Cyclopropanes electrophilic substitution

It should be mentioned that if a tertiary C—H bond is relatively electron-poor, fluorine will not react with it under the ionic conditions. Thus, when the tertiary hydrogen is too close to a strong electron-withdrawing group or otherwise the C—H bond has a low p orbital contribution as in the cyclopropane ring, the electrophilic substitution is no longer ... 

Kobayashi et al. successfully performed asymmetric cyclopropanation using substoichio-metric amounts of catalyst 45 (Scheme 9). [32] The levels of enantioselectivity achieved are in the 70-90 % range. Both, E- and Z-allylic alcohols are readily converted. Vinylstannanes 46 are also appropriate substrates. The resulting enantio-merically pure cyclopropanated stannanes hold great synthetic potential [33]. Thus, the cyclopropanated stannane 48 can be converted into the substituted cyclopropane 49 after successful tin-lithium exchange and electrophilic substitution. 

This chapter will deal mainly with the synthesis and reactivity of electrophilic cyclopropanes and only these procedures and reactions will be investigated which give rise to cyclopropanes geminally substituted with two EWGs. Nevertheless, the preparation of monoactivated cyclopropanes will be mentioned to some extent because a number of procedures for the synthesis of electrophilic cyclopropanes have been developed for cyclopropanes bearing one EWG. Therefore, the synthesis and reactivity of the latter compounds cannot be excluded, due to the close relationship and the numerous studies concerning reaction mechanisms for these compounds. 

The nitration results in equations 13 and 14 " were interpreted as showing that cyclopropane is a meta director in electrophilic substitution . Evidently in these systems with the cyclopropane twisted out of the desirable bisected conformation the alkyl group has a stronger directing effect than cyclopropyl and substitution occurs predominantly o, p to these groups, but this does not indicate an actual m-directing influence of cyclopropyl. 

The stereoselectivity is high. For unsymmetrically substituted cyclopropanes, electrophilic attack by the Hg(II) species can occur with predominant retention or inversion, but there is always inversion of configuration at the site of nucleophilic attack". ... 

Scheme 10.15, which is appreciably shorter than 10.14, uses the same general methods to establish the stereochemical relationships. In step C, the cyclopropane ring is opened by protonation. The incipient carbonium ion is captured intramolecularly, and the cis relationship between the C-2 and C-5 substituent is thereby established. The geometry of the bicyclic ring system and the retention of stereochemistry in the Baeyer-Villiger reaction are used to ensure the cis stereochemistry of the substituents at C-1 and C-3, as in Scheme 10.14. Step A is an electrophilic substitution that is initiated by protonated formaldehyde. The resulting cation is captured by formic acid, and the primary alcohol is also formylated under the reaction conditions.

Additions to cyclopropanes can take place by any of the four mechanisms already discussed in this chapter, but the most important type involves electrophilic attack. For substituted cyclopropanes, these reactions usually follow Markovnikov s rule, though exceptions are known and the degree of regioselectivity is often small. The application of Markovnikov s rule to these substrates can be illustrated by the reaction of 1,1,2-trimethylcyclopropane with The rule predicts that the... 

From the point of view of both synthetic and mechanistic interest, much attention has been focused on the addition reaction between carbenes and alkenes to give cyclopropanes. Characterization of the reactivity of substituted carbenes in addition reactions has emphasized stereochemistry and selectivity. The reactivities of singlet and triplet states are expected to be different. The triplet state is a diradical, and would be expected to exhibit a selectivity similar to free radicals and other species with unpaired electrons. The singlet state, with its unfilled p orbital, should be electrophilic and exhibit reactivity patterns similar to other electrophiles. Moreover, a triplet addition... 

Heteroatom-substituted carbene complexes are less electrophilic than the corresponding methylene, dialkylcarbene, or diarylcarbene complexes. For this reason cyclopropanation of electron-rich alkenes with the former does not proceed as readily as with the latter. Usually high reaction temperatures are necessary, with radical scavengers being used to supress side-reactions (Table 2.16). Also acceptor-substituted alkenes can be cyclopropanated by Fischer-type carbene complexes, but with this type of substrate also heating is generally required. 

