Tandem (2 + 2) Annulation/Retro-4πElectrocyclization/Imino-Nazarov Cyclization Reaction of p-Quinone Methides with Ynamides: Expeditious Construction of Functionalized Aminoindenes

Article abstract of DOI:10.1021/acs.orglett.1c02003

A new tandem annulation of p-quinone methides (p-QMs) with ynamides is described. This cascade reaction features a unique combination of (2 + 2) annulation, retro-4πelectrocyclization, and imino-Nazarov cyclization, wherein vinyl p-quinone methides (p-VQMs) as one of the key intermediates have been identified chemically. Significantly, an unusual structural reconstruction of p-QMs involving the cleavage of the C5-C6 bond and the late-stage formation of the C4-C6 bond is involved, leading to a methodology development for the construction of functionalized aminoindenes.

Full text of DOI:10.1021/acs.orglett.1c02003

pubs.acs.org/OrgLett
Letter
Tandem (2 + 2) Annulation/Retro-4π Electrocyclization/Imino-
Nazarov Cyclization Reaction of p‑Quinone Methides with
Ynamides: Expeditious Construction of Functionalized
Aminoindenes
Ke-Yin Yu, Yu-Hua Deng, Xiao-Min Ge, Xian-Tao An, Peng-Fei Shu, Ye-Xing Cao, Xian-He Zhao,*
and Chun-An Fan*
Cite This: Org. Lett. 2021, 23, 5885−5890
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ABSTRACT: A new tandem annulation of p-quinone methides
(p-QMs) with ynamides is described. This cascade reaction
features a unique combination of (2 + 2) annulation, retro-4π
electrocyclization, and imino-Nazarov cyclization, wherein vinyl p-
quinone methides (p-VQMs) as one of the key intermediates have
been identified chemically. Significantly, an unusual structural
reconstruction of p-QMs involving the cleavage of the C5−C6
bond and the late-stage formation of the C4−C6 bond is involved,
leading to a methodology development for the construction of
functionalized aminoindenes.
candidates for a new mode of tandem annulation of p-QMs
(Scheme 1d), wherein chemically interesting vinyl p-quinone
methide (p-VQM)7a,9 intermediates, which would be gen-
erated in situ via (2 + 2) annulation/retro-4π electrocyclization
cascade, could be unprecedentedly envisaged for imino-
Nazarov cyclization10 to yield the synthetically important
aminoindenes that constitute the crucial structural unit existing
in many bioactive molecules.11,12 Noteworthy is that an
uncommon structural reconstruction of p-QMs would be
logically imposed by the C6 migration from C5 to C4 in this
design. To our knowledge, the tandem chemistry involved in
this methodology is yet to be presented in the synthetic
community. Herein, we report our effort on this subject.
To probe the feasibility of our designed reaction, we
commenced our investigation using p-QM 1a and ynamide 2a
as model substrates. As shown in Table 1, commercially
available and environmentally benign iron salts (e.g., FeCl2,
FeCl3, FeCl3·6H2O, and Fe(OTf)3) as Lewis acid catalysts
were chosen first (entries 1−4). Among iron(II) and iron(III)
catalysts examined at room temperature in CH2Cl2, the use of
FeCl3 afforded the desired aminoindene 3aa in 80% yield
(entry 2). To improve the reaction reactivity, a series of Lewis
p-Quinone methides (p-QMs) featuring a unique bisvinylo-
gous enone system have been known as important structural
units embedded in a lot of natural products,1 and their
transient reactive intermediates generated in situ are also
involved in many biological processes.2 Due to their intrinsic
electrophilicity, partially enhanced by the aromatization driving
force, p-QMs have received considerable attention in the
design and development of methodology for organic syn-
thesis.3 Among the reaction modes chemically initiated by
electrophilic propensity of the quinone methide unit, alkynes
as C1 and C2 synthons have been recently introduced into the
