Rearrangement of an Intermediate Cyclopropyl Ketene in a RhII-Catalyzed Formal [4 + 1]-Cycloaddition Employing Vinyl Ketenes as 1,4-Dipoles and Donor-Acceptor Metallocarbenes

Article abstract of DOI:10.1021/acs.orglett.7b00618

A Rh^II-catalyzed formal [4 + 1]-cycloaddition approach toward spirooxindole cyclopentenones is described. The diastereoselective cyclopropanation of vinyl ketenes with diazooxindoles as C1 synthons initiated a relatively mild formal [1,3]-migra

Full text of DOI:10.1021/acs.orglett.7b00618

Letter
pubs.acs.org/OrgLett
Rearrangement of an Intermediate Cyclopropyl Ketene in a RhII-
Catalyzed Formal [4 + 1]-Cycloaddition Employing Vinyl Ketenes as
1,4-Dipoles and Donor−Acceptor Metallocarbenes
Kevin X. Rodriguez, Nicolai Kaltwasser, Tiffany A. Toni, and Brandon L. Ashfeld*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: A RhII-catalyzed formal [4 + 1]-cycloaddition
approach toward spirooxindole cyclopentenones is described.
The diastereoselective cyclopropanation of vinyl ketenes with
diazooxindoles as C1 synthons initiated a relatively mild formal
[1,3]-migration of an intermediate cyclopropyl ketene to
provide spirooxindoles in good to excellent yields (36−99%).
Scheme 1. Approaches to Cyclopentene Assembly
hether concerted or stepwise, cycloadditions constitute
one of the most exploited methods to rapidly install small
W
and medium structurally dense rings into complex molecular
targets.1 In comparison to the more ubiquitous family of [3 + 2]-
cycloadditions, [4 + 1]-cycloannulations are relatively underutil-
ized in target-directed 5-membered ring construction.2 Owing to
its synthetic versatility and the availability ofstarting components,
the formal [4 + 1]-annulation is an attractive alternative approach
toward fashioning highly substituted cyclopentenes.2b A signifi-
cant challenge in the development of these methods is the
identification of suitable C1 synthons. While metallocarbenes are
formidable reagents for the chemoselective installation of single
carbon atoms, their preference to undergo cyclopropanations has
deterredtheir use infashioning larger rings.3 However, astepwise,
formal [4 + 1]-cycloaddition of diazo compounds and 1,3-dienes
via the ring expansion of vinylcyclopropanes (VCPs) constitutes
an alternative to the direct, concerted assembly of cyclopentenes
(Scheme 1a).
While the thermal rearrangement of vinylcyclopropanes4 has
emerged as a powerful strategy to assemble 5-membered
carbocycles, the high temperatures required to access the
presumptive diradical intermediate can be limiting.4a,c,5 The
development of anion-accelerated variants has lowered the
temperature requirements but can suffer from functional group
incompatibilities.6 Wespeculatedthatimprovedorbitalalignment
with the migrating C−C bond and a polarized transition state
would assuage this kinetic barrier and provide access to the
cyclopentene derivatives under relatively mild conditions. Based
on seminal contributions by Danheiser7 and Rigby,8 we
considered exploiting vinyl ketenes as 1,4-dipoles to achieve this
result(Scheme1b).Whiletheirfindingsdemonstratetheutilityof
vinyl ketenes with nucleophilic carbenes to provide the cyclo-
pentenones via a penultimate 4π-electrocyclic ring closure, we
were inspired to pursue the synthetic potential of these relatively
underutilized 1,3-diene equivalents with electrophilic metal-
Received: February 28, 2017
© XXXX American Chemical Society
A
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Letter
a
locarbenes. Employing diazooxindole 3, spirooxindole cyclo-
pentenone 1 results from the in situ ring expansion of cyclopropyl
ketene 2, obtained from a transition-metal-catalyzed cyclo-
propanation of α-silyl-stabilized vinyl ketene 4 (Scheme 1c).
This retrosynthetic disconnect is directly applicable to the core
spirooxindole cyclopentyl architecture of biologically active
oxindole alkaloids (e.g., tasmanine, cyclopiamine B, etc.). Herein,
we disclose the successful implementation of this formal [4 + 1]-
cycloaddition strategy toward spirooxindole cyclopentenones.
