Cu(I)-catalyzed oxidative cyclization of enynamides: Regioselective access to cyclopentadiene frameworks and 2-aminofurans

Article abstract of DOI:10.1021/acs.orglett.0c02317

An efficient Cu(I)-catalyzed oxidative cyclization of alkynyl-tethered enynamides for the construction of fused bicyclic cyclopentadiene derivatives is disclosed. The cascade proceeds through alkyne oxidation, carbene/alkyne metathesis, and formal (3 + 2)

Full text of DOI:10.1021/acs.orglett.0c02317

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Letter
Cu(I)-Catalyzed Oxidative Cyclization of Enynamides: Regioselective
Access to Cyclopentadiene Frameworks and 2‑Aminofurans
Wen-Bo Shen,* Xiang-Ting Tang, Ting-Ting Zhang, Si-Yu Liu, Jiang-Man He, and Tong-Fu Su
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ABSTRACT: An efficient Cu(I)-catalyzed oxidative cyclization of alkynyl-tethered enynamides for the construction of fused
bicyclic cyclopentadiene derivatives is disclosed. The cascade proceeds through alkyne oxidation, carbene/alkyne metathesis, and
formal (3 + 2) cycloaddition. Employing aryl-tethered enynamides as starting materials, substituted 2-aminofurans can be exclusively
formed.
Scheme 1. Generation of α-Oxo Metal Carbenes
he highly efficient construction of cyclopentadiene
skeletons, which have proven to be versatile building
T
blocks since the first reports of the preparation and
characterization of 1,3-cyclopentadiene in 1896 by Kraemer
and Spilker,1 is an important subject in organic synthesis.
Cyclopentadienes with maleimide derivatives can be smoothly
converted into bicyclo[2.2.1]heptene frameworks, which are
found in drug candidates as well as in bioactive molecules, via
the Diels−Alder reaction.2 Although numerous imposing
methods have been developed for the synthesis of function-
alized cyclopentadienes,3 a practical and efficient approach for
the synthesis of this type of skeleton remains an intriguing
theme for the synthetic community.
Carbo- or heterocycles can be readily constructed by
transition-metal-catalyzed carbene reactions in organic syn-
thesis.4 Among those, carbene/alkyne metathesis reactions
have received particular attention in recent years, as this access
would provide great potential in the assembly of structurally
complex molecules.5 Notably, vinyl metal carbene intermedi-
ates generated via carbene/alkyne metathesis reactions, as
pioneered by Padwa6 and Hoye,7 have been widely applied to
various catalytic annulations, including cycloadditions,8
Buchner reactions,9 and C−H insertions.10 For example,
May et al.10a disclosed the rhodium-catalyzed carbene/alkyne
metathesis, leading to bridged polycyclic products with alkynyl-
tethered diazo substrates (Scheme 1a). In addition, the Xu
group developed a dirhodium-catalyzed intramolecular car-
bene/alkyne metathesis of alkynyl-tethered styryl diazo
substrates to give bicyclic cyclopentadiene derivatives.8a
However, the use of hazardous, not readily accessible diazo
Received: July 11, 2020
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Org. Lett. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

