Synthesis and Applications of Cyclopropanones and Their Equivalents as Three-Carbon Building Blocks in Organic Synthesis

Dedicated to the memory of Prof. Harry H. Wasserman

Abstract

Cyclopropanone derivatives constitute highly strained cycloalkanones with promising applications as three-carbon building blocks in organic synthesis. Due to the presence of a ketone in such a small ring system, all C–C bonds and the carbonyl group are considered to be labile in suitable conditions, leading to a wide variety of synthetic disconnections, including nucleophilic addition, ring expansion, ring-opening, and (formal) cycloaddition. Despite their synthetic potential, the widespread adoption of cyclopropanones as substrates has been considerably hampered by the difficulties associated with the preparation and storage of such unstable compounds, prompting the development of cyclopropanone surrogates that can equilibrate to the parent ketone in situ via elimination. This review summarizes the syntheses and applications of cyclopropanone derivatives and their equivalents, and offers a perspective of the state of the field as well as its expected future directions.

1 Introduction

2 Preparation of Cyclopropanones and Their Equivalents

2.1 Carbenoid Chemistry

2.2 Allene Oxide Rearrangement

2.3 Ring Closure by Dehydrohalogenation or Dehalogenation

2.4 Photolytic Processes

2.5 Miscellaneous Formation of Cyclopropanones

2.6 Cyclopropanone Equivalents

3 Synthetic Applications of Cyclopropanones and Their Equivalents

3.1 Nucleophilic Addition to the Carbonyl Group

3.2 Ring Expansion

3.3 Ring-Opening

3.4 Cycloaddition and Formal Cycloaddition

4 Conclusion and Outlook

Key words

cyclopropanone - ring strain - oxyallyl - Favorskii - homoenolate - ring expansion - ring opening

Biographical Sketches

Yujin Jang received her B.S. in chemistry in 2010 and M.S. in chemistry in 2012 from Kwangwoon University (South Korea) under the supervision of Prof. Heung Bae Jeon, working on the development of new methods for the synthesis of 1,2,3-triazoles and bis-triazoles, and for the deoxygenation of sulfoxides. From 2014 until 2016, she was a visiting scholar at the University of Kentucky (USA), working under the supervision of Prof. Kyung Bo Kim on the development of a novel proteasome inhibitor with anti-cancer properties. She moved to North Carolina State University (USA) in 2016 and received her Ph.D. degree in chemistry in May 2021 under the supervision of Prof. Vincent N. G. Lindsay, working on the development of new synthetic methods using cyclopropanone equivalents. She is currently a postdoctoral fellow at the Korea Research Institute of Chemical Technology (KRICT), working on the development of new antiviral agents.

Roger Machín Rivera received his B.S. in chemistry in 2017 from the University of Puerto Rico at Cayey, working under the supervision of Dr. Claudia A. Ospina Millán (UPR-Cayey) on the isolation of cytotoxic secondary metabolites, and under Prof. Steven T. Diver (SUNY Buffalo, USA) on the development of new synthetic methods. He moved to North Carolina State University (USA) in 2017, where he is working as a Ph.D. student under the supervision of Prof. Vincent N. G. Lindsay on the development of new synthetic methods using cyclopropanone equivalents.

Vincent N. G. Lindsay received his B.Sc. in chemistry from Université de Montréal (Canada) in 2007 where he worked under the supervision of Prof. André B. Charette on the enantioselective Cu-catalyzed addition of diorganozinc reagents to nitroalkenes. He pursued his doctoral studies with Prof. André B. Charette (Université de Montréal) and received his Ph.D. in chemistry in 2012, working on the development of Rh-catalyzed asymmetric cyclopropanation reactions. He moved to the University of California, Berkeley (USA) in 2013 to work as a FRQNT postdoctoral fellow under the supervision of Prof. Richmond Sarpong on the development of modern synthetic strategies to synthesize alkaloids and other N-hetero­cycles. He then moved to North Carolina State University (USA) and began his independent career in 2016, working on the development of novel synthetic methodologies.

1

Introduction

Over the past five decades, cyclopropanone derivatives have received significant attention as highly reactive intermediates in organic synthesis.[1] [2] [3] Their structural characteristics, incorporating a ketone functional group in the smallest possible ring system, confers a unique reactivity to these molecules, where the strain energy is calculated to be around 49 kcal/mol, as compared with 27 kcal/mol for most conventional cyclopropane derivatives.[4] Unlike their unsaturated parents, cyclopropenones,[5] cyclopropanones lack the stabilizing aromatic character that would generally allow for their isolation in pure form. The cyclopropanone ring possesses various reactive sites, which makes it a particularly versatile intermediate towards a wide range of valuable building blocks such as cyclopropanols, alkylidenecyclopropanes, cyclobutanones, β-lactams, cyclopentan(en)ones, and many others. The carbonyl group is known to react with nucleophiles excessively rapidly to release significant strain, and all three C–C bonds of the ring system are susceptible to either homolytic or heterolytic cleavage depending on the conditions and substituents around the ring. Such a cleavage of the C1–C2 or C2–C3 bonds also releases significant strain energy in the molecule and maintains the carbonyl functionality intact for further chemical derivatizations.

Until the late 1960s, cyclopropanones had remained elusive as transient intermediates in specific organic reactions such as the Favorskii rearrangement,[6] the formation of cyclobutanones from diazomethane and ketenes,[7] and in the photolysis of cyclobutane-1,3-diones.[8] Initially, most attempts­ to isolate cyclopropanone itself failed and its existence­ was simply assumed through the isolation of adducts from its reaction with protic nucleophiles leading to hemiketals, or by isolation of cycloadducts from reactions with dienes. It was not until 1966 that cyclopropanone was independently isolated in solution by Turro and de Boer,[9] as evidenced by physical data such as infrared, ultraviolet, and microwave spectroscopy, as well as nuclear magnetic resonance.[2a] The use of cyclopropanone itself as a synthetic building block has been significantly impeded by difficulties associated with its preparation and storage, caused by its important kinetic instability.[10] In seminal examples, the cyclopropanone solution resulting from the reaction of ketene and diazomethane has to be used immediately, as even at low temperature, cyclopropanone readily undergoes various strain-releasing decomposition pathways in the presence of moisture, heat, or light, such as polymerization,[11] decarbonylation to ethylene or nucleophilic attack followed by ring-opening (e.g., Favorskii rearrangement). For this reason, the chemistry of cyclopropanone has over the years been more commonly utilized from its surrogates which are typically 1,2-adducts that can equilibrate to the parent ketone in situ via elimination. The most commonly encountered cyclopropanone equivalents, the hemiketals (cyclopropanone-alcohol adducts) are however unstable and poorly reactive due in part to the poor leaving group ability of alkoxides. Furthermore, the harsh conditions usually needed to equilibrate to cyclopropanone in situ combined with the kinetic instability of cyclopropanone itself often leads to myriad undesired pathways, significantly decreasing the overall yield of the targeted product. For these reasons, the development of stable and well-behaved precursors that can smoothly equilibrate to cyclopropanone under mild conditions in a controlled manner is highly desirable and in continuous evolution, opening the opportunity to further explore the versatility of this highly reactive synthetic intermediate towards more complex and valuable scaffolds.

Earlier reviews on the chemistry of cyclopropanones were independently reported by Turro[1] and Wasserman.[2] Subsequently, Salaün reviewed aspects of the chemistry of cyclopropanone hemiketals and their derivatives, including their use in organic synthesis as cyclopropanone surrogates.[3] The present review is divided in two main sections, the first of which describes the existing synthetic approaches to cyclopropanones via conventional methods such as carbenoid chemistry, allene oxide isomerization, the Favorskii rearrangement and photolytic processes, as well as the synthesis of cyclopropanone adducts employed as surrogates via diverse pathways (Section 2). While the first four methods have historically provided a strong foundation towards access to cyclopropanones and fundamental understanding of their reactivity, there have been very few recent advances in this field and we herein only introduce the topic in a general manner, whereas details of this chemistry can be found elsewhere.[1] [2] [3] The last approach, regarding the use of cyclopropanone adducts as surrogates, has received much more attention in the past few years, and we present herein comprehensive examples of their synthesis and comparison of their properties, including recent access to enantioenriched derivatives. The second part of the review describes the various synthetic applications of cyclopropanone derivatives as three-carbon building blocks and is divided according to different types of disconnections, including nucleophilic addition to the carbonyl group, ring expansion, ring-opening, and (formal) cycloaddition approaches (Section 3).

2

Preparation of Cyclopropanones and Their Equivalents

2.1

Carbenoid Chemistry

In analogy to the formation of cyclopropane derivatives from alkenes,[4e] [f] carbene equivalents such as diazo compounds were early on found to be precursors to cyclopropanones via reaction with ketenes. For example, seminal reports of the reaction of ketene with an excess of diazomethane[7a–c] to yield higher homologues such as cyclobutanone constitute some of the first transformations leading to the hypothesis that such a strained ketone intermediate 1 could actually exist (Scheme [1]).[7d] [12] As mentioned earlier, cyclopropanone (1) was later isolated and characterized as a solution in dichloromethane or diethyl ether under similar conditions by Turro and DeBoer.[9] [10] In this chemistry, the addition of the highly reactive diazoalkane and ketene reagents has to be precise in order to prevent further ring expansion of the cyclopropanone, and the reaction temperature has to be carefully controlled to minimize decomposition and obtain reasonable yields. It was later determined via calculations that in the case of substituted derivatives, the reaction between ketenes and diazoalkanes leading to cyclopropanones was likely proceeding via an oxyallyl-like transition state.[13]

Scheme 1 Cyclopropanone as intermediate in the reaction of diazomethane and ketene

In the 1970s and 1980s, Zaitseva and co-workers reported the synthesis of trialkylsilyl- and trialkylgermyl-substituted cyclopropanones from the corresponding di­azo­alkanes and ketenes (Scheme [2]).[14] These cyclo­propanones 3 and 4 were found to be much more stable than cyclopropanone (1) itself, but remained highly reactive towards­ reduction­ with LiAlH₄, addition of various nucleo­philes, ring-opening/bromination in the presence of Br₂, and ring expansion to β-lactams by reaction with azides.

Scheme 2 Synthesis of silylated and germylated cyclopropanones by reaction of diazoalkanes and ketenes

Arylketenes 5 formed in situ by Rh-catalyzed Wolff rearrangement of α-diazo-β-keto-phosphonates and sulfones have been reported to react with TMS-diazomethane 6 to produce cyclopropanone intermediates in an analogous manner, prone to decarbonylation to the corresponding β-silylstyrene derivatives 7 and 8 (Scheme [3]).[15] Alternatively, the use of a diarylketene in the same reaction leads to an indanone (e.g., 9) via ring expansion of the cyclopropanone intermediate followed by desilylation occurring during chromatography. The presence of an electron-withdrawing group such as a phosphonate or a sulfone presumably stabilizes the diradical or zwitterionic intermediate favoring a decarbonylation process, explaining the observed divergence in reactivities for both types of ketenes.[15a]

Scheme 3 Reactivity of silylcyclopropanones based on substitution

In analogy to the reaction of unstabilized diazoalkanes as carbene equivalents with ketenes, α-diazocarbonyl compounds in the presence of Rh(II) catalysts have been sporadically reported to also act as precursors to cyclopropanones, via significantly different mechanistic pathways. A serendipitous example of such an event was reported in synthetic efforts towards ajmaline,[16] where an intramolecular cyclopropanation/ring-opening was attempted to access polycyclic indoline 12 (Scheme [4]). While the desired product was not observed, spirocyclopropanone 11 was obtained instead in 58% yield as a single stereoisomer, presumably via a [1,3]-hydride shift of the Rh-carbene intermediate followed by cyclization of the resulting iminium ion.

Scheme 4 Unexpected cyclopropanone formation observed during studies towards the total synthesis of ajmaline

2.2

Allene Oxide Rearrangement

Allene oxide (13) was believed, early in the 1960s, to exist in equilibrium with cyclopropanone (1), potentially via an oxyallyl intermediate 14 or the corresponding diradical species (Scheme [5]).[17] [18] However, efforts to observe such an equilibrium by direct epoxidation of allenes and isolation of the cyclopropanone were initially unsuccessful, mainly due to the propensity of allene oxides towards further oxidation to spirodioxide species followed by various exothermic rearrangements. Notably, allene oxide has been calculated to actually have a higher energy content than the notoriously unstable cyclopropanone itself, and therefore should, once formed, spontaneously decompose to cyclopropanone via oxyallyl 14 in a disrotatory fashion.[17d,e] Subsequent work on the oxidation of 1,1-di-tert-butylallene allowed the characterization of the relatively stable 2,2-di-tert-butylcyclopropanone, arising from the isomerization of 1,1-di-tert-butylallene oxide via such an equilibrium (see 21, Scheme [7]).[19]

Scheme 5 The allene oxide–cyclopropanone equilibrium via an oxy­allyl species

In studies from 1974 onwards, Chan and co-workers reported a practical procedure to substituted allene oxide intermediates 16 via desilylation of epoxysilanes 15 (Scheme [6]).[20] The use of milder conditions avoiding the presence of oxidants allowed for a broader scope of allene oxides in this case, thus permitting to get more insight on the allene oxide–cyclopropanone equilibrium via the addition of protic nucleophiles. Key results out of these studies revealed that the identity of the substituent located at the saturated carbon of the allene oxide (R¹) is crucial to its reactivity. Indeed, monoalkyl-substituted allene oxides were found to be more robust towards isomerization to the corresponding cyclopropanone, and ketones 17 are thus obtained resulting from a direct nucleophilic addition to the saturated carbon of the epoxide followed by enolate protonation. In contrast, aryl- and dialkyl-substituted allene oxides rapidly isomerize to cyclopropanones presumably via an oxyallyl intermediate, and ketones 18 are isolated instead following addition of the protic nucleophile to the carbonyl group and ring-opening–protonation, similar to what is observed in the Favorskii­ rearrangement (see Section 2.3).

