Cyclopropanes, from carbene additions

Carbene addition occurs in a syn fashion from either side of the planar double bond. The relative position of substituents in the alkene reactant is retained in the cyclopropane product. Carbene addition is thus a stereospecific reaction, since cis and trans alkenes yield different stereoisomers as products, as illustrated in Sample Problem 26.4. 

Among the methods at hand to synthesize cyclopropane derivatives, carbene addition to alkenes plays a prominent role 63). As a source of vinylcarbenes, cyclopropenes might be useful in this kind of approach. In 1963, Stechl was the first to observe a transition metal catalyzed cyclopropene-vinylcarbene rearrangement64). When treating 1,3,3-trimethylcyclopropene with copper salts, dimerization occurred to give 2,3,6,7-tetramethyl-octa-2,4,6-triene (9), the product from a formal recombination of the corresponding vinylcarbene (Eq. 8). 

The product of thermal isomerization of this cyclopropane, dimethyl (l-naphthyl)malonate, was also formed (5-10%), together withtetramethyl2,3-benzo-ant -tricyclo[5.1.0.0 ]oct-2-ene-5,5,8,8-tetracarb-oxylate (5-15%) and dimethyl 377-benzocycloheptatriene-3,3-dicarboxylate (5-10%) which is likely to arise from an intermediate cyclopropane arising from carbene addition to the 2,3-bond of naphthalene. 

The majority of preparative methods which have been used for obtaining cyclopropane derivatives involve carbene addition to an olefmic bond, if acetylenes are used in the reaction, cyclopropenes are obtained. Heteroatom-substituted or vinyl cydopropanes come from alkenyl bromides or enol acetates (A. de Meijere, 1979 E. J. Corey, 1975 B E. Wenkert, 1970 A). The carbenes needed for cyclopropane syntheses can be obtained in situ by a-elimination of hydrogen halides with strong bases (R. Kdstcr, 1971 E.J. Corey, 1975 B), by copper catalyzed decomposition of diazo compounds (E. Wenkert, 1970 A S.D. Burke, 1979 N.J. Turro, 1966), or by reductive elimination of iodine from gem-diiodides (J. Nishimura, 1969 D. Wen-disch, 1971 J.M. Denis, 1972 H.E. Simmons, 1973 C. Girard, 1974),... 

By application of the Simmons-Smith reaction it is possible to synthesize a cyclopropane from an alkene by formal addition of carbene to the carbon-carbon double bond, without a free carbene being present in the reaction mixture the... 

More useful for synthetic purposes, however, is the combination of the zinc-copper couple with methylene iodide to generate carbene-zinc iodide complex, which undergoes addition to double bonds exclusively to form cyclopropanes (7). The base-catalyzed generation of halocarbenes from haloforms (2) also provides a general route to 1,1-dihalocyclopropanes via carbene addition, as does the nonbasic generation of dihalocarbenes from phenyl(trihalomethyl)mercury compounds. Details of these reactions are given below. 

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... 

Chiral Rh(II) oxazolidinones Rh2(BNOX)4 and Rh2(IPOX)4 (25a,b) were not as effective as Rh2(MEPY)4 for enantioselective intramolecular cyclopropanation, even though the steric bulk of their chiral ligand attachments (COOMe versus i-Pr or CH2Ph) are similar. Significantly lower yields and lower enantioselectivides resulted from dinitrogen extrusion from prenyl diazoacetate catalyzed by either Rh2(4.S -lPOX)4 or Rh2(4S-BNOX)4. This difference, and those associated with butenolide formation [91], can be attributed to the ability of the carboxylate substituents to stabilize the carbocation form of the intermediate metal carbene (3b), thus limiting the Rh2(MEPY)4-catalyzed reaction to concerted carbene addition onto both carbon atoms of the C-C double bond. 

Additions of bromofluorocarbenes to 6-phenylbicyclo[3.2.0]hept-6-ene (72) have been shown to yield a mixture of various indanes (73), which probably arise from the formal ring expansion (cyclopropanation-ring opening) of (74) and (75), themselves coming from ring opening of the cyclopropane obtained by addition of the carbene to (72).59... 

Insight into the nature of the intermediate in the cyclopropanation of electron-rich and electron-poor alkenes was given by laser flash photolysis (LFP) studies of phenyl-bromodiazirine in the presence of various amounts of tetrabutylammonium bromide.23 Electron-rich alkenes react exclusively with the carbene (11) leading to (12). Electron-poor alkenes yield cyclopropanes (13) only slowly with the carbene (11) and more rapidly with the carbanion (14) arising from the addition of the bromide to the carbene. 

