Cyclopropanes from carbenoids

Carbenoid sources other than those derived from diazo precursors for catalytic cyclopropanation reactions are currently limited. Inter- and intramolecular catalytic cyclopropanation using iodonium ylide have been reported. Simple olefins react with iodonium ylides of the type shown in equations 83 and 84, catalysed by copper catalysts, to give cyclopropane adducts in moderate yield127 128. In contrast to the intermolecular cyclopropanation, intramolecular cyclopropanation using iodonium ylides affords high yields of products (equations 85 and 86). The key intermediate 88 for the 3,5-cyclovitamin D ring A synthon 89 was prepared in 80% yield as a diastereomeric mixture (70 30) via intramolecular cyclopropanation from iodonium ylide 87 (equation 87)1 0. 

The Simmons-Smith reaction is a powerful method for preparing cyclopropanes from olefins using zinc carbenoids (IZnCH2I, EtZnCH2I, Zn(CH2X)2).7a,278,278a A variety of versions of this reaction have been developed and new carbenoids species have been made. For recent reviews, see Ref 279 and 279a. 

Other complementary methodologies include the preparation of substituted cyclopropanes from glycals using rhodium acetate carbenoid additions [65,66]. Additionally, acid catalyzed cyclopropane opening reactions in alcoholic solutions afford the 2-C-branched-glycosides. These combined reactions were used to prepare a key intermediate in marine diterpene norrisolide synthesis from D-mannose [67]. 

Intramolecular carbenoid reactions of diazo compounds have been limited to the formation of only a few silicon-substituted cyclopropanes from unsaturated silicon-substituted diazo compounds. 

When diazoalkanes arc employed as the source for carbenoids. strained, bicyclic, or polycyclic olefins are preferentially cyclopropanated from the sterically less crowded side many examples are collected in Vol. E19b, pp 280-291. For bicyclo[2.2.11heptene (norbornenc) and related compounds the usual exo selectivity is observed. The example with diazoethane1(1 again demonstrates that simple diastcreoselectivity is hard to achieve in these transformations. 

In Summary Diazomethane is a useful synthetic intermediate as a methylene source for forming cyclopropanes from alkenes. Halogenated carbenes, which are formed by dehydro-halogenation of halomethanes, and the Simmons-Smith reagent, a carbenoid arising from the reaction of diiodomethane with zinc, also convert alkenes into cyclopropanes. Additions of carbenes to alkenes differ from other addition processes because a single carbon atom becomes bonded to both alkene carbons. 

Carbenes and carbenoids are useful for the synthesis of cyclopropanes from alkenes. 

The reaction of carbenes or carbenoids with olefins to form cyclopropanes represents the most prominent example for [2+1] cycloaddition reactions. Formation of cyclopropanes from intermediate (carbene)iron complexes has been first observed by Pettit et al. by treating a methoxymethyliron complex with tetrafluoroboric acid. Later on reagents containing stoichiometric amounts of iron complexes have been developed to achieve cyclopropanation of olefins (cf. Section 2.2.4.b). Such reagents are (carbene)iron complexes or appropriate precursors forming these complexes in situ. The first catalyti-cally active iron-containing carbene transfer complex has been described by Hossein et al. in the form of [(Cp)Fe(CO)2(THF)] BF4. It allows the formation of cyclopropanes by reaction of ethyl diazoacetate with styrene or a-methylstyrene (Scheme 4-296). 

Diastereoselective Cyclopropanations with Carbenoids Generated from Diazoalkanes... 

From a historical perspective it is interesting to note that the Nozaki experiment was, in fact, a mechanistic probe to establish the intermediacy of a copper carbe-noid complex rather than an attempt to make enantiopure compounds for synthetic purposes. To achieve synthetically useful selectivities would require an extensive exploration of metals, ligands and reaction conditions along with a deeper understanding of the reaction mechanism. Modern methods for asymmetric cyclopropanation now encompass the use of countless metal complexes [2], but for the most part, the importance of diazoacetates as the carbenoid precursors still dominates the design of new catalytic systems. Highly effective catalysts developed in... 

For a reaction as complex as catalytic enantioselective cyclopropanation with zinc carbenoids, there are many experimental variables that influence the rate, yield and selectivity of the process. From an empirical point of view, it is important to identify the optimal combination of variables that affords the best results. From a mechanistic point of view, a great deal of valuable information can be gleaned from the response of a complex reaction system to changes in, inter alia, stoichiometry, addition order, solvent, temperature etc. Each of these features provides some insight into how the reagents and substrates interact with the catalyst or even what is the true nature of the catalytic species. 

Esters of a-diazoalkylphosphonic acids (95) show considerable thermal stability but react with acids, dienophiles, and triphenylphosphine to give the expected products. With olefinic compounds in the presence of copper they give cyclopropane derivatives (96), but with no such compounds present vinylphosphonic esters are formed by 1,2-hydrogen shift, or, when this route is not available, products such as (97) or (98) are formed, resulting from insertion of a carbenoid intermediate into C—C or C—H bonds. The related phosphonyl (and phosphoryl) azides (99) add to electron-rich alkynes to give 1,2,3-triazoles, from which the phosphoryl group is readily removed by hydrolysis. 

