Cyclobutanone oxaspiropentane rearrangement

The required oxaspiropentanes are obtained by epoxidation of alkylidenecyelopropanes (A Section 3.2.2.1.), by reacting aldehydes and/or ketones with diphenylsulfonium cyclopropanide (B Section 3.2.2.2.), and by reacting ketones with 1-bromo-l-lithiocyclopropanes (C Section 3.2.2.3.) or diazocyclopropane (D Section 3.2.2.4.). Most widely used is diphenylsulfoni-um cyclopropanide, but for higher than 2,2-disubstituted cyclobutanones the use of alkylidene-cyclopropanes or 1-bromo-l-lithiocyclopropanes may be advantageous. Once formed, oxaspiropentanes rearrange with extreme ease. 

The procedure described here is a large-scale preparation with satisfactory yields of a still very expensive but simple compound from very cheap and readily available starting materials and with ordinary laboratory equipment. This rearrangement of oxaspiropentanes into cyclobutanones appears to be general for the preparation of substituted cyclobutanones. ... 

Sulfur ylides can also transfer substituted methylene units, such as isopropylidene (Entries 10 and 11) or cyclopropylidene (Entries 12 and 13). The oxaspiropentanes formed by reaction of aldehydes and ketones with diphenylsulfonium cyclopropylide are useful intermediates in a number of transformations such as acid-catalyzed rearrangement to cyclobutanones.285... 

The facility of the rearrangement to cyclobutanones is reflected in the high chemoselectivity. The cases of oxaspiropentanes from epoxyketones offer a particularly difficult challenge. Nevertheless, no problems resulted (Table 2, entries 19, 20, 38 and 39). Oxaspiropentanes which form particularly stabilized carbonium ions frequently rearrange to cyclobutanones during their formation. For example, cyclo-propylmethyl ketone and benzophenone led only to cyclobutanones in their condensations with 9. In one case, further reaction of the ylide with the rearranged cyclobutanone was noted (Eq. 31) 58). 

Substituted cyclopropyl ylides also participate in oxaspiropentane formation (Table 2, entries 4d, 30b, 38, and 39). Of the two cyclopropyl carbons that can move in the rearrangement to cyclobutanones, the carbon that best stabilizes a... 

An efficient synthesis of 2-[(phenylalkylmethylene)amino]cyclobutenecar-boxylates 109, 110 from primary Michael adducts 94 has been developed (Scheme 37) [8]. The key step of this dehydrochlorinative rearrangement is believed to be the lithium iodide-induced reorganization of the azaspiropentane intermediate 103, in close analogy to the well documented rearrangement of oxaspiropentanes to cyclobutanones [67]. 

This type of cyclobutanone annelation is feasible with various dibromocyclopropanes. When diaryl ketones are used as electrophiles, the oxaspiropentane-cyclobutanone rearrangement occurs spontaneously, so that the cyclobutanone is obtained directly (equation 63)"° . When 1-bromo-l-lithiocyclopropanes are allowed to react with aldehydes, the formation of cyclopropyl ketones results" . 

For example, 1-donor-substituted cyclopropancmethanols may be efficiently produced by cyclopropanation of suitably substituted enol ethers, by reaction of 1-donor-substituted 1-lithio-cyclopropanes with carbonyl compounds, or by addition of carbon nucleophiles to 1-donor-substituted cyclopropanecarbaldehydes. Oxaspiropentanes, important precursors of cyclobutanones, may as easily be obtained by epoxidation of methylenecyclopropanes, or by reaction of carbonyl compounds with diphenylsulfonium cyclopropanide and l-bromo-1-lithiocyclopropanes, respectively. Moreover, as the stereochemistry of most rearrangements may be efficiently controlled, asymmetric syntheses begin to appear. 

The first rearrangement of an oxaspiropentane probably occurred in terpene l39 which was isolated from Zieria smithii and later,40 but mistakenly,41 thought to be chrysanthenone (2), to which it readily rearranges. Interestingly, this rearrangement now constitutes one of the most powerful instruments for the construction of cyclobutanones. 

An early report by Crandall,42 that epoxidation of 2,3-diisopropylidene-l-l-dimethylcyclo-propane followed by lithium iodide catalyzed rearrangement of the resulting oxaspiropentane yields 4-isopropylidene-2,2,3,3-tetramethylcyclobutanone (1), marks the beginning of an intense use of alkylidenecyclopropanes for the construction of cyclobutanones. 

However, the low facial selectivity in epoxidations of unsymmetrical alkylidene- and cy-cloalkylidenecyclopropanes can be a serious drawback. Thus, both 2-cyclopropylidenebicy-clo[2.2.1]heptane (10)48 and 10,15-dicyclopropylidenetrispiro[3.1.3.1.3.1.]pentadecan-5-one (U)4<). so produced mixtures of stereoisomeric cyclobutanones on epoxidation and rearrangement of the resulting oxaspiropentanes. 

Diphenylsulfonium cyciopropanide undergoes addition to the C — C double bond of oc,/ -unsat-urated carbonyl compounds to produce spiropentanes,57,58 and to the C —O double bond of aldehydes and ketones to produce oxaspiropentanes. These can be isolated59,60 or rearranged in situ 57,61,62 to produce cyclobutanones. Dimethylaminocyclopropylphenyloxosulfonium cyciopropanide reacts analogously.63,64... 

