Diazoacetates, metal catalyzed

Section B gives some examples of metal-catalyzed cyclopropanations. In Entries 7 and 8, Cu(I) salts are used as catalysts for intermolecular cyclopropanation by ethyl diazoacetate. The exo approach to norbornene is anticipated on steric grounds. In both cases, the Cu(I) salts were used at a rather high ratio to the reactants. Entry 9 illustrates use of Rh2(02CCH3)4 as the catalyst at a much lower ratio. Entry 10 involves ethyl diazopyruvate, with copper acetylacetonate as the catalyst. The stereoselectivity of this reaction was not determined. Entry 11 shows that Pd(02CCH3) is also an active catalyst for cyclopropanation by diazomethane. 

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). 

Allylic C/H insertion accompanied by an allylic rearrangement has been observed for carbenoid reactions of ethyl diazoacetate with allylamines (Scheme 23)1S1). Apparently, metal-catalyzed isomerization 117 118 proceeds the C/H insertion process. Although mechanistic details have not yet been unraveled, T)3-allyl complexes... 

Transition-metal catalyzed decomposition of alkyl diazoacetates in the presence of acetylenes offers direct access to cyclopropene carboxylates 224 in some cases, the bicyclobutane derivatives 225 were isolated as minor by-products. It seems justified to state that the traditional copper catalysts have been superseded meanwhile by Rh2(OAc)4, because of higher yields and milder reaction conditions217,218) (Table 17). [(n3-C3H5)PdCl]2 has been shown to promote cyclopropenation of 2-butyne with ethyl diazoacetate under very mild conditions, too 2l9), but obviously, this variant did not achieve general usage. Moreover, Rh2(OAc)4 proved to be the much more efficient catalyst in this special case (see Table 17). 

Oxa-l -silabicyclo[ . 1,0 alkanes (n = 3 111 n = 4 113) were the only products isolated from the photochemical, thermal or transition-metal catalyzed decomposition of (alkenyloxysilyl)diazoacetates 110 and 112, respectively (equation 28)62. The results indicate that intramolecular cyclopropanation is possible via both a carbene and a carbenoid pathway. The efficiency of this transformation depends on the particular system and on the mode of decomposition, but the copper triflate catalyzed reaction is always more efficient than the photochemical route. For the thermally induced cyclopropanation 112 —> 113, a two-step noncarbene pathway at the high reaction temperature appears as an alternative, namely intramolecular cycloaddition of the diazo dipole to the olefinic bond followed by extrusion of N2 from the pyrazoline intermediate. A direct hint to this reaction mode is the formation of 3-methoxycarbonyl-4-methyl-l-oxa-2-sila-3-cyclopentenes instead of cyclopropanes 111 in the thermolysis of 110. 

For the transition-metal catalyzed decomposition of silyl-substituted diazoacetates 205 [silyl = SiMe3, SiEt3, SiMeiBu-i, SitPr-i SiPtnBiW, SiMe2SiMe3], copper triflate and dirhodium tetrakis(perfluorobutyrate) proved to be the best catalysts114. While these two catalysts induce the elimination of N2 at 20 °C even with bulky silyl substituents, dirhodium-tetraacetate even at 100 °C decomposes only the trimethylsilyl-and triethylsilyl-diazoacetates. When the decomposition reactions are carried out in... 

With the same catalysts, carbene transfer from diazoacetates 205 [silyl groups SiMe3, SiEt3, Si(Pr-i)3] to 1-hexene and styrene was studied4,117. The yields of cyclopropanes were usually higher in the metal-catalyzed than in the photochemical version. Interestingly, the metal-catalyzed procedure gave preferentially -210, whereas... 

Maas, G., Krebs, F., Werle,T., Gettwert, V., and Striegler, R. (1999) Silicon-oxygen heterocycles from thermal, photochemical, and transition-metal-catalyzed decomposition of a-(alkoxysilyl and alkenyloxysilyl)- a-diazoacetates. 

Aliphatic diazocarbonyl and related diazo compounds can be decomposed by either photolysis or pyrolysis (or thermal decomposition), or by transition-metal-catalyzed decomposition generates (Scheme 2.51). For example, pyrolysis of diazoacetic ester at 425°C gives the carbethoxy carbene. 

In 1995 the first examples of enantioselective, metal-catalyzed [2,3]-sigmatropic sulfurylide rearrangements appeared (Scheme 96) [225]. When -cinnamylphenyl sulfide 285 was reacted with ethyl diazoacetate in the presence of a catalytic amount of CuOTf and bisoxazohne 394 [226], a di-astereomeric mixture close to 1 1 of homoallyhc sulfides 393 was produced with 20% ee for the major diastereomer (configuration was not assigned). 

It is worth recalling that the asymmetric cyclopropanation of styrene with ethyl diazoacetate, reported in 1966 by Noyori and co-workers, appears to be the first example of transition metal catalyzed enantioselective reaction in homogeneous phase. This reaction remains a landmark in asymmetric cyclopropanation. On a general standpoint, catalytic asymmetric cyclopropanation continues to attract much attention, due in part to the marked trends toward marketing more and more optically active molecules as the optically pure eutomer. This topic has been much studied in connection, inter alia, with the synthesis of valuable intermediates such as chrysanthemic acid derivatives and cilastatin. The subject has been recently reviewed [17]. 

