Cyclopropanation using diazoalkanes

The limitations of cyclopropanation with diazoalkanes are mainly determined by the nature of the latter, which are hazardous to handle. The use of isolated diazoalkanes is confined to small-scale laboratory applications. 

Palladium(II) compounds have unique characteristics suitable for efficient catalysed cyclopropanation of electron-deficient alkenes using diazoalkanes. Neither copper nor rhodium(II) catalysts have shown comparable reactivity with diazoalkanes, although these catalysts are superior to palladium(II) catalysts for cyclopropanation with diazocarbonyl compounds. A few examples of palladium(II) catalysed cyclopropanation of a,fl-unsaturated carbonyl compounds with diazoalkanes are shown in equations 20-242 °. 

The copper-catalyzed cyclopropanation of alkenes with diazoalkanes is a particularly important synthetic reaction (277). The reaction of styrene and ethyl diazoacetate catalyzed by bis[/V-(7 )- or (5)-a-phenyl-ethylsalicylaldiminato]Cu(II), reported in 1966, gives the cyclopropane adducts in less than 10% ee and was the first example of transition metal-catalyzed enantioselective reaction of prochiral compounds in homogeneous phase (Scheme 90) (272). Later systematic screening of the chiral Schiff base-Cu catalysts resulted in the innovative synthesis of a series of important cyclopropane derivatives such as chrysanthemic acid, which was produced in greater than 90% ee (Scheme 90) (273). The catalyst precursor has a dimeric Cu(II) structure, but the actual catalyst is in the Cu(I) oxidation state (274). (S)-2,2-Dimethylcyclopropanecar-boxylic acid thus formed is now used for commercial synthesis of ci-lastatin, an excellent inhibitor of dehydropeptidase-I that increases the in vivo stability of the caibapenem antibiotic imipenem (Sumitomo Chemical Co. and Merck Sharp Dohme Co.). Attempted enantioselective cyclopropanation using 1,1-diphenylethylene and ethyl diazoacetate has met with limited success (211b). A related Schiff base ligand achieved the best result, 66% optical yield, in the reaction of 1,1-diphenylethylene and ethyl diazoacetate (275). 

Scheme 9.18 Cyclopropanation of dienylboronate using diazoalkanes in the presence of palladium acetate.

A mechanism involving enantioface selective olefin attack upon transient chiral cobalt carbene complexes formed from prochiral diazoalkanes has been proposed to account for the high degree of enantioselectivity observed in cobalt-(ii) catalysed olefin cyclopropanation using chiral diazoalkanes. ... 

Cyclopropanation by diazoalkane in the presence or absence of transition metal catalysts is widely used in organic synthesis [107]. The recent explosion of research reports has enabled many types of formation of cyclopropanes in a diastereo- and enantioselective manner. The most commonly used transition metals are iliodium, copper, and mthenium however, oflier metals, such as palladium and cobalt, are also used. It may not be possible to report all of the results in this chapter, because numerous papers have been published so far. We selected recent representative examples. 

Rhodium porphyrin 156 was also a useful catalyst for cyclopropanation with diazoalkanes. Fumta and coworkers reported that N-confused rhodium porphyrin served as a good catalyst for the cyclopropanation (Scheme 1.74) [119]. frawi-Cyclopropane 157 was produced predominantly. 

Catalytic cyclopropanation of alkenes has been reported by the use of diazoalkanes and electron-rich olefins in the presence of catalytic amounts of pentacarbonyl(rj2-ris-cyclooctene)chromium [23a,b] (Scheme 6) and by treatment of conjugated ene-yne ketone derivatives with different alkyl- and donor-substituted alkenes in the presence of a catalytic amount of pentacarbon-ylchromium tetrahydrofuran complex [23c]. These [2S+1C] cycloaddition reactions catalysed by a Cr(0) complex proceed at room temperature and involve the formation of a non-heteroatom-stabilised carbene complex as intermediate. 

The transition metal-catalyzed cyclopropanation of alkenes is one of the most efficient methods for the preparation of cyclopropanes. In 1959 Dull and Abend reported [617] their finding that treatment of ketene diethylacetal with diazomethane in the presence of catalytic amounts of copper(I) bromide leads to the formation of cyclopropanone diethylacetal. The same year Wittig described the cyclopropanation of cyclohexene with diazomethane and zinc(II) iodide [494]. Since then many variations and improvements of this reaction have been reported. Today a large number of transition metal complexes are known which react with diazoalkanes or other carbene precursors to yield intermediates capable of cyclopropanating olefins (Figure 3.32). However, from the commonly used catalysts of this type (rhodium(II) or palladium(II) carboxylates, copper salts) no carbene complexes have yet been identified spectroscopically. 

Diazoalkanes are the carbene complex precursors most commonly used for the catalytic cyclopropanation of alkenes. Reactions involving this type of ylide will be discussed in this section. 

