Carbene ethyl diazoacetate

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). 

Chlorins are also accessible by carbene additions to C-C double bonds on the periphery of metalloporphyrins. The most effective reaction on a preparative scale is the addition of ethyl diazoacetate in refluxing benzene to copper octaethylporphyrin (4) or meso-tetraphenylpor-phyrin in the presence of copper(I) iodide,100108b 110 which gives a diastereomcric mixture of chlorins, e.g. 5. 

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],... 

The most significant and widely studied reactivity of the ruthenium and osmium porphyrin carbene complexes is their role in catalyzing both the decomposition of diazoesters to produce alkenes and the cyclopropanation of alkenes by diazoesters. Ethyl diazoacetate is used to prepare the carbene complex 0s(TTP)(=CHC02Et)... 

Rh(Por)l (Por = OEP. TPP, TMP) also acts as a catalyst for the insertion of carbene fragments into the O—H bonds of alcohols, again using ethyl diazoacetate as the carbene source. A rhodium porphyrin carbene intermediate was proposed in the reaction, which is more effective for primary than secondary or tertiary alcohols, and with the bulky TMP ligand providing the most selectivity. ... 

The common by-products obtained in the transition-metal catalyzed reactions are the formal carbene dimers, diethyl maleate and diethyl fumarate. In accordance with the assumption that they owe their formation to the competition of olefin and excess diazo ester for an intermediate metal carbene, they can be widely suppressed by keeping the actual concentration of diazo compound as low as possible. Usually, one attempts to verify this condition by slow addition of the diazo compound to an excess (usually five- to tenfold) of olefin. This means that the addition rate will be crucial for the yields of cyclopropanes and carbene dimers. For example, Rh6(CO)16-catalyzed cyclopropanation of -butyl vinyl ether with ethyl diazoacetate proceeds in 69% yield when EDA is added during 30 minutes, but it increases to 87 % for a 6 h period. For styrene, the same differences were observed 65). 

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). 

Palladium(II) acetate was found to be a good catalyst for such cyclopropanations with ethyl diazoacetate (Scheme 19) by analogy with the same transformation using diazomethane (see Sect. 2.1). The best yields were obtained with monosubstituted alkenes such as acrylic esters and methyl vinyl ketone (64-85 %), whereas they dropped to 10-30% for a,p-unsaturated carbonyl compounds bearing alkyl groups in a- or p-position such as ethyl crotonate, isophorone and methyl methacrylate 141). In none of these reactions was formation of carbene dimers observed. 7>ms-benzalaceto-phenone was cyclopropanated stereospecifically in about 50% yield PdCl2 and palladium(II) acetylacetonate were less efficient catalysts 34 >. Diazoketones may be used instead of diazoesters, as the cyclopropanation of acrylonitrile by diazoacenaph-thenone/Pd(OAc)2 (75 % yield) shows142). 

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). 

Similar to the intramolecular insertion into an unactivated C—H bond, the intermolecular version of this reaction meets with greatly improved yields when rhodium carbenes are involved. For the insertion of an alkoxycarbonylcarbene fragment into C—H bonds of acyclic alkanes and cycloalkanes, rhodium(II) perfluorocarb-oxylates 286), rhodium(II) pivalate or some other carboxylates 287,288 and rhodium-(III) porphyrins 287 > proved to be well suited (Tables 19 and 20). In the era of copper catalysts, this reaction type ranked as a quite uncommon process 14), mainly because the yields were low, even in the absence of other functional groups in the substrate which would be more susceptible to carbenoid attack. For example, CuS04(CuCl)-catalyzed decomposition of ethyl diazoacetate in a large excess of cyclohexane was reported to give 24% (15%) of C/H insertion, but 40% (61 %) of the two carbene dimers 289). 

Insertion of a ketocarbene moiety into a C—O bond of orthoesters is normally performed with catalysis by BF3 Et20. Copper(II) trifiouromethanesulfonate was found to be a similarly efficient catalyst also, at least in some cases, whereas Rh2(OAc)4 was much less suited to promote this transformation l60). Besides the C/O insertion product 343, the alcohol insertion product 344 and, in reactions with ethyl diazoacetate, the formal carbene dimers were obtained. In agreement with BF3 EtzO, Cu(OTf)2 did not bring about insertion into a C—O bond of trimethyl... 

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. 

