Letter pubs.acs.org/OrgLett
Rearrangement of an Intermediate Cyclopropyl Ketene in a RhIICatalyzed 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%).
W
Scheme 1. Approaches to Cyclopentene Assembly
hether concerted or stepwise, cycloadditions constitute one of the most exploited methods to rapidly install small 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 underutilized in target-directed 5-membered ring construction.2 Owing to its synthetic versatility and the availability of starting components, the formal [4 + 1]-annulation is an attractive alternative approach toward fashioning highly substituted cyclopentenes.2b A significant 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 deterred their use in fashioning larger rings.3 However, a stepwise, 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 We speculated that improved orbital alignment 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 (Scheme 1b). While their findings demonstrate the utility of vinyl ketenes with nucleophilic carbenes to provide the cyclopentenones via a penultimate 4π-electrocyclic ring closure, we © 2017 American Chemical Society
were inspired to pursue the synthetic potential of these relatively underutilized 1,3-diene equivalents with electrophilic metalReceived: February 28, 2017 Published: April 28, 2017 2482
DOI: 10.1021/acs.orglett.7b00618 Org. Lett. 2017, 19, 2482−2485
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Organic Letters Scheme 3. Structural Diversity of Diazooxindole 3a
locarbenes. Employing diazooxindole 3, spirooxindole cyclopentenone 1 results from the in situ ring expansion of cyclopropyl ketene 2, obtained from a transition-metal-catalyzed cyclopropanation 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 synthons in cyclopropanations,10 and the inherent electrophilicity of metallocarbenes suggests that reactions in the presence of nucleophilic heteroatoms may lead to undesired side products.11 Given the propensity of ketenes to undergo dimerization, we were 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 cyclobutenone 5a with diazooxindole 3a (Scheme 2). Gratifyingly, a slow addition of 3a to 5a in the presence of Rh2(OAc)4 at 100 °C over 10 h led to the formation of spirooxindole cyclopentenone 1a in 60% yield, the structure of which was unambiguously determined by X-ray crystallography.14 Increasing the reaction concentration from 0.01 to 0.1 M and limiting the slow addition to 1 h provided 1a in 91% yield. The absence of Rh2(OAc)4 led to no observable product formation, while a bolus addition of 3a gave 1a in reduced yield (32%). Performing the reaction at room temperature, below the thermal threshold for cyclobutenone ring opening, failed to provide the cycloadduct. It is noteworthy that 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.
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. Scheme 4. Structural Variations within Cyclobutenone 5a
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−f in 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 electrondonating 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 αsilyloxy allylic protons was not observed.3a,15 Cyclobutenones bearing electron-deficient and electron-rich β-aryl groups gave the 2483
DOI: 10.1021/acs.orglett.7b00618 Org. Lett. 2017, 19, 2482−2485
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Organic Letters
We next sought to establish the intermediacy of a cyclopropyl ketene leading to the formation of the observed spirocyclopentenones. Attempts to isolate the presumed cyclopropyl ketene arising from the cyclopropanation of the vinyl ketene derived from cyclobutenone 5a with diazooxindole 3a via chromatography led to rapid ring expansion to the formal cycloadduct 1a. However, addition of benzylamine, following consumption of diazooxindole 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.
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 increased steric encumbrance on the resulting vinyl group slowing the rate of cyclopropanation. Following this trend, the 2,6disubstituted 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.
Scheme 7. Amination of the Spirocyclopropyl Ketene
Scheme 5. Extension to Aryl Diazo Acetates 6a
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 vinyl ketene 4a, readily accessible from the corresponding α-diazo ketone via a photochemical Wolff rearrangement,7d in the presence of Rh2(OAc)4 provided spirooxindole cyclopentenone 1x in 71% yield as a single diastereomer (Scheme 6). Coupled with 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. 2484
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methylene geminal protons (δ = 2.61 ppm; J = 5.0 Hz) were distinct from those of the cyclopentenone (δ = 3.62 ppm; J = 18.0 Hz) and allowed us to tentatively make an analogous structure assignment to known spirocyclopropyl oxindoles.10b,e,17 Spectra were acquired at 30 min intervals and show a steady conversion of 2b to 1o, as illustrated by the indicated signals, over the course of 90 min (t = 180 min). This study, in conjunction with the formation of amide 9 supports our supposition that the formal [4 + 1]-cycloaddition described herein proceeds via a sequence of events involving initial vinyl ketene generation, cyclopropanation, and subsequent strain-driven ring expansion to the cyclopentenone. In summary, we have a developed a RhII-catalyzed formal [4 + 1]-annulation to construct the core spirooxindole cyclopentenone framework found in a diverse array of biologically active, oxindole alkaloid natural products. The reaction mechanism likely involves an initial vinyl ketene cyclopropanation followed by a mild VCP-like rearrangement facilitated by the polarized nature of the intermediate cyclopropyl ketene. The reaction produces spirooxindole cyclopentenones in good to excellent yields from diazooxindoles and aryl diazo acetates. Investigations into the mechanism provide compelling support for a cyclopropyl ketene intermediate undergoing facile ring expansion. Elucidation of a mechanism for the ring expansion event and the development of an enantioselective protocol is currently under investigation and will be reported in due course.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00618. Experimental procedures, spectroscopic data, and crystallographic data (PDF) X-ray data for 1a (CIF) X-ray data for 9 (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Brandon L. Ashfeld: 0000-0002-4552-2705 Notes
The authors declare no competing financial interest.
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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.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b00618 Org. Lett. 2017, 19, 2482−2485
