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. 2024 Apr 25;146(18):12799–12807. doi: 10.1021/jacs.4c03073

Alkyl Cyclopropyl Ketones in Catalytic Formal [3 + 2] Cycloadditions: The Role of SmI2 Catalyst Stabilization

Jack I Mansell 1, Song Yu 1, Muze Li 1, Emma Pye 1, Chaofan Yin 1, Frédéric Beltran 1, James A Rossi-Ashton 1, Ciro Romano 1, Nikolas Kaltsoyannis 1, David J Procter 1,*
PMCID: PMC11082888  PMID: 38662638

Abstract

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Alkyl cyclopropyl ketones are introduced as versatile substrates for catalytic formal [3 + 2] cycloadditions with alkenes and alkynes and previously unexplored enyne partners, efficiently delivering complex, sp3-rich products. The key to effectively engaging this relatively unreactive new substrate class is the use of SmI2 as a catalyst in combination with substoichiometric amounts of Sm0; the latter likely acting to prevent catalyst deactivation by returning SmIII to the catalytic cycle. In the absence of Sm0, background degradation of the SmI2 catalyst can outrun product formation. For the most recalcitrant alkyl cyclopropyl ketones, catalysis is “switched-on” using these new robust conditions, and otherwise unattainable products are delivered. Combined experimental and computational studies have been used to identify and probe reactivity trends among alkyl cyclopropyl ketones, including more complex bicyclic alkyl cyclopropyl ketones, which react quickly with various partners to give complex products. In addition to establishing alkyl cyclopropyl ketones as a new substrate class in a burgeoning field of catalysis, our study provides vital mechanistic insight and robust, practical approaches for the nascent field of catalysis with SmI2.

Introduction

The ability to construct complex molecular frameworks akin to Nature’s building blocks is a fundamental goal of synthetic organic chemistry. Modular routes to such frameworks—especially those involving catalytic reactions—are particularly sought after, as they enable the efficient construction of highly relevant compound libraries that can be used to unlock the correlation between compound structure and biological activity in, for example, the pharmaceutical and agrochemical industries (Figure 1A).1,2 Recent years have seen intense interest in the exploitation of cyclopropyl ketones in formal [3 + 2] cycloaddition reactions with alkene and alkyne partners under radical and photochemical/photocatalytic conditions.3−17 Crucially, advancements in this area have been firmly limited to employing aryl cyclopropyl ketone starting materials (Figure 1B), leading to products largely incongruent with Nature’s sp3-rich building blocks. The reason for this significant limitation and the major challenge associated with the reduction of unactivated aliphatic carbonyl compounds is their low standard redox potential (e.g., cyclohexanone E1/2 = −2.73 V vs SCE).18 In contrast, aryl ketones are easier to reduce by single-electron transfer (SET) (e.g., acetophenone E1/2 = −2.11 V vs SCE) (Figure 1C).19 In this study, we overcome this limitation and introduce alkyl cyclopropyl ketones 1 as versatile substrates for catalytic formal [3 + 2] cycloadditions. Pivotal to our approach is the use of SmI2 as a catalyst.

Figure 1.

Figure 1

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(A) Representative natural products possessing alkyl α-ketocyclopentanoid motifs. (B) Existing intermolecular catalytic couplings of cyclopropyl ketones with alkenes and alkynes are limited to aryl cyclopropyl ketones. (C) Redox potentials of alkyl and aryl ketones. (D) SmI2 catalysis facilitates the first formal [3 + 2] cycloadditions using alkyl cyclopropyl ketones.

Using “stoichiometric reagents” in a catalytic fashion is vital, as sustainability becomes the primary aspect of organic synthesis.20,21 In this context, we have recently showcased the catalytic potential of SmI2, a reagent used in a superstoichiometric fashion for more than 50 years.22−24 The use of SmI2 in substoichiometric amounts not only reduces cost and waste but also has the potential to unveil reactivity paradigms that are hidden when excess SmI2 is present. We have reported the first processes that operate solely with SmI2 as a catalyst and do not require an excess of metal coreductants and additives (e.g., Mg and TMSCl) that compromises the atom economy gained by the move to catalysis.25−40 Our mechanism-based approach to catalysis with SmI2 hinges on the exploitation of radical relays; an electron is donated from and subsequently returned to the samarium center amid a series of bond-breaking and forming steps.

