2.2- dimethyl-cyclobutanones

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. 

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. 

In addition to the application of malonic esters, four-membered ring compounds can also be realized by using methyl methylsulfanylmethyl sulfoxide (14) as the active methylene component.25 27 As demonstrated in the following scheme, when the potassium salt of methyl methylsulfanylmethyl sulfoxide is allowed to react with 1,3-dibromopropane, cyclobutanone dimethyl dithioacetal 5-oxide (16) is isolated in 97% yield.8,10 Of particular interest is that the... 

Cyclobutanone Dimethyl Dithioacetal, S -Oxirle (16) Typical Procedure 25... 

Ketene acetals and thioacetals can be used as ketene equivalents in cyclobutanone synthesis in situations where ketene to alkene cycloadditions are inefficient such as in the case of electron-deficient alkenes.14 Although thermal cycloadditions of ketene acetals and thioacetals with electron-deficient alkenes have been observed (see Section 1,3.2.1.), such cycloadditions proceed more efficiently and under milder conditions with metal catalysts. Efficient cycloadditions between ketene dimethyl acetal and alkenes substituted by a single electron-withdrawing group have been reported.15... 

Ketene thioacetals can also be used as ketene equivalents in the preparation of cyclobutanones and cyclobutanes. Boron trifluoride catalyzes the [2 + 2] cycloaddition of 2-[(l-pyrro-lidinyl)mcthylene]-1,3-dithiane (39) with dimethyl maleate (40).17 Although the cycloadduct is obtained in good yield, stereochemical integrity is not maintained and the thermodynamically most stable isomer predominates. 

Chloro-3,3-dimethyl-2-(2, 2, 2 -trichloroethyl)cyclobutanone Typical Procedure 33... 

Diphenylsulfonium cyciopropanide has been generated irreversibly Method A, by reaction of triphenylsulfonium tetrafluoroborate with cyclopropyllithium in tetrahydrofuran at — 78°C 61,65 or Method B, by treatment of cyclopropyldiphenylsulfonium tetrafluoroborate with sodium methylsulfinylmethanide in 1,2-dimethoxyethane at —40°C.57,65 However, reversible formation from cyclopropyldiphenylsulfonium tetrafluoroborate with Method C, powdered potassium hydroxide in dimethyl sulfoxide at + 25 °C, is easier to perform and gives higher yields of cyclobutanones l.62 A large-scale preparation of cyclopropyldiphenylsulfonium tetrafluoroborate has been reported.65,66... 

Cyclobutanones Prepared Using Diphenylsulfonium Cyclopropanide Generated with Potassium Hydroxide in Dimethyl Sulfoxide General Procedure 62... 

Analogs ofl-lithiocyclopropyl phenyl sulfide bearing a methylsulfanyl instead of a phenyl-sulfanyl group were obtained from dibromocyclopropanes by sequential treatment with butyl-lithium, dimethyl sulfide and butyllithium. Addition to aldehydes occurred readily and rearrangement of the resulting /7-hydroxy sulfides 10 with trifluoroacetic acid yielded cyclobutanones II.172... 

The enolates of both cyclobutanones and acylcyclobutanes are readily formed and react smoothly with alkyl halides152,159 171,341 or carbonyl groups.92,103,, 04 172 175 However, caution is required to avoid O-alkylation in the former case. For example, dimethylation of 2,2,3,3-tetramethylcyclobutanone with potassium hydride and iodomethane gave 2,2,3,3.4,4-hexamethylcyclobutanone (2) together with l-methoxy-2,3,3,4,4-pentamethylcyclobutene (3) in a 93 6 ratio.159... 

All of the usual chromium-based oxidation reagents that have been used for the oxidation of cyclobutanols to cyclobutanones, for example, chromium(VI) oxide (Jones reagent),302 pyri-dinium chlorochromate,304 pyridinium dichromate,307 and chromium(YI) oxide/pyridine (Collins),303 are reported to do so without any serious problems. Alternatively, tetrapropylam-monium perruthenate in the presence of A-methylmorpholine A -oxide. oxalyl chloride in the presence of triethylamine in dimethyl sulfoxide (Swern),158,309,310 or phenyl dichlorophos-phate in the presence of triethylamine and dimethyl sulfoxide in dichloromethane (Pfitzner-Moffatt),308 can be used. The Pfitzner-Moffatt oxidation procedure is found to be more convenient than the Swern oxidation procedure, especially with respect to the strict temperature control that is necessary to achieve good yields in the latter, e.g. oxidation of 1 to give 2.308... 

