Regio- and Stereo-Selective Intermolecular Hydroamidation of Ynamides: An Approach to (Z)-Ethene-1,2-Diamides

Article abstract of DOI:10.1021/acs.orglett.8b02409

An efficient intermolecular trans-selective β-hydroamidation of ynamides to furnish a series of (Z)-ethene-1,2-diamide derivatives with excellent regio- and stereo-selectivities is described. The trans-β-addition reactions have been illustrated for a wide range of substrates and proceeded under basic reaction conditions using readily available materials in the absence of a transition-metal catalyst. The synthetic approach to these novel (Z)-ethene-1,2-diamide derivatives paves the way for further exploration of their synthetic application.

Full text of DOI:10.1021/acs.orglett.8b02409

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Regio- and Stereo-Selective Intermolecular Hydroamidation of
Ynamides: An Approach to (Z)‑Ethene-1,2-Diamides
Zhiyuan Peng, Zhenming Zhang, Yongliang Tu, Xianzhu Zeng, and Junfeng Zhao*
Key Laboratory of Chemical Biology of Jiangxi Province, College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang, 330022 Jiangxi, People’s Republic of China
*
S Supporting Information
ABSTRACT: An efficient intermolecular trans-selective β-
hydroamidation of ynamides to furnish a series of (Z)-ethene-
1
,2-diamide derivatives with excellent regio- and stereo-
selectivities is described. The trans-β-addition reactions have
been illustrated for a wide range of substrates and proceeded
under basic reaction conditions using readily available
materials in the absence of a transition-metal catalyst. The
synthetic approach to these novel (Z)-ethene-1,2-diamide
derivatives paves the way for further exploration of their synthetic application.
1
,2-Endiamide unit is a unique moiety found in nature cyclic
Hydroamidation reaction of alkyne has emerged as a
1
peptides and biologically active compounds. For example,
powerful tool for the construction of enamide derivatives
with 100% atom economy and has received considerable
2
3
4
Callyaerin A, Viomycin, and Capreomycin containing 1,2-
endiamide unit have been used widely in antituberculosis
treatments (see Figure 1). Compared with the extensive
9
attention in the past decades. Ynamides, as special alkynes
containing a nitrogen atom bearing an electron-withdrawing
10
group directly attached to the triple bond, have been used as
useful and versatile building blocks for the synthesis of a series
11
of unknown nitrogen-containing molecules. For instance, a
one-pot alkynylation/intramolecular hydroamidations were
reported to yield tetrahydropyrazine derivatives via a β-
1
2
addition of the ynamide intermediates by Urabe’s group
1
3
and Cossy’s group, independently. Theoretically, the
intermolecular hydroamidation of ynamides would offer an
atom-economic approach to 1,2-endiamides. In 2014, Dodd
reported an efficient access to N-functionalized indoles via an
intermolecular trans-selective β-addition of ynamides with
14
indole derivatives as the nucleophiles. However, the substrate
scope of nucleophiles is limited to indoles and other NH-
containing heteroaromatics and, to the best of our knowledge,
the intermolecular hydroamidation of ynamides with simple
amides as the nucleophile has been kept unexplored. Recently,
our group disclosed that ynamides could be used as
racemization-free coupling reagents to facilitate amide and
Figure 1. Examples of 1,2-endiamide-containing natural cyclic
peptides.
5
studies of the synthesis of saturated 1,2-diamines, only a few
synthetic methods are available for the construction of 1,2-
endiamine derivatives, partially because of their poor stability.