Scheme 6 Formation allene oxide intermediates via desilylation of epoxysilanes and reaction with protic nucleophiles

A summary of the effect of allene oxide substituents on the cyclopropanone equilibrium is presented in Scheme [7]. While 1-tert-butylallene oxide (19) polymerizes at room temperature prior to its isomerization,[20] 1,1-di-tert-butylallene oxide (20) cannot be isolated and rapidly isomerizes to a relatively stable cyclopropanone 21.[19] 1,3-Di-tert-butylallene­ oxide (22) is stable to isolation and requires heat to equilibrate to cyclopropanone 23.[21] However, 1,1,3-tri-tert-butylallene oxide (24) was found to be particularly stable and isomerization to 25 was not observed even after prolonged exposure to heat, presumably due to torsional strain induced by the three tert-butyl groups on the resulting cyclopropanone.[22] While aryl substitution at the C1 position of the allene oxides 28 allows for rapid isomerization to cyclopropanones 27, this is in contrast to aryl substitution at C3 in allene oxides 26, which are found to be relatively stable to isomerization.[20b] [c]

Scheme 7 Effect of the substitution pattern of allene oxides on their propensity to isomerize to cyclopropanones

In order to gain further insight on this equilibrium, Schepp and co-workers reported the photochemical generation of fluorenylidene-allene oxide 31 to eventually determine absolute rate constants for its rearrangement to the corresponding cyclopropanone 30, and to study its reactivity with nucleophiles, such as water and 2,2,2-trifluoroethanol (TFE) (Scheme [8]).[23] The nature of the major product obtained in these cases was found to be highly dependent upon the properties of the nucleophile, typically also acting as solvent or co-solvent. While the use of water as co-solvent solely afforded the α-hydroxy ketone 32 resulting from the direct addition to the terminal position of allene oxide 31, a weaker nucleophile such as TFE allowed the isomerization to cyclopropanone 30 to take place, affording ether 29 after decarbonylation and addition to the resulting exocyclic alkene. An analogous product was also obtained when the reaction was run in another weakly nucleophilic solvent, i.e. hexafluoroisopropanol (HFIP). In addition to the nucleophilicity as a key determining factor of the product obtained, the isomerization of allene oxide 31 to cyclopropanone 30 was found through kinetic studies to be significantly accelerated when performed in more polar and acidic HFIP compared to TFE, pointing towards a polar oxyallyl species as key fleeting intermediate rather than a concerted pathway.

Scheme 8 Effect of the protic nucleophile used on the reaction outcome starting from fluorenylidene-allene oxide

Further corroboration of the existence of the equilibrium between allene oxides and cyclopropanones via oxyallyl intermediates was also established by the development of various (formal) cycloaddition reactions, as well as allene oxide rearrangements leading to cyclopentenones (see Section 3.4).[24]

2.3

Ring Closure by Dehydrohalogenation or Dehalogenation

The Favorskii rearrangement involves the conversion of α-halo ketones such as 33 into carboxylic acid derivatives 35 under basic conditions via the intermediacy of a cyclopropanone 34, formed by intramolecular nucleophilic substitution of the corresponding enolate species (Scheme [9]).[6] [24] Extensive research has been performed to elucidate the mechanism of this reaction,[25] where two main pathways are widely sustained by calculations[26] and experimental data, depending on the substrate structure: the cyclopropanone mechanism (shown here) and the semi-benzilic mechanism (or quasi-Favorskii rearrangement), where a [1,2]-carbon shift occurs from a ketone adduct or its anionic equivalent, typically favored with non-enolizable ketones. In most Favorskii-type processes, the addition of nucleophiles in the last step triggers the ring-opening to occur in a substituent-dependent manner, favoring the most stable incipient β-carbanion (homoenolate). For instance, 2-arylcyclopropanones intermediates 27 afford hydrocinnamic acid derivatives, while 2,2-dimethylcyclopropanone (2) leads to the formation of pivalic acid analogues (see also Section 3.3.1).[9d] The importance of the Favorskii rearrangement as a ring-contraction strategy[27] has been applied in the total synthesis of diverse natural products and biologically active compounds.[28]

Scheme 9 The Favorskii rearrangement of α-halo ketones to carboxylic acids via cyclopropanone intermediates

The mechanism of the reaction was shown to depend on both the substrate structure and the reaction conditions. In acyclic and monocyclic systems, diverse types of α-bromo and α-chloro ketones (e.g., 36 or 37) can undergo rearrangement via a cyclopropanone pathway under a variety of basic conditions, while in the case of bicyclic ketones, the ring size plays an important role (Scheme [10]). For example, the reaction pathway is base-dependent for bicyclic cycloheptanones, while for eight-membered ring systems such as 38, the reaction proceeds via a cyclopropanone pathway regardless of the base (following Bredt’s rule), but can be modulated back to a semi-benzilic mechanism in the presence of silver nitrate as additive.[25l] Notably, the size of the base as well as the solvent used (protic vs. aprotic) can also influence the mechanism. The intermediacy of cyclopropanones in the Favorskii rearrangement has been supported by product isotope distribution studies,[29] in situ cycloaddition with dienes (Scheme [11a], see also Section 3.4),[30] mechanistic studies employing α-chiral ketones,[31] and isolation of more stable cyclopropanones (e.g., 23) or their hemiketal­ derivatives (e.g., 43) (Scheme [11b]).[32]

Scheme 10 Substrates favoring the intermediacy of cyclopropanones in the Favorskii rearrangement

Scheme 11 Evidence of cyclopropanone intermediates in the Favorskii rearrangement via trapping with furan (a) or methanol (b)

Under electrochemical conditions, α,α′-dibromo ketones such as 44 can be reduced to α′-bromo-enolates capable of ring closure to the corresponding cyclopropanones (e.g., 45), isolated as methanol adducts in high yield (e.g., 46) (Scheme [12]).[33] As further evidence of the presence of cyclopropanone intermediates in these studies, solutions of α,α′-dibromo ketones in aprotic solvents containing tetra­ethylammonium bromide (TEAB) were periodically analyzed by infrared spectroscopy during controlled potential electrolysis at room temperature, and the characteristic carbonyl absorption was clearly observed at 1825 cm^–1.

Scheme 12 Electrochemical reduction of α,α′-dihalo ketones under protic solvent to trigger the formation of cyclopropanones

The Favorskii rearrangement is also possible from α-hydroxy ketones such as 47 upon activation of the hydroxyl group in the presence of base and diethyl carbonate, where the intermediacy of a cyclopropanone was supported by ¹⁸O-labeling studies (Scheme [13]).[34a] Similarly, cyclic α,β-epoxy ketones have also been reported to rearrange via cyclopropanone intermediates, leading to the corresponding ring-contracted γ-hydroxycarboxylic acid derivatives.[34`] [c] [d]

Scheme 13 Favorskii rearrangement from α-hydroxy ketones

2.4

Photolytic Processes

Decarbonylation of cyclobutane-1,3-diones such as 51 under photolytic conditions constitute another possible path for the production of sterically hindered cyclopropanones (e.g., 45)[9c] [f] which can be intercepted by other reaction partners (Scheme [14]).[8,35] When performed in aprotic solvents such as benzene, this procedure provides the respective ketene 53 and an olefin 52 via double decarbonylation, a process that has been the subject of several computational studies.[8] [36] In contrast, when protic solvents are used, cyclopropanone hemiketals (e.g., 54)[9c] [37] [38] are obtained along with esters arising from Favorskii-type ring-opening (e.g., 55), with some cases reporting products of ketene addition 56 as minor species.[8a] In the former case, olefin formation comes from the decarbonylation of a cyclopropanone intermediate as identified by its carbonyl IR absorption either in a matrix[8a] [36e] or in solution.[9c] [36e] In the latter case, a single decarbonylation occurs and the resulting cyclopropanone is rapidly trapped by the protic solvent to produce 54 before the second decarbonylation can take place.

Scheme 14 Photodecarbonylation of 2,2,4,4-tetramethylcyclobutane-1,3-dione in different solvents

Although this process has been useful to provide initial physical data of different cyclopropanone derivatives as well as information on their reactivity under photolytic irradiation, it remains rather limited from a synthetic point of view. Since increasing the concentration of the cyclopropanone in solution also increases the rate of decarbonylation, only low to moderate yields of the cyclopropanone can typically be obtained through this approach, which has been reported solely on tetrasubstituted derivatives.[38] In 1999, Neckers and Zang reported that the photolysis of aryl-substituted cyclobutane-1,3-dione 57 can lead to a different pathway and the formation of interesting indan-2-ones such as 58 instead in good yield via intramolecular participation of the aromatic ring in the radical process (Scheme [15]).[39] In benzene, homolysis of the C1–C2 bond generates a 1,4-biradical species 64 capable of decarbonylation and ring closure followed by [1,3]-H shift to afford a indan-2-one 58 or 67 (Scheme [15] and Scheme [16]). The same reaction using isopropyl alcohol as solvent generates the indan­-2-one along with acetal 62, proposed to arise from O–H insertion of a rearranged oxacarbene intermediate in the alcohol solvent.

Scheme 15 Photodecarbonylation of 2,4-diethyl-2,4-diphenylcyclo­butane-1,3-dione leading to 1,3-diethyl-1-phenylindan-2-one

Scheme 16 Divergent mechanistic pathways of the photolytic decarbonylation of cyclobutane-1,3-diones depending on the nature of substituents

Adam and co-workers reported the photolysis of 3,3,5,5-tetramethylpyrazolin-4-one (68) as a distinct precursor of tetramethylcyclopropanone (45) (Scheme [17]).[40] Shorter wavelengths provided denitrogenation followed by cyclopropanone rearrangement to isoprenyl ketone 69 as major product via rupture of the C2–C3 bond. In contrast, longer wavelengths mainly led to cyclopropanone decarbonylation to provide tetramethylethylene (52). In both cases, the presence of a ketazine resulting from the direct decarbonylation of 68 was detected as minor product. This data implies that decarbonylation of cyclopropanone 45 is a low energy process compared to its ring-opening to an oxyallyl intermediate or the corresponding diradical species.

Scheme 17 Photodenitrogenation of 3,3,5,5-tetramethylpyrazolin-4-one to a cyclopropanone

Barber and co-workers reported the photoisomerization of the tricyclic ketone 70 at cryogenic temperatures, leading to the formation of a cyclopropanone 71, presumably via isomerization and ring closure of an allyl radical intermediate formed by cyclopropane homolysis (Scheme [18]).[41] Characteristic carbonyl absorption of 71 was observed by IR spectroscopy, and further irradiation led to formation of the corresponding cyclic diene via cyclopropanone decarbonylation (not shown). To further support the intermediacy of 71 in the process, the solution was warmed in the presence of furan to afford the respective (4+3) cycloadduct 72 (see also Section 3.4).

Scheme 18 Photoisomerization of a tricyclic ketone at cryogenic temperatures

2.5

Miscellaneous Formation of Cyclopropanones

The oxidation of secondary alcohols constitutes one of the most straightforward approaches for the synthesis of ketones. However, examples of the synthesis of cyclopropanones in this manner from secondary cyclopropanols are limited to highly substituted substrates so that the resulting cyclopropanone is stable enough to sustain the oxidation conditions and be isolated in pure form. One elegant example of such an approach was reported by irradiation of 9,9′-dianthrylcarbinol (73), leading to cyclopropanol 74 via intramolecular (4+4) photocycloaddition (Scheme [19]).[42] Subsequent oxidation under Pfitzner–Moffatt conditions provided cyclopropanone 75 as a stable solid.

Scheme 19 Synthesis of a cyclopropanone via photochemical ring closure followed by Pfitzner–Moffatt oxidation

The reaction of aromatic trichlorocyclopropenium tetrachloroaluminate (76) in the presence of an excess of hindered phenol at 0 °C followed by hydrolysis was reported to afford cyclopropenone 77, considered to be in equilibrium with diquinocyclopropanone 78 under oxidative conditions (Scheme [20]).[43] When the same reaction was carried out at 30 °C, the corresponding stable triquinocyclopropane was isolated instead by further reaction of the diquinocyclopropenium intermediate with a third equivalent of the phenol reactant.

Scheme 20 Formation and oxidation of a cyclopropenone leading to a diquinocyclopropanone

Cyclopropenone (81) is a colorless liquid that can readily be isolated in pure form and is known to be much more stable than cyclopropanone (1).[5] [44] Its remarkably high boiling point for such a light cyclic ketone (bp 30 °C/0.45 Torr) is indicative of its very polar character, where its charged resonance form, analogous to a cyclopropenium cation, is considered to be aromatic with 2π electrons and is thus more stable than in cyclopropanone. When employed as a substrate, cyclopropenone can be a reactive dienophile in cycloaddition reactions, resulting in the formation of cyclopropanones. For example, treatment with dienes such as substituted benzofuran 79 or anthracene 80 was reported to afford the desired cyclopropanones 82 and 83 in quantitative yields, both of which can be isolated but rapidly form the corresponding hemiketals in the presence of methanol (Scheme [21]).[44a] [b] Interestingly, performing the same reaction with 79 and 2,3-difluorocyclopropenone instead leads to spontaneous C2–C3 ring-opening of the cyclopropanone intermediate to an oxyallyl species capable of further cyclo­addition (see also Section 3.4).[44c]

Scheme 21 (4+2) Cycloaddition of dienes with cyclopropenone as dienophile

2.6

Cyclopropanone Equivalents

The use of cyclopropanone equivalents, defined as stable surrogates that can equilibrate to cyclopropanone derivatives in situ via elimination, is nowadays much more common in organic synthesis, emerging as a solution to issues associated with the difficulty of handling simple and unhindered cyclopropanones caused by their important kinetic instability.[3] [10] On the other hand, an additional challenge in such an approach consists of controlling the initial equilibrium leading to cyclopropanone as the effective substrate, where its concentration must remain low in order to avoid undesired oligomerization initiated by nucleophilic addition, a common decomposition pathway in this chemistry.[1–3] Cyclopropanone ketals (e.g., 84 and 85) and hemiketals (e.g., 86), which constitute cyclopropanone-alcohol adducts or their corresponding ethers, were among the first to be utilized for such a purpose in the presence of either base, acid, Lewis acid, or heat to trigger the desired equilibrium (Scheme [22a]).[3a] However, due to the poor leaving group ability of alkoxides and the important strain generated in the process, these substrates often require harsh conditions to equilibrate to cyclopropanone, which strongly limits their synthetic utility. Moreover, depending on the substitution pattern around the ring and the conditions used, ring-opening to acyclic esters via C1–C2 bond cleavage can be an important side reaction (see Sections 2.3 and 3.3), decreasing the yield of the desired product. Recently, a new type of cyclopropanone precursors, 1-sulfonylcyclopropanols 88, emerged as a superior alternative to ketals and hemiketals.[45a] [46] These substrates exist as stable crystalline solids, can be stored for long periods of time without decomposition, and equilibrate to cyclopropanone under mild basic conditions at room temperature or below, thus unlocking new possibilities for the use of cyclopropanones as strained building blocks in organic synthesis (Scheme [22b]).