Copper(II) triflate has also been used for the carbenoid cyclopropanation reaction of simple olefins like cyclohexene, 2-methylpropene, cis- or rran.y-2-butene and norbomene with vinyldiazomethane 2 26,27). Although the yields were low (20-38 %), this catalyst is far superior to other copper salts and chelates except for copper(II) hexafluoroacetylaeetonate [Cu(hfacac)2], which exhibits similar efficiency. However, highly nucleophilic vinyl ethers, such as dihydropyran and dihydrofuran cannot be cyclopropanated as they rapidly polymerize on contact with Cu(OTf)2. With these substrates, copper(II) trifluoroacetate or copper(II) hexafluoroacetylaeetonate have to be used. The vinylcyclopropanation is stereospecific with cis- and rra s-2-butene. The 7-vinylbicyclo[4.1.0]heptanes formed from cyclohexene are obtained with the same exo/endo ratio in both the Cu(OTf)2 and Cu(hfacac)2 catalyzed reaction. The... 

Diazomethane is also decomposed by N O)40 -43 and Pd(0) complexes43 . Electron-poor alkenes such as methyl acrylate are cyclopropanated efficiently with Ni(0) catalysts, whereas with Pd(0) yields were much lower (Scheme 1)43). Cyclopropanes derived from styrene, cyclohexene or 1-hexene were formed only in trace yields. In the uncatalyzed reaction between diazomethane and methyl acrylate, methyl 2-pyrazoline-3-carboxylate and methyl crotonate are formed competitively, but the yield of the latter can be largely reduced by adding an appropriate amount of catalyst. It has been verified that cyclopropane formation does not result from metal-catalyzed ring contraction of the 2-pyrazoline, Instead, a nickel(0)-carbene complex is assumed to be involved in the direct cyclopropanation of the olefin. The preference of such an intermediate for an electron-poor alkene is in agreement with the view that nickel carbenoids are nucleophilic 44). 

Only a few results are available concerning competitive cyclopropanation of non-conjugated dienes. The case of 1,4-hexadiene72 (mixture of Z and E isomers) illustrates the reactivity difference between a monosubstituted and a 1,2-disubstituted double bond, whereas in limonene (24)47, a 1,1-disubstituted and a trisubstituted double bond compete for the carbenoid derived from ethyl diazoacetate. In both cases, the less substituted double bond reacts preferentially (Scheme 8). 

The preference for the less substituted double bond also determines the outcome of the copper-catalyzed cyclopropanation of isotetraline with dimethyl diazomalonate which gives 27 and its dehydrogenated relative 2883) the same behavior of the carbenoid derived from ethyl diazoacetate has been reported 84). 

Cyclopropanation of C=C bonds by carbenoids derived from diazoesters usually occurs stereospeciflcally with respect to the configuration of the olefin. This has been confirmed for cyclopropanation with copper 2S,S7,60 85), palladium 86), and rhodium catalysts S9,87>. However, cyclopropanation of c -D2-styrene with ethyl diazoacetate in the presence of a (l,2-dioximato)cobalt(II) complex occurs with considerable geometrical isomerization88). Furthermore, CuCl-catalyzed cyclopropanation of cis-2-butene with co-diazoacetophenone gives a mixture of the cis- and trans-1,2-dimethylcyclopropanes 89). 

Diverging results have been reported for the carbenoid reaction between alkyl diazoacetates and silyl enol ethers 49a-c. Whereas Reissig and coworkers 60) observed successful cyclopropanation with methyl diazoacetate/Cu(acac)2, Le Goaller and Pierre, in a note without experimental details u8), reported the isolation of 4-oxo-carboxylic esters for the copper-catalyzed decomposition of ethyl diazoacetate. According to this communication, both cyclopropane and ring-opened y-keto ester are obtained from 49 c but the cyclopropane suffers ring-opening under the reaction conditions. 

Simultaneous occurence of the pyrazoline and carbenoid route is observed in the presence of bis(campherquinone-a-dioximato)cobalt(II) 95), but the cyclopropanes derived from ethyl diazoacetate and H2C=CHX (X = COOMe, CN) were obtained only in low yield. 

EvenPd(OAc)2 is not effective in catalyzing the cyclopropanation of a,P-unsaturated nitriles by ethyl diazoacetate. Instead, vinyloxazoles 92 are formed from acrylonitrile or methacrylonitrile by carbenoid addition to the CsN bond 143 Diethyl maleate and diethyl fumarate as well as polyketocarbenes are by-products in these reactions the 2-pyrazoline which would result from initial [3 + 2] cycloaddition at the C=C bond and which is the sole product of the uncatalyzed reaction at room temperature, can be avoided completely by very slow addition of the diazoester... 

In contrast to ethyl diazoacetate, diethyl diazomalonate reacts with allyl bromide in the presence of Rh2(OAc)4 to give the ylide-derived diester favored by far over the cyclopropane (at 60 °C 93 7 ratio). This finding bespeaks the greater electrophilic selectivity of the carbenoid derived from ethyl diazomalonate. For reasons unknown, this property is not expressed, however, in the reaction with allyl chloride, as the carbenoids from both ethyl diazoacetate and diethyl diazomalonate exhibit a similarly high preference for cyclopropanation. 

Copper chelates in which the ligands are rigid chiral p-diketonates of type 205 are responsible for the highest optical yields known in carbenoid cyclopropanation reactions 200). The cyclopropane 206 was even obtained enantiomerically pure from 2-diazodimedone and styrene in the presence of CuL (L = 205c). 

Use of a chiral diazo ester proved less rewarding in terms of enantioselective cyclopropanation. Only very low enantiomeric excesses were obtained when styrene was cyclopropanated with the carbenoid derived from diazoacetic esters 219 bearing a chiral ester residue 214). 

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