere of
a
2
2
3
2
2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
combined organic layerswere dried over MgSO
4
and the solvent was removed under reduced
pressure. The crude product was dry-loaded on silica and subjected to flash chromatography.
To the vigorously stirred solution of the 1,1-dibromoethene (1.4 g, 5.0 mmol, 1.0 equiv) in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH
2
Cl
2
(25 mL) at 0 °C, BnEt Cl (1.0 g, 4.4 mmol, 0.88 equiv) was added. Subsequently, a
3
solution of KOH (230 mmol) in H O (10 mL) was added to the reaction mixture. After
2
stirring for 5 h at 0 °C, H O (20 mL) was added to the reaction mixture. The organic layer
2
was separated and the aqueous layer was extracted with CH
2
Cl (3 × 20 mL). The combined
2
organic layer was washed with brine and dried over MgSO . All volatiles were removed
4
under reduced pressure. The product was purified by silica gel flash column
chromatography.
To a dried flask was added
N-methylmethanesulfonamide (479.6 mg, 4.4 mmol, 1.2 equiv),
CuSO ·5H O (475.0 mg, 1.9 mmol, 0.5 equiv), 1,10-phenanthroline (198.0 mg, 1.1 mmol, 0.3
4
2
equiv) and K
2
CO (1021.2 mg, 7.4 mmol, 2.0 equiv), 2-(bromoethynyl)benzonitrile (758.5 mg,
3
3
.7 mmol, 1.0 equiv) and this mixture was subsequently treated with anhydrous toluene (100
mL) and the bromoalkyne. The flask was charged with nitrogen, and the solution was heated
at 80 °C overnight. After completion, the crude reaction mixture was cooled to room
temperature, filtered through CeliteTM, and concentrated in vacuo. Purification of the crude
residue using silica gel flash column chromatography yielded the pure product as white solid
2z (491.6 mg, 52%).
ACS Paragon Plus Environment

Page 21 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
General Procedure 9 for TfOH-Mediated [2+2+2] Cycloadditions of ynamide-nitrile with
ynamide. To a suspension of ynamide-nitrile 1 (0.15 mmol), another ynamide 2 (0.225 mmol)
and 4Å MS (20.0 mg) in dry CH
2
Cl (1.5 mL) was added TfOH (0.18 mmol) dropwise via a
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
syringe pump at room temperature under nitrogen atmosphere. The reaction was monitored by
TLC. when progress appeared to be completed within 1 min or 0.5 h at the same temperature, the
saturated sodium bicarbonate solution was added to the mixture and the resulting mixture was
extracted with CH
2
Cl
2
. The organic layers were washed with sat aq NaCl and dried over MgSO .
4
Filtration and concentration of the mixture in vacuo afforded the crude product that was purified
by flash silica gel column chromatography [gradient eluent: EtOAc in petroleum ether] to obtain
the corresponding products.
1
1c
General Procedure 10 for the removal of tosyl-protection group. To a solution of 4j (52.0
mg, 0.1 mmol) in THF (3 mL) was added tetrabutylammonium fluoride (0.5 mL, 1M in THF, 0.5
mmol). The mixture was refluxed for 1 h, and then quenched by water. Themixture was extracted
with dichloromethane and dried over anhydrous MgSO . The solvent was evaporated under the
4
reduced pressure and the residue was purified by column chromatography on silica gel to afford
the desired product 7 (28.9 mg, 79%).
Characterization of products.
N-(2-cyanophenyl)-N-(phenylethynyl)methanesulfonamide (1a)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Following the general procedure 4; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 8/1 to petroleum ether/ ethyl acetate = 6/1)
o
1
to afford the desired product 1a; white solid; mp: 81 – 83 C; yield: 69%; 2.05 g; H NMR (500
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
MHz, CDCl ) δ 7.84 – 7.65 (m, 3H), 7.60 – 7.45 (m, 3H), 7.34 – 7.27 (m, 3H), 3.46 (s, 3H); C
3
1
{ H} NMR (125 MHz, CDCl
3
) δ 140.5, 134.2, 134.1, 132.2, 130.0, 129.6, 128.8, 128.4, 121.7,
+
1
16.0, 112.1, 80.5, 71.8, 39.6; HRMS (APCI–orbitrap) m/z: calcd. for C16
97.0692, found 297.0689.