methodology design of p-QMs. For example, 1,6-conjugate
additions of p-QMs with terminal alkynes or nucleophilic
species generated in situ from alkynes have been reported for
the synthesis of multisubstituted diarylmethanes (Scheme 1a).4
The (4 + 2) annulations of o-aminophenyl or o-hydroxyphenyl-
substituted p-QMs with ynones or electron-rich alkene
intermediates derived from alkynes have been disclosed for
accessing the aryl-substituted chromanes and hydroquinolines
(Scheme 1b).5 The (3 + 2) annulations of p-QMs with alkynes
as well as a cascade 1,6-conjugate addition/cyclization of
substituted p-QMs having a pendant alkynyl group have also
been revealed to construct spiro[4.5]cyclohexadienones
(Scheme 1c).6 Despite this elegant progress, the exploration
of chemical versatility of alkynes remains in high demand in
the design of innovative chemical transformations of p-QMs. In
connection with our continuing interest in the para-quinone
methide chemistry,7 ynamides8 as one of the heteroatom-
substituted alkyne synthons might be a class of appealing
Received: June 15, 2021
Published: July 19, 2021
https://doi.org/10.1021/acs.orglett.1c02003
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5885−5890
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With the above optimized conditions in hand, as shown in
Scheme 2, the scopes of p-QMs and ynamides were
Scheme 1. Modes of p-QMs with Alkynes and Our Design
Scheme 2. Substrate Scope for Tandem Annulation
a
Table 1. Reaction Conditions Optimization
b
entry
catalyst
FeCl2
FeCl3
FeCl3·6H2O
Fe(OTf)3
Sc(OTf)3
Cu(OTf)2
Zn(OTf)2
Bi(OTf)3
AgOTf
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
EtOAc
acetone
PhCl
16
70
80
79
70
67
54
40
67
73
91
87
85
60
83
0.5
0.5
0.5
2.0
2.5
48
2.0
2.5
3.5
4.0
24
a
Performed at 40 °C.
investigated for this tandem annulation. Compared with the
model p-QM 1a (R1 = Ph), a series of p-QMs (1b−1f, 1i, and
1j) with an electronically different para-substituted aryl R1
group (R1 = 4-C6H4NO2, 4-C6H4CO2Me, 4-C6H4F, 4-C6H4Cl,
4-C6H4Br, 4-C6H4Me, and 4-C6H4OMe) were investigated in
the presence of ynamide 2a. Except for the formation of 3ja in
a low yield of 30%,13 the corresponding annulation products
3ba−3fa and 3ia could be isolated in moderate to good yields
(52−97%). In the case using p-QM 1b (R1 = 4-C6H4NO2), a
prolonged reaction time of 60 h and an elevated reaction
temperature of 40 °C were required for the formation of 3ba in
56% yield, showing a somewhat negative influence of stronger
electron-deficient property of aromatic R1 to this tandem
annulation. In addition to above examples, meta-substituted p-
QM 1g (R1 = 3-C6H4Br) and ortho-substituted p-QM 1h (R1 =
2-C6H4Br) were examined subsequently. Compared with the
case for readily forming the expected product 3ga (3 h, 86%
yield), the presence of unfavorable ortho-steric effects led to
the prolonged time and decreased yield of the desired
aminoindene 3ha (24 h, 65% yield). Based on above evaluation
of C(sp2)-substituted p-QMs 1a−1j (R1 = aryl), one example
using C(sp3)-substituted p-QM 1k (R1 = t-Bu) was also
AgNTf2
AgNTf2
AgNTf2
AgNTf2
6.5
13
AgNTf2
a
Unless otherwise noted, all reactions were performed with 1a (0.1
mmol) and 2a (0.1 mmol) in the presence of catalyst (0.01 mmol) in
the indicated solvent (1.0 mL) at 25 °C. Yield of the isolated
product.
b
acid catalysts including Sc(OTf)3, Cu(OTf)2, Zn(OTf)2,
Bi(OTf)3, AgOTf, and AgNTf2 were then evaluated (entries
5−10). Of them, noteworthy is that AgNTf2 as catalyst could
afford the desired aminoindene 3aa in an optimal yield of 91%
(entry 10). Meanwhile, the solvent effect was also surveyed
using a different reaction medium (e.g., CHCl3, AcOEt,
acetone, and PhCl) (entries 11−14), despite no positive
influence on reaction efficiency.
