Ring-Opening/Recyclization Cascades of Monoactivated Cyclopropanes

Article abstract of DOI:10.1021/acs.orglett.0c01056

A variety of cyclopropyl aryl ketones undergo uncatalyzed cascade ring-opening/recyclization reactions to generate indenones and fluorenones. In addition, a new strategy to access 3-hydroxyindanones possessing two contiguous stereogenic centers, one of th

Full text of DOI:10.1021/acs.orglett.0c01056

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Letter
Ring-Opening/Recyclization Cascades of Monoactivated
Cyclopropanes
Uttam K. Mishra,# Kaushalendra Patel,# and S. S. V. Ramasastry*
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ABSTRACT: A variety of cyclopropyl aryl ketones undergo uncatalyzed cascade
ring-opening/recyclization reactions to generate indenones and fluorenones. In
addition, a new strategy to access 3-hydroxyindanones possessing two contiguous
stereogenic centers, one of them being an all-carbon quaternary center, was also
established. During the course of the investigation, pronounced solvent,
temperature, and substituent effects on the product distribution were discovered.
everal bioactive natural products and pharmaceutically
important compounds embody cyclopropane moiety as
On the other hand, the ring opening of monoactivated
cyclopropanes (D in Scheme 1) is known to be extremely
challenging (Scheme 1b).7 An overview of the literature reveals
that simple cyclopropyl aryl ketones require severe conditions,
such as strong nucleophiles, strong Lewis acids, or organo-
metallic reagents often in stoichiometric quantities, to effect
desired ring-opening transformations.8
Taking cues from the DAC concept, it was envisioned that
the introduction of an additional electron withdrawing group
(EWG) on the arene ring of cyclopropyl aryl ketones could
induce more polar character to the C1−C2 bond, thereby, the
ring cleavage could be accomplished under milder conditions
(Scheme 2). The presence of two electron acceptor groups on
one side can, in principle, mimic cyclopropanes with two
geminal activators (B) and presumably facilitate an easy
cleavage of the C1−C2 bond. Furthermore, it was anticipated
that an appropriate choice of the EWG at the ortho position
could also serve as an electron sink during anionic cyclizations
that might occur during the ring-opening event.
S
the primary structural entity.1 The strained three-membered
carbocycles can undergo a variety of ring transformations to
generate new molecular architectures.2 Among them, the
intermolecular and intramolecular ring-opening cyclization of
“activated cyclopropanes” provide myriad of opportunities for
the synthesis of a wide range of carbocycles and heterocycles.
Broadly, three classes of activated cyclopropanes are tradition-
ally pursued in organic synthesis: (i) donor−acceptor cyclo-
propanes (DACs) (denoted as A),3 (ii) cyclopropanes
possessing two geminal electron-withdrawing groups (B),4
and (iii) vinyl cyclopropanes (C)5 (see Scheme 1a). These
structures can be manipulated under acidic conditions or with
organometallic reagents to participate in a variety of ring-
opening cyclization reactions, and this topic has been the
subject of several excellent reviews.2,6
Scheme 1. Background of Activated Cyclopropanes
Here, we present ring-opening and recyclization reactions of
a new class of monoactivated cyclopropanes under catalyst-free
conditions (see Scheme 2). Depending on the nature of the
EWG in E, synthesis of a variety of indenones and fluorenones
(F−H) with unusual substitution patterns is achieved under
Received: March 23, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01056
© XXXX American Chemical Society
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A

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Letter
aryl ketones. Further encouraged by the fact that pentannu-
lated aromatics are privileged scaffolds, because of their
occurrence in numerous biologically active natural products,
pharmaceuticals, and organic materials,12 we commenced to
evaluate the substrate scope.
Scheme 2. Hypothesis Behind the Substrate Design, and
This Work
Under the optimized condition, a range of cyclopropyl keto-
aldehydes 1 underwent a cascade of transformations for the
formation of a variety of 2-(2-hydroxyethyl)indenones (2b−
2m) in good yields (Scheme 3). Unlike traditional substituent-
Scheme 3. Substrate Scope: 2-(2-Hydroxyethyl)indenones
a b
,
2
thermal conditions. Thereby, a new substrate-based diversity-
oriented folding pathway is also established.9
Based on the hypothesis presented in Scheme 2, the 2-
(cyclopropanecarbonyl)benzaldehyde 1a was prepared and it
was subjected to heating conditions (see Table 1). The
a
Table 1. Optimization of Reaction Parameters
b
c
entry
solvent
DMF
CH3CN
temperature
reaction time, t (d) yield (%)
1
2
3
4
5
6
7
8
9
130
reflux
reflux
110
reflux
130
80
110
130
5
5
5
3
3
4
5
5
3
−
−
−
1,4-dioxane
toluene
1,2-DCE
−
85 (3a)
91 (3a)
75 (3a)
−
a
See the Supporting Information for details regarding the reaction
b
conditions. Chromatographic yields.