Scheme 22 Different classes of cyclopropanone equivalents: (a) cyclopropanone ketals, hemiketals, or hydrate; (b) 1-sulfonylcyclopropanols

2.6.1

Cyclopropanone Ketals and Hemiketals

A classical approach to cyclopropanone hemiketals consists of the formation of the respective cyclopropanone by any of the methods discussed in Sections 2.1–2.5, followed by in situ addition of the corresponding alcohol at room temperature or below, typically used as solvent or co-solvent­. In a large number of cases, the formation of hemi­ketals was utilized as a strategy to trap an unstable cyclopropanone which could not be isolated otherwise to evaluate its accessibility via a given pathway. An alternative approach­ often encountered for unsubstituted derivatives (R² = H) involves the reductive cyclization of β-halo esters 89 with sodium in the presence of trimethylsilyl chloride (Bouveault–Blanc condensation), leading to cyclopropanone alkyl silyl ketals 90 (Scheme [23]).[47] [48] The corresponding hemiketals 91 can be readily obtained by subsequent cleavage of the silyl group under acidic conditions or by stirring in methanol at room temperature. Using a β-bromoisobutyrate (3-bromo-2-methylpropanoate) analogue as substrate, this approach was later demonstrated to be also effective for the production of a 2-substituted cyclopropanone hemiketal.[49]

Scheme 23 Reductive cyclization of β-halo esters to cyclopropanone hemiketals

The cyclopropanation of silyl ketene acetals 92 under modified Simmons–Smith conditions provides access to a wide variety of substituted racemic cyclopropanone alkyl silyl ketals 93 in good yields (Scheme [24]).[50] Unfortunately, an enantioselective version of this transformation remains unknown, preventing the use of such a strategy to access optically active cyclopropanone intermediates.

Scheme 24 Cyclopropanation of silyl ketene acetals under Simmons–Smith conditions

Although the Kulinkovich cyclopropanation is most commonly encountered in the synthesis of tertiary cyclopropanols and related derivatives starting from esters,[51] the use of organic carbonates 94 instead in the presence of terminal alkenes and cyclopentylmagnesium chloride was reported by Cha and co-workers to directly afford cyclopropanone hemiketals 95 in moderate yields (Scheme [25]).[51a] This interesting approach gives access to more complex substituted derivatives in their racemic form, whereas the use of cyclic carbonates provides the corresponding hydroxyl-tethered products with improved yields. However, these hemiketals­ were found to be considerably less stable than more conventional cyclopropanone hemiketals (e.g., 86).

Scheme 25 The Kulinkovich cyclopropanation of organic carbonates

The cyclopropanation of ketene acetals with electrophilic (Fischer-type) carbenes, either as a free dichlorocarbene or as acceptor carbenes stabilized by transition metals [e.g., Rh(II)], can also be used for the synthesis of cyclopropanone ketals.[52] While most of these products could potentially be considered as cyclopropanone equivalents via partial ketal cleavage, they have rather been employed as electron-rich cyclopropane derivatives capable of ring-opening to acyclic systems. Interestingly, the stoichiometric use of chromium carbene complexes 96 in such an approach under CO atmosphere at high pressure produces 2-alkoxy-substituted cyclopropanone ketals 98 difficult to access otherwise in moderate to high yields (Scheme [26]).[53]

Scheme 26 Reaction of Fischer carbene complexes with ketene acetals

The carbometalation of cyclopropenone ketals 99 and subsequent reaction with a proton source or an electrophile was reported by Nakamura and co-workers to provide access to polysubstituted cyclopropanone ketals 100 (Scheme [27]).[54] Stereoselective versions of this transformation were also shown to be efficient when stoichiometric bis-oxazoline (BOX)-ligated allylzinc reagents were used as nucleo­philes or in the presence of chiral Fe(III) catalysts.[54a] [h] [i] Once again, it should be noted that while these products are technically cyclopropanone ketals, they have not been successfully employed as cyclopropanone equivalents and are instead typically encountered as intermediates in ring-opening processes leading to carboxylic acid derivatives (see Sections 3.3.3 and 3.3.4).

Scheme 27 Diastereoselective carbometalation of cyclopropenone ketals­

2.6.2

1-Sulfonylcyclopropanols

Sulfinic acid adducts of aldehydes and imines are commonly employed in nucleophilic addition as base-labile surrogates for unstable substrates. Drawing inspiration from this chemistry, in 2008 Chen and co-workers reported that the benzenesulfinic acid adduct of cyclopropanone 101, a stable crystalline solid, could readily be accessed from hemiketal 86 and was significantly more reactive than classical hemiketals, with equilibration to cyclopropanone taking place in mildly basic conditions at room temperature or below (Scheme [28a]).[45a] In 2020, Lindsay and co-workers optimized this synthetic route to access these surrogates directly from commercially available 85 in one-pot without the need for their recrystallization or for the isolation of unstable and volatile hemiketal intermediate (Schemes 28b).[46] A wide range of sterically and electronically distinct analogues were thus obtained through this method, and their modular character with respect to their rate of equilibration to cyclopropanone was kinetically investigated using a novel pyrazole trapping reaction (Scheme [28c]). Electron-deficient­ (e.g., R = p-CF₃C₆H₄, p-NO₂C₆H₄) and sterically congested (e.g., R = t-Bu, Bn) derivatives were found to equilibrate to cyclopropanone at a significantly higher rate, in accordance with the leaving group ability and the torsional strain inflicted by the sulfinate leaving group, respectively. Importantly, enantioselective access to substituted analogues (e.g., 108–110) was achieved via α-hydroxylation of readily accessible enantioenriched sulfonylcyclopropanes 107, which constitutes the first general synthetic route to optically active cyclopropanone equivalents (Scheme [29]).[46]

Scheme 28 Synthesis and kinetic evaluation of 1-sulfonylcyclopropanols as cyclopropanone precursors

3

Synthetic Applications of Cyclo­propanones and Their Equivalents

3.1

Nucleophilic Addition to the Carbonyl Group

The carbonyl group of cyclopropanone derivatives constitutes a particularly powerful electrophilic site, mainly owing to the ring strain released following its reaction with nucleophiles. Indeed, when a nucleophile is added, the sp²-hybridized carbonyl carbon is re-hybridized to sp³, thereby releasing significant energy (ca. 22 kcal/mol).[4] A number of nucleophiles such as water, alcohols, cyanide, amines, enolates, and organometallic reagents can readily react with cyclopropanones to provide the corresponding 1,2-adducts at low temperature and in mild conditions, a number of which can be isolated in pure form. When present at relatively high concentrations in solution, cyclopropanone is prone to rapid (and often reversible) polymerization in the presence of trace amounts of water or other nucleophiles. Such an event is initiated by their nucleophilic addition to the carbonyl group, thus forming a tertiary hydroxyl capable of further nucleophilic addition to other cyclopropanone species (Scheme [30a]).[1] [2] [3] By ¹H NMR, such a polymer appears as a broad singlet around δ = 1, and a range of molecular weights have been previously reported.[11b,c] Although such a polymerization constitutes one of the main challenges of cyclopropanone chemistry, the formation of oligomeric species can often be suppressed by either (1) the use of a large excess of nucleophile so that the oligomer initially formed eventually equilibrates to the desired monomer, or (2) ensuring a low concentration of the cyclopropanone via the use of a well-behaved cyclopropanone equivalent (see Section 2.6). In the context of cyclopropanone synthesis (see Sections 2.1–2.5), the cyclopropanone generated in situ can readily be converted into the corresponding hemiketal (e.g., 86, 113) or hydrate (e.g., 87) in alcohol solvent or water in mild conditions, respectively,[11c] in order to trap the cyclopropanone in a more stable form (Scheme [30b]). Addition of an excess of hydrogen chloride, acetic acid,[14] [55] or hydrogen cyanide[55] has also been reported to afford the corresponding adducts 114–116 at low temperature.

Scheme 29 Synthesis of enantioenriched cyclopropanone equivalents via α-hydroxylation of sulfonylcyclopropanes

Scheme 30 General electrophilic reactivity of the carbonyl group in cyclopropanone: (a) polymerization; (b) nucleophilic addition

3.1.1

Carbon Nucleophiles

Cyclopropanone precursors such as 1-ethoxycyclo­propyl acetate (117) and 1-ethoxycyclopropanol (86) can be used as substrates in addition reactions to afford tertiary cyclopropanols 118 in a straightforward manner in the presence of excess organometallic reagents (Scheme [31]). In the case of 117, prepared by Simmons–Smith cyclo­propanation of 1-ethoxyvinyl acetate, one equivalent of Grignard reagent is first consumed by addition/elimination on the ester moiety, liberating an alkoxide capable of in situ equilibration to cyclopropanone (Scheme [31a]).[56] At least two more equivalents of Grignard reagent are required to complete the process, one for each of the ketones released in the initial step [cyclopropanone and RC(O)Me], finally affording the desired tertiary cyclopropanol in low to moderate yields. Cyclopropanone hemiketal 86 was later established as a more general cyclopropanone equivalent in this transformation, where one equivalent of Grignard reagent is initially consumed to deprotonate the substrate, leading to a magnesium alkoxide capable of equilibration to cyclopropanone (Scheme [31b]).[50a] [57] A variety of 1-substituted cyclopropanols can be accessed through this strategy, albeit being limited to sp²- and sp-hybridized Grignard reagents. In this specific case, it should be noted that the initial formation of a magnesium alkoxide was found to be necessary, whereas the addition of an excess organolithium reagent to 86, initially forming a lithium alkoxide by deprotonation instead, does not afford the tertiary cyclopropanol in substantial yields.[57d] [58]

Scheme 31 Grignard additions to ketals and hemiketals as cyclopropanone equivalents

In 2020, Lindsay and co-workers reported a general and high-yielding synthesis of tertiary cyclopropanols 120 via the addition of diverse organometallic reagents (M = Mg, Zn, Li) to 1-sulfonylcyclopropanols 119 as precursors of the corresponding cyclopropanones (Scheme [32]).[59a] This method provides a broad scope of tertiary cyclopropanols and is amenable to sp-, sp²-, or sp³-hybridized organometallic C-nucleophiles under mild conditions. When desired, the use of excess Grignard reagent can be avoided through the addition of MeMgBr (0.95 equiv) as initial base to trigger the equilibration to cyclopropanone at –78 °C and loss of methane. In the case of alkyl nucleophiles, the use of softer Si-stabilized zincates generated using Ishihara’s method[60] was found to be key to provide the corresponding adducts in good yields. Since substituted 1-sulfonylcyclopropanols can now be readily accessed in enantioenriched form (see Scheme [29], Section 2.6.2),[46] this approach also provides a rare efficient route to optically active tertiary cyclopropanols via highly diastereoselective additions (see 121–124).

Scheme 32 Synthesis of tertiary cyclopropanols from 1-sulfonylcyclopropanols as cyclopropanone equivalents

When the appropriate substrate and conditions are used, cyclopropanone is also susceptible to the addition of stabilized nucleophiles such as enolates, leading to the corresponding β-hydroxy carbonyl compounds as intermediates (aldol reaction, see also Section 3.2.3). Chen and co-workers reported that the lithium enolate of acetaldehyde, formed in situ by n-BuLi-mediated degradation of tetrahydrofuran, can add to cyclopropanone when 1-sulfonylcyclopropanol 101 is employed as surrogate, affording a β-hydroxy aldehyde that can be trapped as a propargylic alcohol following addition of an alkynyllithium reagent (Scheme [33]).[61] The resulting 1,3-diols 125 are obtained directly from 101 in moderate to good yields and the reaction is shown to be compatible with a variety of alkynyllithium reagents, with the direct addition of organometallic nucleophile to cyclopropanone, leading to 126, observed as an undesired side-reaction.[59b]

Scheme 33 Consecutive nucleophilic additions of a lithium enolate and lithium alkynylides to 1-phenylsulfonylcyclopropanol. ^a Yield of compound 126 in parenthesis.

Salaün and co-workers reported that arylidenecyclopropanes 128a could be accessed via Wittig olefination of cyclopropanone by employing hemiketal 86 as a surrogate (Scheme [34a]).[58] [62a] The substrate is first deprotonated at 0 °C in the presence of methylmagnesium iodide as a base, followed by addition of phosphonium ylides 127 and reflux for 2 days, affording arylidenecyclopropanes 128a in low to moderate yields. Notably, the use of alkyl- or alkynyl-substituted­ Wittig reagents instead in this reaction only afforded the corresponding betaines, with no alkylidene­cyclopropane observed even after prolonged heating in various conditions. An analogous transformation was reported by Spitzner and co-workers, where the use of stabilized phosphonium ylides led to electron-poor alkylidenecyclopropanes 128b in moderate to good yields (Scheme [34b]).[62b] Key to the success of this reaction was the use of benzoic acid as catalytic additive under reflux of benzene. de Meijere and co-workers reported that electron-poor alkylidenecyclopropanes, generated in situ from cyclopropanone hemiketal 113 via Wittig olefination, readily undergo (4+2) cycloaddition with thiophene S-monoxides leading to endo cycloadducts 129 in moderate to good yields (Scheme [34c]).[62`] [d] [e] Both steps require high temperature to proceed, and the cycloaddition was found to be significantly accelerated by strain-release, whereas alkylidenecyclopentanes were found to be unreactive in analogous cycloadditions.

Scheme 34 Synthesis of alkylidenecyclopropanes via Wittig olefination of cyclopropanone hemiketals

3.1.2

Amine Nucleophiles

The addition of amines to cyclopropanones leading to the corresponding hemiaminals and aminals is usually more complicated, due in part to the instability of these products and the various possibilities of mixtures which can be obtained, especially in the case of ammonia or primary amines. The efficiency and outcome of the reaction is often dependent on the type of substitution on the amine nucleophile, the stoichiometry of the substrates, the order of addition as well as the temperature. Hemiaminals initially generated by the reaction of cyclopropanones and aliphatic amines can undergo further amine substitution to afford aminals, presumably via iminium intermediates. For instance, addition of dimethylamine to cyclopropanone (1) resulted in the isolation of aminal 131 instead of the expected carbinol amine 130 (Scheme [35a]).[63a] Hemiaminal 130 could later be isolated by reverse addition, where a cold cyclopropanone solution was slowly added to the amine in CH₂Cl₂ at –50 °C (Scheme [35b]).[10] Any deviation from this protocol also led to significant formation of a dimeric product, where 130 further reacted with another cyclopropanone species. This carbinol amine 130 was later demonstrated to be a versatile intermediate to access other cyclopropylamine derivatives via a cyclopropaniminium intermediate, or to act as cyclopropanone precursor by reaction with ketenes or isocyanates.[63b] Notably, upon prolonged standing at room temperature or heating at 100 °C, slow isomerization to its ring-opened form, N,N-dimethylpropanamide, was observed. In the case of methylamine as nucleophile (Scheme [35c]), the hemiaminal initially formed further reacts with another cyclopropanone molecule to afford the bis(cyclopropyl) derivative 132 at –30 °C.[63a] [c] [d] Warming up this solution to 60 °C leads to the formation of various heterocyclic systems 133–135 via a series of condensation events.