Our studies in SmI2 catalysis have centered on formal [3 + 2] cycloaddition reactions, as exemplified in intra- and intermolecular couplings, and exploited in the synthesis of bioisosteres.25−27 However, to date, the SmI2-catalyzed [3 + 2] cycloaddition reactions of cyclopropyl ketones are limited to aromatic ketone substrates—in line with other catalytic approaches to the transformation, as previously discussed (Figure 1B). This limitation with SmI2 is at first surprising, given that the reagent is known to reduce dialkyl ketones, albeit when used in superstoichiometric amounts and in combination with activating additives and proton sources that increase the reactivity of the reagent.41 Cognizant that such additives could lead to the reduction of radical intermediates, thus undermining the radical-relay approach that underpins SmI2 catalysis, we set out to improve our understanding of working with SmI2 as a catalyst, with the aim of developing catalytic [3 + 2] cycloaddition reactions that embrace alkyl cyclopropyl ketone substrates.25,26

Here, we introduce alkyl cyclopropyl ketones, both simple and more complex, as highly versatile substrates in catalytic [3 + 2] cycloaddition reactions with alkene and alkynes and thus address an unmet challenge (Figure 1D). The SmI2-catalyzed protocol not only expands the scope of cyclopropyl ketone feedstocks that can be engaged in formal [3 + 2] cycloadditions, thus allowing access to sp3-rich architectures, but also has led to the development of robust SmI2 reaction conditions that allow catalyst stabilization. For the most recalcitrant alkyl cyclopropyl ketone substrates, catalysis is “switched-on” using these new robust conditions. Combined experimental and computational studies have identified and probed reactivity trends among aliphatic cyclopropyl ketones, including more complex bicyclic cyclopropyl ketones, which react quickly with various partners to give complex products.

Results and Discussion

Reaction Development

Applying our previously reported catalytic SmI2 conditions in the coupling of hindered aliphatic cyclopropyl ketone 1a with phenylacetylene gave cyclopentene 2a in low yield (Table 1, entry 1).26 We rationalized that the low yield arises from a slow initial SET to the ketone carbonyl resulting from the low redox potential of the alkyl cyclopropyl ketone. In this slow-reacting system, we propose that the rate of SmI2 catalyst deactivation becomes significant compared to the rate of substrate reduction. This hypothesis was corroborated by the observation of samarium salts precipitating out of the solution during the reaction. Although SmI2 solutions can be successfully used over several days when an excess of the reagent is employed, we reasoned that the use of catalytic amounts of SmI2 would be more sensitive to the speciation of the SmI2 solutions and thus be dependent on reagent age. Consequently, fresh SmI2 solution was prepared and used immediately in catalysis to give a significantly improved 65% yield of 2a (Table 1, entry 2), supporting the notion that improving the stability of SmI2 (increasing catalyst half-life) is likely the key to extending SmI2 catalysis to less-reactive substrates, including alkyl cyclopropyl ketones. To stabilize the SmI2 catalyst to oxidative degradation to SmI3, perhaps due to trace oxygen, an equal substoichiometric loading of Sm0 was added. The use of SmI2/Sm0 (15 mol %) had a marked effect, increasing the yield of the product to 77%, even when a 3-day-old batch of SmI2 was employed (Table 1, entries 3 and 4).42−44 Thus, the SmI2/Sm0 catalyst system offers more consistent performance in the catalytic formal [3 + 2] cycloaddition using less-reactive substrates, such as alkyl cyclopropyl ketones. Of note, a significant amount of Sm0 remains after reaction workup, suggesting that a lower Sm0 loading could be employed, although for the practicality of handling, a loading of 15 mol % was used. Control experiments confirmed SmI2 to be the active catalyst; the use of Sm0 or SmI3 resulted in no formation of 2a, and starting materials were recovered (Table 1, entries 5–6). Product 2a was also not obtained when SmIII/Sm0 (30 mol %) was employed, suggesting that comproportionation of SmI3 and Sm0 to form active SmI2 catalyst does not occur efficiently under the reaction conditions, perhaps due to the insolubility of both species when present in substantial amounts (Table 1, entry 7).

Table 1. Optimization of the SmI2-Catalyzed Formal [3 + 2] Cycloaddition of Alkyl Cyclopropyl Ketone 1aa.

