Diazoacetates carbenes from

Selective O-alkylation of 2-pyridones is effected by reaction with diazoacetic esters in the presence of 2 mol% Rh2(OCOCF3)4 <20000L1641>. The reaction proceeds by selective transfer of the carbene from rhodium-carbene... 

Analogous to epoxides, aziridines can be prepared by the methylenation of imines. In this case, ethyl diazoacetate is the most common source of carbenes. For example, the imine derived from p-chlorobenzaldehyde 148 is converted to the c/j-aziridinyl ester 149 upon treatment with ethyl diazoacetate in the presence of lithium perchlorate <03TL5275>. These conditions have also been applied to a reaction medium of the ionic liquid l-n-butyl-3-methylimidazolium hexafluorophosphate (bmimPFe) with excellent results <03TL2409>. An interesting enantioselective twist to this protocol has been reported, in which a diazoacetate derived from (TJ)-pantolactone 150 is used. This system was applied to the aziridination of trifluoromethyl-substituted aldimines, which were prepared in situ from the corresponding aminals under the catalysis of boron trifluoride etherate <03TL4011>. 

Aziridines. A CuOTf complex of ferrocenyldiimine is effective for nitrene transfer from TsN=IPh (and also carbene from diazoacetic esters) to alkenes. 

Cyclopropanation reactions with these catalysts are typically carried out with 0.5-2 mol% (with respect to the diazo compound) of catalyst and a five- to tenfold excess of alkene. Under these conditions, the formation of formal carbene dimers [e.g. diethyl ( )-but-2-enedioate and (Z)-but-2-enedioate from ethyl diazoacetate], arising from the competition between alkene and the metal-carbene intermediate for the diazo compound, can be largely suppressed. It has been shown, however, that the control of the addition rate of the diazoacetic ester has no effect on the cyclopropane yield with (dibenzonitrile)palladium(II) chloride as catalyst, in contrast to tetraacetatodirhodium, Rhg(CO)ig, and CuCl P(OR)3. ... 

The direct transfer of carbene from diazocompounds to olefins catalyzed by transition metals is the most straightforward synthesis of cyclopropanes [3,4]. Reactions of diazoesters with olefins have been studied using complexes of several transition metals as catalysts. In most cases trans-isomers are preferably obtained, but the selectivity depends on the nature of the complex. In general the highest trans-selectivity is obtained with copper catalysts and it is reduced with palladium and rhodium complexes. Therefore, the rhodium mesotetraphenylporphyrin (RhTPPI) [5] and [(r 5-C5H5)Fe(CO)2(THF)]BF4 [6] are the only catalysts leading to a preference for the cis-isomer in the reaction of ethyl diazoacetate with styrene. 

The reaction of carbene (from diazomethane) with N-methyl pyrrolidine gives products resulting from insertion into all of the C-H bonds but no N-methyl piperidine was formed by a Stevens rearrangement of the methyl ylid. However, when phenyl diazoacetate was treated with benzyldimethylamine, benzyl migration occurs presumably via an intermediate ylid 45>. 

Rhodium(III) porphyrins are known to catalyze the insertion of carbethoxy-carbenes from ethyl diazoacetate into the C-H bonds of saturated compounds with yields up to 20-25% corresponding to a large increase of the primary/secondary selectivity [189]. In this case the substrates (Cg to Ci2 n-alkanes) were used as solvents. The rhodium porphyrins, (TPP)Rhl, (TMP)Rhl and (OEP)Rhl efficiently catalyze carbene insertion in 0-H bonds, leading to ethers by using ethyl diazoacetate imder mild conditions [190]. Using (TMP)Rhl as the catalyst, a stereoselective insertion reaction was observed with the order of primary > secondary > tertiary for various alcohols. 

Diazo compounds are commonly used as a carbene source in organic chemistry. A few systems based on metals such as Ru and Rh have been reported for the transfer of carbenes from diazo compounds. P6rez and coworkers reported NHC-copper systems for carbene and nitrene transfer. In the first report, [Cu (Cl)(IPr)] was used for the transfer to olefins, amines, and alcohob [64]. The main transformation was the cyclopropanation of styrene with ethyl diazoacetate (Scheme 8.24). Monitoring of the reaction showed a fast formation of the product (90% conversion in 6 h). The absence of styrene does not lead to the decomposition of EDA even after a long period of time (13 h). Decent stereoselectivity was obtained with styrene (cisitrans 32/68) and cyclooctene exolendo 73/27). 

Analysis The carbene synthon is easy it can be ethyl diazoacetate NiCHCOiEt. The diene can be made by the Wittig reaction from a familiar aUylic bromide (TM 31). 