Scheme 35 Various possible products resulting from the addition of amines to cyclopropanone

Chen and co-workers took advantage of this chemistry for the preparation of 1-alkynylcyclopropylamines 136 in moderate yields starting from 1-sulfonylcyclopropanol 101 as cyclopropanone equivalent (Scheme [36]).[45a] Under mild aqueous conditions, cyclopropanone is formed by sulfinate elimination and can react with a secondary amine to form an hemiaminal in equilibrium with the corresponding iminium, susceptible to Au-catalyzed addition of a terminal alkyne. Considering the important electrophilicity of cyclopropanone, this mechanism was considered in analogy to the known Au-catalyzed addition of terminal alkynes to aldehydes, which can be performed in similar aqueous conditions.[45b]

Scheme 36 Gold(III)-catalyzed coupling reaction of cyclopropanone, terminal alkynes, and dialkylamines

3.2

Ring Expansion

3.2.1

Cyclobutanone Formation

Carbene equivalents such as nucleophilic diazo compounds have sporadically been reported to lead to ring expansion of cyclopropanones to the corresponding four-membered ketones, leading to a significant release of strain. For example, Turro and co-workers studied in more details the direct formation of cyclobutanones 138 and 139 from ketenes 137 and diazoalkanes, which was initially reported in the 1930s[7] and constituted one of the first evidence of the existence of cyclopropanone (Scheme [37]).[64] When employing substituted ketenes and diazomethane, the predominant products 138 were found to derive from the migration of the most substituted carbon, in accordance with a higher-energy HOMO at this position, as commonly observed in Baeyer–Villiger oxidations and related [1,2]-rearrangements (Scheme [37a]). Instead of starting from ketenes 137, CH₂Cl₂ solutions of pure substituted cyclopropanones could be prepared and used as substrates in this reaction (Scheme [37b]). When higher diazoalkanes such as diazo­ethane were employed in these cases, the cis-cyclobutanone products were identified as major diastereomers, in accordance with kinetically controlled rearrangements.

Scheme 37 Formation of cyclobutanones by ring expansion of cyclopropanones with diazoalkanes

Scheme 38 Ring expansion of vinylcyclopropanols to cyclobutanones by reaction with various electrophiles

Wasserman and co-workers reported that vinylcyclopropanols 140 resulting from the addition of vinyl Grignard to cyclopropanone equivalents (see Section 3.1.1) can be converted into various cyclobutanone derivatives by reaction with electrophiles such as bromine (see 141), tert-butyl­ hypochlorite (see 142), perbenzoic acid (see 143), N,N-dibenzylformiminium ion (see 144), or hydrogen bromide (see 145 and 146) (Scheme [38a]).[57a] [c] The electrophilic addition generates a cyclopropylcarbinyl cation intermediate or its equivalent which immediately rearranges to the cyclobutanone via [1,2] shift. In the case of a methyl-substituted vinylcyclopropanol reacting with HBr leading to 146, only the 2,3-dimethylcyclobutanone was produced in 83% yield resulting from the regioselective migration of the most highly substituted carbon.[57c] The diastereomeric ratio (3:1) favoring the trans product is presumably the result of thermodynamic equilibration in these conditions.[64b] In contrast, the same reaction performed in more polar concentrated sulfuric acid led to a mixture of all four possible isomers, including 2,4-dimethylcyclopropanones. Similarly, 1-cyclopentadienylcyclopropanol 147 was found to rearrange to the corresponding spirocyclobutanone 148 when treated with 10% aqueous sulfuric acid in Et₂O (Scheme [38b]).[56b]

3.2.2

β-Lactam Formation

The ring expansion of cyclopropanone to unsubstituted β-lactam 150 was first reported by Wasserman and co-workers by reaction of hemiketal 86 with an excess of sodium azide under buffered acidic conditions, where the 1-azido­cyclopropanol (149) initially formed subsequently rearranges to β-lactam 150 via [1,2] shift and extrusion of nitrogen gas (Scheme [39a]).[57a] [65a] Analogous rearrangements were later developed using activated hydroxylamine derivatives and starting from cyclopropanone solutions obtained from the reaction of diazomethane and ketene (see Section 2.1),[9] allowing access to N-substituted β-lactams such as 152 (Scheme [39b]).[65b] [c] A more general approach affording moderate yields of these β-lactams was achieved in a stepwise procedure employing various primary amines as nucleophiles (Scheme [39c]).[65b] [d] [e] The carbinol amines 153 initially produced by amine addition are oxidized to the N-chlorinated derivatives with t-BuOCl after evaporation of the solvent and dissolution in acetonitrile, then directly treated with an excess of AgNO₃ in the dark to trigger the [1,2] shift, affording β-lactams 155 and formation of AgCl. A modified protocol for such a strategy was later developed by De Kimpe and co-workers using 1-methoxycyclopropylamines instead of the carbinol amines, formed via a Favorskii-type ring-closure of the corresponding α-chloroimines and addition of sodium methoxide, eventually leading to racemic 1,4,4-trisubstituted β-lactams.[65f] Alternatively, the use of ethyl silyl ketal 85 as cyclopropanone precursor in the presence of BF₃·OEt₂ was found by Aubé and co-workers to lead to various N-substituted β-lactams 155 in low to moderate yields when organoazides were employed as nitrene equivalents, via a Schmidt-type rearrangement (Scheme [39d]).[65g] In this work, formation of an unexpected ethyl carbamate side product, presumably from the loss of ethylene and ethanol addition to the resulting isocyanate, was found to efficiently compete with the desired pathway.

Scheme 39 Diverse strategies for the formation of achiral β-lactams by ring expansion of cyclopropanone or its equivalents

Scheme 40 Formal [3+1] cycloaddition of cyclopropanone equivalents and unprotected hydroxylamines leading to β-lactams

In 2020, Lindsay and co-workers reported a ring expansion of cyclopropanones employing 1-sulfonylcyclopropanols 119 as surrogates in the presence of unprotected hydroxylamines as nitrene equivalents, affording β-lactams 157 in mild conditions (Scheme [40a]).[46] The N-hydroxy hemiaminal intermediate 156 initially generated by nucleophilic addition of a chosen hydroxylamine to the corresponding cyclopropanone underwent in situ [1,2] rearrangement to β-lactams in the presence of Al(OTf)₃. The reaction was found to be particularly efficient in the case of substituted cyclopropanone precursors, leading to the corresponding 4-substituted β-lactams 158–161 with complete regiocontrol favoring migration of the most highly substituted carbon (Scheme [40a]). In the case of bicyclic β-lactam 161, a significant reduction in yield was observed presumably due to Favorskii-type ring-opening of the hemiaminal intermediate 156 to the corresponding hydroxamic acid derivative. This procedure was also shown to be efficient in the presence of a catalytic amount of Al(OTf)₃ (1 mol%), although a workup was necessary in this case following formation of 156 in order to eliminate sulfinate salts capable of poisoning the Lewis acid catalyst. Importantly, the reaction was shown to be completely stereospecific, exemplified by the enantioselective synthesis of 4-substituted β-lactam 163 on a gram scale when an optically active cyclopropanone equivalent 108 was employed as substrate (Scheme [40b]).

3.2.3

Aldol- and Wittig-Initiated Ring Expansion

Helquist and co-workers reported that the aldol addition of lithium cyclohexenolate to an equimolar amount of the magnesium alkoxide of cyclopropanone hemiketal 86 leads to the spontaneous formation of a tricyclic cycloheptanone 165 along with small amounts of aldol adduct 164, later shown to be an intermediate in the reaction (Scheme [41]).[66] Experimental evidence demonstrated that the transformation proceeds by aldol addition to cyclopropanone originating from the magnesium alkoxide of 86, leading to a cyclopropoxide (magnesium alkoxide of 164) susceptible to act as electrophile in a second aldol addition of lithium cyclohexenolate still present in solution. The resulting dialkoxide then undergoes ring-opening to a chelated magnesium-homoenolate capable of seven-membered ring closure by intramolecular homo-aldol addition to the remaining ketone, leading to 165 after aqueous workup.

Scheme 41 Direct formation of a tricyclic cycloheptanone initiated by aldol addition to cyclopropanone

The same research group later reported that if the thermodynamic enolate of an α-alkyl ketone is employed as nucleophile in this reaction instead, the resulting congested cyclopropanol (e.g., 167, 170) can undergo rearrangement to the corresponding β-hydroxycyclopentanone (e.g., 168 and 171) by treatment with sodium hydride (Scheme [42]).[67] The transformation is limited to cyclic enolates and presumably proceeds via the formation of a ring-opened sodium-homoenolate followed by intramolecular homo-aldol addition. Although this method provides a valuable approach to access bicyclic systems, the overall efficiency was found to be highly dependent on the substrate, as the initial formation of the cyclopropanol via aldol addition most often proceeded in around 20–30% yield due to various side-reactions.[67a] [b] An exception to this trend was shown with dihydrophenanthrenone 169 as substrate, leading to β-hydroxycyclopentanone 171 in good overall yield over two steps.[67b]

Scheme 42 Formation of bicyclic β-hydroxycyclopentanones via aldol addition of cyclic enolates and rearrangement induced by sodium hydride

Suda and co-workers reported a novel synthetic route to a range of polysubstituted furans 174 and 175 by reaction of stable cis-2,3-bis(trimethylsilyl)cyclopropanone (172) (see also Scheme [2b], Section 2.1) with stabilized phosphorus ylides 173 under reflux of toluene (Scheme [43]; see also Scheme [34b], Section 3.1.1).[68] The same reaction performed at room temperature in CH₂Cl₂ led to the formation of the corresponding alkylidenecyclopropane (Wittig product) in 80% yield, serving as evidence of its intermediacy in the transformation. Heating this product under reflux in toluene triggered a [1,5]-sigmatropic rearrangement to the corresponding polysubstituted furan after rearomatization (90% yield). Notably, attempting the analogous [1,5]-sigmatropic rearrangement on a non-silylated alkylidenecyclopropane derivative instead led to no product formation even after three days under reflux, suggesting that the silyl groups of the intermediate have an important role to play in the success of this pericyclic process.

Scheme 43 Synthesis of polysubstituted furans via tandem Wittig olefination/[1,5] sigmatropic rearrangement of cis-2,3-bis(trimethylsilyl)cyclopropanone. ^a Ratio of compounds 174 and 175 in parentheses (X = SiMe₃ or H).

3.3

Ring-Opening

Cyclopropanone derivatives are susceptible to both homolytic­ and heterolytic cleavage of their C–C bonds under a number of different conditions in a substituent-dependent manner, affording ring-opened acyclic products. The ring-opening process can be induced by the addition of nucleo­philes, electrophiles, oxidants, or specific metal salts. Since the inherent ring strain makes all bonds of cyclopropanones potentially labile, there are several possible reactive sites. In basic conditions, a C1–C2 bond scission is typically favored as exemplified by Favorskii-type rearrangements,[6] while both C1–C2 and C2–C3 bond cleavage can occur under acidic conditions. Moreover, cyclopropanone equivalents such as hemiketals (e.g., 86, 113) constitute powerful substrates for the formation of β-functionalized acyclic carboxylic derivatives by C1–C2 bond cleavage, via either oxidative ring-opening followed by radical trapping or β-carbon elimination and formation of metal-homoenolates, known to be versatile intermediates in a variety of coupling processes.

3.3.1

Ring-Opening under Basic Conditions

Scheme 44 Divergence of reactivity in the base-mediated ring-opening of cyclopropanones and their hemiketals depending on substitution

The deprotonated form of unsubstituted cyclopropanone hemiketal 86 readily decomposes at high temperatures into ethyl propanoate (176) via C1–C2 bond cleavage (Scheme [44a]).[58] In the case of asymmetrically substituted cyclopropanones, the site-selectivity of ring cleavage (C1–C2 or C1–C3) depends on the substitution pattern and is often controlled by the formation of the most stable incipient carbanion intermediate (see also Section 2.3). For instance, the ring-opening of 2,2-dimethylcyclopropanone (2) under basic conditions in methanol exclusively generates a primary carbanion intermediate via C1–C3 bond cleavage, yielding methyl pivalate after protonation (Scheme [44b]).[9d] [69] On the other hand, 2-aryl-substituted cyclopropanone hemiketals rapidly isomerize to 3-arylpropanoic esters 177 under basic conditions at room temperature, presumably via the formation of a more stable benzylic anion intermediate after C1–C2 bond cleavage (Scheme [44c]).[70] With particularly hindered substituents as in 2,2-di-tert-butylcyclopropanone (21), this trend can sometimes be reversed, where the predominant ring-opening product 178 is derived from the least stable (tertiary) incipient carbanion (Scheme [44d]).[19b] [25n] In this particular case, the relief of torsional strain in the transition state of the congested C1–C2 bond cleavage affording 178 dominates over the greater partial negative charge stabilization occurring during C1–C3 bond cleavage leading to 179.

3.3.2

Ring-Opening under Acidic Conditions

Scheme 45 Ring-opening via C1–C2 or C2–C3 bond cleavage of cyclopropanones and their hemiketals mediated by Brønsted acids depending on the substitution pattern

The acid-mediated ring-opening of cyclopropanones and their hemiketals can occur by C1–C2 or C2–C3 bond cleavage, yielding either propanoate esters or propan-2-one derivatives, respectively, where the reactive site is determined by the presence of substituents capable of stabilizing carbocation intermediates. In the case of unsubstituted hemiketals such as 1-methoxycyclopropanol (113), methyl propanoate (180) is formed exclusively under acidic conditions via protonation of the C1–C2 bond (Scheme [45a]).[11c] [69] Since it is known that cyclopropanone (1) reacts with dry HCl to afford 1-chlorocyclopropanol 114 rather than an acyclic product,[11c] [55a] it is reasonable to believe that this type of ring-opening process does not proceed by initial formation of a cyclopropanone intermediate via elimination, but rather involves a direct C1–C2 protonation of the unsubstituted hemiketal. On the other hand, it has been reported that the C2–C3 bond cleavage is favored when cation-stabilizing substituents are present on the ring system, presumably via a 2-hydroxyallyl cation intermediate 183 formed following protonation of the corresponding cyclopropanone (Scheme [45b]).[55] [70] For instance, both 2,2-dimethylcyclopropanone (2) and 1-methoxy-2-phenylcyclopropanol are quantitively converted into isomeric mixtures of functionalized 3-methylbutan-2-ones and phenylpropan-2-ones, respectively, in the presence of various acids. The ratio of isomers obtained is found to be dependent on the solvent as well as the nature of the acid used. Based on thorough mechanistic studies[70] and since both the cyclopropanone and hemiketal substrates lead to similar outcomes of C2–C3 bond scission, it is inferred that protonation of a cyclopropanone intermediate is involved in these cases, where substituents help stabilize the 2-hydroxyallyl cation intermediate 183 formed following ring-opening.