H
13
N
2
2
O S [M+H]
2
N-(2-cyanophenyl)-N-((4-methoxyphenyl)ethynyl)methanesulfonamide (1b)
Following the general procedure 4; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 8/1 to petroleum ether/ ethyl acetate = 6/1)
1
to afford the desired product 1b, pale yellow oil; yield: 82%; 268.1 mg; H NMR (500 MHz,
CDCl ) δ 7.76 (d, J = 7.7 Hz, 1H), 7.75 – 7.69 (m, 2H), 7.55 – 7.51 (m, 1H), 7.49 – 7.44 (m, 2H),
3
1
3
1
6
.86 (d, J = 8.9 Hz, 2H), 3.82 (s, 3H), 3.45 (s, 3H); C { H} NMR (125 MHz, CDCl ) δ 160.2,
3
140.7, 134.3, 134.1, 134.0, 130.0, 129.4, 116.1, 114.0, 113.5, 112.1, 79.3, 71.7, 55.3, 39.5;
+
HRMS (APCI–orbitrap) m/z: calcd. for C17
H
15
N
2
O
3
S [M+H] 327.0798, found 327.0792.
ethyl 4-((N-(2-cyanophenyl)methylsulfonamido)ethynyl)benzoate (1c)
Following the general procedure 4; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 8/1 to petroleum ether/ ethyl acetate = 6/1)
o
1
to afford the desired product 1c; pale yellow solid; mp: 93 – 95 C; yield: 73%; 269.4 mg; H
ACS Paragon Plus Environment

Page 23 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
NMR (500 MHz, CDCl
3
) δ 7.98 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 7.6 Hz, 1H), 7.75 – 7.67 (m, 2H),
7
3
1
.55 (td, J = 6.9 Hz, J = 1.5 Hz, 1H), 7.51 (d, J = 8.3 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.45 (s,
1
3
1
H), 1.38 (t, J = 7.1 Hz, 3H); C { H} NMR (125 MHz, CDCl ) δ 165.9, 140.1, 134.3, 134.1,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
31.4, 130.1, 130.0, 129.8, 129.5, 126.4, 115.9, 112.1, 83.2, 71.4, 61.2, 39.8, 14.3; HRMS
+
(APCI–orbitrap) m/z: calcd. for C19
H
17
N
2
O
4
S [M+H] 369.0904, found 369.0899.
N-(2-cyanophenyl)-N-((4-(trifluoromethyl)phenyl)ethynyl)methanesulfonamide (1d)
Following the general procedure 4; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 8/1 to petroleum ether/ ethyl acetate = 6/1)
1
to afford the desired product 1d; pale yellow oil; yield: 77%; 281.1 mg; H NMR (500 MHz,
CDCl ) δ 7.80 (dd, J = 7.8, 1.6 Hz, 1H), 7.77 – 7.70 (M, 2H), 7.61 – 7.55 (m, 5H), 3.46 (s, 3H);
3
13
1
C { H} NMR (125 MHz, CDCl ) δ 140.1, 134.3, 134.1, 131.9, 130.21(q, J = 32.8), 130.16,
3
129.8, 125.7(q, J = 1.3), 125.3(q, J = 3.8 Hz), 123.8(q, J = 270.8Hz), 115.9, 112.0, 82.7, 70.8,
1
9
3
9.9; F NMR (470 MHz, CDCl ) δ -62.86 (3F, S); HRMS (APCI–orbitrap) m/z: calcd. for
3
+
C
17
H
12
F
3
N
2
O
2
S [M+H] 365.0566, found 365.0561.
N-((4-chlorophenyl)ethynyl)-N-(2-cyanophenyl)methanesulfonamide (1e)
Following the general procedure 4; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 8/1 to petroleum ether/ ethyl acetate = 6/1)
1
to afford the desired product 1e; pale yellow oil; yield: 65%; 430.3 mg; H NMR (500 MHz,
CDCl ) δ 7.78 (d, J = 8.0 Hz, 1H), 7.75 – 7.68 (m, 2H), 7.57 – 7.52 (m, 1H), 7.45 – 7.40 (m, 2H),
3
1
3
1
7.33 – 7.25 (m, 3H), 3.45 (s, 3H); C { H} NMR (125 MHz, CDCl ) δ 140.3, 134.8, 134.2,
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
34.1, 133.4, 130.1, 129.7, 128.7, 120.2, 116.0, 112.0, 81.3, 70.8, 39.7; HRMS (APCI–orbitrap)
+
m/z: calcd. for C16
H12ClN
2
O
2
S [M+H] 331.0303, found 331.0298.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N-(2-cyanophenyl)-N-((4-fluorophenyl)ethynyl)methanesulfonamide (1f)
Following the general procedure 4; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 8/1 to petroleum ether/ ethyl acetate = 6/1)
1
to afford the desired product 1f; pale yellow oil; yield: 86%; 541.8 mg; H NMR (500 MHz,
CDCl ) δ 7.78 (dd, J = 7.8, 1.3 Hz, 1H), 7.75 – 7.68 (m, 2H), 7.54 (td, J = 7.4, 1.7 Hz, 1H), 7.52
3
1
3
1
–
7.47 (m, 2H), 7.05 – 6.99(m, 2H), 3.44 (s, 3H); C { H} NMR (125 MHz, CDCl ) δ 162.9 (d, J
3
=
250.4), 140.4, 134.4 (d, J = 8.6), 134.2, 134.1, 130.1, 129.6, 117.7 (d, J = 3.4), 116.0, 115.7 (d,
19
J = 22.3), 112.0, 80.1, 70.8, 39.6; F NMR (470 MHz, CDCl
3
) δ -109.9 (ddd, J = 13.8, J =8.5, J
+
=5.2); HRMS (APCI–orbitrap) m/z: calcd. for C16
H12FN
2
O
2
S [M+H] 315.0598, found 315.0594.
