Synergistic N-Heterocyclic Carbene/Palladium-Catalyzed [3 + 2] Annulation of Vinyl Enolates with 1-Tosyl-2-vinylaziridine

Article abstract of DOI:10.1021/acs.orglett.0c02935

The synergistic combination of N-heterocyclic carbene organocatalysis and transition-metal catalysis for a formal [3 + 2] annulation between 3-substituted but-2-enoates and 1-tosyl-2-vinylaziridine was developed. This cooperative strategy provides a facile and efficient access to various functionalized (E)-3-ethylidene-4-vinylpyrrolidin-2-ones in a regioselective and stereoselective manner. The preliminary asymmetric studies were also performed, which indicated a potential for enantioselective annulation of vinyl enolate intermediates with transition-metal-π-allyl species.

Full text of DOI:10.1021/acs.orglett.0c02935

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Letter
Synergistic N‑Heterocyclic Carbene/Palladium-Catalyzed [3 + 2]
Annulation of Vinyl Enolates with 1‑Tosyl-2-vinylaziridine
Jian Gao, Jianming Zhang, Shuaishuai Fang, Jie Feng, Tao Lu, and Ding Du*
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ABSTRACT: The synergistic combination of N-heterocyclic
carbene organocatalysis and transition-metal catalysis for a formal
[3 + 2] annulation between 3-substituted but-2-enoates and 1-
tosyl-2-vinylaziridine was developed. This cooperative strategy
provides a facile and efficient access to various functionalized (E)-
3-ethylidene-4-vinylpyrrolidin-2-ones in a regioselective and stereo-
selective manner. The preliminary asymmetric studies were also performed, which indicated a potential for enantioselective
annulation of vinyl enolate intermediates with transition-metal−π-allyl species.
ver the past decades, conventional transition-metal
(TM) catalysis1 and organocatalysis2 have been widely
intermediates, NHC-bound active species such as homoeno-
lates, enolates, and azolium enamides have also been developed
as C2 or C3 synthons for diverse [n+m] annulation12−18 and
arylation19 reactions by synergistic NHC/TMs (Pd, Cu, Ir,
Au) co-catalysis. In view of the importance of synergistic
catalysis and the diversity of NHC-bound intermediates, it is
still highly desirable to explore novel and efficient catalytic
systems based on cooperative NHC/TM catalysis.
Recently, NHC-bound vinyl enolates derived from α,β-
unsaturated acids or their esters, or (α-bromo)enals via γ-
activation, have been used as reactive nucleophilic C4 synthons
or C2 synthons to enable diverse annulation reactions at the γ-
or α-position.20 However, to the best of our knowledge, NHC/
TM co-catalyzed reactions of vinyl enolates have not been
reported yet. We envisioned that NHC-bound vinyl enolates
would also be applicable in combination with TM-activated
electrophiles to realize various formal [n+2] or [4+m]
annulations (Scheme 1c). Herein, as part of our continuous
efforts to enrich vinyl enolate chemistry,21 we report an NHC/
Pd co-catalyzed [3 + 2] annulation of α,β-unsaturated esters 1
with 1-tosyl-2-vinylaziridine 2, a versatile substrate for the
generation of Pd-π-allyl species,22 for the facile construction of
(E)-3-ethylidene-4-vinylpyrrolidin-2-one skeleton 3 that is
frequently found in numerous synthetic compounds or natural
products.23 Notably, (E)-[3 + 2] adducts 3 were obtained
exclusively in a regioselective and stereoselective manner, and
the corresponding [4 + 3] adducts 4 were not observed.
