Synthesis of Succinimides via Intramolecular Alder-Ene Reaction of 1,6-Enynes

Article abstract of DOI:10.1021/acs.orglett.1c00888

A novel and convenient method has been developed for the facile synthesis of functionalized succinimide derivatives via intramolecular Alder-ene reaction of 1,6-enynes. This reaction features mild and metal-free reaction conditions, which offers a green and efficient entry to synthetically important succinimide scaffolds. Preliminary mechanistic studies suggest that a diradical intermediate might be involved in this transformation.

Full text of DOI:10.1021/acs.orglett.1c00888

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Letter
Synthesis of Succinimides via Intramolecular Alder-Ene Reaction of
1,6-Enynes
Xia Chen, Yuling Lu, Zhenhua Guan, Lianghu Gu, Chunmei Chen, Hucheng Zhu, Zengwei Luo,*
and Yonghui Zhang*
Cite This: Org. Lett. 2021, 23, 3173−3178
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ABSTRACT: A novel and convenient method has been developed for
the facile synthesis of functionalized succinimide derivatives via
intramolecular Alder-ene reaction of 1,6-enynes. This reaction features
mild and metal-free reaction conditions, which offers a green and
efficient entry to synthetically important succinimide scaffolds.
Preliminary mechanistic studies suggest that a diradical intermediate
might be involved in this transformation.
uccinimides are some of the most essential scaffolds found
Sin numerous natural products, bioactive compounds, and
pharmaceuticals.1 Due to their unique activities and potential
applications, substantial effort has been devoted to its synthetic
study in the past several decades. Traditionally, succinimides
were prepared from substituted succinic anhydrides and gas
ammonia or liquid amines under heating conditions.2 Recently,
Alcaide3 and You4 independently reported the ring expansion
reactions of β-lactam for the construction of succinimides.
Beller and Rong demonstrated the carbonylation of alkynes
with ammonia or amines5 and radical cascade cyclization/
haloazidation of 1,6-enynes to form succinimides,6 respectively.
Although these methods greatly enriched approaches for the
synthesis of succinimides, the efficient, convenient, and green
synthetic protocols are still in urgent demand.
The Alder-ene reaction was first discovered by Kurt Alder in
1943,7 which has captured a growing amount of attention from
organic chemists due to its efficiency and practicality.8 The
intramolecular Alder-ene (IMAE) reaction of 1,6-enynes is a
compelling approach that has produced a series of architectur-
ally complex five-membered carbo- and heterocycles with high
atom economy and efficiency. The conventional methods
require high temperatures9 or Lewis acid catalysts10 to reach
the aim (Figure 1a), while the harsh reaction conditions,
prolonged reaction time, and low yields limited its synthetic
application. To improve the practicality of this type of reaction,
transition metal catalysts were applied to promote the
cyclization process. For instance, in 1985, Trost reported the
first example of palladium-catalyzed IMAE reactions of 1,6-
enynes under mild conditions (Figure 1b).11 Followed by this
seminal work, IMAE reactions promoted by Pd catalysts as
well as other transition metal catalysts have been widely
studied and achieved much progress, providing facile access to
structurally diversified molecules.12 Very recently, Banwell
reported a palladium-catalyzed and triethylsilyl group-regulated
Figure 1. Intramolecular Alder-ene reaction of 1,6-enynes.
Received: March 15, 2021
Published: April 2, 2021
https://doi.org/10.1021/acs.orglett.1c00888
Org. Lett. 2021, 23, 3173−3178
© 2021 American Chemical Society
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IMAE reaction of O- and N-linked 1,6-enynes (Figure 1c).13
Despite these available methods having their own merits, the
mild IMAE reactions under additive- and metal-free conditions
remain underdeveloped and challenging for organic chemists.
Herein, we report a novel and convenient IMAE reaction of
1,6-enynes for the facile synthesis of succinimides (Figure 1d).
The reaction is characterized as being insensitive to air and
moisture, without utilizing any catalyst or additive, and easy to
operate, with high atom economy and efficiency, delivering a
series of functionalized succinimides in moderate to excellent
yields.
a−c
Scheme 1. Scope of Olefins and Alkynes
In our initial investigation, imide 1ad was chosen as the
model substrate for optimizing the reaction conditions. The
reaction was carried out with toluene as the solvent at 60 °C
for 2 h, and the corresponding product 2ad was obtained as
the only product in 40% yield; the Δ1,4 double bond was
assigned to the 1E,4Z configuration (Table 1, entry 1).
a
Table 1. Optimization of the Reaction Conditions
b
entry
T (°C)
solvent
toluene
toluene
toluene
toluene
toluene
THF
1,4-dioxane
CH3CN
EtOH
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
60
60
80
80
80
80
80
80
80
80
2
6
6
12
20
12
12
12
12
12
40
62
81
89
87
82
85
63
61
a
Standard conditions: 1a or 1b (0.20 mmol), toluene (2.0 mL) in a
b
c
Schlenk tube, under air, oil bath. Isolated yield. At 80 °C for 1 h.