Scheme 46 Formation of ring-opened α-amino-α′-diazomethyl ketones under Schmidt conditions and application in the synthesis of azetidin-3-ones

Strong Lewis acids such as BF₃·OEt₂ can also trigger a C2–C3 bond cleavage of substituted cyclopropanone derivatives through an analogous mechanism involving stabilized oxyallyl intermediates. In 2000, Aubé and co-workers reported the reaction of 2,2-dimethylcyclopropanone methyl silyl ketal 184 with alkyl azides in the presence of BF₃·OEt₂, providing a series of α-amino-α′-diazo-α,α-diazomethyl ketones 185 via C2–C3 bond cleavage (Scheme [46a]).[65g] [71] Notably and in contrast with this particular case, these conditions are typically encountered in Schmidt-type ring expansions, providing the corresponding lactams via C1–C2 bond cleavage when larger cyclic ketones or unsubstituted cyclopropanone equivalents are employed (see Scheme [39d], Section 3.2.2). Here, the stabilized oxallyl species 187 initially formed presumably reacts with the alkyl azide to afford a 1,2,3-triazin-5-one intermediate 188 via a (formal) (3+3) cycloaddition. In analogy to the Brønsted acid mediated ring-opening of substituted cyclopropanones (see Scheme [45b]), it is proposed that the carbocation-stabilizing character of the two methyl groups allows this pathway to predominate over azide addition to the carbonyl and C1–C2 bond cleavage. Subsequent fragmentation of this intermediate leads to a zwitterionic species 189 capable of intramolecular proton transfer, leading to 185. Interestingly, the use of monoalkyl- or aryl-substituted cyclopropanone methyl silyl ketals in similar conditions at high temperatures afforded [1,2,3]oxaborazoles in low to moderate yields instead, also proceeding via C2–C3 bond cleavage of the corresponding cyclopropanone.[65g] The resulting α-amino-α′-diazomethyl ketone products 185 are shown to be effective substrates in a subsequent Rh₂(OAc)₄-catalyzed intramolecular N–H insertion, affording azetidin-3-ones 186 in good yields (Scheme [46b]).[72]

Scheme 47 Thermal rearrangement of fulvenes endoperoxides into 1,5-dicarbonyl compounds or lactol acetates via cyclopropanone intermediates

5,6-Dihydrofulvene endoperoxides 190 have been reported by Erden and co-workers to rearrange to substituted cyclopropanones 191 via the corresponding allene oxides (see also Section 2.2) upon thermolysis (Scheme [47]).[73] Under acidic conditions, the 2-hydroxyallyl cation formed by C2–C3 bond cleavage of the cyclopropanone 191 can rearrange to either a ring-opened 1,5-dicarbonyl compound 192 or a lactol acetate 193 depending on the substitution pattern. In the case of 2,2-disubstituted cyclopropanone intermediates (R¹ ≠ H), the cationic intermediate is directly trapped by an acetate anion in a regioselective manner, affording 192. On the other hand, when R¹ = H, this 2-hydroxyallyl cation is less sterically hindered, allowing an intramolecular (3+2) cycloaddition to take place with the tethered aldehyde, eventually affording lactol 193 after AcOH-mediated cleavage of the resulting bicyclic acetal.[73c]

3.3.3

Oxidative Ring-Opening Processes

Cyclopropane derivatives in general are considered to have lower oxidation potentials than other cyclic alkanes due to a greater p-character of the ring-composing molecular orbitals. In analogy to the ring-opening chemistry of cyclopropanols,[74] the one-electron oxidation of cyclopropanone hemiketals in the presence of either inorganic[75] or organic[76] oxidants constitutes a powerful method for the selective cleavage of the C1–C2 bond, eventually leading to acyclic products (Scheme [48]). The hydroxyl radical 195 formed from such an event undergoes rapid ring-opening to give rise to β-propanoate radicals 196. In the case of asymmetrically substituted cyclopropanones, the most substituted C1–C2 bond is often selectively cleaved to afford a secondary or tertiary radical, by virtue of its increased stability. These radical intermediates then provide access to β-functionalized esters 197 by reaction with a diversity of reaction partners (FG). Seminal studies in this regard by de Boer and co-workers identified effective inorganic oxidants such as AgNO₃, CuSO₄, FeCl₃, and Ce(SO₄)₂, each leading to various typical end products of aliphatic radicals depending on the reaction conditions and the oxidant used (Scheme [48a]).[75] Alternatively, the β-radical intermediate can also be trapped by alkenes or furan derivatives, leading to C–C bond-forming processes in low to moderate yields.[75d] Notably, the reaction of 1-methoxycyclopropanol (113) with ceric sulfate, the β-propanoate radical was observed and characterized by electron spin resonance (ESR) by de Boer and co-workers in 1966, bringing further evidence of such a radical mechanistic pathway.[75a] In the early 1970s, they identified diverse other oxidizing agents (e.g., O₂, ^•CCl₃) including organic oxidants, giving access to various other types of β-functionalized esters (Scheme [48b]).[76]

Scheme 48 Seminal studies of the oxidative ring-opening of cyclopropanone hemiketals involving β-propanoate radical intermediates

On the basis of these seminal studies further work was reported on β-radical trapping with other reagents.[77] In 1994 the Oku group reported a radical coupling of cyclopropanone methyl silyl ketals 198 and arylmethyl methanesulfonates 199 via a photoinduced electron transfer process (Scheme [49a]).[77a] Due to the electron-rich nature of these ketals, the ring-opening process can be achieved following single electron transfer to an excited aromatic radical acceptor under photoirradiation conditions. Loss of a trialkylsilyl mesylate leads to the formation of a transient β-propanoate radical capable of recombination with the benzylic radical to form a new C–C bond (see 200). In 1996, they reported a similar pathway for the coupling of these same ketals with enones, where in this case pyrene was used as an external photosensitizer catalyst to facilitate the electron transfer between both substrates (Scheme [49b]).[77b] Notably, only the cleavage of the most substituted C1–C2 bond of the cyclopropanone alkyl silyl ketals was observed in all cases, in accordance with the increased radical stability of the ring-opened intermediate.

Scheme 49 Radical coupling of cyclopropanone alkyl silyl ketals and arylmethyl methanesulfonates or alkenes via photoinduced electron transfer

Nakamura and co-workers reported the oxidative ring-opening of cyclopropanone ketals 100, obtained via carbometalation of the corresponding cyclopropenone ketals (see Scheme [27], Section 2.6.1), in the presence of TfOH and a stoichiometric amount of either MnO₂ or PbO₂ as oxidant (Scheme [50]).[54a] Various solvents such as alcohols, acetic acid, or acetonitrile could be employed in the reaction, leading to the corresponding β-alkoxy esters, β-acetoxy esters, or β-amino esters, respectively, following addition of water, see 201–208. In all cases, the C1–C2 oxidative bond cleavage takes place at the most substituted carbon, which again is in accordance with the general trend of radical stability. In line with this, the absence of a π-system capable of radical stabilization via resonance was found to be detrimental to the reaction and lead to a much slower process (see 205). When optically active cyclopropanone ketals 100 were employed as substrates, racemic products were obtained likely due to the presence of a ring-opened β-radical intermediate. When a 2-isobutenyl-substituted substrate was employed, a mixture of regioisomers 207 and 208 was observed. To account for these observations, the proposed mechanism involves the formation of an oxocarbenium intermediate via one electron oxidation and ring-opening of the cyclopropane moiety, followed by a second oxidation leading to a carbocation capable of reaction with the solvent used, eventually affording the corresponding β-functionalized esters 201–208 after orthoester hydrolysis.

Scheme 50 Oxidative ring-opening of cyclopropanone ketals with MnO₂ or PbO₂ for the synthesis of β-alkoxy esters, β-acetoxy esters, or β-amino esters

In 2020, Liu, Guo, and co-workers reported an enantio­selective ring-opening cyanation of cyclopropanone alkyl silyl ketals 209 through a copper-catalyzed radical relay strategy in the presence of TMSCN and N-fluorobenzenesulfonimide (NFSI) as stoichiometric oxidant (Scheme [51]).[78] Optically active β-cyano esters 210 were obtained in moderate to good yields with a high level of stereocontrol when 1-aminoindan-2-ol-derived bis(oxazoline) (1S,2R)-L* was employed as chiral ligand. Mechanistic studies including radical trapping experiments have shown that the transformation proceeds via the homolysis of a Cu(II)-cyclopropanoxide complex, leading to a transient oxygen radical 211 capable of rapid ring-opening to a β-radical intermediate 212, once again selectively cleaving the most substituted C1–C2 bond due to increased stability of the resulting benzylic radical. This species then reacts with a L*Cu^II(CN)_n complex to transfer the cyano group in high enantioselectivity, regenerating the Cu(I) catalyst. The presence of an aryl group at the 2-position of the substrate was found to be necessary to stabilize the β-radical intermediate 212 initially formed. In the same report, the use of tertiary cyclopropanols as substrates was also found to be efficient under similar conditions, leading to β-cyano ketones. This work is highly relevant to the field of oxidative ring-opening of cyclopropanols and cyclopropanone (hemi)ketals, as it represents the only example of β-radical trapping with a chiral metal complex to achieve high enantioinduction in the final ring-opened product, and much of the future advances in this realm are expected to stem from similar strategies.

Scheme 51 Enantioselective ring-opening cyanation of cyclopropanone alkyl silyl ketals through a copper-catalyzed radical relay strategy (CuTC = copper(I) thiophene-2-carboxylate)

3.3.4

Metal Homoenolate Chemistry

The parallel between cyclopropanone (hemi)ketals and cyclopropanols, both constituting highly electron-rich cyclopropane derivatives, has been thoroughly extended in the context of metal homoenolate chemistry,[74] where analogous ring-opening via C1–C2 bond cleavage in the presence of specific metal salts leads to the formation of β-nucleophilic esters rather than β-nucleophilic ketones or aldehydes. Seminal studies had shown that the reaction of cyclopropanone alkyl silyl ketals with a variety of transition metal salts such as ZnCl₂ or TiCl₄ affords the β-metalated propanoate esters with high efficiency, which can undergo further functionalization in the presence of electrophiles (Scheme [52]).[79] Notably, in contrast with oxidative ring-opening processes which typically proceed via alkyl radical intermediates (see Section 3.3.3), the least substituted C1–C2 bond is usually cleaved in metal homoenolate chemistry (except when R² = aryl, alkenyl), following the expected stability trend of carbanions (see Section 3.3.1).

Scheme 52 General strategy for the ring-opening functionalization of cyclopropanone alkyl silyl ketals via metal homoenolates

Seminal studies by Kuwajima and Nakamura had demonstrated the viability of such a pathway in carbon–carbon and carbon–heteroatom bond formation via the formation of Zn- or Ti-bound homoenolates (Scheme [53]).[79] The nucleophilic titanium homoenolates can react with electrophiles such as bromine, molecular oxygen, acyl halides, alkyl halides, and aldehydes, yielding the corresponding β-functionalized products. Zinc homoenolates generated in the presence of zinc chloride were demonstrated to be useful synthons for other transformations such as copper-catalyzed conjugate addition.[80] Moreover, palladium homoenolates generated in the presence of a catalytic amount of Pd(II) salts were found to be competent cross-coupling partners in arylation reactions with aryl triflates.[81] Since these key seminal findings, a number of analogous disconnections have been uncovered with a variety of other transition metal salts and (pseudo)electrophilic coupling partners, most of which involve tertiary cyclopropanols as substrates rather than cyclopropanone (hemi)ketals. These have already been thoroughly reviewed elsewhere and thus will not be covered in more details here.[74]

Scheme 53 Selected examples of the formation of β-functionalized esters using metal homoenolate intermediates derived from cyclopropanone (hemi)ketals

3.4

Cycloaddition and Formal Cycloaddition

As mentioned earlier, cyclopropanone derivatives possess multiple reactive sites, where any bond-cleaving step constitutes an exothermic event and leads to significant strain release. Besides nucleophilic addition, ring-expansion and ring-opening processes, this unique behavior is also encountered in cycloaddition and formal cycloaddition. The carbonyl group as well as the C1–C2 or C2–C3 bonds have all been shown to participate in such transformations, leading to a wide diversity of accessible cyclic building blocks using this approach. Turro and co-workers were among the first chemists to study the reactivity of cyclopropanone derivatives in concerted (2+2), (3+2), and (4+3) cycloadditions, most of which were performed from 2,2-dimethylcyclopropanone (2) (Scheme [54]).[82] The carbonyl group in 2 can undergo (2+2) cycloaddition with ketenes or their acetals, affording spiro compounds 213 or 214. Alternatively, C2–C3 bond cleavage can occur to yield an oxyallyl intermediate (see Section 2.2) formally acting as a 1,3-dipole capable of either (3+2), or (4+3) cycloaddition with a variety of dipolarophiles such as carbonyl compounds, sulfur dioxide, or cyclic dienes (see 215–217). This chemistry has previously been described in more details in an earlier review.[2a]

Scheme 54 Representative examples of cycloadditions employing 2,2-dimethylcyclopropanone as substrate

Cyclopropanone ketals 218 were reported by Steinberg and co-workers to react with tetracyanoethylene (219) to afford the corresponding five-membered cycloadducts 220 in good yields (Scheme [55]).[83] [84] In this process, the most substituted C1–C2 bond of the substrate 218 was cleaved with complete site selectivity in most cases, where the nature of the substituents was found to have a profound impact on the reaction rate, with reaction times ranging from five minutes at room temperature to three weeks at reflux. Through experimental mechanistic studies employing mixed ketals as substrates, this transformation was later demonstrated to proceed in thermal conditions via a unique concerted, symmetry-allowed [_π2s+_σ2a] cycloaddition pathway.[84]

Scheme 55 Concerted, symmetry-allowed [_π2s+_σ2a] cycloaddition of cyclopropanone ketals with tetracyanoethylene

When certain substituted cyclopropanones prone to equilibrate to oxyallyl intermediates are employed instead of the corresponding ketals, selective C2–C3 bond cleavage can occur and lead to a different type of cycloadduct by reaction with dipolarophiles. Cookson and co-workers reported that 1,3-dibromo ketone 221 can be reduced by sodium iodide, leading to cyclopropanone intermediate 40 via Favorskii-type ring closure, which is in equilibrium with the corresponding oxyallyl intermediate (Scheme [56], see also Sections 2.2 and 2.3).[24a] [30b] In the presence of specific dipolarophiles such as diethyl azodicarboxylate (Scheme [56a]) or tetracyanoethylene (Scheme [56b]), (3+2) cycloaddition takes place, forming the corresponding five-membered ketones in low yields. Notably, all other dipolarophiles evaluated in this reaction did not lead to any appreciable cycloadduct, with only the cyclic dimer of the oxyallyl intermediate being observed in most cases. In the cycloaddition employing tetracyanoethylene (Scheme [56b]), only the product 223 resulting from HCN elimination could be recovered from the reaction mixture, along with traces of the corresponding cyclopentadienone.

Scheme 56 (3+2) Cycloadditions of 2,3-diphenylcyclopropanone via an oxyallyl intermediate

Crimmins and co-workers reported the use of a zinc homoenolate­ 224 generated in situ from cyclopropanone ethyl silyl ketal 85 in a formal (3+2) cycloaddition with acetylenic esters or amides in the presence of CuBr•SMe₂ as catalyst, leading to cyclopentenones 225 (Scheme [57]).[85] The transformation likely proceeds via a conjugate addition of the metal homoenolate 224 followed by intramolecular acylation of the resulting allenoate intermediate. The scope of this transformation was thoroughly investigated and found to be efficient for a wide range of functionalized acetylenic electrophiles, generally affording the 2-(alkoxycarbonyl)cyclopentenones 225 in good yields.