O
explored and applied in the activation and functionalization of
various chemical bonds to accomplish useful chemical
transformations. Nevertheless, with the development of the
modern organic synthesis, the traditionally single catalytic
systems have also encountered some challenges, such as the
activation efficiency for new types of substrates, and the
control for the reactivity and selectivity. Aiming to get out of
this dilemma, synergistic or cooperative catalysis, especially
synergistic TM catalysis and organocatalysis, has drawn much
attention and has been proven to be a general and effective
strategy to realize inaccessible transformations by single
catalytic approaches previously via independent activation of
separate substrates simultaneously.3
In recent years, N-heterocyclic carbenes (NHCs) have
emerged as efficient and powerful organocatalysts for the
discovery of novel and unconventional synthetic trans-
formations with readily access to a wide array of heterocycles
and bioactive molecules.4 Especially via umpolung activation
mode, a variety of NHC-bound active intermediates have been
approached and widely applied for chemical bond con-
struction. However, because of the strong affinity of NHCs
to TM centers through irreversible binding and coordination, a
disruption of the individually desired catalytic activities of both
NHCs and TMs usually happens (Scheme 1a).5 Thus, the
design and development of synergistic catalysis by merging
NHCs with TMs remain a formidable challenge and only
limited examples were explored (Scheme 1b).6 In 2014, the
Scheidt group7 pioneered an intramolecular allylation and
subsequent acylation reaction of NHC-bound Breslow
intermediates for the construction of dihydrocoumarins
derivatives co-catalyzed by NHC/palladium catalyst. Following
this pioneering work, intermolecular allylation and benzylation
of NHC-bound Breslow intermediates were also achieved by
Ohmiya and co-workers.8−11 Furthermore, other than Breslow
Received: September 1, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02935
© XXXX American Chemical Society
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A

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Scheme 1. Merged N-Heterocyclic Carbene and Transition-
Metal Co-catalysis
Table 1. Selected Results for the Optimization of Reaction
Conditions
a
b
entry NHC-precat.
Pd-cat.
ligand
PPh3
PPh3
PPh3
PPh3
yield of 3a
1
2
A
B
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
−
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd(PPh3)2Cl2
[Pd(allyl)Cl]2
Pd(PPh3)4
11
trace
0
21
0
3
4
5
6
7
8
9
10
11
12
C
D
−
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
PPh3
−
0
P(4-FPh)3
P(4-MePh)3
PCy3
PtBuCy2
xphos
PtBu3
PnHex3
PCy3
PCy3
PCy3
PCy3
PCy3
13
26
38
14
0
0
30
0
46
38
0
38
14
75
13
c
14
15
c
16
c
c
c
17
18
19
Pd(TFA)2
Pd(tBu3P)2
Pd(OAc)2
[Pd(allyl)Cl]2
PCy3
PCy3
d
20
a
Reaction conditions: 1a (0.12 mmol, 1.2 equiv); 2 (0.1 mmol, 1.0
equiv); NHC-precat. (10 mol %); Cs2CO3 (2.5 equiv); Pd-cat. (5
b
mol %); ligand (20 mol %); THF, 2 mL; N2; rt; 24 h. Isolated yields.
c
d
ligand (10 mol %). 1a (0.2 mmol, 1.0 equiv); 2 (0.6 mmol, 3.0
equiv); THF, 4 mL. dba, dibenzylideneacetone; Cy, cyclohexyl; nHex,
We commenced the evaluation of our hypothesis by the
reaction of 4-nitrophenyl-3-phenylbut-2-enoate 1a with 1-
tosyl-2-vinylaziridine 2 using Cs2CO3 as the base in THF
under NHC/palladium co-catalysis (for details, see the
Supporting Information (SI)). We were delighted to find
that the reaction proceeded smoothly to give the formal [3 +
2] annulation product 3a in 11% yield, rather than the [4 + 3]
annulation product 4a, in the presence of carbene precursor A
and Pd2(dba)3·CHCl3 with PPh3 as the ligand (Table 1, entry
1). Subsequent screening of other carbene precursors indicated
that NHC precatalyst D displayed the best catalytic efficiency
for this [3 + 2] annulation reaction (Table 1, entries 2−4).
Notably, the control experiments showed that 3a was not
formed at all in the absence of either NHC or a palladium
catalyst, indicating the synergistically catalytic roles of both
carbene and the palladium catalyst (Table 1, entries 5 and 6).