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entry deviation from above 1H NMR yield (%)b
1 none 11
2c freshly prepared Sml2 (15 mol %) 65
3d,e Sml2 (15 mol %) + Sm0 (15 mol %) 77
4c Sml2 (30 mol %) 65
5 Sm0 instead of Sml2 n.d.
6f Sml3 (15 mol %) instead of Sml2 n.d.
7d,f Sml3 (15 mol %) + Sm0 (15 mol %) n.d.
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a

Reaction conditions: 1a (0.10 mmol), phenylacetylene (0.30 mmol), SmI2 (0.015 mmol) in THF (0.65 mL) under nitrogen at 55 °C for 4 h.

b

Yields were determined by 1H qNMR with CH2Br2 as internal standard (0.05 mmol).

c

SmI2 was prepared, titrated (see the Supporting Information), and used immediately.

d

Sm metal (0.015 mmol) was added prior to SmI2.

e

Using SmI2 that was stirred under nitrogen for 72 h prior to use.

f

SmI3 (0.015 mmol, 15 mol %) was added prior to the solvent. n.d., not detected.

Focusing on the discrepancies in yield obtained using “stored” and freshly prepared SmI2 solutions (Table 1, entries 1 and 2) and aiming to underline the beneficial presence of substoichiometric Sm0, we conducted a catalyst aging study; parallel reactions were performed using conditions A (no Sm0) and B (15 mol % Sm0) while varying the age of the SmI2 solution employed (Figure 2). Notably, with freshly prepared SmI2, the product yield was consistent with previous results (see Table 1, entries 2 and 3). However, over 4 days, using the same stock solution of SmI2, the yield of 2a under conditions A steadily decreased. In these cases, the reaction mixtures underwent a gradual color change from deep blue to yellow, associated with the conversion of SmII to SmIII—typically within the first 2 h. In stark contrast, using conditions B, the yield of 2a remained constant (within the error associated with quantitative 1H NMR [1H qNMR]) as the stock SmI2 solution aged. A color change was not observed in the reactions using conditions B, and visible metallic Sm0 remained in the reaction vessel after the workup. We propose that the addition of substoichiometric Sm0 aids the stabilization of SmI2 by recovering off-cycle SmIII species that form by catalyst decomposition.45−50

Figure 2.

Figure 2

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Catalyst aging study. Reaction conditions: 1a (0.10 mmol, 1.0 equiv), phenylacetylene (0.30 mmol), and SmI2 (15 mol %) in THF (0.65 mL) under nitrogen at 55 °C for 4 h. Yields were determined by 1H qNMR with CH2Br2 as internal standard (0.05 mmol). The stock SmI2 solution in THF (0.1 M) was stirred vigorously under nitrogen.

Substrate Scope

With the optimized conditions in hand, we first examined the scope of SmI2-catalyzed couplings with regard to the aliphatic substituent on the carbonyl group in alkyl cyclopropyl ketones (Scheme 1). Cyclopropyl ketones bearing primary alkyl groups gave products in good yield under conditions A (2b, 2c). However, conditions B were typically required to give acceptable yields when working with less-reactive secondary alkyl cyclopropyl ketone substrates (2a, 2d–i). For example, cycloheptyl-containing product 2i was obtained in 45% yield using conditions A and 90% using conditions B. Strikingly, using a tertiary alkyl cyclopropyl ketone substrate, conditions B were essential to “switch-on” catalysis and 2j was obtained in 90% yield; only traces of 2j were obtained using conditions A.

Scheme 1. Scope of the SmI2-Catalyzed Coupling of Alkyl Cyclopropyl Ketones 1.

Scheme 1

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Reaction conditions A were used on a 0.10 mmol scale, and the isolated yield is reported unless otherwise stated.

Reaction conditions B were used on a 0.20 mmol scale, and the isolated yield is reported unless otherwise stated.

Sm0 (30 mol %) was used. † Yields were determined by 1H qNMR with CH2Br2 as internal standard (0.05 mmol).

To confirm that the newly developed, SmI2-catalyzed coupling of alkyl cyclopropyl ketones extended to other unsaturated partners, we assessed the use of both validated, styrene, and novel, enyne, 2π components. Coupling with a range of styrenes gave ketocyclopentane products (2k-2m) in 61–90% yield. Again, in the more challenging coupling of 2,6-dichlorostyrene to give 2n, the use of conditions B proved to be essential. Alkyl cyclopropyl ketones also underwent efficient coupling to previously unexplored enyne partners, and keto-cyclopentene products 2o–r were obtained in 70–90% yield using conditions B. In the formation of 2p, the use of Sm0 to stabilize the SmI2 catalyst improved the yield from 5 to 70%. Coupling to give 2r highlights the ability to form highly functionalized polyene products with complete selectivity for catalysis at the terminal alkyne unit. Simple alkyl alkyne partners do not undergo productive couplings with alkyl cyclopropyl ketones under either set of conditions (see the Supporting Information.)