Scheme 57 Annulation of acetylenic esters or amides with zinc homoenolates­ derived from cyclopropanone ethyl silyl ketal

Inspired by classical transformations of fulvene endoperoxides affording oxepinone and cyclopentenone derivatives,[86] Erden and co-workers reported a novel rearrangement of alkenyl-substituted 5,6-dihydrofulvene endoperoxides 226 into cyclopentenones 227 (Scheme [58]).[87] Under thermal conditions, the endoperoxide 226 presumably rearranges to an alkenylcyclopropanone 229 via the corresponding allene oxide 228 (see also Scheme [47], Section 3.3.2), which is susceptible to ring-opening to an oxyallyl intermediate 230 capable of ring closure by engaging the attached alkenyl group, furnishing cyclopentenones 227 in moderate to good yields.

Scheme 58 Thermal rearrangement of 5,6-dihydrofulvene endoper­oxides into cyclopentenones via cyclopropanone intermediates

In 2020, Lindsay and co-workers disclosed a novel Ni-catalyzed formal (3+2) cycloaddition of cyclopropanone and internal alkynes via C–C bond activation, employing 1-sulfonylcyclopropanol 101 as cyclopropanone equivalent and providing access to 2,3-disubstituted cyclopentenones 231 (Scheme [59]).[88] Notably, the corresponding products are formed with complete regiocontrol, favoring cyclopentenones with reverse regioselectivity compared to that of the classical Pauson–Khand reaction,[89] with the largest substituent located at C3. A key trimethylaluminum additive is thought to play multiple roles in the process, first as a Brønsted­ base triggering the equilibration to cyclopropanone, then as a source of Lewis acid (e.g., PhSO₂AlMe₂) to activate cyclopropanone (1) towards the subsequent oxidative cyclization and β-carbon elimination.[90]

Scheme 59 Ni-catalyzed formal (3+2) cycloaddition of cyclopropanone and internal alkynes using 1-phenylsulfonylcyclopropanol as precursor

In specific cases, substituted cyclopropenones such as 232 can be used as precursors of cyclopropanones via conjugate addition. Kascheres and co-workers reported that the addition of pyrazole to 232 leads to 2,2,3-trisubstituted cyclopropanone 233 susceptible to C2–C3 ring-opening to an oxyallyl species 234 (see also Section 2.2), which can be trapped with a variety of (hetero)aromatic amines to afford fused heterocycles 235–237 (Scheme [60]).[91] Interestingly, when 2,3-diphenylcyclopropenone was employed as substrate instead, a distinct reactivity was observed due to the propensity of the cyclopropanone intermediate towards C1–C2 ring-opening, affording ketene intermediates rather than oxyallyl species.

Scheme 60 Synthesis of fused heterocycles via trapping of oxyallyl intermediates generated in situ by conjugate addition to a cyclopropenone

(4+3) Cycloadditions involving oxyallyl intermediates have been widely reported.[92] Cha and co-workers reported the (4+3) cycloadditions of cyclopropanone hemiketals and furans in both inter- and intramolecular modes, leading to the corresponding polycyclic ketones 240 and 242, respectively, in moderate to good yields as diastereomeric mixtures (Scheme [61]).[92a] The transformation presumably proceeds via a cyclopropanone intermediate formed by elimination of ethylene glycol, which could then equilibrate via C2–C3 bond cleavage to an oxyallyl species prone to [4+3] cycloaddition. The use of a non-nucleophilic, highly ionizing solvent such as TFE or HFIP was found to be necessary,[92f] [h] [j] [k] in the presence of a catalytic amount of benzoic acid.

Scheme 61 Intermolecular (a) and intramolecular (b) (4 + 3) cycloaddition reactions of cyclopropanone hemiketals with furans

4

Conclusion and Outlook

The unique properties and reactivity of cyclopropanone derivatives has attracted the attention of chemists from multiple disciplines for almost a century, initially as chemical curiosities that might not even exist, then as highly reactive and strained building blocks which could lead to novel valuable disconnections in organic synthesis. The strain energy of this cyclic system allows these molecules to undergo unique chemical transformations unknown to more conventional cyclic or acyclic alkanones. The chemistry of cyclopropanones as a synthetic tool for the construction of complex molecules or biologically relevant products is still a very young field of research, mainly due to their kinetic instability and the lack of appropriate precursors. Throughout the years, myriad approaches were developed for their formation, and much has been learned in terms of their stability and chemical behavior, found to be highly dependent on their substitution patterns. Following seminal reactivity studies on isolated cyclopropanones, much of the recent synthetic success associated with these compounds as building blocks has involved the use of cyclopropanone equivalents such as cyclopropanone ketals, hemiketals, and 1-sulfonylcyclopropanols, all possessing distinct and potentially modular reactivities. Thus, it is expected that future synthetic advances involving cyclopropanone intermediates will entail the development and reactivity studies of novel precursors, where equilibration to cyclopropanones can be controlled and adjusted at will for specific applications. This could eventually enable the general use of these building blocks in modern synthetic realms with improved functional group compatibility such as photoredox catalysis, transition-metal-catalyzed C–C activation and C–H functionalization, for example. Moreover, the continuous development of novel approaches to enantioenriched cyclopropanone equivalents should have a major impact on their use in the context of stereoselective synthesis, relevant to a number of fields such as medicinal chemistry and the total synthesis of complex natural products.

Conflict of Interest

The authors declare no conflict of interest.

V.N.G.L. is grateful to Thieme Chemistry for a Thieme Chemistry Journals Award (2019).

• References

• 1 Turro NJ. Acc. Chem. Res. 1969; 2: 25
• 2a Wasserman HH, Clark GM, Turley PC. Top. Curr. Chem. 1974; 47: 73
• 2b Wasserman HH, Berdahl DR, Lu T.-J. The Chemistry of the Cyclopropyl Group . Rappoport Z. Wiley; Chichester: 1987: 1455
• 3a Salaün J. Chem. Rev. 1983; 83: 619
• 3b Salaün J. Cyclopropanones and Their Precursors . In Science of Synthesis, Vol. 26. Cossy J. Georg Thieme Verlag; Stuttgart: 2005: 607
• 4a Bach RD, Dmitrenko O. J. Am. Chem. Soc. 2006; 128: 4598
• 4b Dudev T, Lim C. J. Am. Chem. Soc. 1998; 120: 4450
• 4c Liebman JF, Greenberg AA. Chem. Rev. 1976; 76: 311
• 4d Liebman JF, Greenberg A. Chem. Rev. 1989; 89: 1225

For recent reviews on the stereoselective synthesis of cyclopropane derivatives, see:
• 4e Lebel H, Marcoux J.-F, Molinaro C, Charette AB. Chem. Rev. 2003; 103: 977
• 4f Roy M.-N, Lindsay VN. G, Charette AB. In Science of Synthesis: Stereoselective Synthesis 1: Stereoselective Reactions of Carbon–Carbon Double Bonds. Georg Thieme Verlag; Stuttgart: 2011: 731

For reviews on cyclopropenone chemistry, see:
• 5a Potts KT, Baum JS. Chem. Rev. 1974; 74: 189
• 5b Eicher T, Weber JL. Top. Curr. Chem. 1975; 57: 1
• 5c Nakamura M, Isobe H, Nakamura E. Chem. Rev. 2003; 103: 1295
• 5d Komatsu K, Kitagawa T. Chem. Rev. 2003; 103: 1371
• 6a Favorskii A. J. Russ. Phys. Chem. Soc. 1894; 26: 559
• 6b Cookson RC, Nye MJ. Proc. Chem. Soc., London 1963; 125
• 6c Cookson RC, Nye MJ, Subrahmanyam G. Proc. Chem. Soc., London 1964; 144
• 6d Kende AS. Org. React. 1960; 11: 261
• 6e Baretta A, Waegell B. React. Intermed. (Plenum) 1982; 2: 527

For recent reviews on the Favorskii rearrangement, see:
• 6f Butkus E. In Comprehensive Organic Synthesis II, 2nd ed., Vol. 3. Knochel P. Elsevier; Amsterdam: 2014: 853-886
• 6g Guijarro D, Yus M. Curr. Org. Chem. 2005; 9: 1713
• 7a Staudinger H, Reber Th. Helv. Chim. Acta 1921; 4: 3
• 7b Lipp P, Köster R. Ber. Dtsch. Chem. Ges. B 1931; 64: 2823
• 7c Lipp P, Buchkremer J, Seeles H. Justus Liebigs Ann. Chem. 1932; 499: 1
• 7d Kaarsemaker Sj, Coops J. Rec. Trav. Chim. Pays-Bas 1951; 70: 1033
• 7e Semenow DA, Cox EF, Roberts JD. J. Am. Chem. Soc. 1956; 78: 3221
• 8a Turro NJ, Byers GW, Leermakers PA. J. Am. Chem. Soc. 1964; 86: 955
• 8b Turro NJ, Cole TJr. Tetrahedron Lett. 1969; 10: 3451
• 9a Turro NJ, Hammond WB. J. Am. Chem. Soc. 1966; 88: 3672
• 9b Schaafsma SE, Steinberg H, de Boer ThJ. Recl. Trav. Chim. Pays-Bas 1966; 85: 1170
• 9c Turro NJ, Hammond W, Leermakers PA. J. Am. Chem. Soc. 1965; 87: 2774
• 9d Hammond WB, Turro NJ. J. Am. Chem. Soc. 1966; 88: 2880
• 9e Pazos JF, Greene FD. J. Am. Chem. Soc. 1967; 89: 1030
• 9f Turro NJ, Hammond WB. Tetrahedron 1968; 24: 6017
• 10 van Tilborg WJ. M, Steinberg H, de Boer ThJ. Synth. Commun. 1973; 3: 189
• 11a Quirk RP, Dunawy JH. Polycyclopropanone Synthesis and Hydrogenolysis . In Chemical Reaction on Polymers, ACS Symposium Series 364. Benham JL, Kinstle JF. American Chemical Society; Washington DC: 1988: 141
• 11b Schaafsma SE, Steinberg H, de Boer ThJ. Recl. Trav. Chim. Pays-Bas 1967; 86: 651
• 11c Turro NJ, Hammond WB. J. Am. Chem. Soc. 1967; 89: 1028
• 12 Rothgery EF, Holt RJ, McGee HA. Jr. J. Am. Chem. Soc. 1975; 97: 4971
• 13 Sorensen TS, Sun F. J. Am. Chem. Soc. 1997; 119: 11327
• 14a Zaitseva GS, Bogdanova GS, Baukov YuI, Lutsenko IF. J. Organomet. Chem. 1976; 121: C21
• 14b Zaitseva GS, Bogdanova GS, Baukov YuI, Lutsenko IF. Zh. Obshch. Khim. 1978; 48: 131
• 14c Zaitseva GS, Kisin AV, Fedorenko EN, Nosova VM, Livantsova LI, Baukov YuI. Zh. Obshch. Khim. 1987; 57: 2049
• 14d Zaitseva GS, Novikova OP, Livantsova LI, Baukov YuI. Zh. Obshch. Khim. 1988; 58: 1676
• 14e Zaitseva GS, Kisin AV, Novikova OP, Livantsova LI, Baukov YuI. Zh. Obshch. Khim. 1988; 58: 1677
• 14f Zaitseva GS, Krylova GS, Perelygina OP, Baukov YuI, Lutsenko IF. Zh. Obshch. Khim. 1981; 51: 2252
• 14g Fedorenko EN, Zaitseva GS, Baukov YuI, Lutsenko IF. Zh. Obshch. Khim. 1986; 56: 2431
• 14h Zaitseva GS, Kisin AV, Baukov YuI, Lorbeth J, Lutsenko IF. J. Organomet. Chem. 1988; 345: 253
• 15a Léost F, Doutheau A. Tetrahedron Lett. 1999; 40: 847
• 15b Dalton AM, Zhang Y, Davie CP, Danheiser RL. Org. Lett. 2002; 4: 2465
• 15c Frey J, Rappoport Z. J. Am. Chem. Soc. 1996; 118: 5182
• 15d Yates P, Abrams GD, Betts MJ, Goldstein S. Can. J. Chem. 1971; 49: 2850
• 16 Ashnagar A, Bailey PD, Cochrane PJ, Mills TJ, Price RA. ARKIVOC 2007; (xi): 161
• 17a Crandall JK, Machleder WH. Tetrahedron Lett. 1966; 7: 6037
• 17b Crandall JK, Machleder WH. J. Am. Chem. Soc. 1968; 90: 7292

For reviews and discussions on oxyallyl species, see:
• 17c Hoffmann R. J. Am. Chem. Soc. 1968; 90: 1475
• 17d Liberles A, Greenberg A, Lesk A. J. Am. Chem. Soc. 1972; 94: 8685
• 17e Noyori R, Hayakawa Y. Org. React. 1983; 29: 163
• 17f Hoffmann HM. R. Angew. Chem., Int. Ed. Engl. 1984; 23: 1
• 17g Mann J. Tetrahedron 1986; 42: 4611
• 17h Hosomi A, Tominaga Y. Comprehensive Organic Synthesis, Vol. 5. Trost BM, Fleming I. Pergamon; Oxford: 1991. Chap. 5.1
• 17i Rigby JH, Pigge FC. Org. React. 1997; 51: 351
• 17j Regnier V, Martin D. Org. Chem. Front. 2015; 2: 1536