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probed for this tandem reaction, and the aminoindene 3ka
could be delivered in 71% yield. The subsequent expansion of
substrate scope was additionally pursued using three C(sp)-
substituted p-QMs 1l−1n having an extended π-conjugate
system, and gratifyingly, the alkynyl-functionalized amino-
indenes 3la−3na were obtained in 65−86% yields at increased
reaction temperature of 40 °C. Furthermore, two p-QMs (1o
and 1p) with different substituents at α and α′ positions (R =
i-Pr, and TMS) were subjected to standard conditions in the
presence of 2a, and the desired aminoindenes 3oa and 3pa
could also be isolated in 89% and 50% yield, respectively. As
shown in Scheme 3, chemically unstable p-QM 1q generated in
Scheme 4. One-Pot Oxidation Based on Tandem
Annulation
Scheme 3. In Situ Protocol for Tandem Annulation
situ from p-hydroxybenzyl alcohol pre-1q was explored under
standard conditions for this tandem reaction, and the
anticipated aminoindene 3qa could be readily afforded in
73% yield. The structure of 3qa was clearly assigned by X-ray
crystallographic analysis (CCDC 2088736).14
As another influencing factor to this reaction, the structural
varieties of ynamides were further examined. As depicted in
Scheme 2, several ynamides (2b−2g) bearing different
substituents were probed in the presence of p-QM 1a, and
generally, the expected products 3ab−3ag could be afforded in
moderate to high yields (60−95%). For example, using
ynamides 2b−2d with a carbamate group and 2e with an
imide group gave the desired aminoindenes 3ab−3ae in 70−
90% yield, wherein styryl-substituted ynamide 2d and silyl-
substituted 2e were suitable for the current transformation.
Moreover, two ynamides with cyclic and acyclic sulfonamide
moieties, 2f (R2 = Ph, N(R3)EWG = dihydrosaccharin-2-yl)
and 2g (R2 = Ph, R3 = Bn, EWG = Ms), were introduced to the
current reaction, leading to the desired products 3af (7 days,
60% yield) and 3ag (12 h, 95% yield) albeit at a decreased rate.
Notably, the occurrence of atropisomers in 3ag (2:1 dr) was
observed in NMR spectra at room temperature, and the related
atropisomerism induced by partially hindered rotation of
a
b
PhI(OAc)2 (2.0 equiv) instead of Ag2O. Ag2O (2.0 equiv).
= cyclopropyl, N(R3)EWG = oxazolidin-2-on-3-yl) and 2j (R2
= cyclohexyl, N(R3)EWG = oxazolidin-2-on-3-yl) were
investigated in a one-pot oxidation procedure modified by
altering the oxidant or its equivalents, and chemically stable
inden-5-ones 4ai and 4aj could be isolated in 44% and 75%
yield, respectively. Moreover, one alkyl-substituted p-QM 1r
(R1 = Me) was used in this one-pot protocol, smoothly giving
the expected indan-5-one 4ra in 89% yield.
It should be noted that the corresponding in situ formed
aminoindene intermediates (3ai, 3aj, and 3ra), which were
involved in the generation of the above-mentioned inden-5-
ones (4ai, 4aj, and 4ra), were chemically unstable during their
chromatographic purification, to some extent manifesting the
importance of the present one-pot oxidation protocol in
expanding the scope of this tandem annulation. Based on such
an investigation, the structural diversity of indenones bearing
an alternative oxidative site, which could be commonly found
in pharmaceutical and bioactive natural products,12 was further
examined by identifying m-CPBA instead of Ag2O as oxidant,
and the tandem one-pot oxidation protocol followed by
dehydration and hydrolysis afforded the structurally useful
inden-1-one 5aa. The structures of 4ac, 4ah, and 5aa were
clearly confirmed by X-ray crystallographic analyses (CCDC
2076243, 2076244, and 2076245).14
1
C(sp2)−N bond was confirmed by variable-temperature H
NMR experiments.15 Interestingly, the recrystallization of 3ag
(2:1 dr) resulted in a crystal sample, which structure was
unequivocally established by X-ray crystallographic analysis
(CCDC 2076242).14 Furthermore, a gram-scale reaction for
accessing 3aa was also performed in good yield of 85%.
Chemically inspired by the serendipitous fact that the air
exposure of product 3aa could result in the partial formation of
inden-5-one 4aa, a one-pot oxidation protocol based on this
tandem annulation was then explored. As illustrated in Scheme
4, a one-pot general procedure was representatively probed
using p-QM 1a and ynamide 2a, followed by addition of the
oxidant Ag2O (1.0 equiv) to the reaction mixture at the end of
tandem annulation. Pleasingly, the indan-5-one product 4aa
was delivered in a good yield of 82%. Subsequently, ynamides
2c (R2 = 4-C6H4NO2, N(R3)EWG = oxazolidin-2-on-3-yl) and
2h (R2 = R3 = Ph, EWG = Ms) were subjected to this protocol
to provide the expected products 4ac (72% yield) and 4ah
(83% yield). In addition, two alkyl-substituted ynamides 2i (R2
To gain insight into this tandem annulation, several control
experiments were run. As shown in Scheme 5, p-QM 1n and
ynamide 2f were used as substrates to capture some chemically
identifiable intermediates. When the title annulation was
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In conclusion, an unprecedented tandem annulation
reaction of p-QMs with ynamides has been developed, wherein
the transformations including (2 + 2) annulation, retro-4π
electrocyclization, and imino-Nazarov cyclization are involved.
