Cyclopropanes from carbenes + alkenes

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... 

An example of double carbon-carbon bond formation in an asymmetric synthesis has been developed by Nakamura et al in an interesting paper on the use of an optically active cobalt reagent for producing cyclopropanes from carbenes and alkenes. For example the cyclopropane (51) was prepared in 70% optical yield in this work. Finally, asymmetric syntheses have been achieved photochemically in chiral crystals (cyclobutanes), and in a chiral solvent (heli-cenes). ... 

Addition reactions with alkenes to form cyclopropanes are the most studied reactions of carbenes, both from the point of view of understanding mechanisms and for synthetic applications. A concerted mechanism is possible for singlet carbenes. As a result, the stereochemistry present in the alkene is retained in the cyclopropane. With triplet carbenes, an intermediate 1,3-diradical is involved. Closure to cyclopropane requires spin inversion. The rate of spin inversion is slow relative to rotation about single bonds, so mixtures of the two possible stereoisomers are obtained from either alkene stereoisomer. 

Furthermore, Rhg(CO)16, which can be used advantageously for cyclopropanation of more electron-rich alkenes, furnished only insignificant amounts of cyclopropane from acrylonitrile or ethyl acrylate and ethyl diazoacetate from methacrylonitrile and ethyl diazoacetate, equally low yields of vinyloxazole, cyclopropane and carbene dimers resulted (Scheme 20)145). The use of Rh2(OAc)4 or [Rh(CO)2Cl]2 as catalysts did not change this situation. 

The generation of the dichloromethane under phase-transfer conditions may be facilitated by the addition of a trace of ethanol. Alkoxide anions, generated under the basic conditions, are more readily transferred across the two-phase interface than are hydroxide ions (see Chapter 1). Although this process may result in the increased solvolysis of the chloroform, it also produces a higher concentration of the carbene in the organic phase and thereby increases the rate of formation of the cyclopropane derivatives from reactive alkenes. 

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... 

These carbene (or alkylidene) complexes are used as either stoichiometric reagents or catalysts for various transformations which are different from those of free carbenes. Reactions involving the carbene complexes of W, Mo, Cr, Re, Ru, Rh, Pd, Ti and Zr are known. Carbene complexes undergo the following transformations (i) alkene metathesis (ii) alkene cyclopropanation (iii) carbonyl alkenation (iv) insertion to C—H, N—H and O—H bonds (v) ylide formation and (vi) dimerization. Their chemoselectivity depends mainly on the metal species and ligands, as discussed in the following sections. 

Optically active metal complexes have been recognized as excellent catalysts for the enantioselective cyclopropanation of carbenes with alkenes. Normally, diazo compounds react under metal catalysts in the dark to afford carbenoid complexes as key intermediates. Katsuki et al. have reported the ds-selective and enantioselective cyclopropanation of styrene with a-diazoacetate in the presence of optically active (R,R)-(NO + )(salen)ruthenium complex 80, supported under illumination (440 nm light or an incandescent bulb) [59]. The irradiation causes dissociation of the apical ligand ON + in 80, and thus avoids the splitting of nitrogen from the a-diazoacetate. 

Intramolecular cyclopropanations of pendant alkenes are more favorable. Heteroatom-substituted 2-aza- and 2-oxabicyclo[3.1.0]hexanes, together with 2-oxabicyclo[4.1.0] heptanes, can be prepared from chromium and tungsten Fischer carbenes having a tethered alkene chain. An interesting carbene formation via a cationic alkylidene intermediate, nucleophilic addition (see Nucleophilic Addition Rules for Predicting Direction), and intramolecular cyclopropanation is shown in Scheme 59. An intramolecular cyclopropanation via reaction of alkenyl Fischer carbene complex (28) andpropyne was used in a formal synthesis of carabrone (Scheme 60). 

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). 