For discussions of the allene oxide–cyclopropanone equilibrium in biosynthetic pathways, see:
• 18a Gardner HW, Simpson TD, Hamber M. Lipids 1993; 28: 487
• 18b Grechkin AN, Lantsova NV, Toporkova YY, Gorina SS, Mukhitova FK, Khairutdinov BI. ChemBioChem 2011; 12: 2511
• 18c Grechkin AN, Ogorodnikova AV, Egorova AM, Mukhitova FK, Ilyina TM, Khairutdinov BI. ChemistryOpen 2018; 7: 336
• 19a Crandall JK, Machleder WH, Thomas MJ. J. Am. Chem. Soc. 1968; 90: 7346
• 19b Crandall JK, Machleder WH. J. Am. Chem. Soc. 1968; 90: 7347
• 19c Sclove DB, Pazos JF, Camp RL, Greene FD. J. Am. Chem. Soc. 1970; 92: 7488
• 19d Liebman JF, Greenberg A. J. Org. Chem. 1974; 39: 123
• 19e Cordes MH. J, Berson JA. J. Am. Chem. Soc. 1996; 118: 6241
• 20a Chan TH, Li MP, Mychajlowskij W, Harpp DN. Tetrahedron Lett. 1974; 15: 3511
• 20b Chan TH, Ong BS. J. Org. Chem. 1978; 43: 2994
• 20c Chan TH, Ong BS. Tetrahedron 1980; 36: 2269
• 20d Shipman M, Thorpe HR, Clemens IR. Tetrahedron 1998; 54: 14265
• 21 Camp RL, Greene FD. J. Am. Chem. Soc. 1968; 90: 7349
• 22 Crandall JK, Machleder WH. J. Heterocycl. Chem. 1969; 6: 777
• 23 Clay MD, Durber J, Schepp NP. Org. Lett. 2001; 3: 3883
• 24a Cookson RC, Nye MJ. J. Chem. Soc. 1965; 2009
• 24b Rosnati V, Pagani G, Sannicoló F. Tetrahedron Lett. 1967; 8: 4545
• 24c Doerr RG, Skell PS. J. Am. Chem. Soc. 1967; 89: 4684
• 24d Cookson RC, Nye MJ, Subrahmanyam G. J. Chem. Soc. C. 1967; 474
• 24e Chenier PJ, Kao JC. J. Org. Chem. 1976; 41: 3730
• 24f Herter R, Föhlisch B. Chem. Ber. 1982; 115: 381
• 24g Engel ChR, Mérand Y, Côté J. J. Org. Chem. 1982; 47: 4485
• 24h De Kimpe N, Palamareva M, Schamp N. J. Org. Chem. 1985; 50: 2993
• 24i Karimi S, Grohmann KG. J. Org. Chem. 1995; 60: 554
• 24j Fohlishc B, Gehriach E, Henle G, Boberlin U, Gekeler M, Geywitz B, Ruck M, Vogl H. J. Chem. Res. 1991; 134
• 24k Gerard G. Bull. Soc. Chim. Fr. 1973; 382
• 25a Jun JG. B, Dewar MJ. S. J. Chem. Soc. 1954; 1201
• 25b Stork G, Borowitz IJ. J. Am. Chem. Soc. 1960; 82: 4307
• 25c House HO, Gilmore WF. J. Am. Chem. Soc. 1961; 83: 3980
• 25d Fort AW. J. Am. Chem. Soc. 1962; 84: 2620
• 25e Conia JM, Ripoll JL. Bull. Soc. Chim. Fr. 1963; 773
• 25f Conia JM, Salaün J. Tetrahedron Lett. 1963; 4: 1175
• 25g Charpentier-Morize M, Mayer M, Tchoubar B. Bull. Soc. Chim. Fr. 1965; 529
• 25h Rappe C. Ark. Kemi 1965; 24: 105
• 25i Rappe C. Ark. Kemi 1965; 24: 315
• 25j Rappe C. Acta Chem. Scand. 1966; 20: 862
• 25k Deghenghi R, Schilling G, Papineau Couture G. Can. J. Chem. 1966; 44: 789
• 25l Warnhoff EW, Wong CM, Tai T. J. Am. Chem. Soc. 1968; 90: 514
• 25m Garbisch EW. Jr, Wohllebe J. Chem. Commun. 1968; 306
• 25n Rappe C, Knutsson L, Turro NJ, Gagosian RB. J. Am. Chem. Soc. 1970; 92: 2032
• 25o Akhrem AA, Ustynyuk TK, Titov YA. Russ. Chem. Rev. 1970; 39: 732
• 25p Rappe C, Knutsson L. Angew. Chem., Int. Ed. Engl. 1972; 11: 329
• 25q Wharton PS, Fritzberg AR. J. Org. Chem. 1972; 37: 1899
• 25r Bordwell FG, Strong JG. J. Org. Chem. 1973; 38: 579
• 25s Verhé R, De Buyck L, De Kimpe N, Kudesia VP, Schamp N. J. Org. Chem. 1977; 42: 1256
• 25t Hamblin GD, Jimenez RP, Sorensen TS. J. Org. Chem. 2007; 72: 8033
• 26a Schaad LD, Hess BA, Zahradnik R. J. Org. Chem. 1981; 46: 1909
• 26b Dua S, Pollnitz AP, Bowie JH. J. Chem. Soc., Perkin Trans. 2 1993; 2235
• 26c Boyer LE, Brazzillo J, Forman MA, Zanoni B. J. Org. Chem. 1996; 61: 7611
• 26d Moliner V, Castillo R, Safont VS, Oliva M, Bohn S, Tuñón I, Andrés J. J. Am. Chem. Soc. 1997; 119: 1941
• 26e Castillo R, Moliner V, Safont VS, Oliva M, Andrés J. J. Mol. Struct.: THEOCHEM 1998; 426: 299
• 26f Yurdaku A, Gurtner C, Jung E.-S, Lorenzi Riatsch A, Linden A, Guggiseg A, Bienz S, Hesse M. Helv. Chim. Acta 1998; 81: 1373
• 26g Castillo R, Andrés J, Moliner V. J. Phys. Chem. B 2001; 105: 2453
• 26h Tsuchida N, Yamazaki S, Yamabe S. Org. Biomol. Chem. 2008; 6: 3109
• 27a Büchi G, Hochstrasser U, Pawlak W. J. Org. Chem. 1973; 38: 4348
• 27b Valent I, Pribus M, Novák F, Plánková S, Blaško J, Kubinec R, Almássy A, Filo J, Sigmundová I, Sebechlebská T, Lawson TB, Noszticzius Z. J. Phys. Chem. A. 2019; 123: 9669
• 28a Viviano Posadas AO, Flores Álamo M, Iglesias Arteaga MA. Steroids 2016; 113: 22
• 28b Xu H, Wang F, Xue W, Zheng Y, Wang Q, Qiu FG, Jin Y. Org. Process Res. Dev. 2018; 22: 377
• 28c Kutsumura N, Koyama Y, Suzuki Y, Tominaga K.-I, Yamamoto N, Saitoh T, Nagumo Y, Nagase H. Org. Lett. 2018; 20: 1559
• 28d Takeshita H, Kawakami H, Ikeda Y, Mori A. J. Org. Chem. 1994; 59: 6490
• 28e Lee E, Yoon CH. J. Chem. Soc., Chem. Commun. 1994; 479
• 29a Loftfield RB. J. Am. Chem. Soc. 1950; 72: 632
• 29b Loftfield RB. J. Am. Chem. Soc. 1951; 73: 4707
• 30a Fort AW. J. Am. Chem. Soc. 1962; 84: 4979
• 30b Cookson RC, Nye NJ. Proc. Chem. Soc., London 1963; 129
• 31a Smissma EE, Hite G. J. Am. Chem. Soc. 1960; 82: 3375
• 31b Smissma EE, Diebold JL. J. Org. Chem. 1965; 30: 4005
• 32 Pazos JF, Pacifici JG, Pierson GO, Sclove DB, Greene FD. J. Org. Chem. 1974; 39: 1990
• 33a Fry AL, Scoggins R. Tetrahedron Lett. 1972; 13: 4079

For related electrochemical cyclopropanone formation and Favorskii rearrangements, see:
• 33b van Tilborg WJ. M, Plomp R, de Ruiter R, Smit CJ. Recl. Trav. Chim. Pays-Bas 1980; 99: 206
• 33c Inesi A, Rossi L, Feroci M, Rizzuto M. New J. Chem. 1998; 22: 57
• 33d Feroci M, Inesi A, Orsini M, Rossi L, Sotgiu G. J. Electroanal. Chem. 2001; 507: 89
• 34a Craig CJ, Dinner A, Mulligan PJ. J. Org. Chem. 1972; 37: 3539
• 34b House HO, Gilmore WF. J. Am. Chem. Soc. 1961; 83: 3972
• 34c Reusch W, Mattison P. Tetrahedron 1967; 23: 1953
• 34d Kametani T, Suzuki Y, Ban C, Honda T. Heterocycles 1987; 26: 1491

For related photolytic rearrangements of cyclobutane-1,2-diones to cyclopropanones via decarbonylation, see:
• 35a de Groot A, Oudman D, Wynberg H. Tetrahedron Lett. 1969; 10: 1529
• 35b Chapman OL, Mattes K, McIntosh CL, Pacansky J, Calder GV, Orr G. J. Am. Chem. Soc. 1973; 95: 6134
• 36a Hayes DM, Zeiss CA, Hoffmann R. J. Phys. Chem. 1971; 75: 340
• 36b Birney DM, Ham S, Unruh GR. J. Am. Chem. Soc. 1997; 119: 4509
• 36c Balcioglu N, Sevin F. J. Mol. Model. 2000; 6: 48
• 36d Sato T, Niino H, Yabe A. J. Phys. Chem. A. 2001; 105: 7790
• 36e Haller I, Srinivasan R. Can. J. Chem. 1965; 43: 3165
• 37 Richey HG, Richey JM, Clagett DC. J. Am. Chem. Soc. 1964; 86: 3906
• 38 Turro NJ, Leermakers PA, Wilson HR, Neckers DC, Byers GW, Vesley GF. J. Am. Chem. Soc. 1965; 87: 2613
• 39 Zang H, Neckers DC. J. Org. Chem. 1999; 64: 2103
• 40a Adam W, Fuss A, Mazenod FP, Quast H. J. Am. Chem. Soc. 1981; 103: 998
• 40b Breda S, Reva I, Fausto R. J. Phys. Chem. A 2012; 116: 2131
• 41 Barber LL, Chapman OL, Lassila JD. J. Am. Chem. Soc. 1969; 91: 3664
• 42 Weinshenker NM, Greene FD. J. Am. Chem. Soc. 1968; 90: 506
• 43a West R, Zecher DC. J. Am. Chem. Soc. 1967; 89: 152
• 43b Zecher DC, West R. J. Am. Chem. Soc. 1967; 89: 153
• 43c West R, Zecher DC, Koster SK, Eggerding D. J. Org. Chem. 1975; 40: 2295
• 43d Starnes WH, Plank DA, Floyd JC. J. Org. Chem. 1975; 40: 1124
• 44a Breslow R, Oda M. J. Am. Chem. Soc. 1972; 94: 4787
• 44b Oda M, Breslow R, Pecoraro J. Tetrahedron Lett. 1972; 13: 4419
• 44c Jacobs CA, Dailey WP. J. Org. Chem. 1995; 60: 7747
• 45a Liu J, An Y, Jiang H.-Y, Chen Z. Tetrahedron Lett. 2008; 49: 490

For an analogous reaction with aldehydes instead of cyclopropanone, see:
• 45b Wei C, Li C.-J. J. Am. Chem. Soc. 2003; 125: 9584
• 46 Poteat CM, Jang Y, Jung M, Johnson JD, Williams RG, Lindsay VN. G. Angew. Chem. Int. Ed. 2020; 59: 18655
• 47 Rühlmann K. Synthesis 1971; 236
• 48a Salaün J. J. Org. Chem. 1976; 41: 1237
• 48b Salaün J, Marguerite J. Org. Synth. 1985; 63: 147
• 48c Crossland I. Acta Chem. Scand., Ser. B 1975; 29: 468
• 48d Diethelm S, Carreira EM. J. Am. Chem. Soc. 2015; 137: 6084
• 49a Nakamura E, Sekiya K, Kuwajima I. Tetrahedron Lett. 1987; 28: 337
• 49b Fadel A, Canet J.-L, Salaün J. Synlett 1990; 89
• 49c Fadel A, Khesrani A. Tetrahedron: Asymmetry 1998; 9: 305
• 49d Fadel A, Tesson N. Eur. J. Org. Chem. 2000; 2153
• 50a Rousseau G, Slougui N. Tetrahedron Lett. 1983; 24: 1251
• 50b Nakamura E, Oshino H, Kuwajima I. J. Am. Chem. Soc. 1986; 108: 3745
• 51a Lee J, Kim YG, Bae JG, Cha JK. J. Org. Chem. 1996; 61: 4878

For reviews on the Kulinkovich cyclopropanation, see:
• 51b Kulinkovich OG, de Meijere A. Chem. Rev. 2000; 100: 2789
• 51c Kulinkovich OG. Russ. Chem. Bull. 2004; 53: 1065
• 51d Kulinkovich O, Isakov V, Kananovich D. Chem. Rec. 2008; 8: 269
• 51e Cha JK, Kulinkovich OG. Org. React. 2012; 77: 1
• 51f Konik YA, Kananovich DG. Tetrahedron Lett. 2020; 61: 152036
• 52a McElvain SM, Weyna PL. J. Am. Chem. Soc. 1959; 81: 2579
• 52b Dowd P, Kaufman C, Paik YH. Tetrahedron Lett. 1985; 26: 2283
• 52c Felpin F.-X, Doris E, Wagner A, Valleix A, Rousseau B, Mioskowski C. J. Org. Chem. 2001; 66: 305
• 53 Wang SL. B, Goldberg DR, Liu X, Su J, Zheng Q.-H, Liptak V, Wulff WD. J. Organomet. Chem. 2005; 690: 6101
• 54a Nakamura M, Inoue T, Nakamura E. J. Organomet. Chem. 2001; 624: 300

For related examples, see:
• 54b Nakamura E, Isaka M, Matsuzawa S. J. Am. Chem. Soc. 1988; 110: 1297
• 54c Isaka M, Nakamura E. J. Am. Chem. Soc. 1990; 112: 7428
• 54d Kubota K, Isaka M, Nakamura M, Nakamura E. J. Am. Chem. Soc. 1993; 115: 5867
• 54e Nakamura M, Arai M, Nakamura E. J. Am. Chem. Soc. 1995; 117: 1179
• 54f Nakamura E, Kubota K. J. Org. Chem. 1997; 62: 792
• 54g Kubota K, Mori S, Nakamura M, Nakamura E. J. Am. Chem. Soc. 1998; 120: 13334
• 54h Nakamura M, Hirai A, Nakamura E. J. Am. Chem. Soc. 2000; 122: 978
• 54i Nakamura M, Inoue T, Sato A, Nakamura E. Org. Lett. 2000; 2: 2193
• 55a van Tilborg WJ. M, Schaafsma SE, Steinberg H, de Boer ThJ. Recl. Trav. Chim. Pays-Bas 1967; 86: 419
• 55b Turro NJ, Hammond WB. Tetrahedron 1968; 24: 6029
• 56a Wasserman HH, Clagett DC. Tetrahedron Lett. 1964; 5: 341
• 56b Wasserman HH, Clagett DC. J. Am. Chem. Soc. 1966; 88: 5368
• 57a Wasserman HH, Cochoy RE, Baird MS. J. Am. Chem. Soc. 1969; 91: 2375
• 57b Stolle A, Ollivier J, Piras PP, Salaün J, de Meijere A. J. Am. Chem. Soc. 1992; 114: 4051
• 57c Wasserman HH, Hearn MJ, Cochoy RE. J. Org. Chem. 1980; 45: 2874
• 57d Brown HC, Rao CG. J. Org. Chem. 1978; 43: 3602
• 58 Salaün J, Bennani F, Compain J.-C, Fadel A, Ollivier J. J. Org. Chem. 1980; 45: 4129
• 59a Machín Rivera R, Jang Y, Poteat CM, Lindsay VN. G. Org. Lett. 2020; 22: 6510

