Of cyclobutanones

C. Cyclobutanone (Note 16). The residue consisting of oxaspiro-pentane (35%) and dichloromethane (about 200 ml.) is added dropwise at room temperature to a magnetically stirred solution containing about 5-10 mg. of lithium iodide in 50 ml. of dichloromethane (Notes 17, 18), at such a rate as to maintain gentle reflux of the solvent. At the end of the addition when the reaction mixture returns to room temperature, the transformation into cyclobutanone is complete. The dichloromethane solution is washed with 20 ml. of saturated aqueous sodium thiosulfate and with 20 ml. of water. After drying over magnesium sulfate and concentration by distillation of the solvent through a 15-cm., helix-packed, vacuum-insulated column, the residual liquid consists of cyclobutanone (95%) and of 3-buten-2-one and 2-methylpropenal... 

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. 

The purity of cyclobutanone was checked by gas chromatography on a 3.6-m. column containing 20% silicone SE 30 on chromosorb W at 65°. The infrared spectrum (neat) shows carbonyl absorption at 1779 cm. - the proton magnetic resonance spectrum (carbon tetrachloride) shows a multiplet at 8 2.00 and a triplet at S 3.05 in the ratio 1 2. 

The cheekers obtained yields of 61-64% on smaller-scale runs ( 10 g. of cyclobutanone). 

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 photochemistry of cyclobutanones differs from that of less strained larger cycloalkanones. Fragmentation to ethylene and ketene (derivatives), decarbonylation and rearrangement to oxacarbenes predominate here. The oxacarbene formation, which occurs with retention of the configuration of the... 

Photochemical transformations of conjugated cyclohexenones, 317 Photochemical transformations of non-conjugatea ketones, 292 Photochemistry of cyclobutanones, 293 Photolysis of nitrites, 253... 

An attractive synthesis of cyclobutanone (253) has been recently described using 1-isocyano-l-tosylcyclobutane(252)(equation 151)144. l-Isocyano-l-tosylcyclobutanes252 can be prepared from (tosylmethyl)isocyanide and alkyl-substituted 1,3-dibromobutanes. This method appears to be superior to previously reported methods for the preparation of cyclobutanone because of high purity and high yields. 

In contrast to alkoxycarbene complexes, most aminocarbene complexes appear too electron-rich to undergo photodriven reaction with olefins. By replacing aliphatic amino groups with the substantially less basic aryl amino groups, modest yields of cyclobutanones were achieved (Table 10) [63], (Table 11) [64]. Both reacted with dihydropyran to give modest yields of cyclobutanone. Thio-carbene complexes appeared to enjoy reactivity similar to that of alkoxycar-benes (Eq. 15) [59]. 

Biooxidation of cyclobutanones is a particularly useful transformation, as the corresponding chiral butyrolactones represent highly valuable building blocks for a large variety of natural products as well as bioactive compounds [165]. 

The oxidation by chromic acid alone leads to a mixture of cyclobutanone and 4-hydroxybutyraldehyde the existence of an isotope effect for the oxidation of I-deuteriocyclohexanol suggests that Cr(VI) produces the ketone and lower oxidation states of chromium produce the cleavage product. 

Cyclopropanes 13 have been prepared from a NHC-rhodium catalysed decarbonylation of cyclobutanones 11 (Scheme 5.4) [6]. The isolated complex 12... 

Cycloadditions of ketenes and alkenes have synthetic utility for the preparation of cyclobutanones.163 The stereoselectivity of ketene-alkene cycloaddition can be analyzed in terms of the Woodward-Hoffmann rules.164 To be an allowed process, the [2ir + 2-tt] cycloaddition must be suprafacial in one component and antarafacial in the other. An alternative description of the TS is a 2irs + (2tts + 2tts) addition.165 Figure 6.13 illustrates these combinations. Note that both representations predict formation of the d.v-substituted cyclobutanone. 

The photoreduction of cyclobutanone, cyclopentanone, and cyclohexanone by tri-n-butyl tin hydride was reported by Turro and McDaniel.<83c> Quantum yields for the formation of the corresponding alcohols were 0.01, 0.31, and 0.82, respectively. Although the results for cyclopentanone and cyclohexanone quenching were not clear-cut (deviations from linearity of the Stem-Volmer plots were noted at quencher concentrations >0.6 M), all three ketone photoreductions were quenched by 1,3-pentadiene, again indicating that triplets are involved in the photoreduction. 

