Diazoesters, reaction with copper

Reaction of ot-diazoester 413 with several copper carboxylate catalysts afforded azocyclooctene 414 along with perhydropyrido[2,l-r ][l,4]oxazin-l-one 415 (Equation 77) <1996TL2165>. 

The first reports of N-H insertion reactions of electrophilic carbene complexes date back to 1952 [497], when it was found that aniline can be N-alkylated by diazoacetophenone upon treatment of both reactants with copper. A further early report is the attempt of Nicoud and Kagan [1178] to prepare enantiomerically pure a-amino acids by copper(I) cyanide-catalyzed decomposition of a-diazoesters in the presence of chiral benzylamines. Low enantiomeric excesses (< 26% ee) were obtained, however. 

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. 

With P-keto-a-diazoester 114 in hand, treatment with copper triflate in dichloromethane set up an elegant cascade reaction to construct pyrroloindole 117. This transformation is proposed to proceed via initial diazo decomposition and cyclopropanation of the indole ring to provide indoline... 

Cu(OTf)2 generally gives yields intermediate between those of the other two catalysts, but with a closer resemblance to rhodium. In competition experiments, the better coordinating norbomene is preferred over styrene, just as in the case with Pd(OAc)2. Cu(acac)2, however, parallels Rh2(OAc)4 in its preference for styrene. These findings illustrate the variability of copper-promoted cyclopropanations, and it was suggested that in the Cu(OTf)2-catalyzed reactions of diazoesters, basic by-products, which are formed as the reaction proceeds, may gradually suppress... 

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). 

Rhodium(II) acetate was found to be much more superior to copper catalysts in catalyzing reactions between thiophenes and diazoesters or diazoketones 246 K The outcome of the reaction depends on the particular diazo compound 246> With /-butyl diazoacetate, high-yield cydopropanation takes place, yielding 6-eco-substituted thiabicyclohexene 262. Dimethyl or diethyl diazomalonate, upon Rh2(OAc)4-catalysis at room temperature, furnish stable thiophenium bis(alkoxycarbonyl)methanides 263, but exclusively the corresponding carbene dimer upon heating. In contrast, only 2-thienylmalonate (36 %) and carbene dimer were obtained upon heating the reactants for 8 days in the presence of Cul P(OEt)3. The Rh(II)-promoted ylide formation... 

The stereoselectivities in this reaction are governed by steric interactions in the formation of metallacyclobutane 60 (35). Of two possible intermediates (Fig. 5), 61 suffers from steric interactions between the ligand and the ester functionality. Avoidance of these interactions and minimization of 1,2-interaction in the metallacyclobutane leads to the formation of the observed major enantiomer and dias-tereomer (trans). The model suggests that increased diastereoselectivity should be observed with increasing steric bulk of the diazoester, a relationship that has already been established as discussed (cf. Eqs. 24 and 26). It is interesting to note that this model loosely corresponds to the stereochemical model proposed by Aratani for the Sumitomo cyclopropanation with one important difference the Aratani model is based on a tetrahedral metal while the Evans-Woerpel model is predicated on square-planar copper. Applying the Aratani model to the Evans ligand would predict formation of the opposite enantiomer as the major product (35). 

In 1996, Burgess et al. (34) reported one of the first examples of a formal attempt to use a parallel approach in the optimization of a catalytic reaction. Previously, Sulikowski reported the copper catalyzed C-H insertion of a diazoester. In an attempt to optimize the selectivity for this reaction, three different bis(oxa-zoline) ligands, a bis(salicylidine)ethylenediamine(salen)-type ligand and sparteine were screened in combination with seven different metals and four different solvents (Scheme 13). Ligand 116 in tetrahydrofuran (THF) solvent at slightly reduced temperature proved to be the best reaction conditions, giving a 3.9 1 product ratio and good yield. 

