Access to (Z)-β-Substituted Enamides from N1-H-1,2,3-Triazoles

Article abstract of DOI:10.1021/acs.orglett.1c02087

A direct ring-opening/nucleophilic substitution reaction of N1-H-1,2,3-triazoles has been described. Divergent (Z)-β-halogen- or sulfonyl-substituted enamides could be stereospecifically synthesized in a tunable manner. This strategy might not only enable

Full text of DOI:10.1021/acs.orglett.1c02087

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Letter
Access to (Z)‑β-Substituted Enamides from N1‑H-1,2,3-Triazoles
Tao Wang, Zongyuan Tang, Han Luo, Yi Tian, Mingchuan Xu, Qixing Lu, and Baosheng Li*
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ABSTRACT: A direct ring-opening/nucleophilic substitution reaction of N1-H-1,2,3-triazoles has been described. Divergent (Z)-β-
halogen- or sulfonyl-substituted enamides could be stereospecifically synthesized in a tunable manner. This strategy might not only
enable a new ring-opening method of N1-H-1,2,3-triazoles under nonmetal catalysis and mild reaction conditions but also offer a
good opportunity to reliably access versatile (Z)-β-substituted enamides that could be used as synthetic precursors for further
synthetic transformations.
β-Halogenated enamides are versatile and practical synthetic
precursors in organic transformations. The special alkenyl
halides ensure that some extraordinarily useful carbon−
carbon1 or carbon−heteroatom2 bonds can be constructed
by further transition-metal-catalyzed cross-coupling reactions.3
In addition, the structural units of β-halogenated enamides can
be found in some biologically important natural products, such
as chartellines and chartellamides4 (Figure 1). Accordingly, the
for the construction of (Z)-β-halogenated enamides is still
required.
In recent years, as one of the most important branches in
organic synthesis, 1,2,3-triazole chemistry has received
considerable attention.7 The unique aromaticity and stability
make it commonly applied in the fields of medicine8 and
materials.9 With the introduction of an electron-withdrawing
group on the N1 position,10 such as N1-sulfonyl-1,2,3-
triazoles,11 the compound can promote the cleavage of the
N1−N2 bond. This cleavage can generate synthetically
valuable α-imino diazo intermediates that can trigger a series
of useful transformations, including metal-catalyzed cycliza-
tions,12 O−,13 N−,14 and C−H15 insertions, rearrangements,16
and cycloaddition17 reactions (Scheme 1a). Nonmetal-
catalyzed methods for the formation of α-imino diazo
compounds from 1,2,3-triazoles18 might be very challenging,
while offering more potential for applications in synthetic and
medicinal chemistry.
In 2019, Li and co-workers reported a compelling boron
trifluoride (BF3) promoted ring-opening/fluorination reaction
of N1-sulfonyl-1,2,3-triazoles, in which a fluorine atom could
be introduced via Et2O·BF3 to produce β-fluorinated enamines
(Scheme 1b).19 Recently, Beier and co-workers pioneered a
Figure 1. Natural products containing β-halogenated enamides.
development of a straightforward methodology to produce
these types of compounds is significantly important in organic
synthesis. Although considerable efforts have been made,5 the
stereospecific synthesis of β-halogenated enamides remains an
intriguing challenge. To the best of our knowledge, there are
several addition reactions of substituted alkynes that are
available for the stereospecific preparation of (Z)-β-halogen-
ated enamides.6 Therefore, the development of new strategies
Received: June 21, 2021
https://doi.org/10.1021/acs.orglett.1c02087
© XXXX American Chemical Society
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A

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a b
,
Scheme 1. Background and Our Proposal
Table 1. Optimization of Reaction Conditions
entry
solvent
T (°C)
yield (%)
1
2
3
4
5
6
7
PhMe
PhF
THF
80
80
80
80
80
70
90
33
30
26
48
74
66
33
DCE
CHCl3
CHCl3
CHCl3
a
All reactions of 1a (0.1 mmol) and 2a (0.2 mmol) were carried out
in solvent (1.0 mL) in a sealed tube for 10 h under an Ar atmosphere.
b
Isolated yields.
increasing or decreasing the reaction temperature resulted in
lower yields (entries 6 and 7).
