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. 

When derived from aliphatic ketones, the intermediate oxaspiropentanes rearranged to give 1 regiospecifically with exclusive migration of the more substituted carbon atom (Tabic 6), but with oxaspiropentanes derived from benzophenone both regioisomers 2 and 3 were formed.78... 

Entry Aldehyde or ketone Salt, method0 Oxaspiropentane° Rearrangement method13 Cyciobutanone Yietdd Ref. 

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 chemical versatility of the oxaspiropentanes makes these compounds exceedingly useful building blocks. Being a strained epoxide, they are very labile towards acid catalyzed rearrangements accompanied by carbon bond migration leading to... 

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. 

Oxaspiropentanes substituted in the cyclopropane part rearrange with preferential migration of the more substituted carbon atom. This is exemplified by the lithium iodide induced rearrangement of 4,4-dimethyl-l-oxaspiropentane which predominantly yielded 3,3-dimethylcy-clobutanone (3).44... 

Oxaspiropentanes generally rearrange with inversion at the migrating terminus (see Section 3.2.2.2.). However, if a primary cation is involved, cyclopropylmethyl to cyclopropyl-methyl rearrangement with formation of a more stable secondary cation may precede the ring enlargement, and the stereochemistry of substituents in the cyclopropane part of the oxaspiropentane may be lost. This was found to be true for /ram-4,5-dimethyl-l-oxaspiropentane (5) where a considerable amount of m-2,3-dimethylcyclobutanone (m-6) was formed.47... 

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. 

Oxaspiropentanes have been generated and rearranged in a large variety of different environments. A series of alkylidene- and allylidenecyclopropanes, present in the structures of bicy-clo[3.1.0]hexanes or bicyclo[4.1.0]heptanes, were epoxidized and rearranged in situ to bicyclic ketones with the alkyl or allyl group preferentially to exclusively in the exo position (Table 4).51 This corresponds to a preferential to exclusive epoxidation of the corresponding alkenes from the sterically less demanding exo face. 

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. 

Oxaspiropentanes 15 and 18, prepared by the reaction of cyclopentanone and 4-tm-butylcyclo-hexanone, respectively, with diphenylsulfonium 2-methylcyclopropanide, rearranged regiose-lectively with preferential migration of the higher substituted carbon atom. Within the stereoisomeric spiro[3.5]nonan-l-ones 19 formed, a pronounced cis selectivity was observed.62... 

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... 

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