Despite the extensive literature on metallocarbenes,3a−c,9 the
viability of a metal-catalyzed vinyl ketene cyclopropanation with
diazooxindoles was unclear at the outset of this study. We found
relatively few examples of diazooxindoles employed as C1
synthonsincyclopropanations,10 andtheinherentelectrophilicity
of metallocarbenes suggests that reactions in the presence of
nucleophilic heteroatoms may lead to undesired side products.11
Giventhepropensityofketenestoundergodimerization, wewere
motivated by Danheiser’s historical work to examine their in situ
generation from α-silyl cyclobutenones 4.7d,12 However, we were
aware that these conditions may prove incompatible with
metallocarbene generation and subsequent cyclopropanation.13
We began our studies by examining the formal [4 + 1]-
cycloaddition of the α-silyl vinyl ketene derived from cyclo-
butenone 5a with diazooxindole 3a (Scheme 2). Gratifyingly, a
slow addition of 3a to 5a in the presence of Rh2(OAc)4 at 100 °C
over10hledtotheformationofspirooxindolecyclopentenone1a
in 60% yield, the structure of which was unambiguously
determined by X-ray crystallography.14 Increasing the reaction
concentrationfrom0.01to0.1Mandlimitingtheslowadditionto
1 h provided 1a in 91% yield. The absence of Rh2(OAc)4 led to no
observableproductformation,whileabolusadditionof3agave1a
in reduced yield (32%). Performing the reaction at room
temperature, below the thermal threshold for cyclobutenone
ringopening,failedtoprovidethecycloadduct.Itisnoteworthythat
while elevated temperatures allow for shorter reaction times, this
appears required only for generation of the vinyl ketene. For example,
heating of 5a for 30 min at 100 °C followed by slow addition of 3a
at 40 °C led to a comparable yield of 1a after 12 h.
Scheme 3. Structural Diversity of Diazooxindole 3
a
Conditions: slow addition of 3 (0.12 mmol) over 1 h to 5a (0.10
mmol) and Rh2(OAc)4 (5 mol %) at 100 °C. See the Supporting
Information for detailed experimental procedures.
TES, and TIPS substitution gave uniformly high yields (87 →
99%) of the corresponding cyclopentenones 1j−l, while the
presence of an α-TBDPS group led to 66% yield of 1m.
a
Scheme 4. Structural Variations within Cyclobutenone 5
Scheme 2. Initial Findings
With optimized conditions in hand, we sought to evaluate the
architectural variability of the diazooxindole component. In
general, the reaction proved tolerable to N-acyl, benzyl, allyl, and
propargyl substitution yielding the formal [4 + 1]-cycloadducts
1b−fin good to excellent yields (Scheme 3). Methyl and bromide
substitution at C5 of the oxindole arene provided the
corresponding spirooxindoles 1g and 1h in 77% and 99% yields,
respectively. However, incorporation of a strongly electron-
donating methoxy group at that position resulted in diminished
yield of the formal cycloadduct 1i.
Likewise, variations of the cyclobutenone component gave the
formal [4 + 1]-cycloadducts in good to excellent yields (Scheme
4). While the nature of the α-silyl group appeared to not
significantly affect the efficiency of the formal [4 + 1]-
cycloaddition, the larger silicon group did lead to a slightly
diminished yield of the cycloadduct. For example, TMS, TBS,
a
Conditions: slow addition of 3a (0.12 mmol) over 1 h to 5 (0.10
mmol) and Rh2(OAc)4 (5 mol %) at 100 °C. See the Supporting
Information for detailed experimental procedures.
Examination of electronic factors within the β-aryl group by
varying the para substituent revealed that phenyl and alkyl
substitution did not adversely affect the yield of formal
cycloadducts 1n−p. The formation of cyclopentenone 1p is
particularly noteworthy in that the TBS-ether proved resilient to
protodesilylation, and a competitive C−H insertion into the α-
silyloxy allylic protons was not observed.3a,15 Cyclobutenones
bearingelectron-deficientandelectron-richβ-arylgroupsgavethe
B
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corresponding spirooxindole cyclopentenones 1q−s in good to
excellent yields. Neither substitution at the meta position nor
increasing the number of electron-donating groups hindered the
formation of cycloadducts 1t and 1u. However, alkyl substitution
at the ortho position led to a 32% yield of 1v, presumably due to
increasedstericencumbranceontheresultingvinylgroupslowing
the rate of cyclopropanation. Following this trend, the 2,6-
disubstituted aryl substituent in 1w effectively retarded the
reaction, leading to strictly dimerization of 3a.
Attempts to extend this formal [4 + 1]-cycloaddition to aryl
diazo acetates 6 highlighted the disparate reactivity of
diazooxindoles as donor−acceptor carbene precursors (Scheme
5). Employing our previously optimized conditions led to
significant dimerization of cyclobutenone 5b. Thus, increasing
the concentration of 5b (3 equiv) provided the corresponding
cycloadducts in moderate to good yields. Even with this
modification, phenyl-, p-tolyl-, and p-BrC6H4-substituted diazo
esters provided the corresponding adducts 7a−c in 28−58%
yields. However, the electron-rich p-MeOC6H4 diazo ester
provided cyclopentenone 7d in 78% yield.