Variation of substitution on the cyclopropane ring was next explored. Spirocyclic alkyl cyclopropyl ketones underwent smooth coupling to give 2s–u in 64–74% yield using conditions B for SmI2 catalysis; the use of conditions A led to lower yields that were more sensitive to the nature of the substrate, presumably due to varying rates of reaction of the substrates with SmI2. Monoalkyl substitution on the cyclopropane is currently not well-tolerated; conditions B gave 2v in low yield. Finally, the use of more complex alkyl cyclopropyl ketones, prepared from monoterpenoids citral and pulegone, with differing or additional alkyl substitution on the cyclopropane was investigated. Cyclopropane-containing 2w was formed efficiently with complete selectivity for the opening of the cyclopropane unit adjacent to the ketone carbonyl. Formation of 2x again showcased the compatibility of SmI2 catalysis with unsaturation elsewhere in the alkyne partner. Finally, a tetrasubstituted alkyl cyclopropyl ketone substrate underwent challenging catalytic coupling to give spirocycle 2y, bearing a quaternary stereocenter, in 60% yield. Again, in all three cases, the use of conditions B proved to be important, with our strategy for catalyst stabilization being particularly effective in the formation of 2x and 2y; only traces of product were observed in the absence of Sm0.

We next sought to exploit our new-found ability to work with alkyl cyclopropyl ketones by studying the preparation of fused bicyclic architectures akin to those found in Nature using bicyclic alkyl cyclopropyl ketone substrates (Scheme 2). Complex alkyl cyclopropyl ketone 3a, readily prepared from the monoterpene 3-carene,51 was subjected to conditions A with phenylacetylene as a partner, forming ketone 4a in 81% yield and as a single diastereoisomer. The structure of 4a was confirmed by X-ray crystallography. A range of arylacetylenes bearing electron-donating alkyl (4b, 4c, 4n) and alkoxy (4d, 4e, 4o) substituents, or electron-withdrawing trifluoromethyl (4f), fluoro (4g, 4k), bromo (4h), chloro (4i), and carbomethoxy (4j) groups, proved compatible with catalysis, affording the corresponding products in moderate to high yield. Interestingly, bicyclic alkyl cyclopropyl ketone 3a proved sufficiently reactive that the use of conditions B was necessary only to obtain a satisfactory yield of thiophene-containing product 4m.

Scheme 2. Scope of the SmI2-Catalyzed Coupling of Bicyclic Alkyl Cyclopropyl Ketone 3a.

Scheme 2

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Reaction conditions A were used on a 0.10 mmol scale.

Reaction conditions B were used on a 0.20 mmol scale. † Yields were determined by 1H qNMR with CH2Br2 as internal standard (0.05 mmol). ‡ Reaction run on a 1.0 mmol scale.

Bicyclic alkyl cyclopropyl ketone 3a also underwent smooth coupling with styrenes to form products 4p–4t as mixtures of two diastereoisomers with moderate diastereocontrol. In the coupling with styrene to form 4p, the relative stereochemistry of the major diastereoisomer was confirmed by X-ray crystallography. Good functional group compatibility was again observed with the trifluoromethyl (4q), fluoro (4s), and chloro (4t) substituents tolerated. Enynes were also competent coupling partners with bicyclic alkyl cyclopropyl ketone 3a, delivering complex products 4u-w in 52–68%; for these more challenging couplings, the use of conditions B was crucial in giving satisfactory yields (Scheme 2).

The bicyclic alkyl cyclopropyl ketone substrates could also be varied. Tuning the substitution at the 5-position of substrates 3 allowed access to products 4x-ab in good yield upon coupling with phenylacetylene (Scheme 3). The beneficial impact on catalysis of adding substoichiometric Sm0 was particularly striking in the preparation of 4ab, with only traces of product obtained using conditions A. 5-Membered bicyclic alkyl cyclopropyl ketone 5 also underwent efficient coupling with both phenylacetylene and styrene, giving 6a and 6b, respectively, in good yield. The use of conditions B was particularly crucial for efficient SmI2 catalysis in the formation of 6a.

Scheme 3. Variation of Fused Bicyclic Alkyl Cyclopropyl Ketones 3.

Scheme 3

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Reaction conditions A were used on a 0.10 mmol scale

Reaction conditions B were used on a 0.20 mmol scale. † Yields were determined by 1H qNMR with CH2Br2 as internal standard (0.05 mmol). ‡ Modified conditions B: SmI2 (5 mol %) and THF (0.5 M) with 800 rpm stirring on a 2.0 mmol scale.

