Cyclopropanation of active methylene compounds

Cyclopropanation of active methylene compounds has been achieved with ethylene carbonate as the cyclopropanating agent in the presence of potassium carbonate at 150 °C and a mechanism suggested (Scheme 54).88... 

Michael acceptors which carry a good leaving group at the a-carbon atom or whose electron-withdrawing group itself can serve as the leaving group may be cyclopropanated by active methylene compounds under basic conditions via a prototropic shift subsequent to the Michael addition as outlined in equation 139. Thus, the basicity of the carbanions involved must be balanced to allow the requisite prototropic shift otherwise, the reaction will be very slow or will not work. 

A convenient procedure for the preparation of geminally disubstituted cyclopropanes is the successive alkylation and cyclization of active methylene compounds with 1,2-dihaloal-kanes. - This reaction can be termed a substitution initiated ring-closure reaction (SIRC), in analogy with the Michael initiated ring-closure reaction discussed in Section 1.1.3.7. 

Halogenated ligands were also employed in the asymmetric cyclopropanation reaction. For example, a rhodium complex with brominated TTL ligand 185 promoted the chiral synthesis of cyclopropanes from active methylene compounds in the presence of iodosylbenzene (Scheme 1.86) [132]. Cyclopropanes 186 were obtained in good optical purity. 

Radialenes which are structurally related to 44, i.e. cyclopropanes bearing two quinoid and another acceptor-substituted methylene substituent, were obtained by condensation of bis(4-hydroxyphenyl)cyclopropenones with active methylene compounds, followed by oxidation (Scheme 6)19. Radialenes 45a-f are brilliantly colored solids that are blue or blue-violet in solution but appear metallic gold or red in reflected light. Instead... 

Finally, Nikishin and coworkers have reported that the mediated oxidations of doubly activated methylene compounds can be used to synthesize cyclopropane derivatives (Scheme 17) [30]. Reactions using dimethyl malonate, ethyl cyanoacetate, and malononitrile were studied. Metal halides were used as mediators. When the activated methylene compound was oxidized in the absence of a carbonyl compound, three of the substrate molecules were coupled together to form the hexasubstituted product. Interestingly, when the ethyl cyanoacetate substrate was used the product was formed in a stereoselective fashion (18b). In an analogous reaction, oxidation of the activated methylene compounds in the presence of ketones and aldehydes led to the formation of cyclopropane products that had incorporated the ketone or aldehyde (20). In the case of 19a, the reactions typically led to a mixture of stereoisomers. 

An alternative cyclopropane synthesis via an active methylene compound can also be enhanced by sonication [110]. The number of examples quoted in the literature is low but in the case of ethyl cyanoacetate and dibromoethane sonicated with potassium carbonate and polyethylene glycol in ethylene dichloride the expected cyclopropane is generated in 85 % yield (Eq. 3.19). 

Treatment of vinylselenones (388) with active methylene compounds in basic medium also leads to the formation of electrophilic cyclopropanes (equation... 

In most cases, treatment of allylic halides containing one ASG with a nucleophile does not result in formation of electrophilic cyclopropanes (MIRC product) instead, other reaction pathways are followed, e.g. addition, substitution, rearrangement and elimination reactions.However, with certain alkenes or nucleophiles or under the appropriate conditions a conjugate addition-nucleophilic substitution pathway is favored, resulting in cyclopropanes substituted with one ASG. Representative examples are compiled in Tables 20 and 21 where organometallic compounds or active methylene compounds are used as the nucleophilic species in combination with allyl bromides containing an ester or a sulfone as ASG. 

The reaction of doubly activated allyl halides with active methylene compounds does not produce cyclopropanes, although they do occur as intermediates. Ring opening of the initially formed cyclopropanes gives products in which the position of the substituents are rearranged. 

A special case of the MIRC reaction is observed with electron-deficient alkenes where the leaving group is situated in an a-position relative to the ASG (Scheme 3 c, p 69). In this manner, cyclopropanes with three electron-withdrawing groups were synthesized from activated a-halogenated alkenes and active methylene compounds (Table 24) entries 4-8 show the high stereoselectivity of this MIRC reaction. 

The most widely explored method is the formation of tri- and tetrasubstituted cyclopropanes by reaction of vinylsulfonium salts with methylene compounds activated by ester, ketone, nitrile, or sulfone substituents. A series of examples is collected in Table 25. A variant of this method, where cyclopropanedicarboxylates cis-1 were actually obtained by intramolecular cyclization of the sulfonium salt Cj building block is also shown.Alkylthiocyclopropane derivatives 8 were obtained by the reaction of a ketene dithioacetal monosulfonium salt with carbanions derived from doubly activated methylene compounds. ... 

Treatment of vinyl selenones with active methylene compounds in a basic medium gave electrophilic cyclopropanes via a similar procedure (Table 30). 

Obtained from active methylene compounds, such as malonic esters, -0x0 esters and jS-oxo sulfones, iodonium ylides serve as precursors of the corresponding carbenes. Their decomposition by a catalytic amount of a copper salt in the presence of a C-C double bond has been used for inter- and intramolecular cyclopropanation reactions. Thus, reaction of cyclohexene with bis(methoxycarbonyl)methylene(phenyl)iodine(III) under the catalytic action of bis(acetylacetonato)copper(II) yielded dimethyl bicyclo[4.1.0]heptane-7,7-dicarboxylate (1) (38%, mp 91-93°C) in addition to tetrakis(methoxycarbonyl)ethene (41%). ... 

The cisjtrans ratio of the cyclopropanes formed in this transformation depends to some extent on the nature of the salts and the solvent. A particularly high cisitram ratio was obtained when copper(II) acetate, calcium chloride, and ethanol were employed (no values given). Cyclopropane synthesis from active methylene compounds and nonactivated alkenes was also possible with the help of iodine and a base under phase-transfer conditions. Intra-and intermolecular reactions to give 6 and 5, respectively, have been carried out. The intramolecular reaction is nonstereospecific with respect to the C-C double bond. Although an iodo-substituted intermediate has been isolated in one case, all the details of the reaction mechanism are not yet clear. 

In a related transformation, cyclopropanes 7 were obtained from active methylene compounds and electron-deficient alkenes by the action of iodine and potassium fluoride supported on solid alumina. 

As shown previously (see Section 1.5.6.1.1.), vinylcyclopropanes substituted with two anionic stabilizing groups can be opened by palladium(O) to give trans-7t-allyl complexes38. The zwit-terion thus generated serves as a base to deprotonate the active methylene compound, which is introduced syn to the cyclopropane bond and distal to the stericallv demanding substituent. Only small amounts of the regioisomeric C-2-alkylated product are isolated. 

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