Rearrangement of oxaspiropentanes

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. ... 

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]. 

LiBp4 promotes a high-yield rearrangement of oxaspiropentanes to cyclobuta-nones, and in this regard, is reported to be superior to LiC104 (Sch. 69) [118]. 

The addition of phenylselenide to oxaspiropentanes is highly accelerated by protic solvents which protonate and weaken the C-O bond, thus increasing its tendency toward nucleophilic attack. Furthermore, the epoxide opening by selenide is stereospecific and the stereochemistry obtained is opposite to that normally produced by the acid-catalysed rearrangement of oxaspiropentane (see equation 87). The selenoxide seems to play the role... 

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

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. 

Cyclobutauones. Trost s original cyclobutanone synthesis (4, 211-214 definitive papers ) by rearrangement of oxaspiropentanes with lithium salts results in selective formation of the cyclobutanone in which the new carbon to carbonyl bond is introduced on the more sterically hindered face of the ketone. He and Scudder have now found that the isomeric cyclobutanone becomes the predominant product if the oxaspiropentane is rearranged through a selenoxide. An example is the rearrangement of 1. When lithium perchlorate is used the cyclobutanone 2 is obtained. On treatment with sodium selenophenolate followed by oxidation, the cyclobutanone 4 becomes the major product. In some cases this new selenoxide route is stereospecific and results in essentially only one cyclobutanone. 

UBF4 promotes a high-yield rearrangement of oxaspiropentanes to cyclobu-tanones (Scheme 3.28) [50]. In this reaction, UBF4 gave superior results than LiC104. 

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). 

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... 

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. 

The reaction can proceed with a high degree of stereoselectivity. Thus treatment of 4-r-butylcyelohexanone with this sulfur ylide followed by rearrangement of the intermediate oxaspiropentane with Lu(fod), gives the spirobutanonc (4) in 80% yield... 

Rearrangements related to the C3 - C4 ring expansion of oxaspiropentanes occur on treating methylenecyclopropane (69) with iV-bromosuccinimide (NBS) and water in DM SO or on reaction of 1-hydroxycyclopropylmethanol (122) with p-toluenesulphonyl chloride in pyridine (equation 93). ... 

Besides the thermal rearrangement of 1-vinylcycIopropanols and of oxaspiropentanes (cf. Sections III.B and III.C) cyclopropane derivatives can undergo other kinds of C3 - C4 ring expansion. For example, thermolysis at 180°C of the sodium salt of cyclopropyl-methyl ketone tosylhydrazone (155) affords 1-methylcyclobutene (156) in 92% yield (equation 108) . ... 

Fig. (12) The Wieland-Miescher Ketone (1) is converted to the ketone (138) by standard organic reactions. Its condensation with diphenysulfonium cyclopropylide leads the formation of oxaspiropentane (139) which undergoes thermal rearrangement to afford enol silyl ether as a mixture of epimers which on oxidation, metal ammonia reduction and trapping of the enolate yields enol silyl ether (140) as major product. On subjection to allylation, hydroboration, oxidationand further oxidation afforded the ketone (145). Its conversion to aphidicolin (148) was accomplished by methylenation of the ketone function folowed by hydroxylation and hydrolysis.

The cyclobutanones derived from a,p-epoxyketones present several unique opportunities for further synthetic transformations. The oxaspiropentanes are formed in over 90% yield by the cyclopropylide reaction under the same conditions utilized previously. Rearrangement of the spiroepoxide in the presence of a second epoxide can be carried out with aqueous fluoroboric... 

The reaction involving P-hydroxyalkyl selenones o - o is by far the less attractive route to epoxides among those cited above due to the difficulties usually encountered in the oxidation step and the easy rearrangement of the p-hydroxyalkyl selenones to caibonyl compounds (Scheme 184, b and c). This meth is, however, particularly useful for the synthesis of oxaspiropentanes (especially for those bearing a fully alkyl-substituted epoxide ring) from l-seleno-l-(l -hydroxyalkyl)cyclopropanes (Scheme 163, e Scheme 183), which caimot be obtained under other conditions. ... 

The oxaspiropentane — cyclobutanone rearrangement has been used to prepare the previously unknown 2-acylcyclobutanones (43) and their mono-acetal derivatives (acetal of side-chain ketone),while a related rearrangement of cyclopropylmethanols (44) provides an entry into 2-vinylcyclobutanones (45). Chiral 2-methylcyclobutanones have been obtained from 1,3-dibromo-propanes by condensation with an optically active TosMIC derivative. ... 

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... 

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... 

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" . 

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