Formation of CK-configurated cyclobutanones has also been observed with 2-methylcyclopen-tanone and 2-methylcyclohexanone/8 However, stereoreversed eyclobutanone formation can be achieved by opening the intermediate oxaspiropentane with sodium phenyl selenide, oxidation of the resulting / -hydroxy selenide with 3-chloroperoxybenzoic acid and subsequent rearrangement in the presence of pyridine/18 Thus, from one oxaspiropentane 8, either stereoisomeric eyclobutanone cis- or lrans-9 was produced. The stereoreversed eyclobutanone formation proceeds from a stereohomogenous / -hydroxy selenoxide and is thought to be conformationally controlled. 

Bromo-l-lithiocyclopropanes, readily obtained by transmetalation of 1,1-dibromocyclo-propanes with butyllithium in tetrahydrofuran at — 100 CC, undergo addition to aldehydes and ketones forming bromohydrins. On warming, before workup, the adducts from ketones (but not from aldehydes) eliminate lithium bromide and cyclizc to oxaspiropentanes, which may be rearranged to cyclobutanones by treatment with acids (Table 6).76-78... 

Meifaylenecyclopropanes undwgo oxidative ring expansion in a two-step sequence peroxy acid oxidation K> an oxaspiropentane followed by lithium i de induced rearrangement yields a cyclobutanone in moderate yield, as illustrated in equation (49). Cyclobutanone is a minor product from the reaction of... 

Besides ylids, carbenoids (366) can also be used since they too can condense with ketones to yield oxaspiropentanes p67) or heteroatom-substituted cyclopropylcarbinols (368), both of which rearrange to cyclobutanone derivatives (369) under acid catalysis. The 1-ethoxycyclopropyllithium is the carbenoid reagent of choice because of its ease of... 

Strained -oxidoalkyl i enyl selenoxides, such as l-oxido-l-(r-phenylsdenoxyalkyl)cyclopropanes, derived from oxaspiropentanes with tetraalkyl-substituted oxirane rings, and l-(r-hydroxyalkyl)-l-selenoxycyclobutanes, - obtained on oxidation of the corresponding selenides or on reaction of a-li-thioalkyl selenoxides with cyclobutenones, possess a high propensity to rearrange to cyclobutanones... 

Spiroannulation The overall conversion of a ketone, RCOR, to a di-a-substituted cyclobutanone. The reaction may be performed by the addition of diphenylsulphoniumcyclopropylide with the ketone RCOR to give the oxaspiropentane that, on treatment with a proton or a Lewis acid, rearranges to give the cyclobutanone. 

Cyclobutanols. Grignard reagents induce rearrangement of oxaspiropentanes to cyclobutanones which react further. Benzylic reagents provide some cyclopropanols. 

This reaction is limited only by the sensitivity of the oxaspiropentane system towards acids which causes rearrangement to the isomeric cyclobutanone derivative. When benzylidenecy-clopropane or (diphenylmethylene)cyclopropane were oxidized with 3-chloroperoxybenzoic acid only the phenyl-substituted cyclobutanones were isolated in excellent yield.In the case of the oxidation of ethyl ( )-2-ethylidene-rra .5-3-methylcyclopropanecarboxylate with 4-ni-troperoxybenzoic acid the spiro intermediate was isolated in 80% yield. ... 

Oxaspiropentanes rapidly and efficiently rearrange to cyclobutanones when reacted with Lewis acids.The parent cyclobutanone (73) was obtained in almost quantitative yield from oxaspiropentane by treatment with a catalytic amount of lithium iodide. ... 

An elegant and general method for the synthesis of cyclobutanones via oxaspiropentanes 80 involves the nucleophilic addition of various 1-bromocyclopropyllithiums 79 to ketones followed by ring enlargement. In some cases rearrangement takes place spontaneously under the reaction conditions. Addition of mineral acid completes the cyclobutanone 81 formation. Some representative examples are given in Table 1. 

An alternative and excellent route to oxaspiropentanes 83 and thus of cyclobutanones 84 proceeds through the condensation of cyclopropyldiphenylsulfonium tetrafluoroborate (82) with aldehydes and ketones. Table 2 presents some illustrative examples. With cyclopropyl methyl ketone and benzophenone as substrates, the oxaspiropentanes cannot be isolated but rapidly rearrange to the corresponding cyclobutanones." Here ring expansion is facilitated by the presence of excellent carbenium ion stabilizing groups. 

A stereoreversed cyclobutanone formation was realized starting from oxaspiropentanes by using the selenoxide function as a leaving group. Treating oxaspiropentanes 94 with sodium benzeneselenolate in ethanol affords j8-hydroxy selenides 95 which, on oxidation with 3-chloro-peroxybenzoic acid at — 78 to — 30 °C, led directly to the corresponding cyclobutanones 96 (Table 3). The stereochemistry in this reaction is opposite to that normally observed in the acid-catalyzed rearrangement of oxaspiropentanes. 

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