For a related transformation specific to the addition of alkynyllithium nucleophiles, see:
• 59b An Y, Liu J, Jiang H.-Y, Wang Y, Chen Z. Tetrahedron Lett. 2008; 49: 3124
• 60 Hatano M, Ito O, Suzuki S, Ishihara K. J. Org. Chem. 2010; 75: 5008
• 61 Liu J, An Y, Wang Y, Jiang H, Zhang Y, Chen Z. Chem. Eur. J. 2008; 14: 9131
• 62a Salaün J. Tetrahedron Lett. 1979; 20: 4375
• 62b Spitzner D, Swoboda H. Tetrahedron Lett. 1986; 27: 1281

For related examples of the Wittig olefination of cyclopropanone equivalents, see:
• 62c Thiemann T, Ohira D, Li Y, Sawada T, Mataka S, Rauch K, Noltemeyer M, de Meijere A. J. Chem. Soc., Perkin Trans. 1 2000; 2968
• 62d Osborne NF. J. Chem. Soc., Perkin Trans. 1 1982; 1435
• 62e de Meijere A, Teichmann S, Seyed-Mahdavi F, Kohlstruk S. Liebigs Ann. Chem. 1996; 1989
• 63a van Tilborg WJ. M, Schaafsma SE, Steinberg H. Recl. Trav. Chim. Pays-Bas 1967; 86: 417
• 63b van Tilborg WJ. M, Steinberg H, de Boer ThJ. Recl. Trav. Chim. Pays-Bas 1974; 93: 290
• 63c van Tilborg WJ. M, Steinberg H, de Boer ThJ. Recl. Trav. Chim. Pays-Bas 1974; 93: 294
• 63d Jongejan E, van Tilborg WJ. M, Steinberg H, de Boer ThJ. Recl. Trav. Chim. Pays-Bas 1977; 96: 40
• 64a Turro NJ, Gagosian RB. J. Chem. Soc. D 1969; 949
• 64b Turro NJ, Gagosian RB. J. Am. Chem. Soc. 1970; 92: 2036
• 65a Wasserman HH, Baird MS. Tetrahedron Lett. 1971; 12: 3721
• 65b Wasserman HH, Adickes HW, de Ochoa OE. J. Am. Chem. Soc. 1971; 93: 5586
• 65c Wasserman HH, Glazer EA, Hearn MJ. Tetrahedron Lett. 1973; 14: 4855
• 65d Wasserman HH, Hlasta DJ. J. Am. Chem. Soc. 1978; 100: 6780
• 65e Wasserman HH, Glazer E. J. Org. Chem. 1975; 40: 1505
• 65f De Kimpe N, Tehrani KA, Fonck G. J. Org. Chem. 1996; 61: 6500
• 65g Grecian S, Desai P, Mossman C, Poutsma JL, Aubé J. J. Org. Chem. 2007; 72: 9439
• 66a Carey JT, Knors C, Helquist P. J. Am. Chem. Soc. 1986; 108: 8313
• 66b Fehr C, Galindo J, Etter O, Thommen W. Angew. Chem. Int. Ed. 2002; 41: 4523
• 67a Carey JT, Helquist P. Tetrahedron Lett. 1988; 29: 1243
• 67b Reydellet V, Helquist P. Tetrahedron Lett. 1989; 30: 6837
• 67c Bradlee MJ, Helquist P. Org. Synth. 1997; 74: 137
• 67d Narasimhan NS, Patil PA. Tetrahedron Lett. 1986; 27: 5133
• 67e Narasimhan NS, Sunder NM. Tetrahedron Lett. 1988; 29: 2985
• 67f Sunder NM, Patil PA, Narasimhan NS. J. Chem. Soc., Perkin Trans. 1 1990; 1331
• 68 Takanami T, Ogawa A, Suda K. Tetrahedron Lett. 2000; 41: 3399
• 69 Depuy CH, Breitbeil FW, Debruin KR. J. Am. Chem. Soc. 1966; 88: 3347
• 70 Bakker BH, van Ramesdonk HJ, Steinberg H, de Boer ThJ. Recl. Trav. Chim. Pays-Bas 1975; 94: 64
• 71 Desai P, Aubé J. Org. Lett. 2000; 2: 1657
• 72a Regitz M, Maas G. Diazo Compounds: Properties and Synthesis . Academic; Orlando: 1986: 596
• 72b Baumann H, Duthaler RO. Helv. Chim. Acta 1988; 71: 1035
• 72c Podlech J, Seebach D. Helv. Chim. Acta 1995; 78: 1238
• 72d Axenrod T, Watnick C, Yazdekhasti H, Dave PR. J. Org. Chem. 1995; 60: 1959
• 73a Erden I, Amputch MA. Tetrahedron Lett. 1987; 28: 3779
• 73b Erden I, Drummond J, Alstad R, Xu F. Tetrahedron Lett. 1993; 34: 1255
• 73c Erden I, Drummond J, Alstad R, Xu F. Tetrahedron Lett. 1993; 34: 2291

For recent reviews on the metal homoenolate chemistry and other ring-opening reactions of cyclopropanols and cyclopropanone (hemi)ketals, see:
• 74a McDonald TR, Mills LR, West MS, Rousseaux SA. L. Chem. Rev. 2021; 121: 3
• 74b Mills LR, Rousseaux SA. L. Eur. J. Org. Chem. 2019; 8
• 74c Nikolaev A, Orellana A. Synthesis 2016; 48: 1741
• 74d Rosa D, Nikolaev A, Nithiy N, Orellana A. Synlett 2015; 26: 441
• 74e Kimura M. In Comprehensive Organic Synthesis II, 2nd ed., Vol. 2. Knochel P. Elsevier; Amsterdam: 2014: 606
• 74f Reissig H.-U, Zimmer R. Chem. Rev. 2003; 103: 1151
• 75a Schaafsma SE, Steinberg H, de Boer ThJ. Recl. Trav. Chim. Pays-Bas 1966; 85: 70
• 75b Schaafsma SE, Steinberg H, de Boer ThJ. Recl. Trav. Chim. Pays-Bas 1966; 85: 73
• 75c Schaafsma SE, Molenaar EJ. F, Steinberg H, de Boer ThJ. Recl. Trav. Chim. Pays-Bas 1967; 86: 1301
• 75d Schaafsma SE, Jorritsma R, Steinberg H, de Boer ThJ. Tetrahedron Lett. 1973; 14: 827
• 76a Bakker BH, Schilder GJ. A, Bok TR, Steinberg H, de Boer ThJ. Tetrahedron 1973; 29: 93
• 76b de Boer ThJ. Angew. Chem. Int. Ed. Engl. 1972; 11: 321

For a related study on the use of organic oxidants in the radical ring-opening of cyclopropanone ketals, see:
• 76c Abe M, Oku A. Tetrahedron Lett. 1994; 35: 3551
• 77a Abe M, Oku A. J. Chem. Soc., Chem. Commun. 1994; 1673
• 77b Abe M, Nojima M, Oku A. Tetrahedron Lett. 1996; 37: 1833

For another example of β-radical trapping with alkenes following oxidative ring-opening, see:
• 77c Iwasawa N, Hayakawa S, Funahashi M, Isobe K, Narasaka K. Bull. Chem. Soc. Jpn. 1993; 66: 819
• 78 Wu L, Wang L, Chen P, Guo Y, Liu G. Adv. Synth. Catal. 2020; 362: 2189
• 79a Nakamura E, Kuwajima I. J. Am. Chem. Soc. 1977; 99: 7360
• 79b Nakamura E, Kuwajima I. J. Am. Chem. Soc. 1983; 105: 651
• 79c Oshino H, Nakamura E, Kuwajima I. J. Org. Chem. 1985; 50: 2802
• 79d Nakamura E, Shimada J, Kuwajima I. Organometallics 1985; 4: 641
• 79e Nakamura E, Kuwajima I. Tetrahedron Lett. 1986; 27: 83
• 79f Nakamura E, Aoki S, Sekiya K, Oshino H, Kuwajima I. J. Am. Chem. Soc. 1987; 109: 8056
• 79g Tamaru Y, Nakamura T, Sakaguchi M, Ochiai H, Yoshida Z. J. Chem. Soc., Chem. Commun. 1988; 610
• 79h Ochiai H, Nishihara T, Tamaru Y, Yoshida Z. J. Org. Chem. 1988; 53: 1343
• 79i Tamaru Y, Tanigawa H, Yamamoto T, Yoshida Z.-i. Angew. Chem. Int. Ed. Engl. 1989; 28: 351
• 79j Kuwajima I, Nakamura E. Top. Curr. Chem. 1990; 155: 1
• 79k Fujimura T, Aoki S, Nakamura E. J. Org. Chem. 1991; 56: 2809
• 79l Aoki S, Nakamura E. Tetrahedron 1991; 47: 3935

For related seminal studies performed on cyclopropanols, see:
• 79m Nickon A, Lambert JL, Oliver JE, Covey DF, Morgan J. J. Am. Chem. Soc. 1976; 98: 2593
• 80a Nakamura E, Kuwajima I. J. Am. Chem. Soc. 1984; 106: 3368
• 80b Nakamura E, Kuwajima I. Org. Synth. 1987; 66: 43
• 81 Aoki S, Fujimura T, Nakamura E, Kuwajima I. J. Am. Chem. Soc. 1988; 110: 3296
• 82a Turro NJ, Edelson SS, Williams JR, Thomas RD. J. Am. Chem. Soc. 1968; 90: 1926
• 82b Turro NJ, Edelson SS. J. Am. Chem. Soc. 1968; 90: 4499
• 82c Turro NJ, Edelson SS, Williams JR, Darling TR, Hammond WB. J. Am. Chem. Soc. 1969; 91: 2283
• 82d Turro NJ, Edelson SS, Gagosian RB. J. Org. Chem. 1970; 35: 2058
• 83a Noordstrand AA. P, Steinberg H, de Boer ThJ. Tetrahedron Lett. 1975; 16: 2611
• 83b Wiering PG, Steinberg H. J. Org. Chem. 1981; 46: 1663
• 84a Wiering PG, Verhoeven JW, Steinberg H. J. Am. Chem. Soc. 1981; 103: 7675
• 84b Oku A, Abe M, Iwamoto M. J. Org. Chem. 1994; 59: 7445
• 85a Crimmins MT, Nantermet PG. J. Org. Chem. 1990; 55: 4235
• 85b Crimmins MT, Nantermet PG, Trotter BW, Vallin IM, Watson PS, McKerlie LA, Reinhold TL, Cheung AW. H, Stetson KA, Dedopoulou D, Gray J. J. Org. Chem. 1993; 58: 1038
• 86a Skorianetz W, Schulte-Elte KH, Ohloff G. Helv. Chim. Acta 1971; 54: 1913
• 86b Skorianetz W, Schulte-Elte KH, Ohloff G. Angew. Chem., Int. Ed. Engl. 1972; 11: 330
• 86c Harada N, Uda H, Ueno H. Chem. Lett. 1972; 1: 663
• 86d Harada N, Suzuki S, Uda H, Ueno H. Chem. Lett. 1972; 1: 803
• 86e Harada N, Suzuki S, Uda H, Ueno H. J. Am. Chem. Soc. 1972; 94: 1777
• 86f Harada N, Uda H, Ueno H, Utsumi S. Chem. Lett. 1973; 2: 1173
• 87 Erden I, Xu F.-P, Drummond J, Alstad R. J. Org. Chem. 1993; 58: 3611
• 88 Jang Y, Lindsay VN. G. Org. Lett. 2020; 22: 8872
• 89a Khand IU, Knox GR, Pauson PL, Watts WE, Foreman MI. J. Chem. Soc., Perkin Trans. 1 1973; 975

For reviews on the Pauson–Khand reaction, see:
• 89b Brummond KM, Kent JL. Tetrahedron 2000; 56: 3263
• 89c Blanco-Urgoiti J, Anorbe L, Perez-Serrano L, Dominguez G, Perez-Castells J. Chem. Soc. Rev. 2004; 33: 32
• 89d Kurteva VB, Afonso CA. M. Chem. Rev. 2009; 109: 6809

For an analogous mechanism employing cyclobutanones instead of cyclopropanone, see:
• 90a Murakami M, Ashida S, Matsuda T. J. Am. Chem. Soc. 2005; 127: 6932
• 90b Murakami M, Ashida S, Matsuda T. J. Am. Chem. Soc. 2006; 128: 2166
• 90c Murakami M, Itahashi T, Ito Y. J. Am. Chem. Soc. 2002; 124: 13976
• 90d Murakami M, Ashida S. Chem. Commun. 2006; 4599
• 90e Liu L, Ishida N, Murakami M. Angew. Chem. Int. Ed. 2012; 51: 2485
• 90f Ho KY. T, Aïssa C. Chem. Eur. J. 2012; 18: 3486
• 91a Kascheres A, Correa Filho J, Cunha S. Tetrahedron 1993; 49: 381

For related transformations of cyclopropenones, see:
• 91b Kascheres A, Kascheres C, Rodrigues JA. R, Santana AR. A. J. Org. Chem. 1976; 41: 3546
• 91c Eicher T, Angerer EV, Hansen A.-M. Liebigs Ann. Chem. 1971; 746: 102
• 92a Cho SY, Lee HI, Cha JK. Org. Lett. 2001; 3: 2891

For other selected examples of (4+3) cycloadditions involving oxyallyl intermediates, see:
• 92b Noyori R, Baba Y, Makino S, Takaya H. Tetrahedron Lett. 1973; 14: 1741
• 92c Takaya H, Makino S, Hayakawa Y, Noyori R. J. Am. Chem. Soc. 1978; 100: 1765
• 92d Vinter JG, Hoffmann HM. R. J. Am. Chem. Soc. 1973; 95: 3051
• 92e Schmid R, Schmid H. Helv. Chim. Acta 1974; 57: 1883
• 92f Föhlisch B, Gehrlach E, Herter R. Angew. Chem., Int. Ed. Engl. 1982; 21: 137
• 92g Föhlisch B, Joachimi R. Chem. Ber. 1987; 120: 1951
• 92h Jin S.-j, Choi J.-R, Oh J, Lee D, Cha JK. J. Am. Chem. Soc. 1995; 117: 10914
• 92i Kim H, Ziani-Cherif C, Oh J, Cha JK. J. Org. Chem. 1995; 60: 792
• 92j Lee K, Cha JK. Org. Lett. 1999; 1: 523
• 92k Cho SY, Lee JC, Cha JK. J. Org. Chem. 1999; 64: 3394

Publikationsverlauf

Eingereicht: 08. Mai 2021

Angenommen nach Revision: 27. Mai 2021

Accepted Manuscript online:
27. Mai 2021

Artikel online veröffentlicht:
08. Juli 2021