Diazo ester

Aziridination remains less well developed than epoxidation. Nevertheless, high selectivity in inline aziridination has been achieved through the use of chiral sulfi-nimines as auxiliaries. Highly successful catalytic asymmetric aziridination reactions employing either sulfur ylides or diazo esters and chiral Lewis acids have been developed, although their scope and potential applications in synthesis have yet to be established. 

The BF3 Et20-catalyzed aziridination of compounds 47 (Scheme 3.15) with a diazo ester derived from (R)-pantolacetone gave aziridine-2-carboxylates 48 [59]. The reaction exhibited both high cis selectivity (>95 <5) and excellent diastereose-lectivity. Treatment of a-amino nitrile 49 (Scheme 3.16) with ethyl diazoacetate in the presence of 0.5 equivalent of SnCl4 afforded aziridines 50 and 51 in 39% yield in a ratio of 75 25 [60]. 

The reaction has also been applied to compounds with other leaving groups. Diazo ketones, diazo esters, diazo nitriles, and diazo aldehydes react with trialkylboranes in a similar manner, for example. 

Reaction of halo esters or diazo esters with boranes... 

The starting diazo esters 110 were prepared by diazo transfer from the corresponding malonate esters 109. A selection of chiral Hgands in conjunction with 2mol% (with respect to the diazo compound) of [Cu(OTf)2] in (CH2C1)2 was then examined at 65 °C (Scheme 31). All of the Hgands tested were sufficiently reactive to produce diazo decomposition at 65 °C, although the yields of cyclopropanation products were quite variable. Even tertiary... 

A closely related reaction employs a-diazo esters or a-diazo ketones.25 With these compounds, molecular nitrogen acts as the leaving group in the migration step. The best results are achieved using dialkylchloroboranes or monoalkyldichloroboranes. 

A number of these alkylation reactions are illustrated in Scheme 9.2. Entries 1 and 2 are typical examples of a-halo ester reactions. Entry 3 is a modification in which the highly hindered base potassium 2,6-di-f-butylphenoxide is used. Similar reaction conditions can be used with a-halo ketones (Entries 4 and 5) and nitriles (Entry 6). Entries 7 to 9 illustrate the use of diazo esters and diazo ketones. Entry 10 shows an application of the reaction to the synthesis of an amide. 

These reactions involve addition of the diazo ester to an adduct of the carbonyl compound and the Lewis acid. Elimination of nitrogen then triggers migration. Triethyloxonium tetrafluoroborate also effects ring expansion of cyclic ketones by ethyl diazoacetate.83... 

Benzoyl groups are also selectively cleaved during diazo transfer. This method has been used to prepare diazo ketones and diazo esters.142... 

The combined ether solutions are then subjected to distillation at 20° or below under the vacuum obtainable from a water pump until all the ether is removed. Prolonged distillation results in decomposition of the diazo ester and in a decreased yield. The yellow residual oil is practically pure ethyl diazoacetate and is satisfactory for most synthetic purposes (Note 3). The yield is about 98 g. (85%) (Notes 4 and 5). 

Decomposition of the diazo ester 395 in presence of dirhodium tetraacetate gives the zwitterionic intermediate 396, which undergoes a 1,3-dipolar cycloaddition with the double bond of the adjacent vinylindole. The bridged compound is isolated in good yield when the reaction is carried out at room temperature however, at 50 °C or above, compound 397 is the only compound isolated, again in good yield (Scheme 93) <2005JOC2206>. 

From ref. 64 b Reaction conditions 22 °C molar ratio 3000 (olefin)/l(catalyst)/200 (diazo ester) c 54% isolated yield reported in reference 70. Reaction conditions room temp. molar ratio 7400 (olefin)/l(catalyst)/1020(diazo ester). 

Table 6. Cyclopropanation reactions with ethyl diazoacetate using equimolar amounts of alkene and diazo ester" b... 

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). 

Conditions 22 °C molar ratio 800 (diene)/200 (diazo ester)/1 (catalyst)... 

Cycloheptatriene, as an example of a conjugated triene, is mainly cyclopro-panated at an outer double bond (Scheme 6). This is true for Rh2(OAc)4, Cu(OTf)2 and Pd(OAc)2, but the highest yield is obtained again with the rhodium catalyst72>. Twofold cyclopropanation occurs to only a minor extent, as long as an excess of olefin is applied. With equal amounts of diazo ester and cycloheptatriene, double cyclopropanation increases and even traces of the triply cyelopropanated triene are found with Rh2(OAc)4 and Cu(OTf)2. This behavior essentially parallels the earlier... 