N-(2-cyanophenyl)-N-(naphthalen-1-ylethynyl)methanesulfonamide (1g)
Following the general procedure 4; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 8/1 to petroleum ether/ ethyl acetate = 6/1)
1
to afford the desired product 1g; pale yellow oil; yield: 51%; 353.9 mg; H NMR (500 MHz,
CDCl ) δ 8.38 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.1, 4.3 Hz, 2H), 7.82 – 7.78 (m, 2H), 7.77 – 7.72
3
1
3
1
(m, 2H), 7.64 – 7.59 (m, 1H), 7.57 – 7.52 (m, 2H), 7.46 – 7.42 (m, 1H), 3.53 (s, 3H); C { H}
NMR (125 MHz, CDCl
3
) δ 140.5, 134.2, 134.1, 133.5, 133.2, 131.1, 130.1, 129.7, 129.2, 128.3,
ACS Paragon Plus Environment

Page 25 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
27.1, 126.5, 126.1, 125.2, 119.4, 116.2, 112.2, 85.0, 70.2, 39.8; HRMS (APCI–orbitrap) m/z:
+
calcd. for C20
H
15
N
2
O
2
S [M+H] 347.0849, found 347.0844.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N-(2-cyanophenyl)-N-(thiophen-3-ylethynyl)methanesulfonamide (1h)
Following the general procedure 4; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 8/1 to petroleum ether/ ethyl acetate = 6/1)
1
to afford the desired product 1h; pale yellow oil; yield: 81%; 490.8 mg; H NMR (500 MHz,
CDCl ) δ 7.76 (d, J = 7.9 Hz, 1H), 7.73 – 7.67 (m, 2H), 7.57 – 7.50 (m, 2H), 7.28 (dd, J = 5.0, 3.1
3
1
3
1
Hz, 1H), 7.17 (dd, J = 5.1, 1.2 Hz, 1H), 3.44 (s, 3H); C { H} NMR (125 MHz, CDCl ) δ 140.5,
3
134.2, 134.1, 130.7, 130.4, 130.0, 129.6, 125.5, 120.5, 116.0, 112.1, 80.1, 66.9, 39.6; HRMS
+
(APCI–orbitrap) m/z: calcd. for C14
H
11
N
2
O
2
S [M+H] 303.0257, found 303.0253.
2
1
1c
N-(2-cyanophenyl)-4-methyl-N-(pyridin-3-ylethynyl)benzenesulfonamide (1i)
Following the general procedure 6; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 4/1 to petroleum ether/ ethyl acetate = 2/1)
1
to afford the desired product 1i; pale yellow solid; yield: 68%; 499.8 mg; H NMR (500 MHz,
CDCl ) δ 8.62 (s, 1H), 8.51(d, J = 3.5, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.72 – 7.63 (m, 3H), 7.52 (t,
3
1
3
1
J = 8.6 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.23 (dd, J = 7.6, 5.0 Hz, 1H), 2.48 (s, 3H); C { H}
NMR (125 MHz, CDCl ) δ 152.4, 148.7, 146.2, 140.0, 138.8, 134.3, 133.7, 132.6, 130.0, 129.7,
3
129.6, 128.6, 123.0, 119.4, 115.1, 112.7, 84.4, 68.3, 21.8.
