Electrophilic cyclopropanes reduction

From our previous discussion about electrophilic cyclopropanes (see Problem 15), it should be remembered that a marked reduction of electron density in the three-membered ring occurs when strong electron withdrawing groups are substituted either directly or in conjugation with the trimethylene ring and... 

In contrast to allyl halides substituted with one ASG, the cyclopropanation reaction proceeds relatively smoothly when a second ASG is present. Generally, the best results are obtained with sodium borohydride, sodium cyanide, potassium cyanide, and the sodium salts of alcohols or thiols as the nucleophilic species (Table 22, entries 3-26). Even spiroalkanes can be synthesized with the nucleophiles described above (Table 23). Examples illustrating this route are the conversion of a tetracyclic enamino ester with potassium cyanide to the corresponding electrophilic cyclopropane 2, and the facile one-pot synthesis of 1,1 -bis(hydroxymethyl)cyclo-propanes 3 by reduction of halogenated alkylidene malonates with lithium aluminium hydride. ... 

Takaki reports that ketone enolates add to dimethylstyryl sulfonium perchlorate (155) or methyl styryl sulfone (156) in a Robinson-type annulation sequence to afford the corresponding 3-hydroxythiadecalin (157) or 5-dioxide (158), respectively subsequent reductive desulfonation of (158) affords diene (159).131 However, additions to acceptor (155) suffer from competing cyclopropanation which is dependent on the electrophilicity of the carbonyl group and the ring size of the ketone (Scheme 61). As an aside, DeLucchi reports that l,l-bis(benzenesulfonyl)ethylene (160) adds to ketones at the more substituted a-carbon under neutral conditions in refluxing acetonitrile (equation 18).132... 

Baizer et al. (1972) extensively studied the electroreduction of carbon tetrachloride in the presence of electrophiles for synthetic purposes. Since then the formation of the dichloro-dianion (CCl ) or -carbene (Takita et al. 1990) was considered for the synthesis of cyclopropane derivatives. Recently, carbene formation was observed in the direct reduction of CC14 and DDT (1,1 -bis(p-chlorophenyl)-2,2,2-trichloroethane) on hemin-modified TiC>2 supports (Stromberg et al. 2006). 

Treatment of a,p-unsaturated tosylhydrazones with NaBH4 in MeOH affords principally allylic ethers from cyclic derivatives and pyrazoles with most noncyclic examples. This divergent behavior compared to saturated tosylhydrazones has been attributedto a lessening of the electrophilicity of conjugated imine ir-bonds, which allows initial abstraction of the acidic N—H proton by BH4 to compete with reduction, and gives alternative reactions related to the Bamford-Stevens process as depicted in Scheme 4. An exception to this may be the deoxygenation of conjugated vinyl triflates (entry 11, Table 6). The cyclopropanation and elimination products produced in entry 4, Table 6 also probably arise from similar, alternative reaction paths. ... 

Solution phase reaction of an electrophile with cyclopropane(s) requires favorable interaction of the LUMO of the electrophile with the HOMO degenerate, symmetric or anti-symmetric, orbitals of cyclopropane . The Is orbital of H or one lobe of the p-orbital of a carbocation or electrophile can react with the anti-symmetric (3e ) orbital (Figure 2) with consequent reduction in bonding in adjacent carbon-carbon bonds and relief of C(2)-C(3) antibonding. Completion of this carbon-proton or carbon-electrophile bond results in a corner-protonated cyclopropane (39). Reaction of an electrophile, e.g. proton or carbocation, with the degenerate symmetric 3e orbital (Figure 3) will give an... 

Unactivated cyclopropanes can be cleaved by strongly electrophilic reagents like the proton, halogens or certain metal ions, unfortunately often with low regioselectivity only. So far, only mercury(Il)-induced openings have been of synthetic value. They incorporate suitable nucleophiles and reduction of the products can form radicals capable of additions to electrophilic olefins (equation 14) . ... 

As mentioned above, one major drawback of the Trost methodology is its restriction to the parent compound. It was the Cohen group who found an alternative approach to phenylthiocyclopropyl lithium chemistry by using a reductive lithiation of readily accessible cyclopropanone dithioketals which also works for alkyl-substituted cyclopropanes. The anions obtained by reduction with two equivalents of lithium naphthalene or preferably lithium l-(dimethylamino)naphthalene (LDMAN) can effectively be trapped by apt electrophiles (equation 112). 

Cyclic p-kcio esters and )9-diketones (596) smoothly effect ring-opening of 1,1-bis(benzenesulphonyl)cyclopropane (412) under basic conditions. Reductive cleavage of the resulting sulphones (597) by lithium arylides provides routes to 598 and 599 (equation 210) The bis-benzenesulphonyl compound appears to fulfil the requirements for a propylene 1,3-dipole. The fact that the sulphones can be sequentially removed permits selective introduction of from one to three electrophiles (E) (equation 211). In the case of )5-keto esters, such versatility created a novel three carbon insertion between the ester group and the ketone or a cyclopentane annulation. ... 