DMSO
DMSO
DMSO
−
dependent reactivity patterns exhibited by cyclopropanes, the
reaction worked efficiently even with unsubstituted cyclo-
propanes (2b and 2c). Even the presence of alkyl groups, and
aryl groups bearing either electron-donating or withdrawing
groups at R1 were well-tolerated (2d−2m). Evidently, the
electronic nature of the substituents on the arene backbone
had the least influence on the course of the reaction (2b, 2c,
2e, 2f, 2k−2m). A narrow yield range (60%−73%) across the
substrates verified herein is an indicative of the robustness of
the method. It is interesting to note that alcohol elimination
product (leading to 2-vinylindenones) was never realized
during the course of the study. On the other hand, the reaction
of the substrate 5a, possessing the aldehyde functionality para
to cyclopropylketo group, gave no product, even after
prolonged reaction time, indicating that the indenone
formation was the driving force for the otherwise-difficult
cyclopropane ring opening.
61 (2a)
a
See the Supporting Information for details regarding the reaction
b
conditions. DMF = dimethylformamide; 1,2-DCE = 1,2-dichloro-
ethane; DMSO = dimethylsulfoxide. Chromatographic yields.
c
formation of 4a was expected based on the general reactivity
pattern of cyclopropyl ketones;10 however, only the indenone
2a was isolated.11 A pronounced solvent and temperature
dependence on the product formation was realized during the
evaluation of reaction parameters. For example, 1a remained as
such when heated in dimethylformamide (DMF), acetonitrile,
or 1,4-dioxane, whereas in toluene and 1,2-dichloroethane, the
formation of the oxidized product 3a was observed (Table 1,
entries 1−5). The role of the solvent (dimethylsulfoxide,
DMSO) was further evident when 1a was heated neat, it only
generated the acid 3a (Table 1, entry 6). On the other hand,
the reaction of 1a in DMSO at 130 °C resulted in the
formation of 2a, while no product formed at lower temper-
atures (Table 1, entries 7−9).
Having evaluated the reactivity of monosubstituted and
disubstituted cyclopropanes, the 1,1,2-trisubstituted cyclo-
propyl ketone 6a was prepared and subjected to the optimal
conditions (see Scheme 4). An unexpected product 7a
possessing two contiguous stereogenic centers, one of them
To our knowledge, the transformation of 1a to 2a represents
the first uncatalyzed ring-opening/recyclization of cyclopropyl
B
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a b
,
Scheme 4. Substrate Scope: 2,2-Disubstituted-3-
Hydroxyindanones 7 and 8
Scheme 5. Substrate Scope: 2-Styryl-3-arylindenones 10
a,b,c
a
See the Supporting Information for details regarding the reaction
b
c
conditions. Chromatographic yields. Diastereomeric ratio (dr)
determined from crude H NMR.
1
being an all-carbon quaternary center, was isolated in good
yield and moderate diastereoselectivity. This method was
realized to be general and provided efficient access to other
significant analogues 7b−7e. The structure including the
relative stereochemistry of the major diastereomer was
confirmed from the X-ray diffraction (XRD) analysis of 7a.13
Interestingly, the formation of terminal olefins was observed
with alkyl substituents at R1 (8a and 8b). From Schemes 3 and
4, it is evident that a substituent-dependent product formation
is established.
While exploring the scope of the method, the cyclopropyl
keto−ketone 9a was prepared and subjected under the
optimized condition (see Scheme 5). Unexpectedly, 2-styryl-
3-phenylindenone 10a was isolated in good yield. Since the
synthesis of such scaffolds has been rarely described in the
literature,9c,14 a few other 2-styrylindenones were prepared in
an analogous manner.
a
See the Supporting Information for details regarding the reaction
b
conditions. Chromatographic yields.
fluorenones (12b−12h) were synthesized. Monosubstituted
fluorenones such as 12i can also be accessed from
unsubstituted cyclopropyl keto-enone 11i. An attractive feature
of this method is that it facilitates the rapid assembly of various
types of symmetric and unsymmetric fluorenones, as well as
monosubstituted, disubstituted, trisubstituted, and tetrasub-
stituted fluorenones, under reagent-free conditions.