1
1c
N-(2-cyanophenyl)-4-methyl-N-(prop-1-yn-1-yl)benzenesulfonamide (1j)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Following the general procedure 7; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 8/1 to petroleum ether/ ethyl acetate = 6/1)
1
to afford the desired product 1j; white solid; yield: 89%; 551.8 mg; H NMR (500 MHz, CDCl
3
)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
δ 7.70 (d, J = 7.7 Hz, 2H), 7.67 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.46 (t, J = 7.7 Hz,
1
3
1
1H), 7.40 – 7.32 (m, 3H), 2.47 (s, 3H), 1.91 (s, 3H); C { H} NMR (125 MHz, CDCl ) δ 145.5,
3
140.9, 134.1, 133.5, 132.9, 129.8, 129.4, 129.1, 128.6, 115.3, 112.9, 71.7, 67.0, 21.8, 3.2.
N-(2-cyanophenyl)-N-ethynylmethanesulfonamide (1k)
Following the general procedure 3; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 8/1 to petroleum ether/ ethyl acetate = 6/1)
o
1
to afford the desired product 1k; white solid; mp: 99 – 101 C; yield: 60%; 6.63 g; H NMR
(
500 MHz, CDCl ) δ 7.77 (dd, J = 7.9, 1.3 Hz, 1H), 7.72 (td, J = 7.8, 1.5 Hz, 1H), 7.67 – 7.63 (m,
3
1
3
1
1
H), 7.55 (td, J = 7.7, 1.1 Hz, 1H), 3.43 (s, 3H), 3.05 (s, 1H); C { H} NMR (125 MHz, CDCl )
3
δ 139.7, 134.2, 134.0, 129.9, 129.8, 115.9, 112.3, 74.3, 60.8, 39.7; HRMS (APCI–orbitrap) m/z:
+
calcd. for C10
H
9
N
2
O
2
S [M+H] 221.0379, found 221.0377.
1
1c
N-(2-cyanophenyl)-4-methyl-N-(phenylethynyl)benzenesulfonamide (1l)
Following the general procedure 6; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 8/1 to petroleum ether/ ethyl acetate = 6/1)
1
to afford the desired product 1l; white solid; yield: 67%; 498.5 mg; H NMR (500 MHz, CDCl
3
)
δ 7.78 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.54 – 7.47 (m, 2H),
ACS Paragon Plus Environment

Page 27 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
3
1
7
.44 – 7.40 (m, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.34 – 7.28 (m, 3H), 2.49 (s, 3H); C { H} NMR
(
125 MHz, CDCl ) δ 145.9, 140.5, 134.2, 133.6, 132.7, 132.0, 129.9, 129.7, 129.3, 128.7, 128.5,
3
128.3, 122.0, 115.2, 112.8, 81.5, 71.3, 21.8.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N-(2-cyanophenyl)-4-nitro-N-(phenylethynyl)benzenesulfonamide (1m)
Following the general procedure 6; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 8/1 to petroleum ether/ ethyl acetate = 6/1)
o
1
to afford the desired product 1m; pale yellow solid; mp: 93 – 95 C; yield: 73%; 589.8 mg; H
NMR (500 MHz, CDCl ) δ 8.46 – 8.41 (m, 2H), 8.13 – 8.08 (m, 2H), 7.75 – 7.69 (m, 2H), 7.61 –
3
1
3
1
7
1
1
4
.55 (m, 2H), 7.46 – 7.43 (m, 2H), 7.37 – 7.30 (m, 3H); C { H} NMR (125 MHz, CDCl ) δ
3
51.2, 141.2, 139.8, 134.4, 134.0, 132.3, 130.1, 130.0, 129.8, 129.1, 128.5, 124.6, 121.2, 114.8,
+
12.3, 80.1, 72.1; HRMS (APCI–orbitrap) m/z: calcd. for C21
04.0696.
H
14
N
3
O
4
S [M+H] 404.0670, found
N-(2-cyano-4-methylphenyl)-N-(phenylethynyl)methanesulfonamide (1n)
ollowing the general procedure 4; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 6/1 to petroleum ether/ ethyl acetate = 4/1)
1
to afford the desired product 1n; pale yellow oil; yield: 67%; 416.7 mg; H NMR (500 MHz,
CDCl ) δ 7.58 – 7.54 (m, 2H), 7.52 – 7.46 (m, 3H), 7.34 – 7.30 (d, J = 5.2 Hz, 3H), 3.42 (s, 3H),
3
1
3
1
2.43 (s, 3H); C { H} NMR (125 MHz, CDCl ) δ 140.5, 137.9, 134.9, 134.3, 132.1, 129.7, 128.7,
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 83
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
28.4, 121.8, 116.2, 111.8, 80.8, 71.5, 39.5, 20.9; HRMS (APCI–orbitrap) m/z: calcd. for
+
C
17
H
15
N
2
O
2
S [M+H] 311.0849, found 311.0845.
