A Robust One-Step Approach to Ynamides

Article abstract of DOI:10.1021/acs.orglett.7b03665

A robust one-step synthetic strategy for ynamide with cheap and easily available stock chemicals vinyl dichlorides and electron deficient amides as the starting material is described. In the absence of transition-metal catalyst, the reaction proceeds under mild reaction conditions in open air and thus rendering a convenient operation. This strategy is not only suitable for both terminal and internal ynamide synthesis but also amenable for large-scale preparation. Broad substrate scopes with respect to vinyl dichloride as well as electron-deficient amide were observed.

Full text of DOI:10.1021/acs.orglett.7b03665

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Robust One-Step Approach to Ynamides
Yongliang Tu,†,§ Xianzhu Zeng,†,§ Hui Wang,† and Junfeng Zhao*,†,‡
†Key Laboratory of Chemical Biology of Jiangxi Province, College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang 330022, Jiangxi, P. R. China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A robust one-step synthetic strategy for
ynamide with cheap and easily available stock chemicals
vinyl dichlorides and electron deficient amides as the starting
material is described. In the absence of transition-metal
catalyst, the reaction proceeds under mild reaction conditions
in open air and thus rendering a convenient operation. This strategy is not only suitable for both terminal and internal ynamide
synthesis but also amenable for large-scale preparation. Broad substrate scopes with respect to vinyl dichloride as well as
electron-deficient amide were observed.
hypervalent iodine reagents are difficult to prepare, and
expensive and strong basic lithium reagents are used. To
address such disadvantages, alkyne reagents including alkynyl
bromides,8 alkynes,9 copper acetylides,10 potassium alkynyltri-
fluoroborates,11 propiolic acid derivatives12 (Scheme 1, eq 2),
and vinyl dibromides (Scheme 1, eq 3)13 have been employed
as the alkyne component for ynamide synthesis via copper-
catalyzed cross-coupling reactions. However, all of these
strategies are limited to internal ynamides, and copper-
catalyzed homocoupling of the alkyne component is a
notorious issue for these strategies. A highly efficient synthetic
strategy for ynamides, especially for terminal ynamides,14 is still
a great challenge for organic chemists. Herein, we report a
robust transition-metal-free approach to both terminal and
internal ynamides from easily available stock chemicals in one
simple operation (Scheme 1, eq 4).
Ynamine could be synthesized via the nucleophilic
substitution of alkynyl chloride with amine.15 It is attractive
but challenging to apply this strategy for ynamide synthesis
because of the low nucleophilicity of amide. On the other
hand, vinyl halides are cheap and easily available alkyne
surrogates.16 We hypothesized that it would be possible to use
vinyl dichlorides, which could release alkynyl halides in situ
under basic reaction conditions, as the masked alkyne halide. If
successful, a one-step synthesis of terminal as well as internal
ynamides would be expected (Scheme 1, eq 4).
namides, bearing an additional electron-withdrawing
Ygroup on the nitrogen atom, display many advantages
such as thermal stability, synthetic accessibility, and easy
handling over their ynamine congeners due to the optimal
balance between stability and reactivity. However, ynamides
have not received much attention since they were introduced
in 1972 by Viehe,1 which might be attributed to their
insufficient synthetic availability. Decades later, Hsung,2
Evano,3 and others4 reinvestigated ynamides and facilitated
the renaissance of ynamide chemistry. Thanks to these efforts,
ynamides have evolved as versatile functionalities finding wide
use in an increasing array of organic transformations.
Meanwhile, a series of synthetic strategies have been developed
for various ynamides. Elimination of haloenamides is the
earliest and reliable approach to ynamides.1,5 However, tedious
multisynthetic steps are required for haloenamides.6 The first
one-step synthesis of ynamide was accomplished by employing
the direct coupling of electron-deficient amides with
alkynyliodonium salts (Scheme 1, eq 1).7 However, the
Scheme 1. One-Step Strategy for Ynamide Synthesis
The cheap, commercially available, and nonlachrymatory
1,1-dichloroethylene was chosen as a model substrate to test
the validity of our proposal. Preliminary study disclosed that
this proposal was feasible, but the reaction efficiency was
sensitive to the reaction conditions (for details of reaction
condition optimization, see Table S1). To our delight, the
terminal ynamide 3a could be obtained in 96% yield from 1,1-
dichloro-ethylene and N,4-dimethylbenzenesulfonamide with
Received: November 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03665
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
NaH as the base. With the optimized reaction conditions in
hand, the substrate scope of the transition-metal-free, one-step
terminal ynamide synthetic strategy was examined. As shown
in Scheme 2, a broad range of N-alkylsulfonamides proceeded
the standard reaction conditions of terminal ynamide.
Interestingly, excellent yield could be obtained with slight
modification of the reaction conditions by replacing NaH with
Cs2CO3 as the base. The substrate scope with respect to amide
moiety was investigated, and the results are summarized in
Scheme 3. Various alkyl sulfonamides reacted smoothly to