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). 

Diazoalkanes, in particular diazomethane, can efficiently transfer a methylene unit to olefinic double bonds via a metal catalysed process. The range of alkenes that may be used as substrates in this cyclopropanation is vast. The efficiency of the cyclopropanation of various types of alkenes can be very dependent upon the particular catalyst chosen for the reaction. 

The range of alkenes that may be used as substrates in these reactions is vast Suitable catalysts may be chosen to permit use of ordinary alkenes, electron deficient alkenes such as a,(3-unsaturated carbonyl compounds, and very electron rich alkenes such as enol ethers. These reactions are generally stereospecific, and they often exhibit syn stereoselectivity, as was also mentioned for the photochemical reactions earlier. Several optically active catalysts and several types of chiral auxiliaries contained in either the al-kene substrates or the diazo compounds have been studied in asymmetric cyclopropanation reactions, but diazocarbonyl compounds, rather than simple diazoalkanes, have been used in most of these studies. When more than one possible site of cyclopropanation exists, reactions of less highly substituted alkenes are often seen, whereas the photochemical reactions often occur predominantly at more highly substituted double bonds. However, the regioselectivity of the metal-catalyzed reactions can be very dependent upon the particular catalyst chosen for the reaction. 

Diazocarbonyl compounds, especially diazo ketones and diazo esters [19], are the most suitable substrates for metal carbene transformations catalyzed by Cu or Rh compounds. Diazoalkanes are less useful owing to more pronounced carbene dimer formation that competes with, for example, cyclopropanation [7]. This competing reaction occurs by electrophilic addition of the metal-stabilized carbocation to the diazo compound followed by dinitrogen loss and formation of the alkene product that occurs with regeneration of the catalytically active metal complex (Eq. 5.5) [201. 

Carbene itself ( CH2) is extremely reactive and gives many side reactions, especially insertion reactions (12-21), which greatly reduce yields. This competition is also true with rhodium-catalyzed diazoalkane cyclopropanations (see below). When it is desired to add CH2 for preparative purposes, free carbene is not used, but the Simmons-Smith procedure (p. 1241) or some other method that does not involve free carbenes is employed instead. Halocarbenes are less active than carbenes, and this reaction proceeds quite well, since insertion reactions do not interfereThe absolute rate constant for addition of selected alkoxychlorocar-bene to butenes has been measured to range from 330 to 1 x 10 A few of the many ways in which halocarbenes or carbenoids are generated for... 

Polymer-supported benzenesulfonyl azides have been developed as a safe diazotransfer reagent. ° These compounds, including CH2N2 and other diazoalkanes, react with metals or metal salts (copper, paUadium, and rhodium are most commonly used) to give the carbene complexes that add CRR to double bonds. Diazoketones and diazoesters with alkenes to give the cyclopropane derivative, usually with a transition-metal catalyst, such as a copper complex. The ruthenium catalyst reaction of diazoesters with an alkyne give a cyclopropene. An X-ray structure of an osmium catalyst intermediate has been determined. Electron-rich alkenes react faster than simple alkenes. ... 

Optically active complexes have been used for enantioselective cyclopropane synthesis. Decomposition of diazoalkanes in the presence of chiral rhodium copper, or ruthenium complexes leads to optically active cyclopropanes. 

The diastereoselective and enantioselective preparation of cyclopropanes has attracted attention since chiral cyclopropanes were found to occur in many natural products [11]. Moreover, cyclopropanes are useful intermediates in organic synthesis. There are many methods of cyclopropane ring opening that transfer stereochemical information from the substrate to acyclic products in a stereocontrolled manner [12]. Among the methods used for the preparation of cyclopropanes from olehns, the Simmons-Smith and related reactions as well as reactions of diazoalkanes catalyzed by rhodium, copper and cobalt salts have frequently been applied [13]. The preparatively simple Makosza reaction [14] has scarcely been used. 

In contrast to the wealth of chemistry reported for catalyzed reactions of diazocarbonyl compounds, there are fewer applications of diazomethane as a carbenoid precursor. Catalytic decomposition of diazomethane, CH2N2, has been reported as a general method for the methylenation of chemical compounds [12]. The efficacy of rhodium catalysts for mediating carbene transfer from diazoalkanes is poor. The preparative use of diazomethane in the synthesis of cyclopropane derivatives from olefins is mostly associated with the employment of palladium cat-... 

For the synthesis of formyl-substituted cyclopropanes, acetal-substituted compounds, the functional equivalent of the formyl-substituted compounds, are employed. Either an acetal substituent is incorporated into the diazoalkane (e.g. 2,2-dimethoxy-l-diazoethane can be used ) or on the double bond. Here it provides sufficient activation for the addition step, as is seen in the synthesis of formylcyclopropane (31) and /ra .v-l,2-diformylcyclopropane (32). ... 

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