2ab in 91% yield. To the best of our knowledge, synthetic
approaches that create quaternary all-carbon stereocenters and
spiro structures have attracted considerable attention from
organic chemists.14 Delightfully, the optimal reaction condition
realized the synthesis of a series of quaternary all-carbon chiral
centers as well as unique spirocyclic architectures with high
efficiency (2ac−2af). In addition, exocyclic olefin was well
tolerated in this procedure and led to the result that olefin
migrated into the ring (2ag). Surprisingly, substrate 1ah
offered a completely different outcome. Substrate 1ah worked
well under the optimal reaction conditions, delivering a 1,3-
diene rather than a 1,4-diene product, which can be used as a
diene in DA reaction to construct six-membered rings. It is
noteworthy that this phenomenon has been scarcely observed
in previously reported thermal IMAE reactions. For 1,3-diene
product 2ah, it holds appropriate steric hindrance and
possesses a larger conjugation structure, which should be
more stable than its isomer 1,4-diene product.
Next, the scope of the substituents connected with the
alkyne part was investigated (Scheme 1). A series of
substituents, including F, Cl, Br, CH3, and OCH3, at the
para, ortho, and meta positions of the aromatic ring were
amenable under the standard conditions and finished the
corresponding products in moderate to good yields (2ba−
2bk). Furthermore, the halogen groups (F, Cl, and Br)
remained intact during this conversion, which offered the
potential for further transformations by cross-coupling
reactions. In addition, the structure of 2ba as well as 2ca
was unambiguously confirmed by X-ray crystallographic
analysis (CCDC 2049453 and 2049452). The naphthyl-
substituted alkyne behaved slightly less expediently to give
c
10
toluene
88
a
Standard conditions: 1ad (0.20 mmol), solvent (2.0 mL) in a
b
c
Schlenk tube, under air, oil bath. Isolated yield. Under Ar.
Encouraged by this promising result, we screened other
parameters such as reaction time, reaction temperature, and
solvent as follows. Prolonging the reaction time proved to be
beneficial for improving the yield (entry 2). Pleasantly, further
prolonging the reaction time and improving the reaction
temperature succeed in giving a better result (entries 3−5).
Furthermore, other solvents were investigated during this
procedure, which showed that THF and 1,4-dioxane were also
good options, delivering the cyclized products in 82% and 85%
yields, respectively (entries 6 and 7, respectively). Other
solvents such as CH3CN and EtOH were inferior to toluene
(entries 8 and 9). In addition, the reaction was conducted
under an argon atmosphere, and it failed to afford a higher
yield (entry 4 vs entry 10).
With the optimized reaction conditions in hand, sub-
sequently, the substrate scope of the reaction was examined. As
shown in Scheme 1, the process can allow various substituted
olefins and alkynes to be converted with high efficiency and
stereoselectivity. First, the effects of substituents on the olefin
part were investigated. Interestingly, when material 1aa reacted
at 80 °C for 1 h, it furnished cyclized product 2aa in 94% yield.
Substrate 1ab reacted smoothly to produce desired compound
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corresponding product 2bl in 52% yield. Notably, the
heteroaromatic alkynes were also accommodated for the
optimal reaction condition and realized the desired molecule
in good yield (2bm). The alkyl-substituted alkynes worked
well, and the corresponding products were formed with yields
of 93% and 90%, respectively (2bn and 2bo, respectively).
Lastly, aryl and alkyl substituents on the N atom were
evaluated under the standard reaction conditions (Scheme 2),
Scheme 3. Gram Scale Reaction and Synthetic
Transformations
a−c
Scheme 2. Scope of Amines
a
Standard conditions: 1c (0.20 mmol), toluene (2.0 mL) in a Schlenk
b
c
tube, under air, oil bath. Isolated yield. At 80 °C for 1 h.
and both of them were tolerated in this procedure, providing
the corresponding cyclized products in moderate to excellent
yields consisting of only the Z isomer. N-Phenyl derivatives
1ca and 1cb could be converted to the desired products 2ca
and 2cb, respectively, in moderate to good yields. As a
supplement, the electron-rich substituent on the phenyl ring
proved to be positive for this transformation (2cc). Moreover,
alkyl-substituted amines all produced target molecules in
excellent yields (2cd−2cf). To further illustrate the synthetic
practicality of this strategy, a 2.0 g scale reaction was carried
out under the standard reaction conditions, delivering the
target cyclized product 2aa in 87% yield, which further
illustrated its synthetic utility (Scheme 3a). In addition, we
applied this approach to amino acid ester 2d and a series of
natural products 2e−2h (Scheme 3b). Delightfully, all of these
materials reacted efficiently to give the corresponding products
in good to excellent yields and increased the complexity of
these molecules concomitantly.