When the diazoesters (240) and (241) were thermally decomposed in the presence of copper(II) acetoacetate ester as catalyst, an intermolecular carbene reaction occurred, the resulting benzo[c]furans (242) and (243) were not isolated but were trapped as the Diels-Alder adducts with N- methylmaleimide and dimethyl acetylenedicarboxylate (76CL287). 

Dichlorocarbene is a typical singlet ground-state carbene which is commonly used for cydopropanation reactions, since it gives satisfactory yields in many cases, but in general, carbene synthesis implies a metal catalyst (usually copper) together with a diazo compound as the carbene precursor. In (he particular case of the O -H insertion reaction, sulfur dioxide has been reported as being an efficient catalyst for the insertion of carbalkoxycarbenes generated from diazoesters. 

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. ... 

The use of chiral additives with a rhodium complex also leads to cyclopropanes enantioselectively. An important chiral rhodium species is Rh2(5-DOSP)4, which leads to cyclopropanes with excellent enantioselectivity in carbene cyclopro-panation reactions. Asymmetric, intramolecular cyclopropanation reactions have been reported. The copper catalyzed diazoester cyclopropanation was reported in an ionic liquid. ° It is noted that the reaction of a diazoester with a chiral dirhodium catalyst leads to p-lactones with modest enantioselectivity Phosphonate esters have been incorporated into the diazo compound... 

Dirhodium(II) catalysts that possess chiral 2-pyrrolidone-5-carboxylate ester ligands (mepy) are the most effective among those of dirhodium or copper for highly diastereoselective and enantioselective intermolecular cyclopropenation reactions between l-alkynes and diazoesters (eq. (9)). Product yields are moderate, and enantiomeric excesses range from 40 to 98 %. Interestingly, the (R) or (5) catalyst produces the cyclopropene-l-carboxylate respectively with the (/ ) or (5) configuration [26]. 

Rhodium(II) acetate was found to be much more superior to copper catalysts in catalyzing reactions between thiophenes and diazoesters or diazoketones The outcome of the reaction depends on the particular diazo compound With f-butyl... 

However, at this stage relatively little progress has been made in research on asymmetric catalytic carbene transfer to imines. In 1995, Jacobsen and Jorgensen reported independently that reaction of ethyl diazoacetate with selected imines can be catalyzed by copper salts [27,28]. In the former case [27], moderate levels of enantioselection were found to be imparted by bisoxazoline ligands associated with the copper catalyst (Scheme 11). The observation of racemic pyrrolidine byproducts in the reaction was taken to support a mechanism of catalysis involving initial formation of a copper-bound azomethine yhde intermediate (Scheme 12 ). Collapse of this intermediate to the optically active aziridine apparently competes with dissociation of the copper to a free azomethine ylide. The latter can react with fumarate formed by diazoester decomposition in a dipolar cycloaddition to afford racemic pyrrolidine. 

Bis-oxazolines provide a similar stereochemical environment around the copper, but are generally easier to prepare. At about the same time, the research groups of Masamune, Evans and Pfaltz all reported the use of bis-oxazolines for copper-catalysed cyclopropanation. These ligands, including structures (9.07) and (9.08), provide excellent stereocontrol for many intermolecular examples of cyclopropanation. The use of the very hindered diazoester (9.09) enhances the trans selectivity of the cyclopropanation reaction of styrene (9.04). Monocyclopropanation of diene (9.11) is also achieved with very good stereocontrol. 

The [2,3]-Stevens rearrangement is a thermal sigmatropic rearrangement of an ammonium ylide (38) to form unnatural amino acid derivatives 39 (Scheme 12). Traditionally, the ammonium ylides have been formed through alkylation of aminoesters 36 with aUcyl halides 37 to form quaternary salts followed by treatment with base. Although effective, the harsh conditions lead to side products and limited substrate scope. More recently, the coupling of diazoesters 40 and allylic amines 41 in the presence of metals like copper, rhodium, and palladium has been developed for the direct constmction of ammonium ylides 38 via metal carbenoid intermediates. " Although this approach represented an advance over the traditional alkylation chemistry, the use of diazoesters still limits the synthetic utility of these reactions. 

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