Different ligands, under the co-catalysis of carbene D and
Pd2(dba)3·CHCl3, were then further examined (Table 1,
entries 7−13). As a result, tricyclohexylphosphine (PCy3)
proved to be the best ligand for this annulation, and 38% yield
of 3a could be obtained (Table 1, entry 9). Encouraged by this
result, we then tested various other palladium catalysts (Table
1, entries 14−20). Gratifyingly, a 46% yield of 3a could be
achieved when [Pd(allyl)Cl]2 was used as the metallic catalyst
in combination with PCy3 (Table 1, entry 15). Lastly, we
found that an excess amount of 2 was critical to this
transformation, because of the dimerization of 2, and the
reaction yield could be enhanced to 75% (Table 1, entry 20).
n-hexyl; TFA, trifluoroacetate.
Note that the configuration of the CC double bond of the
product can be established by NMR analysis of 3a, which is a
known compound.24
With the optimal reaction conditions in hand, the substrate
scope of the annulation between 3-substituted-(4-
nitrophenyl)but-2-enoates 1 and 1-tosyl-2-vinylaziridine 2
was investigated as shown in Scheme 2. Inspiringly, a wide
array of 3-(substituted phenyl)-(4-nitrophenyl)but-2-enoates
were compatible to the present annulation system. The nature
and position of the substituents on the phenyl ring seemed to
have certain impact on the reaction results. Substrates bearing
either electron-withdrawing groups or electron-donating
groups at the para position of the phenyl ring could be well-
tolerated, affording the corresponding desired products 3b−3i
in moderate to good yields. However, when a cyclic amino
group was anchored on the para position of the phenyl ring,
only 28% yield was achieved for the corresponding product 3j.
In terms of 3-(meta-substituted phenyl)-(4-nitrophenyl)but-2-
enoates, substrates with electron-withdrawing groups, such as
halogens (3k−3m) and methoxy group (3o) were found to be
better than those bearing an electron-donating group, such as
methyl (3n). When it comes to 3-(ortho-substituted phenyl)-
(4-nitrophenyl)but-2-enoates, the steric effect from the
substituents was obvious. The yields decreased significantly
with the increase of the volume of substituents at the ortho
B
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a
Scheme 2. Substrate Scope
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (0.6 mmol, 3.0 equiv), NHC-D (10 mol %), Cs2CO3 (2.5 equiv), [Pd(allyl)]Cl2 (5 mol %), PCy3
(20 mol %), THF, 4 mL, rt, 24 h; isolated yields are based on 1.
position (3p−3t). Furthermore, atropisomerism was observed
for products 3q−3t bearing bigger groups at ortho position,
because of the generation of a chiral axial. Similarly, the
reaction of 3-(1-naphthyl) enoate gave the corresponding
product 3u in 66% yield with a diastereomeric ratio (dr) of
1.5:1. 3-(2-Naphthyl and 2-heteroaryl phenyl) enoates were
also applicable to the present protocol. Although lower yields
were obtained for 2-(2-furyl)-, 2-(2-thienyl)-, and 2-(2-
benzofuryl)-substituted enoates (3w−3y), upper-medium
yields could be obtained for 2-naphthyl and 2-benzothienyl-
derived enoates (3v and 3z). Lastly, 3-alkyl-(4-nitrophenyl)
but-2-enoates were also tested to evaluate the generality of our
present reaction system. Fortunately, medium yields could be
achieved under the identical reaction conditions for two typical
aliphatic substrates (3aa and 3ab).
To further explore the synthetic utility of this methodology,
a scale-up synthesis of product 3a and several synthetic
applications were then performed (see Scheme 3). Product 3a
was obtained in a maintained yield with a 1 mmol scale under
the standard conditions (see Scheme 3a). Moreover, 3d could
be used for late-stage modification for different synthetic
purposes. For example, the Suzuki coupling with phenyl-
boronic acid and Hartwig-Buchwald coupling with piperidine
could proceed smoothly to afford the target compounds 3i and
3j, respectively (Scheme 3b), indicating the generality for late-
stage functionalization of the annulation products. In addition,
the N-protecting group could also be easily removed under
mild conditions to produce pyrrolidin-2-one derivative 5 in a
good yield (see Scheme 3c). Under catalytic hydrogenation
conditions, the two CC double bonds of product 3a were
completely reduced together, giving a trans-reduced product 6
in a high yield (Scheme 3c). Finally, a preliminary asymmetric
annulation study was performed (Scheme 2d). Unsatisfyingly,
after the screening of various reaction parameters (for details,
see the SI), 3a could be obtained in 31% yield with 65%
enantiomeric excess (ee) in the presence of chiral carbene
precursor E, using chiral diamine F as the additive.