It is evident from Scheme 5 that substituents at R1, R2, and
R3, possessing a variety of steric and electronic characters, were
well-tolerated and generated the respective 2-styryl-3-arylinde-
nones 10b−10k in good yields. For example, (i) electron-rich
as well as electron-poor arene rings can be placed at R1 (10e,
10g, 10i−10k); (ii) 10c is a special case; having a 1-pyrenyl
group at R2, it exhibits interesting physicochemical proper-
ties;15 (iii) 10d and 10e are incorporated with sterically
encumbered ortho-tolyl substituent at R2; (iv) electron-
donating groups on the arene backbone also fared well
(10f−10k); and (v) 10k represents as an analogue of
resveratrol-based natural products, such as paucifloral F,
ampelopsin D, caraphenol B, and others.16 Unlike the case
of cyclopropylketo-aldehydes (1a−1d), unsubstituted cyclo-
propylketo-ketones 10l and 10m were not tolerated under the
optimized conditions.
Encouraged by the results obtained for cyclopropyl keto-
aldehydes (1) and cyclopropyl keto−ketones (9), the reaction
of cyclopropyl keto-eneone 11a under the prototypical
conditions was considered (see Scheme 6). To our surprise,
the 2,3-disubstituted fluorenone 12a was isolated in 77% yield.
Having realized the significance of fluorenones in natural
products chemistry as well as in materials science,17 a few more
The critical role of DMSO on the aforementioned
transformations is evident from experimental results. In
addition, a few control experiments were performed, as
shown in Scheme 7 , to elucidate mechanistic details: (i) the
reaction of 1g in anhydrous DMSO and H218O yielded 2g in
70%, with no evidence of the incorporation of 18O, indicating
that the source of oxygen in the hydroxyl group of 2g is not
water (eq 1); (ii) 18O-incorporated cyclopropylketo-aldehyde
1g-18O under optimized conditions gave 2g devoid of 18O,
suggesting that the source of hydroxyl group in 2g also is not
the aldehyde functionality (eq 2); (iii) the outcome of the
reaction of 1g performed under anhydrous conditions, to
ascertain whether water assists DMSO during the trans-
formation, shows that DMSO holds an independent role (eq
3); (iv) the reaction of 1g was also conducted in a mixture of
toluene-DMSO (eq 4). However, there was no indication of
the formation of 2g, further, the starting compound 1g was
realized to be decomposing slowly. Based on these results, in
C
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Scheme 6. Substrate Scope: 2,3-Disubstituted Fluorenones
12
Scheme 8. Plausible Mechanism
a b
,
a
See the Supporting Information for details regarding the reaction
b
conditions. Chromatographic yields.
Scheme 7. Control Experiments
elimination of DMSO and water from O affords 10 (Scheme
8c).
The formation of 2,3-disubstituted fluorenones 12 might be
involving a cascade of events, as depicted in P and Q (Scheme
8d). Thus, a sequence of ene-type cyclization, deprotonation
and dehydration reactions generates the dihydrofluorenone R,
which, upon oxidative aromatization, forms 12.19
In summary, an unprecedented metal- and acid-free ring-
opening/recyclization cascade of cyclopropyl aryl ketones has
been established. All the new strategies described herein
provide straightforward and efficient access to unique
pentannulated aromatics such as 2-(2-hydroxyethyl)indenones,
2,2-disubstituted-3-hydroxyindanones, 2-styryl-3-arylinde-
nones, and 2,3-disubstituted fluorenones. Intriguing mecha-
nistic details governing these processes are also elucidated.
Some of the key advantages of this work include (i) the ease of
operation, (ii) readily accessible starting materials, and (iii)
high atom economy. Efforts to apply the methods described
herein for the synthesis of bioactive natural products are in
progress, and the results will be communicated shortly.
addition to related literature reports,18 a plausible mechanism
is proposed in Scheme 8.
The reaction leading to the formation of 2 presumably
commences with a DMSO-assisted ring-opening of cyclopropyl
ketones I (see Scheme 8a). The zwitterionic species J then
reorganizes to K (or L), which undergoes a 1,4-proton shift
and a concomitant loss of DMSO to generate indenones 2.
The formation of 7 and 8 can be explained via the
intermediacy of M (see Scheme 8b). The elimination of
DMSO, followed by a deprotonation−protonation sequence,
provides indanones 7 or 8, depending on the substitution
pattern.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01056.