With the optimized reaction conditions in hand, we turned
our intention to explore the substrate scope (Scheme 2). The
contrasting transformation from N-fluoroalkyl-substituted
1,2,3-triazoles to synthesize β-sulfonyloxy enamides in the
presence of acid.20a They subsequently developed two high-
value methods for the construction of synthetically important
β-halogenated substituted enamides as well as their deriva-
tives.20b,c All of the realized ring-opening/nucleophilic
substitution reactions of 1,2,3-triazole need to reserve an
electron-withdrawing group on the N1 position and require an
additional Lewis acid. Being interested in 1,2,3-triazole
chemistry, we investigated whether it was possible for direct
ring-opening/substitution reactions of N1-H-1,2,3-triazoles to
stereospecifically generate β-substituted enamides under
thermodynamic conditions. Conceptuality and practicality
aside, we recognized that such a design might offer a new
blueprint for preparing synthetically versatile β-substituted
enamides from simple and readily available starting materials.
Specifically, we assumed that the N1-H-1,2,3-triazoles would
react with acyl chloride to generate N1-acyl-1,2,3-triazoles in
situ that would go through a thermodynamically favorable ring-
opening reaction to generate the zwitterionic intermediates I.
A subsequent protonation and nucleophilic substitution of
vinyl diazo compounds would afford the desired (Z)-β-
substituted enamides (Scheme 1c). However, the sulfonyl
group is used as a classic electron-withdrawing group to
promote the ring-opening reaction of 1,2,3-triazole. Therefore,
it was unclear whether the α-imino diazo compound could be
effectively generated from N1-acyl-1,2,3-triazoles. Herein, we
report the realization of this cascade reaction to provide
structurally versatile (Z)-β-substituted enamides.
Scheme 2. Substrate Scope for (Z)-β-Halogenated
a b
,
Enamides
To verify the feasibility of this assumption, we initially
investigated the reactivity of C4-(p-tolyl)-N1-H-1,2,3-triazole
(1a) and benzoyl chloride (2a) (Table 1). We realized that the
key to the success of this strategy is the thermodynamic
cleavage of the N1−N2 bond. Therefore, this transformation
was first explored at 80 °C. Fortunately, after treatment of 1a
and 2a in PhMe at 80 °C, the expected (Z)-β-chloride enamide
(3a) could be obtained in 33% yield (entry 1). The outcome
encouraged us to further optimize the reaction conditions.
Evaluation of a variety of solvents revealed that the reaction
exhibited higher yields in chlorinated solvents than in other
types of solvents. Using CHCl3 as solvent furnished the desired
product in the highest yield (74%) in all cases. Subsequently,
a
Reaction conditions: all reactions of 1,2,3-triazoles (0.1 mmol) and
acyl halogens (0.2 mmol) were performed under the standard reaction
b
conditions. Isolated yields.
B
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C4-aryl-substituted 1,2,3-triazoles bearing various electron-
donating groups on the benzene ring could react with benzoyl
chloride to provide products 3a−e in 70−85% yields. 1,2,3-
Triazole with C4-phenyl and -naphthyl substitutions reacted
well to afford the desired products 3f,g in 43% and 42% yields.
Unfortunately, the C4 position with p-Br-Ph-, p-CO2Me-Ph-,
and p-NO2-Ph-substituted 1,2,3-triazoles could not produce
the expected product. Perhaps this occurred because the
electron-withdrawing group reduced the nucleophilicity of the
1,2,3-triazole or the stability of the carbon cation in the ring-
opening intermediate. Moreover, various C4 heteroaromatic
group substituted 1,2,3-triazoles were investigated under the
same reaction conditions, and all substrates reacted well to give
the desired products 3h−m in 67%−92% yields. The structure
of 3a could be unambiguously determined by an X-ray
crystallographic analysis and extrapolated to other products.