This reaction is characterized by partially structural recon-
struction of p-QMs involving the shift of C6 from C5 to C4
through the cleavage of C5−C6 bond in retro-4π electro-
cyclization and subsequent formation of the C4−C6 bond in
imino-Nazarov cyclization, providing an effective approach to
the expeditious assembly of various highly functionalized
aminoindenes. Notably, p-VQMs as one of the key
intermediates of this tandem annulation are chemically
identified via control experiments. Moreover, one-pot
oxidation protocol based on this cascade annulation has also
been established to yield structurally useful indenones. The
present tandem annulation methodology not only furnishes a
new method for assembling synthetically interesting, function-
alized aminoindenes, and indenones but also enriches the
chemistry of p-quinone methides in organic synthesis.
Scheme 5. Control Experiments
conducted under standard conditions, the aminoindene 3nf
could be isolated in 48% yield with a reaction time of 8 days
(route ①). Importantly, the slow conversion of this reaction
enables an observation of vinyl p-quinone methide (p-VQM)
6nf, which could be isolated in 85% yield after 12 h (route ②).
The structure of 6nf was clearly assigned by X-ray crystallo-
graphic analysis (CCDC 2076246).14 Interestingly, while p-
VQM 6nf was subjected to the standard conditions, the
desired aminoindene 3nf could be obtained with analogous
efficiency (46% yield, 7 days) (route ③), mostly implying the
possibility of p-VQM 6nf as an intermediate in this tandem
annulation.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02003.
Experimental procedures and spectral data (PDF)
Accession Codes
CCDC 2076242−2076246 and 2088736 contain the supple-
mentary 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 Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Based on the above experimental results, a plausible
mechanism was proposed in Scheme 6. Initially, the (2 + 2)
Scheme 6. Plausible Mechanism
AUTHOR INFORMATION
Corresponding Authors
■
Chun-An Fan − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China; orcid.org/
0000-0003-4837-3394; Email: fanchunan@lzu.edu.cn
Xian-He Zhao − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China;
Email: zhaoxh@lzu.edu.cn
Authors
Ke-Yin Yu − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Yu-Hua Deng − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education, School of Chemical
Science and Technology, Yunnan University, Kunming
650091, China; orcid.org/0000-0002-1983-8490
Xiao-Min Ge − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Xian-Tao An − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
annulation of p-QMs 1 with ynamides 2 proceeded to yield the
spirocyclobutenyl p-dienones B through an intramolecular
dearomatizing cyclization of keteniminium ion species A,
resulting from 1,6-conjugate addition of ynamides 2 to p-QMs
1. Driven by the release of ring strain of the cyclobutene
framework, a retro-4π electrocyclization involving a C5−C6
cleavage might account for the formation of p-VQMs 6, which
have been chemically verified through X-ray crystallographic
analysis. Then, an unusual imino-Nazarov cyclization10 via
zwitterionic 6′ as a resonance contributor of 6 took place to
give the aminoindenes 3 having a partial C−C bond
reconstruction.
Peng-Fei Shu − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
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Cascade Cyclization/1,6-Conjugate Addition of Homopropargyl
Sulfonamides to p-Quinone Methides: An Approach to Diverse 3-
Diarylmethine Substituted Dihydropyrroles. J. Org. Chem. 2020, 85,
15038.
Ye-Xing Cao − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02003
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from NSFC (21825104,
22071091, 21801103, 21801221), China Postdoctoral Science
Foundation (2020M683603), FRFCU (lzujbky-2021-28,
lzujbky-2021-pd02), the Yunnan Province Government
(YNQR-QNRC-2018-005, 202101AT070156), and PCSIRT
(IRT_15R28).
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(13) In addition to the desired product 3ja, a regular cyclization
product 3ja′ was isolated in 50% yield. This side product resulted
from a competitive intramolecular keteniminium ion-initiated
Friedel−Crafts cyclization (for details, see page S11 of the Supporting
Information).
(14) The intensity data were collected on an Agilent SuperNova
(Dual, Cu at zero, Eos) diffractometer using graphite-monochromated
Cu Kα (λ = 1.54184 Å) radiation.
(15) For details, see the Supporting Information.
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