There have been three reported syntheses of 1,2-diazocines by means of ring-expansive cycloaddition reactions. In the first case, Sasaki and coworkers reacted 4,4-dimethyl-3,5-diphenylisopyrazole 25 with diphe-nylcyclopropenone to obtain diazocine 26 (73SC249). The second cycloaddition was achieved by Haddadin et al., who condensed cyclobutanone with tetrazine 27 (Ar = Ph) to afford diazocine 28 (Ar = Ph, X = O) or 29, depending on whether methanolic base or diethylamine was used as catalyst (84TL2577). A similar reaction was used to prepare a triazocine see Section IV,A,1. 

The photochemical transformations of a series of 2-isopropylidenecyclobutanones in alcoholic media have been reported (15b,36). Irradiation of 2-isopropylidene-cyclobutanone [79a] in methanol afforded a quantitative yield of ring-expanded acetal [80a] with a quantum efficiency (at 313 nm) of 0.11. When irradiations were carried out in methanol-O-d, the acetal [80a] isolated contained >95% deuterium incorporation (nmr) at the indicated position. Completely analogous results were obtained with the 4,4-dimethyl derivative [79b] and 3,3,-... 

The 2,4-disubstituted derivatives of the aforementioned 3-metallacyclobutanones allow for cis and trans isomers, much as for cyclobutanone and cyclobutane. It is found that the diphenyl species [Pt CHPhC(0)CHPh (PPh3)2] is synthesized with predominantly cis stereochemistry. This is consistent with stereochemical expectations—however, disconcertingly, there are no examples of disubstituted cyclobutanes (or derivatives) for which the enthalpy of formation of both the cis and trans isomers are both known to confirm this expectation. Gibbs free energy differences have been determined for the dimethyl , dichloro, dibromo and diiodo ° species, again in the expected order °. Indeed, the only case where the trans isomer is known to be more stable than the cis is the enigmatic bis-phenylsulfonyl species for which no explanation has been offered ... 

In hydrogenolyses with HAICU, the dimethyl acetals of cyclobutanone and cyclohexanone are cleaved more slowly than that of 3-pentanone, while those of cyclopentanone and cycloheptanone are cleaved more rapidly (Table 1), as would be expected for a carbonium ion process. The differences in rate are small, suggesting that carbonium ion character is not strongly developed in the transition state. With the dimethyl acetal of 4-t-butylcyclohexanone, the hydride addition step occurs with strongly predominating axial addition when HAlCh is used Zn(BH4)2 with TMS-Cl, and TMS-H with TMSO-Tf are less selective (Table 2). Equatorial attack predominates, however, in the reduction of the ketone itself with TBDMS-H and TBDMS-OTf. ... 

The basicity of the sulfoxide oxygen has been investigated by observing infrared shifts in protic solvents. ° In this way, it was shown that thietane 1-oxide is more basic than cyclobutanone, but less basic than tetramethylene sulfoxide (thiolane 1-oxide) or pentamethylene sulfoxide (thiane l-oxide). ° Toward phenol, the order of basicity is as follows thiolane 1 -oxide > diethyl sulfoxide > thiepan 1-oxide > dimethyl sulfoxide > thiane 1-oxide > 9-thiabicyclo[3.3.1]nonane 9-oxide > 7-thiabicyclo[2.2.1]heptane 7-oxide > thietane 1-oxide.ThepKaof the conjugate acid of thietane 1-oxide is — 1.92, as determined in aqueous sulfuric acid. =... 

A pressure increase, brought about by an increase in the concentration of the ketone or by the addition of an inert gas, enhances the formation of the unsaturated aldehyde as compared to that of CO. The value of awehyde increases at the expense of 0co> thus, the ketone consumption yield is independent of pressure. This seems to be generally valid in the photolysis of the cyclic ketones it was confirmed, for instance, for cyclopentanone °, cyclohexanone 2-methyl cyclohexanone and 2,6-dimethyl cyclohexanone . An increase in wavelength also favours the formation of the aldehyde as compared to decarbonylation in the photolysis of cyclobutanone , cyclopentanone and cyclohexanone . At 3130 A, the decrease in temperature has a similar effect on the product distribution in the photolysis of cyclopentanone , cyclohexanone , 2-methyl cyclohexanone , and 2,6-dimethyl cyclohexanone to that caused by the increase in wavelength or pressure. However, at shorter wavelengths, the quantum yields seem to be independent of temperature . ... 

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