Generation of Alkyl and Cycloalkyl Carbenes - Photolysis or thermolysis of a series of alkylchlorodiazirines (16) (Scheme 7) in the presence of alkenes, such as tetramethylethene, results in 1,2-H shifts, giving the corresponding vinyl chorides (18), in competition with additions of the carbenes (17) to the alkenes, yielding cyclopropanes (19). The mechanism of these reactions is discussed in the light of results obtained from photoacoustic calorimetry, and the ratio of vinyl chloride to cyclopropane seems to depend on the excited states of the carbene precursors and also on carbene-alkene complexes. Similar reactions of related diazirines have been investigated by flash photolysis. 

The catalytic activity of low-valent ruthenium species in carbene-transfer reactions is only beginning to emerge. The ruthenium(O) cluster RujCCO), catalyzed formation of ethyl 2-butyloxycyclopropane-l-carboxylate from ethyl diazoacetate and butyl vinyl ether (65 °C, excess of alkene, 0.5 mol% of catalyst yield 65%), but seems not to have been further utilized. The ruthenacarborane clusters 6 and 7 as well as the polymeric diacetatotetracarbonyl-diruthenium (8) have catalytic activity comparable to that of rhodium(II) carboxylates for the cyclopropanation of simple alkenes, cycloalkenes, 1,3-dienes, enol ethers, and styrene with diazoacetic esters. Catalyst 8 also proved exceptionally suitable for the cyclopropanation using a-diazo-a-trialkylsilylacetic esters. ... 

Historically, potassium /er/-butoxide was the first base used for the preparation of 1,1-dibromo-cyclopropanes from bromoform and an alkene. Since generation and cycloaddition of dibromo-carbene to alkenes proceeds rapidly, this method is still in laboratory practice. 

The base-induced monodehydrochlorination reaction was originally introduced as the second step of a convenient two-step synthesis of methylenecyclopropanes from alkenes. The first step involves carbene-type cyclopropanation of the alkene with a 1,1-dichloroalkane and either butyllithium or sodium bishexamethyldisilazanide as the base. The dehydrochlorination is then carried out by reacting the intermediate 1-alkyl-1-chlorocyclopropane with potassium tert-butoxide in dimethyl sulfoxide. For ordinary unhindered chlorocyclopropanes this procedure gives from about 60% to nearly quantitative yields of products (Table 1). The ready availability of the starting materials and reagents makes the base-induced dehydrochlorination a most useful 1,2-elimination reaction for preparation of methylenecyclopropanes. The procedure is illustrated by the synthesis of l,l-dimethyl-2-methylenecyclopropane (3) from 2-methylpropene ( ) ... 

Cyclopropanation from alkenes and carbenes with alkyl gem dihalides and Zn-Cu couple (Simmons-Smith) or Et2Zn (Furukawa) EtgAI (Yamamoto) or Sm (Molander) with high diastereoselectivity (see 1st edition). 

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... 

Some alternative species are encountered that also make cyclopropanes from alkenes these are called car-benoids because they act like carbenes without actually being carbenes. Like carbenes they contain a special carbon atom capable of reacting as an electrophile with the tt bond of the alkene to form one carbon-carbon bond and also supplying an electron pair to form a second carbon-carbon bond. 

Simmons-Smith reaction Areactionin which a cyclopropane ring is produced from an alkene. It uses the Simmons-Smlth recent, which was originally diiodo-methane (CH2I2) with aZn/Cu couple. Usually, diethyl zinc is used rather than Zn/Cu. The mechanism involves the formation of H2C(I) (Znl) and carbene transfer from the zinc to the double bond of the alkene. 

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 formation of cyclopropanes from o(,P-unsaturated esters occurs under conditions at least as severe as those employed in the phosphine substitution and CO exchange reactions of carbene complexes. Coordinatively unsaturated carbene complexes are therefore reasonable intermediates for these reactions. Complexation of an alkene to the metal complex provides a means of bringing the carbene and alkene ligands into close proximity. Formation of a metallocyclobutane and reductive elimination of a cyclopropane complete our suggested mechanism (see Scheme 8). 

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