Transition-metal-catalyzed, thermal, or photochemical nitrogen extrusion from allyloxysilyl-substituted diazoacetates 6 leads to formation of the 2-oxa-l-silabicyclo[3.1.0]hexanes... 

Transition-metal catalyzed decomposition of alkyl diazoacetates in the presence of acetylenes offers direct access to cyclopropene carboxylates 224 in some cases, the bicyclobutane derivatives 225 were isolated as minor by-products. It seems justified to state that the traditional copper catalysts have been superseded meanwhile by RhjCOAc), because of higher yields and milder reaction conditions (Table 17). 

A side reaction encountered in most metal-catalyzed processes of diazo compounds is the coupling of two diazo compounds to give an alkene. In cyclopropanations with ethyl diazoacetate, e.g., mixtures of diethyl fumarate and maleate are always formed to some extent. Obviously, the diazo compound and the olefin compete in the reaction with the metal-carbene intermediate. In order to suppress this undesired side reaction, the concentration of the diazo compound has to be kept low by slow addition, preferably by means of a syringe pump. 

Diazo compounds, most commonly diazoesters or diazoketones, are the reagents of choice for metal-catalyzed cyclopropanation of alkenes (Eq. 1) [31]. Of the two, diazoesters, and particularly ethyl diazoacetate (EDA), are the more frequently used in synthesis. 

Asymmetric versions of copper-catalyzed cyclopropanations constitute the first examples of transition metal catalyzed asymmetric C —C bond formation37. These initial examples gave optically active cyclopropane products with only 6-8% ee by the conversion of styrene with ethyl diazoacetate, or ( i )-l -phenyl-l-propenc with diazomethane, in the presence of a chirally modified copper catalyst containing -(a-methylbenzytysalicylaldimine37- 3S. 

Addition of carbenoids derived from a-diazo carbonyl compounds to prostereogenic olefins can furnish two diastereomeric cyclopropane derivatives (dsjtrans- or euefo/exo-isomers). The metal-catalyzed transfer of alkoxycarbonyl carbenes has been closely investigated it usually furnishes the mwv-substituted cyclopropanes with moderate to good preference. The rhodium(II/-catalyzed reaction of ethyl diazoacetate with various olefins typically demonstrates that the d.r. (trans/cis) increases when the substituent on the olefin becomes sterically more demanding5. 

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). 

Metal catalyzed enantioselective C-H insertions of carbenes have so far not been studies in great detail. Copper catalysts are of no use for this type of reaction, rhodium(Il) catalysts, however, allow intramolecular C-H insertions, for example, in the alkyl group of diazoacetates with longer chains. The formation of five-membered rings such as y-lac-tones is favored. [Rh2(55-mepy)4] affords... 

Intramolecular [3+2] cycloaddition reactions of unsaturated diazocarbonyl compounds as well as transition-metal-catalyzed intramolecular carbene-type reactions of diazo compounds constitute an important strategy in contemporary synthesis of alicyclic and heterocyclic systems [1]. In a program directed towards the synthesis of silaheterocycles according to this concept, we have used various silicon-functionalized (silyl)diazoacetates [2] as starting materials. In this communication, we report on the synthesis of silaheterocycles from a-(alkynyloxy)silyl-a-diazoacetates [3], which can be prepared easily by successive reaction of a silyl bis(triflate) with an alkyl diazoacetate and a propargyl alcohol [4],... 

In the intermolecular approach, the cyclopropylindole III-18 would be formed after metal-catalyzed cyclopropanation of III-17 with ethyl diazoacetate (EDA) [63-69]. In the intramolecular approach, cyclopropylindole III-20 would be obtained from the diazoindole III-19 [70-80]. 

In 1980 and 1982, Callot and co-workers reported that Rh(Por)l catalyzed the reaction between alkenes and ethyl diazoacetate to give syn cyclopropoanes as the major products (Eq. 25). " This was unusual as most transition metal catalysts for this reaction give the anti isomers as the predominant products. Kodadek and co-workers followed up this early report and put considerable effort into trying to improve the syn/anti ratios and enantioselectivity using porphyrins with chiral substituents. 

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). 

Ethyl diazopyruvate, under copper catalysis, reacts with alkynes to give furane-2-carboxylates rather than cyclopropenes u3) (Scheme 30). What looks like a [3 + 2] cycloaddition product of a ketocarbenoid, may actually have arisen from a primarily formed cyclopropene by subsequent copper-catalyzed ring enlargement. Such a sequence has been established for the reaction of diazoacetic esters with acetylenes in the presence of certain copper catalysts, but metallic copper, in these cases, was not able to bring about the ring enlargement14). Conversely, no cyclopropene derivative was detected in the diazopyruvate reaction. 

Aziridines have been synthesized, albeit in low yield, by copper-catalyzed decomposition of ethyl diazoacetate in the presence of an inline 260). It seems that such a carbenoid cyclopropanation reaction has not been realized with other diazo compounds. The recently described preparation of 1,2,3-trisubstituted aziridines by reaction of phenyldiazomethane with N-alkyl aldimines or ketimines in the presence of zinc iodide 261 > most certainly does not proceed through carbenoid intermediates rather, the metal salt serves to activate the imine to nucleophilic attack from the diazo carbon. Replacement of Znl2 by one of the traditional copper catalysts resulted in formation of imidazoline derivatives via an intermediate azomethine ylide261). 

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. 

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