A tentative mechanism of the NHC/palladium co-catalyzed
annulation of vinyl enolates with 1-tosyl-2-vinylaziridine was
proposed as outlined in Scheme 4.7a,13−15 Herein, this
synergistic annulation was successfully realized through the
concomitant catalytic generation of two reactive species: a
nucleophilic NHC-bound vinyl enolate II and a highly
electrophilic Pd-π-allyl species IV. The nucleophilic attack of
carbene D′ generated upon the deprotonation of D with
Cs2CO3 to 1a afforded the acyl azolium intermediate I.
Subsequent deprotonation of γ-H of I with a base produced
NHC-bound vinyl enolate II. In a parallel palladium catalytic
C
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catalytic cycle. Lastly, tautomerization of VII furnished the
more stable final product 3a.
Scheme 3. Synthetic Applications and Preliminary
Enantioselective Study
In conclusion, we have demonstrated the first [3 + 2]
annulation reaction of NHC-bound vinyl enolates with a Pd-π-
allyl species via a dual organo-metal catalytic process. Under
the properly optimized conditions, the free carbene catalyst
and the Pd catalyst could work well independently to
accomplish their own catalytic roles without quenching each
other. The rapid and stereoselective construction of (E)-3-
ethylidene-4-vinylpyrrolidin-2-one skeletons could be achieved
successfully in medium to good yields with excellent
compatibility of functional groups. In addition, encouraged
by the preliminary results of the asymmetric study, further
enantioselective annulation of NHC-bound vinyl enolates with
diverse transition metal-π-allyl species and other synthetic
applications are underway in our laboratory.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02935.
General information, experimental procedures, com-
pound characterizations, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Ding Du − Department of Chemistry, State Key Laboratory of
Natural Medicines, China Pharmaceutical University, Nanjing
210009, People’s Republic of China; orcid.org/0000-0002-
4615-5433; Email: ddmn9999@cpu.edu.cn
cycle, through the coordination of 2 to the palladium catalyst,
an active electrophilic Pd-π-allyl species IV could be generated
via the ring opening of aziridine. At this point, the NHC-
bound vinyl enolate II could undergo a nucleophilic attack to
the in-situ-formed Pd-π-allyl species IV with the formation of
intermediate V. Following this C−C bond formation, the
release of the Pd(0) gave rise to acyl azolium VI. This species
then underwent a N-acylation annulation to produce the cyclic
intermediate VII and regenerate carbene D′ for the next
Authors
Jian Gao − Department of Chemistry, State Key Laboratory of
Natural Medicines, China Pharmaceutical University, Nanjing
210009, People’s Republic of China; orcid.org/0000-0003-
0071-1972
Jianming Zhang − Department of Chemistry, State Key
Laboratory of Natural Medicines, China Pharmaceutical
University, Nanjing 210009, People’s Republic of China
Scheme 4. Proposed Reaction Mechanism
D
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Shuaishuai Fang − Department of Chemistry, State Key
Laboratory of Natural Medicines, China Pharmaceutical
University, Nanjing 210009, People’s Republic of China
Jie Feng − Department of Chemistry, State Key Laboratory of
Natural Medicines, China Pharmaceutical University, Nanjing
210009, People’s Republic of China; orcid.org/0000-0002-
8662-2198
Tao Lu − Department of Chemistry, State Key Laboratory of
Natural Medicines, China Pharmaceutical University, Nanjing
210009, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02935
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21572270 and 21702232) and the “Double First-
Class” University Project (Nos. CPU2018-GY02 and
CPU2018GY35) for financial support.
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