Ketones oxaspiropentanes

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 direct high yield synthesis of oxaspiropentanes from almost any type of aldehyde or ketone represents a particularly useful transformation because of the high reactivity of such compounds. This approach proves to be exceptionally simple. The DMSO reaction mixture can be directly extracted with pentane or hexane, the hydrocarbon solvent removed and the product isolated by distillation or crystallization. Since diphenyl sulfide is the only by-product extracted with the oxaspiropentane, the mixture can normally be used for most further synthetic transformations. Table 2 summarizes some of the oxaspiropentanes prepared by this method. 

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). 

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" . 

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. 

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... 

The spiroannulation of cyclic a-epoxy ketones proceeded stereospecifically, but with acyclic a-epoxy ketones the stereospecificity was lost during the oxaspiropentane-forming step, e.g. formation of cyclic a-epoxy ketones 11a, b and acyclic a-epoxy ketones 12/12. 69... 

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... 

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... 

Better yields of cyclobutanones were obtained with steroidal ketones.85 86 In the reaction of 5a-cholestan-3-one (5) with diazocyclopropane, spiroannulation to give 6 (30%) dominated insertion to give 7 (24%), and with 3/ -acetoxy-5a-pregnane-l 1,20-dione (8) only spiroannulation to give 9 (60%) was observed.85 A comparable high yield (78%) of a spiroannulation product 11 was obtained with trispiro[2.0.2.0.2.1]decan-10-one (10).84 It is apparent that efficient formation of oxaspiropentanes as direct precursors of cyclobutanones only takes place with sterically hindered ketones. 

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

Besides by these epoxidations, oxaspiropentanes have been prepared through the nucleophilic addition of 1-lithio- 1-bromocyclopropanes to ketones at low temperature. Thus for example, the dibromocyclopropane 96 prepared by addition of dibromo-carbene to cyclohexene 52) underwent metalation with butyllithium to give the lithio-bromocyclopropane 97 which was converted into the oxaspiropentane 98 upon simple addition to cyclohexanone, Eq. (28) 53,54). 

Oxaspiropentanes have been obtained from the cyclopropylide 103, prepared by treatment of cyclopropyldiphenylsulfonium tetrafluoroborate 102 either with sodium methylsulfmyl carbanion in dimethoxyethane at —45 °C or with potassium hydroxide in dimethylsulfoxide at 25 °C. While the reaction of the ylide 103 with a,p-unsaturated carbonyl compounds has resulted in selective cyclopropylidene transfer to the a, 3-carbon-carbon double bond leading to spiropentanes, condensation of 103 with non-conjugated aldehydes and ketones led to oxaspiropentanes such as 104, which have been isolated in 59-100% yields, Eq. (30) 57). 

A severe limitation of this method, however, is the failure of the ylide 103 to yield oxaspiropentanes vide supra) from a,p-unsaturated ketones and the poor yields of vinylcyclopropanes obtained from its reactions with hindered ketones or with con-formationally rigid six-membered rings. Moreover, attempts to extend the oxaspiro-pentane ring opening to compounds containing an adjacent tertiary center have failed thus, oxaspiropentane 110 did not lead to 111, Eq. (33) 57). 

While the nucleophilic addition of 1-lithio-l-bromocyclopropanes to ketones gave oxaspiropentanes, precursors of 1-donor substited vinylcyclopropane derivatives vide supra, Sect. 4.5, Eq. (28)), addition of n-BuLi at low temperature to 1,1-di-bromocyclopropane 199 (prepared in 75 % yield from the addition of dibromocarbene... 

The rich, synthetically valuable chemistry of these carbanions is mainly due to the independent efforts of two groups ". As outlined in equation 129 addition of a ketone to the carbanion is the basis for the preparation of cyclobutanones obtained after acid treatment of the intermediate oxaspiropentanes. In contrast, aldehydes as electrophiles give isolable bromoalcohols, which undergo redox isomerization to cyclopropyl ketones. 

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... 

Vinylcyclopropanols can be prepared either from the readily available cyclopro-panone hemiacetaP, from 1-hydroxycyclopropanecarboxaldehyde derivativesfrom a,a -dichloroacetone, from the silver Simmons-Smith cyclopropanation of a-ethylenic ketone silyl enol ethers from the dye-sensitized photo-oxygenation of alkylidene-cyclopropanes or from the ring-opening of oxaspiropentanes (cf. Section III.C). Consequently, they become participants of choice in a number of useful chemical transformations (see also Section IV.A). 

The intermediacy of oxaspiropentanes was first proposed in some reactions i.e. the addition of diazomethane to cyclohexanone the reaction of dimethyloxosulphonium methylide with a-haloketones and the reaction of iV,iV-dimethylaminophenyloxo-sulphonium cyclopropylide with ketones . The parent oxaspiropentane (115) has been obtained from the p-nitroperbenzoic acid oxidation of a methylene chloride solution of methylenecyclopropane (69) at - 10°C (equation 82). ... 

Oxaspiropentanes have been also obtained in 59-100 % yields from the condensation of aldehydes and ketones with the diphenylsulphonium cyclopropylide prepared by treatment of the cyclopropyldiphenylsulphonium fluoroborate (119) with solid potassium hydroxide in dimethyl sulphoxide at 25°C (equation... 

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) . ... 

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. 

When a mixture of a cyclopropyl phenyl selenone and a ketone or an aldehyde is treated with potassium tert-butoxide in tetrahydrofuran, metalation of the selenone takes place preferentially and the metalloselenone formed immediately reacts with the carbonyl compound. Oxaspiropentanes are produced almost quantitatively when ketones are used whereas a mixture of oxaspiropentanes and cyclopropyl ketones are obtained when the reaction is carried out with aldehydes, for example, formation of 5 and... 

A number of oxaspiropentanes have also been obtained by treating 1,1-dibromocyclopropanes successively with butyllithium and a ketone below — 90When the ketone is replaced by an aldehyde, a l-bromo-l-(l-hydroxyalkyl)cyclopropane is formed instead (Section 5.2.1.1.17.2.1.3.). During the spiropentane generation, however, lithium bromide is also formed, and this salt might catalyze conversion of the primary product to cyclobutanone derivatives. The method has therefore rarely been used to prepare quantities of oxaspiropentanes. 

Isomeric mixtures of oxaspiropentanes have also been obtained by treating stereoidal ketones with diazocyclopropanes, but the products are rather difficult to isolate and are therefore obtained in low yields. ... 

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. 

Trost and co-workers used this type of rearrangement to generate oxaspiropentane derivatives that were converted to cyclo-butane derivatives. In section 8.8.B.ii, oxaspiropentanes such as 61 were prepared by the reaction of ketones and sulfur stabilized cyclopropyl ylids. Treatment of 61 with aqueous tetrafluoroboric acid (HBF4) gave cation 62, which rearranged to 63. Loss of a proton gave the final product, ketone 64. ... 

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.

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. 

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