Scheme 4. Control Experiments and KIE Experiment
Subsequently, to gain insight into the mechanism of this
reaction, several control experiments were conducted. First, to
identify the source of the H atom in newly formed alkenes,
deuterium reagents were used as the solvent in the following
two reactions (Scheme 4a,b). On the basis of the results
obtained, the assumption that the H atom came from the
solvent has been excluded. Moreover, deuterated substrate 1aa
was performed under the standard conditions and offered
deuterated product 2aa in 91% yield. It was inferred that the H
atom came from the terminal methyl group of the alkene
(Scheme 4c). Subsequently, the intermolecular kinetic isotope
(KIE) control experiment was conducted. The result
demonstrated no kinetic isotope effect in the intermolecular
experiment (kH/kD = 1.19), which indicated that the C(sp3)−
H bond cleavage of the methyl group is not the rate-
determining step (Scheme 4d). As depicted in the literature,
KIE experiments were a powerful diagnostic tool for the
judgment between stepwise and concerted mechanisms.15
A
large KIE (kH/kD > 2) has often been taken as evidence of a
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concerted mechanism,16 whereas for the stepwise mechanism,
kH/kD should be close to unity.17 At the same time, other
radical trapping experiments, such as TEMPO and BHT
experiment, were conducted, but no positive results were
obtained.
AUTHOR INFORMATION
Corresponding Authors
■
Zengwei Luo − Hubei Key Laboratory of Natural Medicinal
Chemistry and Resource Evaluation, School of Pharmacy,
Tongji Medical College, Huazhong University of Science and
Technology, Wuhan 430030, China; Email: luozengwei@
hust.edu.cn
Yonghui Zhang − Hubei Key Laboratory of Natural
Medicinal Chemistry and Resource Evaluation, School of
Pharmacy, Tongji Medical College, Huazhong University of
Science and Technology, Wuhan 430030, China;
orcid.org/0000-0002-7222-2142; Email: zhangyh@
mails.tjmu.edu.cn
According to the KIE experimental results (kH/kD
=
1.19)15−17 as well as literature precedent,15a,18 we proposed a
plausible diradical mechanism for the present IMAE reaction,
as depicted in Scheme 5. Initially, imide A underwent a
Scheme 5. Tentative Mechanism
Authors
Xia Chen − Hubei Key Laboratory of Natural Medicinal
Chemistry and Resource Evaluation, School of Pharmacy,
Tongji Medical College, Huazhong University of Science and
Technology, Wuhan 430030, China
Yuling Lu − Hubei Key Laboratory of Natural Medicinal
Chemistry and Resource Evaluation, School of Pharmacy,
Tongji Medical College, Huazhong University of Science and
Technology, Wuhan 430030, China
Zhenhua Guan − Hubei Key Laboratory of Natural Medicinal
Chemistry and Resource Evaluation, School of Pharmacy,
Tongji Medical College, Huazhong University of Science and
Technology, Wuhan 430030, China
Lianghu Gu − Hubei Key Laboratory of Natural Medicinal
Chemistry and Resource Evaluation, School of Pharmacy,
Tongji Medical College, Huazhong University of Science and
Technology, Wuhan 430030, China
Chunmei Chen − Hubei Key Laboratory of Natural
Medicinal Chemistry and Resource Evaluation, School of
Pharmacy, Tongji Medical College, Huazhong University of
Science and Technology, Wuhan 430030, China
Hucheng Zhu − Hubei Key Laboratory of Natural Medicinal
Chemistry and Resource Evaluation, School of Pharmacy,
Tongji Medical College, Huazhong University of Science and
Technology, Wuhan 430030, China
cyclization process to produce diradical intermediate B under
thermal conditions. Subsequently, intermediate B underwent
an intramolecular H atom migration process to deliver target
compound C.
In conclusion, a versatile and gentle IMAE reaction of 1,6-
enynes for the facile synthesis of succinimide derivatives has
been established. The reaction is efficient and has advantages
as (1) it was conducted under milder reaction conditions
compared to those of previously reported thermal IMAE
reactions, (2) it lacks the requirement for transition metal
catalysts, additives, acid, and base, (3) it is operationally
simple, (4) it is insensitive to air and moisture, and (5) it has
good functional group tolerance, high efficiency, and excellent
stereoselectivity. In addition, high atom economy and ready
scalability make it an elegant and attractive alternative,
especially for the construction of succinimides, as well as a
promising approach for mild IMAE reactions.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00888
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
ASSOCIATED CONTENT
This work is financially supported by the Program for
Changjiang Scholars of Ministry of Education of the People’s
Republic of China (T2016088), the National Natural Science
Foundation for Distinguished Young Scholars (81725021), the
National Natural Science Foundation for Excellent Young
Scholars (81922065), the National Science and Technology
Project of China (2018ZX09201001-001-003), Innovative
Research Groups of the National Natural Science Foundation
of China (81721005), and the Academic Frontier Youth Team
of HUST (2017QYTD19).
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00888.
Experimental procedures and copies of NMR spectra
(PDF)
Accession Codes
CCDC 2049452−2049453 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.
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Organic Letters
pubs.acs.org/OrgLett
Letter
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https://doi.org/10.1021/acs.orglett.1c00888
Org. Lett. 2021, 23, 3173−3178