The robustness of the protocol was illustrated by scale-up experiments that, for example, enabled the use of significantly lower SmI2 loading (5 mol %) under slightly modified conditions B for the formation of 4a in 88% yield (2.0 mmol scale, 452 mg of 4a prepared) (Scheme 3). Of note, increasing the concentration and stirring speed proved essential for full conversion of 3a; presumably, this helps ensure the return of off-cycle SmIII species to the catalytic cycle.

Mechanistic Study

Intrigued by the fact that efficient catalytic conversion of some alkyl cyclopropyl ketone substrates required the presence of a substoichiometric amount of Sm0 in addition to SmI2 (conditions B) while other substrates did not (conditions A), reaction progress was monitored by 1H NMR in a series of processes involving representative substrates. For example, monitoring the conversion of cyclopropyl ketone 1f to cyclopentene 2f under conditions A, using freshly prepared and titrated SmI2, showed an exponential decay of the starting material with concomitant formation of the product (Figure 3A).

Figure 3.

Figure 3

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Mechanistic studies. (A) Reaction progress monitoring using conditions A with substrate 1f; gray circles and squares correspond to the conversion of the starting material and the product formation, respectively, determined by 1H qNMR using CH2Br2 as internal standard; all lines represent nonlinear best-fit curves. (B) Reaction progress monitoring using conditions A with substrates 3a (circle), 1f (square), 1s (right-side up triangle), and 1b (upside down triangle); all lines represent nonlinear best-fit curves. (C) Gibbs energy profiles ΔG and, in parentheses, electronic (SCF) energies ΔE of the SmI2-catalyzed coupling reactions of 1f and 3x with phenylacetylene (See the Supporting Information for computational details). (D) Electronic and entropic contributions to the Gibbs energy changes of the SET step and spin density distributions (isovalue = 0.005 e–/au3) with numerical values (in e–) of key atoms of Int-I1f and Int-I3x. (E) Epimerization of diastereoisomerically enriched bis-cyclopropyl ketone 7 serves as a probe for the reversibility of ketone reduction and cyclopropane ring-opening. Reaction on a 0.10 mmol scale with mass balance determined by 1H qNMR with CH2Br2 as internal standard (0.10 mmol). Larger scale two-directional coupling using bis-cyclopropyl ketone 7 and recycling of the Sm metal. ‡Modified conditions B: phenylacetylene (6.0 equiv) and THF (0.33 M) on a 2.0 mmol scale. *Sm metal was recycled and used again on a 2.0 mmol scale.

Similar reaction monitoring using a variety of alkyl cyclopropyl ketone substrates clearly illustrated that primary alkyl cyclopropyl ketones (such as 1b) typically react more quickly than analogous secondary alkyl cyclopropyl ketones (such as 1f) (Figure 3B). This is presumably due to steric hindrance impeding coordination of the SmI2 catalyst to the ketone carbonyl prior to inner-sphere SET.52 One exception is primary spirocyclic alkyl cyclopropyl ketone 1s, which reacts slowly, presumably due to steric hindrance associated with the tertiary radical intermediate hindering coupling. In stark contrast, the reaction of bicyclic alkyl cyclopropyl ketone 3a was found to proceed to completion within 5 min. These results fit well with the hypothesis that SmI2 catalyst stabilization, using Sm0 (conditions B), becomes crucial with less-reactive substrates; the slower-reacting spirocyclic alkyl cyclopropyl ketone 1s required the use of conditions B to achieve satisfactory yields of the product while the faster-reacting bicyclic alkyl cyclopropyl ketone 3a did not.