Several reaction sequences have been reported in which Fischer-type carbene complexes are converted in situ into non-heteroatom-substituted carbene complexes, which then cyclopropanate simple olefins [306,307] (Figure 2.22). This can, for instance, be achieved by treating the carbene complexes with dihydropyridines, forming (isolable) pyridinium ylides. These decompose thermally to yield pyridine and highly electrophilic, non-heteroatom-substituted carbene complexes (Figure 2.22) [46]. 

In cyclopropanations with electrophilic carbene complexes, yields of cyclopropanes tend to improve with increasing electron density of the alkene. As illustrated by the examples in Table 3.5, cyclopropanations of enol ethers with aryldiazomethanes often proceed in high yields. Simple alkyl-substituted olefins are, however, more difficult to cyclopropanate with diazoalkanes. A few examples of the cyclopropanation of enamines with diazoalkanes have been reported [650]. 

Most electrophilic carbene complexes with hydrogen at Cjj will undergo fast 1,2-proton migration with subsequent elimination of the metal and formation of an alkene. For this reason, transition metal-catalyzed cyclopropanations with non-acceptor-substituted diazoalkanes have mainly been limited to the use of diazomethane, aryl-, and diaryldiazomethanes (Tables 3.4 and 3.5). 

Ylides other than acceptor-substituted diazomethanes have only occasionally been used as carbene-complex precursors. lodonium ylides (PhI=CZ Z ) [1017,1050-1056], sulfonium ylides [673], sulfoxonium ylides [1057] and thiophenium ylides [1058,1059] react with electrophilic transition metal complexes to yield intermediates capable of undergoing C-H or N-H insertions and olefin cyclopropanations. 

The different synthetic applications of acceptor-substituted carbene complexes will be discussed in the following sections. The reactions have been ordered according to their mechanism. Because electrophilic carbene complexes can undergo several different types of reaction, elaborate substrates might be transformed with little chemoselectivity. For instance, the phenylalanine-derived diazoamide shown in Figure 4.5 undergoes simultaneous intramolecular C-H insertion into both benzylic positions, intramolecular cyclopropanation of one phenyl group, and hydride abstraction when treated with rhodium(II) acetate. 

The reaction of acceptor-substituted carbene complexes with alcohols to yield ethers is a valuable alternative to other etherification reactions [1152,1209-1211], This reaction generally proceeds faster than cyclopropanation [1176], As in other transformations with electrophilic carbene complexes, the reaction conditions are mild and well-suited to base- or acid-sensitive substrates [1212], As an illustrative example, Experimental Procedure 4.2.4 describes the carbene-mediated etherification of a serine derivative. This type of substrate is very difficult to etherify under basic conditions (e.g. NaH, alkyl halide [1213]), because of an intramolecular hydrogen-bond between the nitrogen-bound hydrogen and the hydroxy group. Further, upon treatment with bases serine ethers readily eliminate alkoxide to give acrylates. With the aid of electrophilic carbene complexes, however, acceptable yields of 0-alkylated serine derivatives can be obtained. 

Interestingly, sulfonium ylides generated from electrophilic carbene complexes and sulfides can react with carbonyl compounds, imines, or acceptor-substituted alkenes to yield oxiranes [1320-1325], aziridines [1321,1326,1327] or cyclopropanes [1328,1329], respectively. In all these transformations the thioether used to form the sulfonium ylide is regenerated and so, catalytic amounts of thioether can be sufficient for complete conversion of a given carbene precursor into the... 

The reaction of heteroatom-substituted alkenes with electrophilic carbene complexes can lead to the formation of highly reactive, donor-acceptor-substituted cyclopropanes. This type of cyclopropane usually undergoes ring fission and rearrangement reactions under milder conditions than do unsubstituted cyclopropanes (Figure 4.22). 

While a large number of studies have been reported for conjugate addition and Sn2 alkylation reactions, the mechanisms of many important organocopper-promoted reactions have not been discussed. These include substitution on sp carbons, acylation with acyl halides [168], additions to carbonyl compounds, oxidative couplings [169], nucleophilic opening of electrophilic cyclopropanes [170], and the Kocienski reaction [171]. The chemistry of organocopper(II) species has rarely been studied experimentally [172-174], nor theoretically, save for some trapping experiments on the reaction of alkyl radicals with Cu(I) species in aqueous solution [175]. 

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