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Letter
a
compounds has severely limited further synthetic applications
of this strategy. Consequently, the development of alternative
and general approaches is still highly desirable.
Table 1. Optimization of Reaction Conditions
Recently, gold catalysis has been rapidly developed, which
has provided a fungible method for the formation of carbenes11
via alkyne oxidations, as pioneered by L. Zhang.12 Among
these advances, enyne oxidations have attracted increasing
attention, and various synthetic methods have been devel-
oped.13 For instance, Liu et al.13a disclosed the gold-catalyzed
oxidative enyne cyclization, affording 3-carbonyl-1H-indene
compounds (Scheme 1b). Although a few other variants have
been discovered by Tang,13b J. Zhang,13c L. Zhang,13d and
Li,13e these enyne oxidations have been restricted to noble-
metal catalysts, which has severely hampered the practical
application of this approach. To our knowledge, non-noble-
metal-catalyzed alkynyl-tethered enyne oxidation to generate
vinyl metal carbene intermediates has not been reported to
date.
Inspired by the previously described results, we envisaged
that α-oxo metal carbene might be formed through the non-
noble-metal-catalyzed oxidative cyclization of alkynyl-tethered
enynamides 1 with N-oxides 2 (Scheme 1c). The carbene
intermediate, probably highly electrophilic, could be further
attacked by the tethered alkynyl group to lead to a carbene/
alkyne metathesis reaction, giving bicyclic cyclopentadiene
derivatives 3. However, two possible competitive reactions are
confronted: (1) This type of carbene intermediate is easily
dioxidized by an N-oxide,13b,14 and (2) the generated alkenyl
metal carbene can proceed to an oxa-Nazarov cyclization via a
metal-stabilized allylic cation intermediate.13f,15 Herein we
disclose a novel procedure for the highly regioselective
synthesis of a range of cyclopenta[c]pyrrol-1(2H)-ones. Of
particular note is that this protocol represents the first
generation of α-oxo copper carbenes via the copper-catalyzed
intermolecular reaction of alkynyl-tethered enynamides and N-
oxides.
entry
cat. (x mol %)
oxidant
T (°C)
yield (%)
1
2
3
4
5
6
7
8
Cu(OTf)2 (10)
CuOTf (10)
Cu(CH3CN)4BF4 (10)
Cu(CH3CN)4PF6 (10)
Zn(OTf)2 (10)
2a
2a
2a
2a
2a
2a
2a
2a
2b
80
80
80
80
80
80
60
25
60
60
60
60
60
60
45
48
42
62
11
16
84
10
21
<1
<1
<1
23
10
Y(OTf)3 (10)
Cu(CH3CN)4PF6 (10)
Cu(CH3CN)4PF6 (10)
Cu(CH3CN)4PF6 (10)
Cu(CH3CN)4PF6 (10)
TsOH (10)
MsOH (10)
Ph3PAuCl/AgNTf2 (5)
[Rh(CO)2Cl]2 (5)
9
10
11
12
13
14
2a
2a
2a
2a
a
Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), catalyst (5−10
mol %), 0.05 M.
a
Scheme 2. Reaction Scope Study
As shown in Table 1, the reaction of enynamide 1a and
oxidant 2a, by using copper catalysis, was first investigated. To
our delight, the desired cyclopenta[c]pyrrol-1(2H)-one 3a was
indeed formed in 45% yield (entry 1). Later, additional copper
catalysts were further screened, and Cu(CH3CN)4PF6 could
commendably catalyze this reaction to give 3a in 62% yield
(entries 2−4). Moreover, 3a can be also obtained when other
Lewis acids such as Zn(OTf)2 and Y(OTf)3 are used as the
catalyst, but in significantly decreased yields (entries 5 and 6).
Subsequently, a temperature screening was carried out, and 3a
could be generated in 84% yield when this cascade reaction
worked best at 60 °C (entries 7 and 8). Further screening of
oxidants revealed that 3a was obtained in 21% yield by the use
of 3,5-dichloropyridine N-oxide 2b (entry 9), and no
formation of 3a was observed in the absence of an oxidant
(entry 10). No 3a was detected when Brønsted acids such as
TsOH and MsOH were used as the catalyst (entries 11 and
12). Notably, cyclopenta[c]pyrrol-1(2H)-one 3a was formed in
only 23 and 10% yield in the presence of typical noble-metal
catalysts Ph3PAuCl/AgNTf2 and [Rh(CO)2Cl]2, respectively
(entries 13 and 14).
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), Cu-
(CH3CN)4PF6 (10 mol %), DCE (4.0 mL), 60 °C (60 °C, heating
mantle temperature) in vials. Isolated yields are reported. PG =
protecting group. Bn = benzyl.
With the optimized reaction conditions in hand, we then
studied the scope of this transformation. As shown in Scheme
2, the reaction successfully proceeded with various alkynyl-
tethered enynamide substrates 1, and the yields ranged from
66 to 87%. We first examined the different N-protecting groups
of enynamides, and Ms-protected enynamide 1a reacted to
give the best yields (entries 1−4). We then investigated a range
of aryl-substituted enynamides (R5 = Ar), which delivered the
B
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Letter
desired cyclopenta[c]pyrrol-1(2H)-ones 3e−k in 68−86%
yields (entries 5−11). Of particular note is the fact that the
heterocycle-substituted enynamide 1l was applicable to this
procedure to yield 3l in 70% yield (entry 12). Moreover,
products 3m−o were readily obtained in 67−74% yields
(entries 13−15). We tried the reaction using 1u, where R1 was