As stated previously, the photolysis of cyclobutanone in ethanol solution results in an 8% yield of an acetal, presumably formed from ethanol addition to a carbene intermediate. Alkylation of the a positions of cyclobutanone increases the yield of this rearrangement product,(22)... 

From the reactions presented in this section one can conclude that cyclic acetal formation via addition to a carbene intermediate is a general reaction for type I cleavage of cyclobutanones, tricyclic compounds, and certain bridged bicyclics as minor products. No acetal has been isolated from photolyses of cyclopentanones or cyclohexanones except for the special case of an a-sila ketone previously discussed. 

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]. 

Addition of alkyllithium to cyclobutanones and transmetallation with VO(OEt)Cl2 is considered to give a similar alkoxide intermediates, which are converted to either the y-chloroketones 239 or the olefinic ketone 240 depending on the substituent of cyclobutanones. Deprotonation of the cationic species, formed by further oxidation of the radical intermediate, leads to 240. The oxovanadium compound also induces tandem nucleophilic addition of silyl enol ethers and oxidative ring-opening transformation to produce 6-chloro-l,3-diketones and 2-tetrahydrofurylidene ketones. (Scheme 95)... 

The fragmentation is stereospecifically anti as shown by complementary geometry obtained in the cleavage of the epimeric pair of epoxycyclobutanones 91 and 92 (Eq. 110). The fragmentation product 93 of cyclobutanone 91 is transformable into the dimethyl ester of the pheromone of the Monarch butterfly. Considering the availability of the starting epoxy ketones from enones, the oxasecoalkylation serves to reorient the oxidation pattern with chain extension as summarized in Eq. 111. 

The preparation of cyclobutanones can easily be realized by using the thermal-[2 + 2]cycloaddition of haloketenes to olefinic compounds (Eq. (2))49). 

A systematic study of the Baeyer-Villiger oxidation of cyclobutanones was recently reported by Jeffs71). The cycloalkenes (206) reacted readily with dichloro-ketene to give the gem-dichlorocyclobutanone (205), which were reduced by Zn to the cyclobutanone (204). Baeyer-Villiger oxidation of (204) yielded the y-lactone (207) in fair yields. (Table 11)71). 

Treatment of cyclobutanones (232) with NaOMe and diphenyldisulfide in MeOH at reflux temperature led to to-sulfenylation and subsequent ring cleavage to furnish compounds (233) (Table 14)78>. 

Several comparative procedures are included. The formation of 1-BENZYLINDOLE and GERANYL CHLORIDE by two different procedures are representative. An interesting comparison of three of the recent adaptations of the Claisen rearrangement on the same substrate is presented in the preparations of N.N-DIMETHYL-5/ -CHOLEST-3-ENE-5-ACETAMIDE, ETHYL-5/S-CHOLEST-3-ENE-5-ACETATE, and 5/9-CHOLEST-3-ENE-5-ACETALDEHYDE. For the utility of the procedure itself as well as for comparison with previously presented syntheses, the preparation and use of triflates in the synthesis of CYCLOBUTANONE is included. 

The reaction of enynes with Fischer-type carbene complexes can also lead to the formation of cyclobutanones (Figure 2.23) [315]. The mechanism for this reaction is likely to be rearrangement of the intermediate, non-heteroatom-substituted vinylcarbene complex to a vinylketene, which undergoes intramolecular [2 -i- 2] cycloaddition to form the observed cyclobutanones. 

Subjection of the mixture of cyclobutanones rac-43 and rac-44 to mild acidic conditions resulted in the rearrangement of cyclobutanone rac-43 to its more stable isomer rac-45, whereas rac-44 remained unchanged. The ob-... 

In the past few years, new approaches for the enantioselective synthesis of / -benzyl-y-butyrolactones appeared in the literature. Some of these approaches involve the asymmetric hydrogenation of 2-benzyl-2-butenediols (j [34]), the radical mediated rearrangement of chiral cyclopropanes (r [35]), the transition metal catalyzed asymmetric Bayer-Villiger oxidation of cyclobutanones n [36]), or the enzymatic resolution of racemic succinates (g [37]). 

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" . 

If the 3-position is a tertiary, rather than a quaternary, stereocenter, Rh(I)/Tol-BINAP effects an intriguing parallel kinetic resolution - thus, one enantiomer of the substrate selectively undergoes hydroacylation to generate a cyclobutanone, while the other enantiomer is transformed into a cyclopentanone (Eq. 22) [24]. This observation is quite interesting, given the limited number of examples of parallel kinetic resolutions, particularly catalytic processes that involve carbon-carbon bond formation, and catalytic methods for the construction of cyclobutanones. 

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