Oxaspiropentanes

Caution The preparation of methylenecyclopropane must be carried out in an efficient hood because ammonia is evolved. The preparation and handling of oxaspiropentane should be carried out behind a safety screen. 

If the oil bath temperature reaches 80°, the residue consists of cyclobutanone (75%) and oxaspiropentane (25%). Distillation of this residue at 97-103° (760 mm.) yields cyclobutanone and oxaspiropentane. 

Caution Addition of lithium iodide catalytic amount to a dichloromethane solution containing more than 30% oxaspiropentane leads to a very vigorous reaction. 

This method for the preparation of cyclobutanone via oxaspiropentane is an adaptation of that described by Salaiin and Conia. The previously known large-scale preparations of cyclobutanone consist of the reaction of the hazardous diazomethane with ketene, the oxidative degradation or the ozonization in presence of pjrridine of methylenecyclobutane prepared from pentaerythritol, or the recently reported dithiane method of Corey and Seebach, which has the disadvantage of producing an aqueous solution of the highly water-soluble cyclobutanone. A procedure involving the solvolytic cyclization of 3-butyn-l-yl trifluoro-methanesulfonate is described in Org. Syn., 54, 84 (1974). 

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 same epoxide 335 was easily obtained in mild conditions (0°C, 5 min) by m-ehloroperbenzoic acid oxidation [13b]. Epoxidation of alkylidenecyclo-propanes by m-chloroperbenzoie acid has been greatly exploited as a route to the synthesis of cyclobutanones 638 via the well known ring expansion of oxaspiropentanes 637 (Scheme 98) [176,177,8]. 

Table 2. Oxaspiropentanes and Cyclobutanones Using Sulfonium Cyclopropylides... 

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 diastereoselectivity is striking. Even when steric factors are not overwhelming (eq. Table 2, entries 5, 9, 22, 29, 30, and 33) only a single oxaspiropentane was detected. A particularly useful aspect of this reaction deals with carbonyl partners that are easily epimerized at the a-carbon. It appears that epimerization is faster than carbonyl addition. However, since one of the two epimers reacts faster than the other, only a single diastereomeric oxaspiropentane still results. For example, 2-isopropyl-5-methylcyclopentanone exists as an Zs.Z-mixture (see Eq. 29)47). For steric reasons, the Z isomer reacts faster than the E isomer which leads to 12 as the... 

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... 

Table 3. Stereoreversed Cyclobutanone Formation from Oxaspiropentanes...

A second major reaction of oxaspiropentanes as reactive epoxides is their elimination to form vinylcyclopropanols 29,49,62). A rapid elimination to vinylcyclo-propanols occurs when the oxaspiropentanes are exposed to lithium dialkylamides in hexane or pentane as exemplified in Eq. 34 and Table 4. 

An alternative procedure to effect elimination resolves this problem. Opening the oxaspiropentane 26 with selenide anion in a non-protic solvent effects a direct elimination via a merged substitution — elimination mechanism to give the vinyl-... 

Realization of this scheme initially encountered two obstacles. Opening of the oxaspiropentane 196 failed with base. The previously discussed merged substitution-... 

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. 

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. 

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. 

To a solution of methylenecyclopropane (5.4 g, 0.10 mol) in CH2C12 (50 mL) cooled to — 80 °C was added 4-nitroperoxybenzoic acid (18.3 g, 0.10 mol) and the mixture was warmed with stirring. At about 0°C, a highly exothermic reaction occurred and occasional euoling in an ice-waicr bath was necessary. The mixture was stirred at rt overnight, filtered, and the filtrate was distilled under reduced pressure (15 Torr) at rt. The residue (ca. 5 g) was 4-nitrobenzoic acid. The distillate was a solution of oxaspiropentane in CH2C12 which was concentrated by distillation under ordinary pressure. 

A solution of oxaspiropentane, prepared from methylenecyclopropane (58 g, 1.07 mol) as described above, in CH,C12 (200 mL) was added dropwise to a stirred suspension of Lil (5 mg) in CH2CT2 (50 mL) at such a rate as to maintain gentle reflux. When the addition was complete, the solution was washed with sat. aq Na2S203 (20 mL) and H20 (20 mL), and dried (Na2S04). The solution was concentrated and the residue distilled at 760 Torr through a 50-cm spinning-band column yield 41 g (64%) bp 100 101 C. 

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... 

---