15
peptide bond formation with cis-selective α-hydroacylox-
ylation of carboxylic acids to ynamides under acidic reaction
conditions as a key feature. Later, we developed a novel
synthetic strategy for ynamides from commercially available
1
2
For example, a method for the synthesis of N ,N ,1,2-
tetraphenylethene-1,2-diamine under harsh reaction conditions
6
has been reported. In this regard, 1,2-endiamides are useful
16
7
starting materials. Herein, we reported an intermolecular
surrogates, because of their increased stability. However,
trans-selective β-addition of simple amides to ynamides to
afford a broad range of (Z)-ethene-1,2-diamides with excellent
regio- and stereo-selectivities under basic reaction conditions.
general synthetic approaches to (Z)-ethene-1,2-diamide
derivatives, which would have many potential applications in
8
organic and peptide chemistry, are not available yet. Hence,
the development of an efficient strategy for the synthesis of
(
Z)-ethene-1,2-diamide derivatives from readily available
Received: July 29, 2018
starting materials is highly desirable.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02409
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
An initial attempt disclosed that the intermolecular hydro-
amidation reaction of ynamide (1a) and N,4-dimethylbenze-
nesulfonamide (2a) could indeed afford the target product
Scheme 1. Substrate Scope of Secondary Amides
(
Z)-ethene-1,2-diamide 3a with excellent regio- and stereo-
selectivity (Z:E > 99:1) in 93% yield with NaH as a base (see
Table 1, entry 1). The structure of 3a was further confirmed by
a
Table 1. Optimization of the Reaction Conditions
b
entry
base
NaH
BuONa
solvent
temperature (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
50
50
50
50
50
rt
14
12
18
8
20
24
24
48
24
24
24
93
61
20
95
60
96
79
68
99
89
91
t
K CO3
2
Cs CO3
2
NaOH
Cs CO3
2
Cs CO3
2
rt
rt
rt
rt
Cs CO3
2
THF
c
9
0
1
Cs CO
2
DMSO
DMSO
DMSO
3
d
1
1
Cs CO3
2
,
ce
Cs CO3
2
rt
a
Reaction conditions: unless otherwise specified, the reaction was
performed with 1a (0.2 mmol), 2a (0.4 mmol), and base (0.4 mmol)
b
in solvent (1.0 mL). Isolated yields. Z:E > 99:1 (determined by
1
c
d
crude H NMR). Cs CO (0.2 mmol) was used. Cs CO (0.1
2
3
2
3
e
mmol) was used. 2a (0.2 mmol) was used.
X-ray crystallography (see the Supporting Information for
details). In order to make this reaction as a general approach to
(
Z)-ethene-1,2-diamide derivatives, further optimization of the
reaction conditions was performed and the representative
results are summarized in Table 1. Base, temperature, and
solvent used in this reaction have remarkable effects on the
reaction efficiency. Evaluation of the base disclosed that
Cs CO offered the best result (Table 1, entries 1−5).
2
3
Decreasing the reaction temperature has a beneficial effect
on the reaction efficiency (Table 1, entry 6). Investigations on
the solvents revealed that diemthylsulfoxide (DMSO) was the
optimal choice (Table 1, entries 7 and 8). Screening of the
loading of base identified that 1.0 equiv of Cs CO lead to (Z)-
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol) and Cs CO (0.2
2
3
mmol) in DMSO (1.0 mL) at room temperature (rt). Isolated yields.
Z:E > 99:1 (determined by crude H NMR). At 100 °C.
1
b
2
3
ethene-1,2-diamide 3a in quantitative yield (Table 1, entry 9).
A clean reaction was observed, even with a stoichiometric
amount of 1a and 2a, when the reaction was conducted in
DMSO at room temperature (Table 1, entry 11).
indole, and carbazole, could also exhibit high reactivity with
retaintion of excellent regio- and stereo-selectivities to form the
hydroamidation products (3u−3x) in moderate to excellent
yields.
The substrate scope of the intermolecular hydroamidation
reaction was examined after the optimal reaction conditions
were established. The ynamide substrate N-methyl ynetolue-
nesulfonamide (MYTsA 1a) was treated with a series of
secondary amides under the optimized reaction conditions,
and the results are listed in Scheme 1. For the N-alkyl
ynetoluenesulfonamides, a broad range of alkyl substituents are
tolerated to give the corresponding products (3a−3j) in good
to excellent yields. The evaluation of N-alkyl-arylsulfonyla-
mides disclosed that the electronic effects of the aryl rings have
little influence on the reaction efficiency (3k−3o). N-
Methylmethanesulfon amide, 2-oxazolidones, and succinimide
were also compatible in this transformation to afford the
desired products (3p−3t) in 46%−99% yields. In addition, the
NH-containing aromatic heterocycles, such as benzotriazole,
Then, the exploration of ynamides revealed that a series of
alkyl and aryl substituents on the N atom were all tolerated to
furnish the target products (see Scheme 2, 4a−4f) in high to
excellent yields. Beside terminal ynamides, internal alkyne
sulfonamide was also compatible for this reaction to give
desired product 4g in 66% yield, albeit a higher reaction
temperature was required. Interestingly, the hydroamidation
products 3b and 3p could also be synthesized in 90% and 99%
yield by the addition of MYTsA 1a with the corresponding
17
secondary sulfonamide. Such features offered one more
synthetic route for choosing when one of the starting materials
is difficult available for certain 1,2-endiamides.