As already mentioned for rhodium carbene complexes, proof of the existence of electrophilic metal carbenoids relies on indirect evidence, and insight into the nature of intermediates is obtained mostly through reactivity-selectivity relationships and/or comparison with stable Fischer-type metal carbene complexes. A particularly puzzling point is the relevance of metallacyclobutanes as intermediates in cyclopropane formation. The subject is still a matter of debate in the literature. Even if some metallacyclobutanes have been shown to yield cyclopropanes by reductive elimination [15], the intermediacy of metallacyclobutanes in carbene transfer reactions is in most cases borne out neither by direct observation nor by clear-cut mechanistic studies and such a reaction pathway is probably not a general one. Formation of a metallacyclobu-tane requires coordination both of the olefin and of the carbene to the metal center. In many cases, all available evidence points to direct reaction of the metal carbenes with alkenes without prior olefin coordination. Further, it has been proposed that, at least in the context of rhodium carbenoid insertions into C-H bonds, partial release of free carbenes from metal carbene complexes occurs [16]. Of course this does not exclude the possibility that metallacyclobutanes play a pivotal role in some catalyst systems, especially in copper-and palladium-catalyzed reactions. 

A number of substituted cyelopropanes have been prepared by reductive lithiation of various l,l-bis(phenylsulfanyl)cyclopropanes followed by reactions of the resulting a-phenylsulfanyl-cyclopropyl anions with selected electrophiles. Metalation can be carried out by several methods, cf 1, ° but reduction with two equivalents of lithium naphthalenide in tetrahyd-rofuran at — 70°C is the most efficient. The product yields are generally satisfactory with carbon dioxide and benzaldehyde as trapping agents. Thus, when 2-methyl-1,1-bis(phenylsul-fanyl)cyclopropane was used as starting material, 2-methyl-l -(phenylsulfanyl)cyclopropanecar-boxylic acid (2 b) and (2-methyl-l-phenylsulfanylcyclopropyl)(phenyl)methanol (3 c) were obtained in 86 and 76% yield, respectively. ... 

The electrophilic bromine cation can also be generated from A -bromosuccinimide (NBS). When 2-methylene-6,6-dimethylbicyclo[3.1.0]hexane with an ester function at the bridgehead position was treated with NBS in diethyl ether the electrophilic attack took place at the terminal position of the C—C double bond and the cyclopropane ring was opened to give a cyclopentene derivative. Due to the lack of a reactive nucleophile, a proton was eliminated. The reduction of the ester function did not change the course of this reaction. With tert-hvAy hypochlorite, the corresponding chloro product was obtained. ... 

The cyclopropane ring, due to its ring strain, can be considered as a functional group comparable to the double bond with the synthetic potential to generate functionalized three carbon chains via ring opening. Besides thermal-, photochemical-, oxidative-, reductive-, radical-, nucleophile- and Lewis acid or electrophile-mediated activation, the conversion of cyclopropanes mediated by transition metals plays an important role in synthetic uses of small-ring compounds. In most of these cases, prior to conversion, a complexation of the cyclopropane system by the transition metal is necessary. 

A more common strategy for stepwise asymmetric cyclopropanation is the use of chiral electrophiles. Meyers has used bicyclic lactams (c/. Scheme 3.19, 3.20) [145,146] as electrophilic auxiliaries in sulfur ylide cyclopropanations [147]. These auxiliaries, for reasons that are not entirely clear, are preferentially attacked from the a-face. After separation of the diastereomers, the amino alcohol auxiliary may be removed by refluxing in acidic methanol or reductively [145]. This methodology has been used in asymmetric syntheses of cw-deltamithrinic acid and dictyopterene C, illustrated in the inset of Scheme 6.40 [145]. 

For the synthesis of cyclopropyl amino acids, Williams has used an oxazinone auxiliary (cf. Scheme 3.12) as an electrophilic component in a sulfur ylide cyclopropanation using Johnson s sulfoximines, as illustrated in Scheme 6.41 [148]. Surprisingly, the sulfur ylide approaches from the P face the authors speculate that there may be some sort of 7t-stacking between the phenyls on the oxazinone ring and the phenyl in the sulfoximine to account for this [149]. With Corey s [147] dimethylsulfonium methylide, the diastereoselectivity was only about 75%, but with Johnson s sulfoximines (used in racemic form), only one diastereomer could be detected for most substrates studied (with the exception of R = H, [149]). Dissolving metal reduction afforded moderate yields of the cyclopropyl amino acids. 

Cyclopropanation can occur by the two pathways in Scheme 13.9. First, a [2+2] process can occur between the metal-carbene unit and the olefin ir-bond to generate a metallacy-clobutane ring system. Reductive elimination of this metallacycle would generate a reduced metal fragment and a cyclopropane. Alternatively, the olefin could act as a nucleophile that attacks the electrophilic carbene carbon. This interaction would initiate formation of the cyclopropane without the intermediacy of a metallacycle. 

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