We next sought to establish the intermediacy of a cyclopropyl
ketene leading to the formation of the observed spirocyclopente-
nones. Attempts to isolate the presumed cyclopropyl ketene
arisingfromthecyclopropanationofthevinylketenederivedfrom
cyclobutenone 5a with diazooxindole 3a via chromatography led
to rapid ring expansion to the formal cycloadduct 1a. However,
additionofbenzylamine,followingconsumptionofdiazooxindole
3a, resulted in formation of α,β-unsaturated amide 9 (Scheme 7).
Presumably, addition of benzylamine to cyclopropyl ketene 2a
initiates a π-assisted cyclopropane opening of adduct 8, which
upon proton transfer to C3 of the oxindole yields amide 9.
Scheme 7. Amination of the Spirocyclopropyl Ketene
a
Scheme 5. Extension to Aryl Diazo Acetates 6
While unsuccessful at isolating the presumed cyclopropyl
ketene, we could visualize the formation of 2b as a single
diasetereomer from diazooxindole 3a and cyclobutenone 5b and
its conversion to cyclopentenone 1o by in situ 1H NMR (Figure
1). Upon consumption of 3a in PhMe-d8 at 50 °C, as determined
by TLC, a 1H NMR (t = 90 min) spectrum of the reaction mixture
indicated partial conversion of 2b to cycloadduct 1o in a ratio of
1:1.3. The diagnostic signals associated with the cyclopropyl
a
Conditions: slow addition of 6 (0.15 mmol) over 1 h to 5b (0.23
mmol) and Rh2(OAc)4 (5 mol %) at 100 °C. See the Supporting
Information for detailed experimental procedures.
To gain mechanistic insight, we began by assessing whether the
formal [4 + 1]-cycloaddition is initiated by a vinyl ketene
cyclopropanation event or direct strain-driven ring insertion into
the cyclobutenone.16 Treatment of diazo oxindole 3a with the
isolable vinylketene 4a, readily accessible fromthe corresponding
α-diazo ketone via a photochemical Wolff rearrangement,7d in the
presence of Rh2(OAc)4 provided spirooxindole cyclopentenone
1xin71%yieldasasinglediastereomer(Scheme6).Coupledwith
our previous observation that the cycloadduct failed to form
without an initial thermal incubation period, this supports our
supposition that electrocyclic ring opening of the cyclobutenone,
and not a mechanism involving C−C bond insertion into the
strained 4-membered ring, precludes the formal cycloaddition
event.
Scheme 6. Annulation of Isolable Vinyl Ketene 4a
Figure 1. Spectroscopic (1H NMR) evidence for conversion of
cyclopropyl ketene 2b to spirooxindole cyclopentenone 1o.
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b00618.
Experimentalprocedures,spectroscopicdata,andcrystallo-
graphic data (PDF)
X-ray data for 1a (CIF)
X-ray data for 9 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bashfeld@nd.edu.
ORCID
Brandon L. Ashfeld: 0000-0002-4552-2705
Notes
The authors declare no competing financial interest.
(11)Wang,H.;Guptill,D.M.;Varela-Alvarez,A.;Musaev,D.G.;Davies,
H. M. L. Chem. Sci. 2013, 4, 2844.
(12) Benda, K.; Knoth, T.; Danheiser, R. L.; Schaumann, E. Tetrahedron
Lett. 2011, 52, 46.
(13) Chen, P.-h.; Dong, G. Chem. - Eur. J. 2016, 22, 18290.
(14) See the Supporting Information for full experimental details.
(15) Davies, H. M. L.;Coleman, M. G.;Ventura, D. L. Org. Lett. 2007, 9,
4971.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CAREER CHE-1056242) and Walther Cancer. K.X.R. was
supported by a Walther Cancer Foundation ENSCCII Training
Grant. We thank Dr. Allen G. Oliver (University of Notre Dame)
for assistance with the X-ray crystallography.
(16)(a)Li,B.-S.;Wang,Y.;Jin,Z.;Zheng,P.;Ganguly,R.;Chi,Y.R.Nat.
Commun. 2015, 6, 6207. (b) Chen, P.-h.; Sieber, J.; Senanayake, C. H.;
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Chem., Int. Ed. 2014, 53, 9640. (e) Ko, H. M.; Dong, G. Nat. Chem. 2014,
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