To further broaden the substrate scope, we next explored the
the reactivity of C4 alkenyl group substituted 1,2,3-triazoles
under the optimal reaction conditions. We were delighted to
find that both cyclic and linear alkenes worked well and
afforded the corresponding conjugated diene products 3n,o in
92% and 64% yields, respectively. Interestingly, when a C4-
cyclopropyl-substituted 1,2,3-triazole was subjected to the
reaction, the nonconjugated (Z)-β-chloride enamide 3p could
also be obtained in 77% yield.
Subsequently, we investigated the reactivity of various acyl
halides with 1,2,3-triazole. The reactions of 1a with
naphthalenecarbonyl and 4-Me-benzoyl- and 4-MeO-benzoyl
chlorides proceeded smoothly to furnish the desired products
3q−s in 53%−76% yields. An alkenyl acyl chloride also worked
well and offered the corresponding product 3t in 41% yield. In
addition, to further ascertain whether a nonconjugated acyl
chloride was suitable for the current reaction system,
phenylacetyl chloride was detected and gave the corresponding
product 3u in 42% yield. Finally, benzoyl bromide and fluoride
were also subjected to the same reaction conditions to obtain
diverse β-halogenated enamides. Fortunately, the reactions of
benzoyl bromide with various 1,2,3-triazoles could also be
achieved under the standard reaction conditions, providing the
β-bromide-substituted enamides 3v−x in good yields. How-
ever, the reaction of benzoyl fluoride with 1,2,3-triazole 1a
resulted in a complex system, and none of the desired β-
fluorinated enamide product was detected.
Scheme 3. Substrate Scope for (Z)-β-Sulfonated
Enamides
a b
,
a
Reaction conditions: all reactions of 1,2,3-triazoles (0.1 mmol), acyl
chlorides (0.2 mmol), and sodium salts (0.1 mmol) were performed
b
at 60 °C for 16 h under an Ar atmosphere. Isolated yields.
examined the reactivities of alkenyl acyl and p-Me-benzoyl; the
results showed that the variation of acyl chlorides could also
provide the corresponding products 5f,g in 47% and 55%
yields. To our delight, when NaOTf was replaced by NaSO3Ph
to further expand the substrate diversity, the latter worked well
under the same reaction conditions, affording the correspond-
ing product 5h in 58% yield. It is worth mentioning that
excellent reactivity and selectivity were also maintained for the
three-component cascade pattern. Furthermore, the structure
of 5h could be unambiguously confirmed by an X-ray
crystallographic analysis and the structures of other products
could be deduced by NMR spectra. However, when NaI, KI,
NaF, and KF were added to the standard reaction conditions
to produce β-iodine- and β-fluorine-substituted enamides, the
desired halogenation products could not be detected in these
reactions: only the decomposition of the starting materials. In
general, the divergent synthesis provides an ideal platform to
construct β-sulfonyl-substituted enamides and further enrich
the applicability of the current strategy.
To further achieve divergent syntheses, we added sodium
trifluoromethanesulfonate (NaOTf) into the reaction system
to see whether the synthetically important alkenyl-OTf unit
could be constructed (Scheme 3). Subsequently, the optimal
reaction conditions of the three-component cascade reaction
were explored by screening various temperatures and solvents.
The results indicated that the β-chloride-substituted enamide
could be restrained (only trace amounts of β-chloride-
substituted enamide were observed by crude NMR) and a β-
sulfonyl-substituted enamide could be effectively formed by
decreasing the reaction temperature from 80 to 60 °C (for
details of the screening of the conditions, please see page S6 in
the Supporting Information). Next, the substrate scope of the
three-component cascade reaction was investigated.