It has been pointed out earlier that the anti/syn ratio of ethyl bicyclo[4.1,0]heptane-7-carboxylate, which arises from cyclohexene and ethyl diazoacetate, in the presence of Cul P(OMe)3 depends on the concentration of the catalyst57). Doyle reported, however, that for most combinations of alkene and catalyst (see Tables 2 and 7) neither concentration of the catalyst (G.5-4.0 mol- %) nor the rate of addition of the diazo ester nor the molar ratio of olefin to diazo ester affected the stereoselectivity. Thus, cyclopropanation of cyclohexene in the presence of copper catalysts seems to be a particular case, and it has been stated that the most appreciable variations of the anti/syn ratio occur in the presence of air, when allylic oxidation of cyclohexene becomes a competing process S9). As the yields for cyclohexene cyclopropanation with copper catalysts [except Cu(OTf)2] are low (Table 2), such variations in stereoselectivity are not very significant in terms of absolute yields anyway. 

Baldwin et al. have used the same catalyst/diazo ester combination for the synthesis of optically active deuterated phenylcyclopropanes (Scheme 28) 197). From cis-1,2-dideuteriostyrene, d/-menthyl a-deuteriodiazoacetate and (+)-195d, the cis- and mnw-cyclopropanes 196 were obtained, both with 90% optical purity. The dominant enantiomer of trans-196 had (+)-(15, IS, 35) configuration. Analogously, the cyclopropanes c -198 and trans-198, obtained from styrene, d/-menthyl a-deuteriodiazoacetate and (+)-195d with subsequent transesterification of cisjtrans-197, had optical purities of 86 and 89%, respectively. The major optical isomer of cis-198 had (IS, 2R) configuration, that of trans-198 (IS, 2S) configuration. 

Ethyl 2-phenylcyclopropanecarboxylate, obtained in the presence of 207a, has S configuration at C-l in both the cis- and trans-isomer. As that carbon has been furnished by the diazo ester, this result indicates enantiofacial selection at the carbenoid. In contrast, hardly any discrimination between the enantiofaces of the prochiral olefin occurs. Only when the ester substitutents become bulkier, does this additional stereochemical feature gain importance, and the S configuration at C-2 of the cyclopropane is favored. 

Use of a chiral diazo ester proved less rewarding in terms of enantioselective cyclopropanation. Only very low enantiomeric excesses were obtained when styrene was cyclopropanated with the carbenoid derived from diazoacetic esters 219 bearing a chiral ester residue 214). 

In 1966, Nozaki et al. reported that the decomposition of o-diazo-esters by a copper chiral Schiff base complex in the presence of olefins gave optically active cyclopropanes (Scheme 58).220 221 Following this seminal discovery, Aratani et al. commenced an extensive study of the chiral salicylaldimine ligand and developed highly enantioselective and industrially useful cyclopropanation.222-224 Since then, various complexes have been prepared and applied to asymmetric cyclo-propanation. In this section, however, only selected examples of cyclopropanations using diazo compounds are discussed. For a more detailed discussion of asymmetric cyclopropanation and related reactions, see reviews and books.17-21,225... 

For the cyclization of a vinylogue of diazo ester, the copper complex (102) bearing a biphenyl fc(oxazoline) ligand was found to be the catalyst of choice (Scheme 75).278... 

Methyl diazoacetate was obtained according to a procedure for ethyl diazoacetate (Searle, N.E. Org. Synth., Coll. Vol. A/1963, 42). Although the experiments were usually performed with distilled methyl diazoacetate (bp 43°C at 25 mm, bath temperature below 60°C) without any problems, the cyclopropanation reaction described works equally well with undistilled diazo compound. If distilled diazo compound is desired, the submitters have stated that "a spatula of K2CO3 Is added to the crude diazo ester to trap traces of add and then distill behind a safety shield . The checkers did not evaluate this aspect of the procedure. 

Doyle s rhodium(n) carboxamidate complexes are undisputedly the best catalysts for enantioselective cyclizations of acceptor-substituted carbenoids derived from diazo esters and diazoacetamides, displaying outstanding regio- and stereocontrol.4 These carboxamidate catalysts consist of four classes of complexes pyrrolidinones... 

A very impressive application of this chemistry is the total synthesis of (—)-ephedradine A 102.222 The key intermediate /rcarboxylic acid ester 101 was synthesized by intramolecular C-H insertion reaction. Upon treatment with a catalytic amount of Rh2(Y-DOSP)4, aryl diazo ester 100 possessing a chiral auxiliary underwent a C-H insertion reaction to give 101 in 63% yield and 86% de (Equation (83)). 

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