A few specific examples of cyclopropanation using the above methods are shown in Scheme 2.134. The naturally occurring insecticide /ra -chrisanthemic acid 396 served as an obvious target to check the viability of carbene addition as a preparative method. This compound was first synthesized (in the mixture with the cis isomer) by the monocyclopropanation of 2,5-dimethyl-2,4-hexadiene. Since then, numerous analogs of 396 were prepared by similar reactions. Some of the analogs are now widely used as efficient and ecologically safe pesticides. The formation of the tricyclic hydrocarbon 397 from 1,5-hexadiene proceeds as a sequence of inter- and intramolecular carbene transfer reactions. An initial carbene precursor, CHBr3, is actually employed here as an equivalent of a unique tetradentate Ci synthon The preparation of 398 via intramolecular [2 + 1] photocycloaddition is a typical example of the efficiency of this route for the construction of the polycyclic framework frequently encountered in the structures of natural compounds. 

A sequence of carbene additions to methylenetriangulanes can be used to build branched triangulanes. i - 3 3 When chloro(methyl)carbene generated from 1,1 -dichloroethane with butyl-lithium is used, new exocyclic double bonds for further cyclopropanation reactions can be generated by HCl elimination. For the same purpose l,l-dichloro-3-methoxypropane... 

Silver complexes have also been described for the cyclopropanation reaction. When using benzene, the use of Tp Ag(thf) (where Tp "" =hydrotris(3, 5-bis(trisfluoromethyl)pyrazolyl)borate for the rules of nomenclature of Tp" ligands see reE ) provided products derived from the addition of the carbene moiety to the arene ring (Scheme 7a), followed by ring expansion into a cycloheptatriene, in the... 

Until the last decade, product studies formed the main evidence for carbene formation singlet carbenes formed cyclopropanes from alkenes stereospecifically, while triplet carbenes formed cyclopropanes non-stereospecifically. Formation of a cyclopropane (though not by addition to an alkene) via a carbocation route was demonstrated and, more recently, it has been shown that p values for insertion-addition selectivity and for cyclopropanation stereoselectivity vary as to photochemical or thermal generation of the carbene. The authors of this latter study suggest that a ground state diazo compound could be masquerading as a carbene in its thermal reaction with olefins, possibly by electrocyclic... 

In the vapor phase, there are two additional considerations that are very important in understanding of carbene chemistry. The first point reflects the fact that carbene reactions are normally highly exothermic (about 90kcal mol for insertions or additions). Thus, a product molecule is frequently produced with a large amount of excess internal energy. In the vapor phase without solvent molecules to help dissipate the excess vibrational energy, the molecule may be subject to further reactions. Such reactions are often called hot molecule reactions. Cyclopropanes from cycloaddition reactions are particularly susceptible to hot molecule decomposition to the thermodynamically more stable olefin, since for cyclopropane isomerization is only 64kcal mol . ... 

Method using Base and a Substituted Halogenomethane. The influence of catalyst anions (as their tetrabutylammonium salts) and cations (as chlorides or bromides) on the generation of dichlorocarbene from chloroform-sodium hydroxide has been studied under standard conditions by determining the yield of dichloronorcarane produced from the addition of the carbene to cyclohexene. The presence of olefin appears to be necessary since in its absence only very slow decomposition of the trichloromethyl anion occurs. Dehmlow has also devised a new procedure for phase-transfer-catalysed cyclopropanation. Treatment of an alkene (or cycloalkene) with sodium trichloroacetate and a tetra-alkylammonium salt in chloroform without... 

The mononuclear complex 13 was also employed for carbene transfer reactions from ethyl diazoacetate (EDA) in a range of reactions that led to the alkenation of aldehydes, cyclopropanation, and carbene insertion into N—H and O—H bonds [32]. The complex proved particularly adept at the last process, especially aromatic amines and aliphatic alcohols. Addition of the PIN ligand (l-isopropyl-3-(5,7-dimethyl-l,8-naphthyrid-2-yl)imidazol-2-ylidene) to [Ru2(CO)4(OAc)2], foUowed by treatment with Na[BAr 4] gave the dinuclear complex [Ru2(PIN)2(CO)4][[BAr 4] 2, which showed some improved reactivity compared to 13, particularly in the transfer of CH(C02Et) to aldehydes [109]. 

The Puddephatt-Tipper team " have shown that reductive elimination involving the formation of cyclopropanes from platinacyclopropanes appears to involve a concerted process rather than the production of carbene-alkene intermediates (as does also the oxidative addition involving the reverse reaction, and the skeletal isomerization of platinacyclopropanes). They " have also proposed a similar concerted behavior for a reaction which could be looked upon either as a reductive elimination or a substitution, namely, the overall process in equation (46). 

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