Electrophilic cyclopropanes chemistry

The discovery of carbene and carbenoid additions to olefins was the major breakthrough that initiated the tapping of this structural resource for synthetic purposes. Even so, designed applications of cyclopropane chemistry in total syntheses remain limited. Most revolve around electrophilic type reactions such as acid induced ring opening or solvolysis of cyclopropyl carbinyl alcohol derivatives. One notable application apart from these electrophilic reactions is the excellent synthesis of allenes from dibromocyclopropanes 2). 

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]. 

Metal catalysed decomposition of diazocarbonyl compounds in the presence of alkenes provides a facile and powerful means of constructing electrophilic cyclopropanes. The cyclopropanation process can proceed intermolecularly or intramolecularly. Early work on the topic of intramolecular cyclopropanation (mainly using diazoketones as precursors) has been surveyed31. With the discovery of powerful group VIII metal catalysts, in particular the rhodium(II) derivatives, metal catalysed cyclopropanation of diazocarbonyls is currently the most fertile area in cyclopropyl chemistry. In this section, we will review the efficiency and versatility of the various catalysts employed in the cyclopropanation of diazocarbonyls. Cyclopropanations have been organized according to the types of diazocarbonyl precursors. Emphasis is placed on recent examples. 

It is the hope of the authors that the compilation of the results gained hitherto in the field of electrophilic cyclopropanes will stimulate further interest in this area. The numerous reactions described in this survey article are an indication of the potential of the title compounds in organic chemistry. Their utility has already been demonstrated in various domains, including natural product synthesis, selective transformations, ring expansions, etc. However, only the basic chemistry of the electrophilic cyclopropanes has been unraveled and results originating from the application of new and modern selective reagents will certainly broaden the scope of its possibilities. 

R. Verhe and N. de Kimpe, in Z. Rappoport, ed.. Synthesis and Reactivity of Electrophilic Cyclopropanes (The Chemistry of the Cyclopropyl Group, Vol. 1, Part 1), John Wiley Sons, Inc., Chichester, UK, 1987, Chapt. 9. 

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... 

The organometallic chemistry of alkynylcyclopropanes involves primarily the formation and reactions of carbon-metal er-bonds. Metals come essentially from the main group elements, with lithium playing a major role. The two metallation sites are the cyclopropyl and the acetylenic positions, which are expected to differ considerably in their acidity values (t-butylacetylene, pKa = 25230, cyclopropane, pKa = 46183) but less in the reactivity of their metal conjugated bases towards electrophiles. 

An excellent review by Paquette who developed much of the silylcyclopropane chemistry, gives a first insight into this field. Strong electrophiles cleave silyl-substituted cyclopropanes, but regioselectivity problems diminish the synthetic practicability ... 

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). 

Since they are equivalent to homobutadienes, cyclopropanes interacting directly with an olefin unit display a particularly rich chemistry. Pericyclic reactions come into play in this specific area. Similar to other cyclopropane derivatives, the reactivity of vinylcyclopro-panes with nucleophiles, electrophiles and radicals as well as their general chemical behaviour will be governed by substituents at the cyclopropane core and at the double bond. ... 

Another application of rhodium carbenoid chemistry relates to the synthesis of strained-ring nitro compounds as high energy-density materials. Nitrocyclo-propanes are the simplest members of this class of compounds and catalyzed additions of a nitrocarbene to an olefin have only been described recently [40], Detailed studies have shown that the success of the reaction is, as expected, dependent on both the alkene and the nitrodiazo precursor. Consistently with the electrophilic character of rhodium carbenoids, only electron-rich alkenes are cyclopropanated. The reaction has been extended to the synthesis of nitrocyclo-propenes but the yields are good for terminal acetylenes only [41]. 

On the other hand, there have been hardly any kinetic investigations of the many reactions that have proven to be among the most useful or unique applications of Fischer carbene complex chemistry. Hence they are not part of this chapter although a few of the most prominent ones need to be mentioned. They include cyclopropanation of electrophilic olefins (e.g., equation 5), metathesis (e.g., equation 6) and reactions of a,j8-unsaturated carbene complexes such as 6 (see equation 3) that lead to what de Meijere et al have called an... 

Transient carbenes display a rich and diverse chemistry as stoichiometric reagents, for example, in reactions such as olefin cyclopropanation, C-H insertion, dimerization, 1,2-migration, and so on. Carbenes are important in several synthetic methods and are growing in importance, especially the intramolecular versions. Carbenes are electron deficient, and unless strong resonance interaction is possible the reactions will be electrophilic. The chemical behavior of a carbene depends to some extent on its method of preparation, electronic state, and also on the presence or absence of certain metals or metallic salts. The state in which the carbene is produced depends on the method of generation, that is, singlets... 

Protonated cyclopropane has been reported in the gas phase" "" to be ca 8 kcal mol" in energy above the isopropyl cation. The bent bonds of the cyclopropane ring are susceptible to electrophilic attack leading to the expectation that cyclopropane will be more basic than saturated alkanes and that protonation will occur on the C—C bond, i.e. the edge-protonated isomer will have the lowest energy. There is, however, considerable evidence from solution chemistry that corner-protonated cyclopropanes exist as intermediates in 1,2-alkyl shifts in carbocations. There have been several reviews of protonated cyclopropanes " and, in the current work, only the very recent theoretical work will be reviewed. 

Saners, R. R. A natural bond orbital analysis of carbanions (2012). Computational and Theoretical Chemistry, 999,43. Apeloig, Y., Kami, M., Rappoport, Z. (1983). Nncleophibc attacks on carbon-carbon double bonds. Part 29. Role of hyperconjugation in determining the stereochemistry of nucleophilic epoxidation and cyclopropanation of electrophilic olefins. Journal of the American Chemical Society, 105(9), 2784—2793. 

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