Furan and thiophene undergo addition reactions with carbenes. Thus cyclopropane derivatives are obtained from these heterocycles on copper(I) bromide-catalyzed reaction with diazomethane and light-promoted reaction with diazoacetic acid ester (Scheme 41). The copper-catalyzed reaction of pyrrole with diazoacetic acid ester, however, gives a 2-substituted product (Scheme 42). 

Synthesis of aziridines by treatment of carbenes with imines was reported by Jacobsen [56]. A metallocarbene 104 derived from ethyl diazoacetate and copper fluorophosphate was treated with N-arylaldimines to form aziridines with reasonable diastereoselectivities (>10 1 in favor of cis) but with low enantioselectivities (about 44% ee). This was shown to result from a competitive achiral reaction path-... 

This area of research has only recently attracted the attention of synthetic organic chemists, but there has been a flurry of impressive activity in the area. Simple (i. e., unstabilized) carbenes suffer from many of the problems of nitrenes (vide infra) and most reported synthetically useful procedures use carbenoids the majority of recent reports have focussed upon reactions between a-diazoesters and imines in the presence of a range of catalysts. In one of the earliest reports of enantioselective carbene-imine reactions, for instance, Jacobsen and Finney reported that ethyl diazoacetate reacts with N-arylaldimines in the presence of cop-per(i) hexafluorophosphate with mediocre stereoselectivity to give N-arylaziridine carboxylates. Though the diastereoselectivities of the reaction were often acceptable (usually >10 1, in favor of the cis isomers) the observed enantioselectivity was low (no more than 44% ee Scheme 4.27) [33],... 

Carbenes and substituted carbenes add to double bonds to give cyclopropane derivatives ([1 -f 2]-cycloaddition). Many derivatives of carbene (e.g., PhCH, ROCH) ° and Me2C=C, and C(CN)2, have been added to double bonds, but the reaction is most often performed with CH2 itself, with halo and dihalocarbenes, " and with carbalkoxycarbenes (generated from diazoacetic esters). Alkylcarbenes (HCR) have been added to alkenes, but more often these rearrange to give alkenes (p. 252). The carbene can be generated in any of the ways normally used (p. 249). However, most reactions in which a cyclopropane is formed by treatment of an alkene with a carbene precursor do not actually involve free carbene... 

These complexes can be isolated in some cases in others they are generated in situ from appropriate precursors, of which diazo compounds are among the most important. These compounds, including CH2N2 and other diazoalkanes, react with metals or metal salts (copper, palladium, and rhodium are most commonly used) to give the carbene complexes that add CRR to double bonds. Ethyl a-diazoacetate reacts with styrene in the presence of bis(ferrocenyl) bis(imine), for example, to give ethyl 2-phenylcyclopropane-l-carboxylate. Optically active complexes have... 

As it is known from experience that the metal carbenes operating in most catalyzed reactions of diazo compounds are electrophilic species, it comes as no surprise that only a few examples of efficient catalyzed cyclopropanation of electron-poor alkeiies exist. One of those examples is the copper-catalyzed cyclopropanation of methyl vinyl ketone with ethyl diazoacetate 140), contrasting with the 2-pyrazoline formation in the purely thermal reaction (for failures to obtain cyclopropanes by copper-catalyzed decomposition of diazoesters, see Table VIII in Ref. 6). 

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. 

Based on a detailed investigation, it was concluded that the exceptional ability of the molybdenum compounds to promote cyclopropanation of electron-poor alkenes is not caused by intermediate nucleophilic metal carbenes, as one might assume at first glance. Rather, they seem to interfere with the reaction sequence of the uncatalyzed formation of 2-pyrazolines (Scheme 18) by preventing the 1-pyrazoline - 2-pyrazoline tautomerization from occurring. Thereby, the 1-pyrazoline has the opportunity to decompose purely thermally to cyclopropanes and formal vinylic C—H insertion products. This assumption is supported by the following facts a) Neither Mo(CO)6 nor Mo2(OAc)4 influence the rate of [3 + 2] cycloaddition of the diazocarbonyl compound to the alkene. b) Decomposition of ethyl diazoacetate is only weakly accelerated by the molybdenum compounds, c) The latter do not affect the decomposition rate of and product distribution from independently synthesized, representative 1-pyrazolines, and 2-pyrazolines are not at all decomposed in their presence at the given reaction temperature. 

Reaction of the imine moiety of 278 with excess ethyl diazoacetate in the presence of Cu(acac)2 led to the cyclopentane-annulated product 279 the structure of which was confirmed by an X-ray analysis 262. It is assumed that 279 results from reaction between a carbene dimer (diethyl fumarate) and an intermediate N-ylide or the... 

