Cyclopropanes with electrophiles

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]. 

Alkynes can be converted into cyclopropenes by inter- [587,1022,1052,1060-1062] or intramolecular [1070] cyclopropanation with electrophilic carbene complexes, Because of the high reactivity of cyclopropenes, however, in some of these reactions unexpected products can result from rearrangement or other transformations of the cyclopropenes initially formed (cf. Section 4,1,3),... 

At least three genereil pathways need to be considered for the ringopening reactions of cyclopropanes with electrophiles, each of which could proceed with either inversion or retention. The most straightforward mechanism would involve a direct, single-step reaction leading to a carbonium ion, a reaction which could truly be considered an Se2 process. 

Numerous other examples for the conversion of oxygen functionalized cyclopropanes with electrophiles in the presence of transition-metal complexes have been reported. 1-Vinyl-or 1-acetylenyl-substituted siloxycyclopropanes in similar conversions lead to cyclopentanone derivatives. Hydroxycyclopropanes with enolates give other l,n-diketones in inter- and... 

The Corey-Chaykovsky reaction entails the reaction of a sulfur ylide, either dimethylsulfoxonium methylide (1, Corey s ylide, sometimes known as DMSY) or dimethylsulfonium methylide (2), with electrophile 3 such as carbonyl, olefin, imine, or thiocarbonyl, to offer 4 as the corresponding epoxide, cyclopropane, aziridine, or thiirane. ... 

Negishi E, Tan Z (2005) Diastereoselective, Enantioselective, and Regioselective Carbo-alumination Reactions Catalyzed by Zirconocene Derivatives. 8 139-176 Netherton M, Fu GC (2005)Pa]ladium-catalyzed Cross-Coupling Reactions of Unactivated Alkyl Electrophiles with Organometallic Compounds. 14 85-108 Nicolaou KC, King NP, He Y (1998) Ring-Closing Metathesis in the Synthesis of EpothUones and Polyether Natmal Products. 1 73-104 Nishiyama H (2004) Cyclopropanation with Ruthenium Catalysts. 11 81-92 Noels A, Demonceau A, Delaude L (2004) Ruthenium Promoted Catalysed Radical Processes toward Fine Chemistry. 11 155-171... 

When the cis/trans stereoselectivity of cyclopropanation with ethyl diazoacetate in the presence of CuCl P(0-z-Pr)3, Rh6(CO)16 or PdCl2 2 PhCN was plotted against that obtained with Rh2(OAc)4, a linear correlation was observed in every case, with slopes of 1.74,1.04 and 0.59, respectively (based on 22 olefins, T = 298 K) S9). These relationships as well as the results of regioselectivity studies carried out with 1,3-dienes point to the similar nature of the intermediates involved in Cu-, Rh-and Pd-catalyzed cyclopropanation. Furthermore, obvious parallels in reactivity in the transformations of Scheme 45 for a variety of catalysts based on Cu, Rh, Fe, Ru, Re and Mo suggest the conclusion that electrophilic metal carbenes are not only involved in cyclopropanation but also in ylide-forming reactions66. ... 

It is supposed that the nickel enolate intermediate 157 reacts with electrophiles rather than with protons. The successful use of trimethylsilyl-sub-stituted amines (Scheme 57) permits a new carbon-carbon bond to be formed between 157 and electrophiles such as benzaldehyde and ethyl acrylate. The adduct 158 is obtained stereoselectively only by mixing nickel tetracarbonyl, the gem-dibromocyclopropane 150, dimethyl (trimethylsilyl) amine, and an electrophile [82]. gem-Functionalization on a cyclopropane ring carbon atom is attained in this four-component coupling reaction. Phenyl trimethyl silylsulfide serves as an excellent nucleophile to yield the thiol ester, which is in sharp contrast to the formation of a complicated product mixture starting from thiols instead of the silylsulfide [81]. (Scheme 58)... 

Calculations [28] on the formation of cyclopropanes from electrophilic Fischer-type carbene complexes and alkenes suggest that this reaction does not generally proceed via metallacyclobutane intermediates. The least-energy pathway for this process starts with electrophilic addition of the carbene carbon atom to the alkene (Figure 1.9). Ring closure occurs by electrophilic attack of the second carbon atom... 

Fig. 1.9. Possible mechanism of the cyclopropanation of alkenes with electrophilic carbene complexes [28].

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). 

Calculations performed for cyclopropanation with Fischer-type carbene complexes [28] indicate that the electrophilic attack of the carbene complex at the alkene and the final ring closure are concerted. Extrapolation from this result to the C-H insertion reaction (in which a a-bond instead of a 7i-bond is cleaved) suggests that C-H bond cleavage and the formation of the new C-C and C-H bonds might also be concerted (Figure 3.38). 

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 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. 