The synthetic utility of this intermolecular hydroamidation
reaction was further explored. A gram-scale experiment
B
DOI: 10.1021/acs.orglett.8b02409
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
18
Scheme 2. Substrate Scope of Ynamides
to act as an effective 1,4-addition acceptor. Consequently, the
1
2
−
β-addition of anion R R N to ynamide could generate the
anion intermediate A or B via a trans- or cis-1,4-addition,
respectively. According to the literature, DFT calculations
demonstrated that the corresponding free energy of
14
intermediate A is lower than that of the intermediate B. In
other words, coulombic repulsion between the N lone-pair
1
2
electrons of the R R N group and the negative charge of
carbanion at Cα in intermediate B overwhelms the steric
hindrance between two amide groups of intermediate A. Thus,
the formation of trans-addition intermediate A is favored and
the protonation of A afforded the final trans-addition product
with excellent regio- and stereo-selectivity.
In conclusion, we have developed an efficient strategy for the
preparation of unknown (Z)-ethene-1,2-diamides with ex-
cellent regio- and stereo-selectivities, which are difficult to
access via the traditional approach. Note that the base-
promoted intermolecular trans-selective β-hydroamidation of
ynamides proceeded smoothly in the absence of a transition-
metal catalyst. This transformation displays excellent functional
group tolerance and broad substrate scopes, with respect to
both ynamides and secondary amides. Given the easy
availability of starting materials, mild reaction conditions and
the potential application of (Z)-β-endiamides in organic
synthesis, a broad interest for this novel approach will be
expected.
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), and Cs CO3
2
(
0.2 mmol) in DMSO (1.0 mL) at rt. Isolated yields. Z:E > 99:1
determined by crude H NMR). At 100 °C.
1
b
(
between ynamide 1a and N,4-dimethylbenzenesulfonamide 2a
demonstrated that 1.77 g of the corresponding product 3a
could be obtained in 90% yield. Furthermore, hydrogenation of
ASSOCIATED CONTENT
■
*
S
Supporting Information
3
a in the presence of Pd/C provided ethane-1,2-diamide 5a in
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02409.
9
3% yield (see Scheme 3).
Scheme 3. Gram-Scale Experiment and Synthetic
Application
Experimental procedures, compounds characterization
data, and copies of NMR spectra (PDF)
Accession Codes
CCDC 1840556 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
A plausible reaction mechanism was proposed, based on our
experimental results (see Scheme 4). Deprotonation of
nucleophilic secondary amide by base provides the amide
anion R R N . The amide functional group of ynamide not
only polarized the C−C triple bond but also enabled ynamide
*
E-mail: zhaojf@jxnu.edu.cn.
ORCID
1
2
−
Zhenming Zhang: 0000-0001-8550-5398
Junfeng Zhao: 0000-0003-4843-4871
Notes
Scheme 4. Plausible Reaction Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
2
The National Natural Science Foundation of China (Nos.
1462023, 21778025, and 21762021), the Natural Science
Foundation of Jiangxi Province (No. 20161BAB213069) and
the Science and Technology Project of Jiangxi Provincial
Education Department (Nos. GJJ150297, GJJ150324) are
acknowledged for support of this research.
C
DOI: 10.1021/acs.orglett.8b02409
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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DOI: 10.1021/acs.orglett.8b02409
Org. Lett. XXXX, XXX, XXX−XXX