Experimental details; complete characterization data of
all new compounds (melting points, IR, NMR, and
HRMS); X-ray crystallographic data of 2g′ and 7a
(PDF)
The mechanism for 2-styryl-3-arylindenones 10 presumably
involves the zwitterionic intermediate N, which undergoes a
1,4-proton shift analogous to L to generate O. An eventual
D
https://dx.doi.org/10.1021/acs.orglett.0c01056
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Organic Letters
Accession Codes
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Letter
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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, U.K.; fax: + 44 1223
336033.
AUTHOR INFORMATION
Corresponding Author
■
S. S. V. Ramasastry − Organic Synthesis and Catalysis Lab,
Department of Chemical Sciences, Indian Institute of Science
Education and Research (IISER) Mohali, S A S Nagar, Punjab
140306, India; orcid.org/0000-0001-5814-9092;
Email: ramsastry@iisermohali.ac.in
Authors
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Org. Lett. 2004, 6, 2225. (b) Shi, M.; Yang, Y.-H.; Xu, B. Tetrahedron
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50, 12067. (e) Xu, P.-W.; Liu, J.-K.; Shen, L.; Cao, Z.-Y.; Zhao, X.-L.;
Yan, J.; Zhou, J. Nat. Commun. 2017, 8, 1619. (f) Li, J.; Zhu, S.; Xu,
Q.; Liu, L.; Yan, S. Org. Biomol. Chem. 2019, 17, 10004.
(9) (a) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004,
Uttam K. Mishra − Organic Synthesis and Catalysis Lab,
Department of Chemical Sciences, Indian Institute of Science
Education and Research (IISER) Mohali, S A S Nagar, Punjab
140306, India
Kaushalendra Patel − Organic Synthesis and Catalysis Lab,
Department of Chemical Sciences, Indian Institute of Science
Education and Research (IISER) Mohali, S A S Nagar, Punjab
140306, India
43, 46. (b) Plesniak, M. P.; Garduno-Castro, M. H.; Lenz, P.; Just-
̃
Baringo, X.; Procter, D. J. Nat. Commun. 2018, 9, 4802. (c) Mishra, U.
K.; Patel, K.; Ramasastry, S. S. V. Org. Lett. 2019, 21, 175.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01056
́
(10) (a) Richmond, E.; Vukovic, V. D.; Moran, J. Org. Lett. 2018, 20,
574. (b) Gupta, A.; Kholiya, R.; Rawat, D. S. Asian J. Org. Chem.
2017, 6, 993.
Author Contributions
#U.K.M. and K.P. contributed equally.
Notes
(11) The structure of 2a was assigned based on the X-ray diffraction
analysis of 2g′.
(12) For recent reviews, see: (a) Satpathi, B.; Mondal, A.;
Ramasastry, S. S. V. Chem. - Asian J. 2018, 13, 1642. (b) Vivekanand,
T.; Satpathi, B.; Bankar, S. K.; Ramasastry, S. V. RSC Adv. 2018, 8,
18576.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(13) Please see the Supporting Information for details.
(14) (a) Wang, S.; Zhu, Y.; Wang, Y.; Lu, P. Org. Lett. 2009, 11,
2615. (b) Li, B. J.; Wang, H.-Y.; Zhu, Q.-L.; Shi, Z.-J. Angew. Chem.,
Int. Ed. 2012, 51, 3948.
(15) See the Supporting Information for details about the
photophysical properties of 10c.
(16) For paucifloral F, see: (a) Bankar, S. K.; Singh, B.; Tung, P.;
Ramasastry, S. S. V. Angew. Chem., Int. Ed. 2018, 57, 1678. For
ampelopsin D, see: (b) Snyder, S. A.; Zografos, A. L.; Lin, Y. Angew.
Chem., Int. Ed. 2007, 46, 8186. For caraphenol B, see: (c) Sudhakar,
G.; Satish, K. Chem. - Eur. J. 2015, 21, 6475. (d) Klotter, F.; Studer, A.
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Org. Lett. 2011, 13, 5524.
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B.; Wagulde, S. V.; Ramasastry, S. S. V. Chem. Commun. 2017, 53,
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(19) To a certain extent, the mechanism described in Scheme 8 can
also be explained by invoking the loss of dimethyl sulfide. However,
we could not gain any evidence in favor of this reaction pathway.
IISER Mohali is thanked for funding, and for the NMR, as well
as mass and departmental X-ray facilities. S.S.V.R. thanks DST
for the Swarnajayanti fellowship (No. DST/SJF/CSA-01/
2017-18), and SERB for the Core Research Grant (No. CRG/
2018/000016). U.K.M. and K.P. thank IISER Mohali for
research fellowships.
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