One of the most efficient procedures for the synthesis of cyclopropanes is the reaction of alkenes with electrophilic carbene complexes. In this process up to three stereogenic centers can be generated in one step. Cyclopropanes are a key structural element encountered in many natural products with interesting biological activity. Further, by virtue of the ability of cyclopropanes to undergo ring-opening reactions these compounds can be valuable synthetic intermediates. 

Since the first experiments with chiral copper complexes reported by Nozaki [650] and Aratani [1027] many different catalysts have been examined, both for intermolecular and intramolecular cyclopropanations (for a review, see [1369]). Syntheses of natural products [955,1370] and drugs [1371] using asymmetric cyclopropanation with chiral electrophilic carbene complexes have been reported. A selection of useful catalysts is given in Figure 4.20 (see also Experimental Procedure 4.1.1). 

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). 

See in this paper the very valuable compilation of references concerning successful generation and reactions with electrophiles of metalaled unsub-stituted and substituted cyclopropanecarboxy-lates and other cyclopropane nucleophiles with electron-withdrawing substituents. 

In 1977, an article from the authors laboratories [9] reported an TiCV mediated coupling reaction of 1-alkoxy-l-siloxy-cyclopropane with aldehydes (Scheme 1), in which the intermediate formation of a titanium homoenolate (path b) was postulated instead of a then-more-likely Friedel-Crafts-like mechanism (path a). This finding some years later led to the isolation of the first stable metal homoenolate [10] that exhibits considerable nucleophilic reactivity toward (external) electrophiles. Although the metal-carbon bond in this titanium complex is essentially covalent, such titanium species underwent ready nucleophilic addition onto carbonyl compounds to give 4-hydroxy esters in good yield. Since then a number of characterizable metal homoenolates have been prepared from siloxycyclopropanes [11], The repertoire of metal homoenolate reactions now covers most of the standard reaction types ranging from simple... 

The increased reactivity of cyclopropanes results from the presence of bent bonds which can interact with electrophiles, and can be more easily cleaved thermally than ordinary C C bonds. One indication of the consequences of the distortion is found in the strain energies (SE)37 that are calculated as the difference between the observed heat of formation and that estimated for a strain-free model. One might, for example, consider cyclohexane as strain-free, and then a model for cyclopropane would be half the heat of formation for cyclohexane. The available data for heats of formation of cyclopropane and cyclobutane derivatives are given in Table 2,38 The heat of formation of cyclohexane is — 29.4 kcal/mol, and the strain energy of cyclopropane is 12.7-0.5( — 29.4) or 27.5 kcal/mol. 

The calculated energies again confirm that cyclopropane is much more easily attacked by electrophiles than is cyclobutane, and this accounts for the common observation that cyclobutanes are much less reactive toward electrophiles than are cyclopropanes, despite the similar strain energy relief for these compounds.55 The reactions of cyclopropane with other electrophiles, such as mercuric ion,65 and metal radical cations,67 have also been studied. 

This dominance of sulfur in the reactions with electrophiles is well brought out in the addition of carbenes to the-two monocycles. Tire allylic sulfide (5,6-dihydro-2jF/- thiopyran) only affords the products of reaction at sulfur, while the vinylic sulfide (3,4-dihydro-2f/-thiopyran), in which the alkene is a little more nucleophilic due to the small interaction with the heteroatom, shows dichotomous behaviour. Dichlorocarbene affords the cyclopropane product (78) in 70% yield, but the stabilized ylide (76) is produced from bismethoxycar-bonylmethylide and (75). In fact it is possible that the initial reaction with dichlorocarbene is reaction at sulfur and subsequent rearrangement of this less stabilized ylide. Schemes 6 and 7 illustrate the results and proposed mechanisms (77JOC3365,64JOC2211). 

Reviews have featured epoxidation, cyclopropanation, aziridination, olefination, and rearrangement reactions of asymmetric ylides 66 non-phosphorus stabilized carbanions in alkene synthesis 67 phosphorus ylides and related compounds 68 the Wittig reaction 69,70 and [2,3]-Wittig rearrangement of a-phosphonylated sulfonium and ammonium ylides.71 Reactions of carbanions with electrophilic reagents, including alkylation and Wittig-Homer olefination reactions, have been discussed with reference to Hammett per correlations.72... 

The cyclopropyl effect has controlled the regioselectivity of the cross-coupling reactions of propargylic/allenylic metallic species with electrophiles afford alkynic cyclopropanes (Scheme 9).70 Cyclopropyl ring strain, which makes the formation of vinylidenecyclopropanes unfavourable, is believed to control the regioselectivity. 

An extension of the synthetic applicability of lithium halomethanes is achieved by the simultanous presence of another main group heteroatom at the same carbon. Thus, if one of the chlorine atoms of dichloromethyllithium is replaced by a sulfonylamin group, the following products are obtained by reaction with electrophiles (Eq. (23)) 25). The substituted carbenoid can be converted to normal carbonyl adducts as well as to olefins and cyclopropanes. 

---