a
Scheme 2. Substrate Scope for the Terminal Ynamides
a
Scheme 3. Substrate Scope for Internal Ynamides
a
Reaction conditions: Unless otherwise specified, the reactions were
carried out with 1 (0.2 mmol), 2 (0.4 mmol), and NaH (5.0 equiv) in
b
c
DMSO (1.0 mL) at 70 °C. 10 mmol scale. 100 °C.
a
smoothly to give the target terminal ynamides in good to
excellent yields. Terminal ynamides derived from aniline
sulfonamides, difficult substrates for other ynamide synthetic
methodologies, could also be prepared efficiently with 1,1-
dichloroethylene as the alkyne surrogate (3f−m). The
presence of a weak electron-donating group (3g−j) on the
phenyl ring of aniline sulfonamides has little effect on the
reaction efficiency. However, strong electron-donating (3k)
and -withdrawing groups (3l, 3m) have some deleterious
effects on the reaction efficacy. Oxazolidinone demonstrated to
be viable substrate for this transformation (3o). It is noted that
N-alkynylation of aromatic azacycles such as indole and
carbazole could also be accomplished to give terminal
ynamines in excellent yields (3p−r). Additionally, the
biynamide could be synthesized efficiently by this method
(3s).
Reaction conditions: Unless otherwise specified, the reactions were
carried out with 1 (0.2 mmol), 4 (0.4 mmol), and Cs2CO3 (5.0 equiv)
in DMSO (1.0 mL) at 70 °C. 10 mmol scale. 100 °C.
b
c
furnish the internal ynamides in good to excellent yields
(Scheme 4). The steric hindrance of the alkyl group was
tolerated, albeit longer reaction times were required for bulky
sulfonamides (5f−k). The aniline sulfonamide was a poor
substrate for internal ynamides synthesis (5l). Other N-
methylbenzenesulfonamides with electron-donating and -with-
drawing groups on the phenyl group were compatible (5m−p).
Acyclic carbonates as well as oxazolidinones were valid
substrate for this reaction, although a higher reaction
temperature was required to obtain good yields (5q−s).
Similar to that of terminal ynamines, the alkynylation aromatic
azacycles proceeded smoothly to furnish the internal ynamines
in excellent yields (5t−w). The potential application of this
strategy was further showcased by the synthesis of a biynamide
5x in excellent yield.
With the success on the synthesis of terminal ynamides, we
went further for the synthesis of internal ynamides with (2,2-
dichloroethenyl)benzene 4 as the model substrate. However,
only moderate yield of internal ynamide was obtained under
B
DOI: 10.1021/acs.orglett.7b03665
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
contrary, β-position addition of nitrogen nucleophile and
protonation would produce β-chloroenamide VI (path b). The
substituent R2 plays an important role for the selection
between path a and path b. The ynamide was obtained when
R2 is an aryl group which can stabilize the minus charge of
intermediate II. On the contrary, path b is preferred to give β-
chloroenamide when R2 is an alkyl group.
Scheme 4. . Substrate Scope for Internal Ynamides
In conclusion, we have developed a robust transition-metal-
free synthetic method for ynamides with nonlachrymatory and
inexpensive vinyl dichloride as the alkyne surrogate. Both
internal and terminal ynamides could be synthesized efficiently
via such one-step strategy with commercially available or easily
prepared chemicals as the starting material. A broad range of
functional groups and substituents are compatible for both
coupling partners. No transition-metal catalyst was used, thus
avoiding the homocoupling side reaction of alkyne reagents
encountered in other copper-catalyzed synthetic strategies.
Undoubtedly, this highly efficient strategy will find broad
application in ynamide synthesis and facilitate the application
of ynamide chemistry in other research fields.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03665.
Experimental procedures, compounds characterization
data, and NMR spectra (PDF)
a
Reaction conditions: Unless otherwise specified, the reactions were
carried out with 1a (0.2 mmol), 6 (0.4 mmol), and Cs2CO3 (5.0
equiv) in DMSO (1.0 mL) at 70 °C.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhaojf@jxnu.edu.cn.
ORCID
Next, the generality of the reaction regarding to vinyl
dichlorides was also investigated. A variety of 2-arylvinyl
dichlorides reacted smoothly with N,4-dimethylbenzenesulfo-
namide to afford the corresponding internal ynamides in good
to excellent yields (7a−o). Both the electron-donating and
electron-withdrawing groups were compatible on the phenyl
ring of 2-arylvinyl dichlorides. Heterocyclic aryl groups such as
thiophene and benzo[b]thiophene were also tolerated (7j−l).
However, no target ynamide but β-chloroenamides 7p and 7q
were obtained when 2-alkylvinyl dichlorides 6p and 6q were
employed as the substrates.
A plausible reaction mechansim was proposed to rationalize
the experimental outcome (Scheme 5). The alkynyl chloride
intermediate II would be formed in situ upon elimination of
HCl under the basic reaction conditions. The direct α-position
nucleophilic substitution of alkynyl chloride II by nitrogen
nucleophile would furnish the ynamide IV (path a). On the
Junfeng Zhao: 0000-0003-4843-4871
Author Contributions
§T.Y. and Z.X. contributed equally
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The National Natural Science Foundation of China
(21462023, 21778025) and the Education Department of
Jiangxi Province (150297) are acknowledged for support of
this research.
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