A variety of C4 aryl-substituted 1,2,3-triazoles, including 4-
methyl-, 4-chloride-, and 4-fluorine-Ph, were tolerated and
delivered the expected (Z)-β-sulfonyl substituted enamides
5b−d in 49%−78% yields. In addition, C4-naphthyl-1,2,3-
triazole was also a suitable substrate, providing the
corresponding product 5e in 52% yield. Furthermore, we
To demonstrate the practicality of this strategy, a scaled-up
reaction of 1a and 2a was conducted under the standard
reaction conditions and the result indicated that increasing to a
gram scale had no obvious influence on the yield of 3a
(Scheme 4a). To demonstrate the potential utility of this
protocol, we also performed several synthetic transformations
(Scheme 4b,c). The β-sulfur-substituted enamide 6 can be
effectively prepared via a nonmetal-catalyzed cross-coupling
under the action of the radical initiator AIBN. The diaryl-
substituted oxazoline product 7 could be effectively formed by
a base-promoted intramolecular cyclization process. Further-
more, a series of structurally diverse β-substituted enamides
was synthesized by the metal-catalyzed cross-coupling
reactions from β-sulfonated enamide 5a. The β-diaryl-
substituted enamide 8 could be prepared via the palladium-
catalyzed Suzuki coupling of phenylboronic acid with 5a. The
β-alkynyl-substituted enamide 9 could also be synthesized via a
Sonogashira coupling of phenylacetylene with 5a.
According to related literature reports20 and our exper-
imental results, we propose a plausible mechanism for the
C
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Scheme 4. Gram-Scale Synthesis and Synthetic
Transformations
General procedures, characterization, X-ray data, and
NMR spectra (PDF)
Accession Codes
CCDC 2077202−2077203 contain the supplementary crys-
tallographic 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Baosheng Li − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400044, People’s Republic
of China; orcid.org/0000-0002-6953-687X;
Email: libs@cqu.edu.cn
Authors
Tao Wang − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400044, People’s Republic
of China
Zongyuan Tang − School of Chemistry and Chemical
Engineering, Chongqing University, Chongqing 400044,
People’s Republic of China
current cascade reaction (Scheme 5). First, the acylation of
N1-H-1,2,3-triazoles generates intermediates, which would
Scheme 5. Proposed Mechanism
Han Luo − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400044, People’s Republic
of China
Yi Tian − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400044, People’s Republic
of China
Mingchuan Xu − School of Chemistry and Chemical
Engineering, Chongqing University, Chongqing 400044,
People’s Republic of China
Qixing Lu − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400044, People’s Republic
of China
result in the cleavage of the N1−N2 bond through a
thermodynamically triggered electrocyclization process to
produce intermediates I. The protonation that followed
resulted in the formation of intermediates II. Finally, the β-
sulfonyl- or halogen-substituted enamides could be obtained
by temperature-tunable nucleophilic substitution of the
diazonium salt intermediates II. It is worth noting that the
whole process maintains the (Z)-alkene configuration to
stereospecifically provide (Z)-β-substituted enamides.
In conclusion, a direct ring-opening/substitution reaction of
N1-H-1,2,3-triazoles has been developed. The entire process
avoids the reservation of an electron-withdrawing group on the
N1 position and proceeds efficiently under mild reaction
conditions. Both (Z)-β-halogen- and (Z)-β-sulfonyl-substi-
tuted enamides could be stereospecifically synthesized through
slight modifications, respectively. Moreover, the β-halogen- or
β-sulfonyl-substituted enamide units are versatile synthetic
precursors as well. The strategy provides a new ring-opening
method of N1-H-1,2,3-triazoles and an ideal platform to
construct a variety of β-substituted enamides.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02087
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSFC (No.
21772019), and The Venture & Innovation Support Program
for Chongqing Overseas Returnees (cx2019007 and
cx2020047). We also thank the Analytical and Testing Center
of Chongqing University. The authors wish to acknowledge
Mr. Xiangnan Gong of the Analytical and Testing Center of
Chongqing University for the single-crystal X-ray diffraction
analysis of products 3a and 5h.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
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