an alkyl group, but no desired product was observed. This
reaction proceeded smoothly with a range of substituted
enynamides, and the resulting products were efficiently
afforded. This protocol displayed good functional group
When the scope of this Cu catalysis was extended to aryl-
tethered enynamide 4o, the corresponding 2-aminofuran 5oa
was obtained in 31% yield, and the ketoamide 5ob was formed
in 48% yield (eq 1). These results indicated that the methyl
group stabilized the allylic cation toward an oxa-Nazarov
cyclization. Moreover, it was found that subjecting 2-
cyclohexenyl-1-ethynylamide 4p to copper catalysis generated
dienylamide 5p in 61% yield (eq 2).
n
compatibility, and enynamides with substituents, such as Pr,
cyclopropyl, cyclopentyl, cyclohexyl, and Bn, were well
tolerated, yielding the desired products 3p−t in 76−87%
yield (entries 16−20). Thus this reaction provided a powerful
strategy for the construction of bicyclic cyclopentadiene
derivatives for organic synthesis.
Apart from alkynyl-tethered enynamides, aryl-tethered
enynamides reacted under similar conditions to provide
substituted 2-aminofurans via an oxa-Nazarov cyclization.
This is an unprecedented Cu(I)-catalyzed oxidative cyclization
of aryl-tethered enynamides for the construction of substituted
furans, which is an alternative approach to the gold-catalyzed
oxidative enynamide oxa-Nazarov cyclization, as previously
reported by Liu.13f Thus the reaction of aryl-tethered
enynamides 4 with 3,5-dichloropyridine N-oxide 2b in the
presence of Cu(CH3CN)4PF6 (10 mol %) smoothly furnished
2-aminofurans 5a−n in 69−92% yields (Scheme 3). Of note,
Further synthetic transformations of the synthesized cyclo-
pentadiene frameworks were also explored, as shown in
Scheme 4. The treatment of cyclopenta[c]pyrrol-1(2H)-one
Scheme 4. Transformation of the Products
Scheme 3. Reaction Scope for the Formation of 2-
a
Aminofurans 5
3a with N-aryl-substituted maleimide led to the corresponding
adduct 6 in 76% yield through the Diels−Alder reaction.
Furthermore, 2-aminofuran 5a could be converted into the 2-
amino-3-thiocyanatofuran 7 in 82% yield via a palladium-
catalyzed sp2 C−H bond thiocyanation.16 The treatment of 5a
with N-iodosuccinimide (NIS) delivered product 8 in 68%
yield.
A possible mechanism for the formation of 3a and 5a is
presented (Scheme 5). First, A is formed through the
coordination of the catalytic [CuI] species to the aminated
triple bond, which is site-selectively trapped by the 8-
methylquinoline N-oxide 2a or 3,5-dichloropyridine N-oxide
2b to give α-oxo alkenylcopper carbene intermediate C.17
Subsequently, this species is attacked by the internal alkynyl
group and converted to intermediate D1 through carbene/
alkyne metathesis. D1 then undergoes cyclization to yield
bicyclic intermediate E1 rather than the previously observed
second oxidation to form the diketone compound.13b,14
Finally, proto-demetalation/proton transfer proceeds smoothly
to provide the final product 3a. When R3 = Ph, carbene
intermediate C, with its resonance contributor E2, undergoes
an oxa-Nazarov cyclization. Proton transfer and ligand
exchange furnish product 5a.
a
Reaction conditions: 4 (0.2 mmol), 2b (0.3 mmol), Cu-
(CH3CN)4PF6 (10 mol %), DCE (4.0 mL), 80 °C (80 °C, heating
mantle temperature) in vials. Isolated yields are reported. 1.0 mmol
scale.
b
substituted aromatic rings of different electronic properties
were readily tolerated. The molecular structure of 5l was
confirmed by X-ray diffraction. This transformation presum-
ably involved an oxa-Nazarov cyclization of copper-stabilized
allylic cations.
In summary, prior to this study, intermolecular oxidation
reactions of enynes with pyridine N-oxides or quinoline N-
oxides were limited to noble-metal catalysts. Herein we report
a copper-catalyzed oxidative cyclization of alkynyl-tethered
enynamides, leading to various bicyclic cyclopentadiene
C
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Tong-Fu Su − College of Sciences, Henan Agricultural
University, Zhengzhou, Henan 450002, China
Scheme 5. Plausible Reaction Mechanism for the Formation
of 3a and 5a
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02317
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Top-Notch Talents Program of Henan
Agricultural University (30500739) for financial support.
■
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AUTHOR INFORMATION
Corresponding Author
■
Wen-Bo Shen − College of Sciences, Henan Agricultural
University, Zhengzhou, Henan 450002, China; orcid.org/
0000-0003-0416-3571; Email: wenboshen@henau.edu.cn
Authors
Xiang-Ting Tang − College of Sciences, Henan Agricultural
University, Zhengzhou, Henan 450002, China
Ting-Ting Zhang − College of Sciences, Henan Agricultural
University, Zhengzhou, Henan 450002, China
Si-Yu Liu − College of Sciences, Henan Agricultural University,
Zhengzhou, Henan 450002, China
Jiang-Man He − College of Sciences, Henan Agricultural
University, Zhengzhou, Henan 450002, China
D
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