The reaction, formally speaking a [3 + 2] cycloaddition between the aldehyde and a ketocarbene, resembles the dihydrofuran formation from 57 a or similar a-diazoketones and alkenes (see Sect. 2.3.1). For that reaction type, 2-diazo-l,3-dicarbonyl compounds and ethyl diazopyruvate 56 were found to be suited equally well. This similarity pertains also to the reactivity towards carbonyl functions 1,3-dioxole-4-carboxylates are also obtained by copper chelate catalyzed decomposition of 56 in the presence of aliphatic and aromatic aldehydes as well as enolizable ketones 276). No such products were reported for the catalyzed decomposition of ethyl diazoacetate in the presence of the same ketones 271,272). The reasons for the different reactivity of ethoxycarbonylcarbene and a-ketocarbenes (or the respective metal carbenes) have only been speculated upon so far 276). 

The EfZ ratio of stilbenes obtained in the Rh2(OAc)4-catalyzed reaction was independent of catalyst concentration in the range given in Table 22 357). This fact differs from the copper-catalyzed decomposition of ethyl diazoacetate, where the ratio diethyl fumarate diethyl maleate was found to depend on the concentration of the catalyst, requiring two competing mechanistic pathways to be taken into account 365), The preference for the Z-stilbene upon C ClO -or rhodium-catalyzed decomposition of aryldiazomethanes may be explained by the mechanism given in Scheme 39. Nucleophilic attack of the diazoalkane at the presumed metal carbene leads to two epimeric diazonium intermediates 385, the sterically less encumbered of which yields the Z-stilbene after C/C rotation 357,358). Thus, steric effects, favoring 385a over 385 b, ultimately cause the preferred formation of the thermodynamically less stable cis-stilbene. 

The Lewis acid-Lewis base interaction outlined in Scheme 43 also explains the formation of alkylrhodium complexes 414 from iodorhodium(III) meso-tetraphenyl-porphyrin 409 and various diazo compounds (Scheme 42)398), It seems reasonable to assume that intermediates 418 or 419 (corresponding to 415 and 417 in Scheme 43) are trapped by an added nucleophile in the reaction with ethyl diazoacetate, and that similar intermediates, by proton loss, give rise to vinylrhodium complexes from ethyl 2-diazopropionate or dimethyl diazosuccinate. As the rhodium porphyrin 409 is also an efficient catalyst for cyclopropanation of olefins with ethyl diazoacetate 87,1°°), stj bene formation from aryl diazomethanes 358 and carbene insertion into aliphatic C—H bonds 287, intermediates 418 or 419 are likely to be part of the mechanistic scheme of these reactions, too. 

The Ru porphyrin complex (8) has also been used as a catalyst for the cyclization of allylic diazoacetates,258 albeit with limited success only the cyclization of F-cinnamyl diazoacetate shows high enantioselectivity (Scheme 81). It is noteworthy that a carbenoid species prepared from allyl o-phenyl-o-diazoacetate and complex (8) has been isolated and subjected to X-ray diffraction analysis, though it does not undergo the desired cyclization. In the structure, the carbene plane lies almost halfway between the two adjacent Ru—N bonds. 

Quite different methods employ carbene intermediates. Spencer and his colleagues generate a carbenoid species from ethyl diazoacetate (CuS04 catalyst) and allow it to attack an enol ether of a 1,3-diketone.102 Scheme... 

An alternative strategy for selective intermolecular G-H insertions has been the use of rhodium carbenoid systems that are more stable than the conventional carbenoids derived from ethyl diazoacetate. Garbenoids derived from aryldiazoacetates and vinyldiazoacetates, so-called donor/acceptor-substituted carbenoids, have been found to display a very different reactivity profile compared to the traditional carbenoids.44 A clear example of this effect is the rhodium pivalate-catalyzed G-H insertion into cyclohexane.77 The reaction with ethyl diazoacetate gave the product only in 10% yield, while the parallel reaction with ethyl phenyldiazoacetate gave the product in 94% yield (Equation (10)). In the first case, carbene dimerization was the dominant reaction, while this was not observed with the donor/acceptor-substituted carbenoids. 

Certain transition metal complexes catalyze the decomposition of diazo compounds. The metal-bonded carbene intermediates behave differently from the free species generated via photolysis or thermolysis of the corresponding carbene precursor. The first catalytic asymmetric cyclopropanation reaction was reported in 1966 when Nozaki et al.93 showed that the cyclopropane compound trans- 182 was obtained as the major product from the cyclopropanation of styrene with diazoacetate with an ee value of 6% (Scheme 5-56). This reaction was effected by a copper(II) complex 181 that bears a salicyladimine ligand. 

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