Computational studies have been employed to probe the origin of the high reactivity of bicyclic alkyl cyclopropyl ketones 3. In so doing, we have employed a modification of our previous computational approach,27 now applying the Douglas–Kroll–Hess second-order scalar relativistic Hamiltonian coupled with all-electron basis sets. This revised methodology is based on our further investigation of a previously studied catalytic cycle,26 as set out in the Supporting Information, Section 3.1, exploring the differences between reaction energy profiles obtained at the ECP and all-electron (both scalar and spin–orbit) levels: all-electron SET barriers better match experimental observations. The Gibbs energy profiles (Figure 3C) reveal that the reaction involving bicyclic alkyl cyclopropyl ketone 3x has a slightly lower overall reaction barrier at TS-I (24.5 kcal mol–1) compared with that of cyclohexyl cyclopropyl ketone 1f (25.4 kcal mol–1). This aligns well with experimental findings showing that bicyclic alkyl cyclopropyl ketones exhibit more favorable kinetics in the SmI2-catalyzed reactions (Figure 3B). Importantly, the reduced barrier associated with bicyclic compound 3x does not originate from more facile ring fragmentation (Int-I to TS-I) but is attributable to a more favorable initial SET from Sm(II) to the substrate (Reactant to Int I). This latter difference can be ascribed to smaller electronic and entropic terms contributing to a reduced Gibbs energy change during SET to 3x (Figure 3C). The lower electronic energy (ΔE) observed for 3x may derive from two factors: (i) 3x has lower electron density at the carbonyl carbon and a more polarized carbonyl group, which manifests as a slightly lower LUMO energy (see the Supporting Information) and thus greater reactivity toward reductive SET; (ii) Int-I of 3x benefits from a small hyperconjugation effect that disperses the spin density of the ketyl radical over the adjacent C–C bond of the cyclopropane ring, consequently stabilizing this intermediate (Figure 3D). Furthermore, the SET step is concomitant with a decrease in the length of the Sm–O bond, owing to an increased electrostatic attraction between the more positive trivalent metal and substrate (the Sm–O distance varies from 2.50 to 2.10 Å for 1f and from 2.57 to 2.09 Å for 3x). This results in a more compact intermediate complex with a decrease in the entropy and an increase in the −TS term. Bicyclic compound 3x exhibits a less-pronounced increase in Δ(−TS), indicative of a smaller decrease in the entropy. This is likely because the compact and rigid skeleton of 3x undergoes minimal geometric changes during the shortening of the Sm–O distance associated with the SET step.

An additional mechanistic experiment using bis-cyclopropyl ketone 7 was conducted – in the absence of a coupling partner – to probe the reversibility of SET to the ketone and cyclopropyl ring-opening; 7 (dr 1.9:1) was found to undergo epimerization—presumably by ketone SET reduction, ring-opening, ring-closure, and BET to Sm(III)—to give 7 (dr 1:1) after exposure to catalytic SmI2 (30 mol % SmI2 in d8-THF, 55 °C, 16 h, 80% recovery by 1H qNMR) (Figure 3E). Finally, the same substrate 7 was used in a two-directional coupling on a 2.0 mmol scale to give bis-cyclopentene 8 in 71% yield. The Sm metal from the coupling was recovered and reused in conjunction with 15 mol % SmI2 to convert 7 into 8 in 61% yield, also on a 2.0 mmol scale.

Conclusions

We have introduced alkyl cyclopropyl ketones as versatile substrates for catalytic formal [3 + 2] cycloadditions with alkenes, alkynes, and new enyne partners, efficiently delivering complex, sp3-rich products. The key to effectively engaging this relatively unreactive new substrate class is the use of SmI2 as a catalyst in combination with Sm0, the latter likely acting to prevent catalyst deactivation by returning SmIII to the catalytic cycle. In the absence of Sm0, background degradation of the SmI2 catalyst can outrun product formation. In several examples involving the most recalcitrant alkyl cyclopropyl ketones, the use of these new robust conditions for SmI2 catalysis resulted in a dramatic “switching-on” of the reactivity and delivery of otherwise unattainable products. Combined experimental and computational studies have been used to probe the reactivity of different alkyl cyclopropyl ketones, including more complex bicyclic cyclopropyl ketones, which react quickly with various partners to give complex products. Crucially, in addition to establishing alkyl cyclopropyl ketones as a new substrate class in a burgeoning field of catalysis, our study provides valuable mechanistic insight and robust, practical approaches for the nascent field of catalysis with SmI2.

Acknowledgments

We thank the University of Manchester (Dean’s Award to J.I.M. and Lectureships to J.A.R.-A. and C.R.), EPSRC EP/W016354/1 (PDRA to S.Y. and C.R.), EPSRC EP/R029938/1 (PDRA to F.B.), and the EPSRC Centre for Doctoral Training in Integrated Catalysis EP/S023755/1 (PhD studentship to E.P.). We thank the NMR and MS services at the University of Manchester for assistance with spectroscopic measurements and analysis, Dr George Whitehead for X-ray crystallographic analysis, and the University of Manchester for its Computational Shared Facility and associated support services.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c03073.

  • Additional experiments, experimental procedures, characterization data, X-ray data, and NMR spectra for all new compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ja4c03073_si_001.pdf (18.9MB, pdf)

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