N-(4-bromo-2-cyanophenyl)-N-(phenylethynyl)methanesulfonamide (1o)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Following the general procedure 4; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 6/1 to petroleum ether/ ethyl acetate = 4/1)
1
to afford the desired product 1o; pale yellow oil; yield: 74%; 553.5 mg; H NMR (500 MHz,
CDCl ) δ 7.88 (d, J = 2.3 Hz, 1H), 7.83 (dd, J = 8.7, 2.3 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.52 –
3
1
3
1
7.48 (m, 2H), 7.36 – 7.31 (m, 3H), 3.45 (s, 3H); C { H} NMR (125 MHz, CDCl ) δ 139.6,
3
137.4, 136.5, 132.2, 131.3, 128.9, 128.4, 123.2, 121.4, 114.7, 113.7, 80.0, 72.1, 39.7; HRMS
+
(APCI–orbitrap) m/z: calcd. for C16
H12BrN
2
O
2
S [M+H] 374.9797, found 374.9792.
N-(3-cyanothiophen-2-yl)-4-methyl-N-(phenylethynyl)benzenesulfonamide (1p)
Following the general procedure 6; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 6/1 to petroleum ether/ ethyl acetate = 4/1)
o
1
to afford the desired product 1p; pale yellow solid; mp: 274 – 276 C; yield: 56%; 449.1 mg; H
NMR (500 MHz, CDCl ) δ 7.79 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 7.2 Hz, 2H), 7.40 (d, J = 7.9 Hz,
3
1
3
1
2H), 7.35 – 7.29 (m, 4H), 7.10 (d, J = 5.7 Hz, 1H), 2.49 (s, 3H); C { H} NMR (125 MHz,
CDCl
3
) δ 148.0, 146.4, 132.1, 131.7, 130.1, 128.74, 128.65, 128.3, 127.5, 125.8, 121.6, 112.1,
+
108.7, 80.7, 71.5, 21.9; HRMS (APCI–orbitrap) m/z: calcd. for C20
H
14
N
2
O
2
2
S Na [M+Na]
401.0394, found 401.0385.
ACS Paragon Plus Environment

Page 29 of 83
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N-(2-cyanoethyl)-4-methyl-N-(phenylethynyl)benzenesulfonamide (1q)
Following the general procedure 2; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 6/1 to petroleum ether/ ethyl acetate = 4/1)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
to afford the desired product 1q; white solid; mp: 94 – 96 C; yield: 88%; 570.0 mg; H NMR
(500 MHz, CDCl ) δ 7.86 (d, J = 8.3 Hz, 2H), 7.42 – 7.37 (m, 4H), 7.34 – 7.30 (m, 3H), 3.75 (t, J
3
1
3
1
=
7.2 Hz, 2H), 2.79 (t, J = 7.2 Hz, 2H), 2.48 (s, 3H); C { H} NMR (125 MHz, CDCl ) δ 145.5,
3
133.9, 131.6, 130.1, 128.39, 128.38, 127.8, 122.0, 116.4, 80.6, 71.9, 47.3, 21.7, 17.5; HRMS
+
(APCI–orbitrap) m/z: calcd. for C18
H
17
N
2
O
2
S [M+H] 325,1005, found 325.1004.
1
1c
N-(2-cyanophenyl)-N-ethynyl-4-methylbenzenesulfonamide (1r)
Following the general procedure 5; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 6/1 to petroleum ether/ ethyl acetate = 4/1)
1
to afford the desired product 1r; white solid; yield: 77%; 455.8 mg; H NMR (500 MHz,
CDCl ) δ 7.76 – 7.71 (m, 2H), 7.69 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.51 (t, J = 7.7
3
13
1
Hz, 1H), 7.43 – 7.35 (m, 3H), 2.90 (s, 1H), 2.48 (s, 3H); C { H} NMR (125 MHz, CDCl
3
) δ
146.0, 139.8, 134.2, 133.7, 132.7, 130.0, 129.6, 129.5, 128.7, 115.1, 113.0, 75.0, 60.0, 21.8.
1
1e
3-(phenylethynyl)oxazolidin-2-one (2a)
Following the general procedure 2; the residue was purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 2/1 to petroleum ether/ ethyl acetate = 1/1)
o
1
to afford the desired product 2a; white solid; mp: 84 – 85 C; yield: 62%; 260.4 mg; H NMR
ACS Paragon Plus Environment