A somewhat unusual copper catalyst, namely a zeolite in which at least 25% of its rhodium ions had been exchanged by Cu(II), was active in decomposition of ethyl diazoacetate at room temperature 372). In the absence of appropriate reaction partners, diethyl maleate and diethyl fumarate were the major products. The selectivity was a function of the zeolite activation temperature, but the maleate prevailed in all cases. Contrary to the copper salt-catalyzed carbene dimer formation 365), the maleate fumarate ratio was found to be relatively constant at various catalyst concentrations. When Cu(II) was reduced to Cu(I), an improved catalytic activity was observed. 

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. 

When the cis/trans stereoselectivity of cyclopropanation with ethyl diazoacetate in the presence of CuCl P(0-z-Pr)3, Rh6(CO)16 or PdCl2 2 PhCN was plotted against that obtained with Rh2(OAc)4, a linear correlation was observed in every case, with slopes of 1.74,1.04 and 0.59, respectively (based on 22 olefins, T = 298 K) S9). These relationships as well as the results of regioselectivity studies carried out with 1,3-dienes point to the similar nature of the intermediates involved in Cu-, Rh-and Pd-catalyzed cyclopropanation. Furthermore, obvious parallels in reactivity in the transformations of Scheme 45 for a variety of catalysts based on Cu, Rh, Fe, Ru, Re and Mo suggest the conclusion that electrophilic metal carbenes are not only involved in cyclopropanation but also in ylide-forming reactions66. ... 

Strong evidence exists for the intermediacy of a tungsten ethoxycarbonyl carbene 425 in cyclopropanation of various enol ethers, 1,3-dienes and cyclohexene with ethyl diazoacetate in the presence of catalytic amounts of (CO)5W = C(OMe)Ph 413). The following equations could account for the obtained products ... 

When the possibility of 1,4-addition is precluded by incorporation of the —N=N—C=0 system into a ring, then 1,2-addition of the carbene should be possible. However, only one example has so far been reported. Ethyl diazoacetate reacts exothermically with PTAD at 0C C to liberate nitrogen and give a 1 1 adduct which was assigned the diaziridine structure shown in Eq. (5).71... 

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. 

The catalytic activity of rhodium diacetate compounds in the decomposition of diazo compounds was discovered by Teyssie in 1973 [12] for a reaction of ethyl diazoacetate with water, alcohols, and weak acids to give the carbene inserted alcohol, ether, or ester product. This was soon followed by cyclopropanation. Rhodium(II) acetates form stable dimeric complexes containing four bridging carboxylates and a rhodium-rhodium bond (Figure 17.8). 

Experimental results [1361] and theoretical treatment [28] indicate that the cyclo-propanation of alkenes by electrophilic carbene complexes is a concerted process. Z-Olefins normally lead to the formation of the corresponding c7. -cyclopropanes, and -olefins yield fran -cyclopropanes. The relative configuration of the carbene-bound substituent and the substituents of the alkene in the final cyclopropane seems to be mainly determined by the steric bulk of these groups. In cyclopropanations of terminal alkenes with ethyl diazoacetate low diastereoselectivities are often observed [1024,1351]. These can be improved by increasing the steric demand of the substituents at the carbene or at the alkene [1033,1362]. High diastereoselectivities can, e.g., often be achieved with terf-butyl, neopentyl or 2,6-di(rerr-butyl)phenyl diazoacetate [1362] as carbene complex precursors (Figure 4.19). 

Wenkert and Khatuya (51) examined the competition between direct insertion of a carbene into furan (via cyclopropanation) and ylide formation with reactive side-chain functionality such as esters, aldehydes, and acetals. They demonstrated the ease of formation of aldehyde derived carbonyl ylides (Scheme 4.30) as opposed to reaction with the electron-rich olefin of the furan. Treatment of 3-furfural (136) with ethyl diazoacetate (EDA) and rhodium acetate led to formation of ylide 137, followed by trapping with a second molecule of furfural to give the acetal 138 as an equal mixture of isomers at the acetal hydrogen position. 

Mononuclear oxazolines have been less studied. Moderate enantioselectivities (up to 60%) were obtained using PyrOx as ligands for the copper(l)-catalyzed carbene-transfer reaction of ethyl diazoacetate to styrene." " " However, the diastereo-selectivities (cis/trans) in these reactions were generally poor. 

In 1981 it was shown that rhodium(II) carboxylates smoothly catalyze the addition of ethyl diazoacetate to a variety of alkanes11. While some differentiation between possible sites of insertion was observed, selectivity is not as high for this carbenoid process as it is for the free radical process above. Rhodium-catalyzed intermolecular C-H insertion is thought to proceed via electrophilic addition of an intermediate rhodium carbene into the alkane C—IT bond. 

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