A-diazoesters

Chloroximes and enamines have provided aminoisoxazolines which could readily be converted to isoxazoles with acid (610-612). Pyrrazoles were usually obtained from addition of chlorohydrazones to enamines (610,613). The intermediate aminopyrazolines could only be isolated from the reaction of the cyclopentenyl enamine system. Pyrazoles were also obtained from the reactions of enamines with a-diazoketones and a-diazoesters (614). 

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],... 

Dirhodhun (II) carboxylate catalyzed cyclization of a series of y-alkoxy-a-diazoesters has been shown to proceed with substantial diastereoselectrvity, producing the 2,3,5-trisubstituted tetrahydrofiirans. Hie diastereo selectivity of the cyclization improved as the electron-withdrawing ability of the substituent R increased (Scheme 22, <96JOC6706>). 

Another Rhn-catalyzed decomposition of a a-diazoester as described by Sabe and coworkers [198] was used for the synthesis of indolizidine alkaloids (Scheme 6/2.8). It can be assumed that, first, an ammonium ylide is formed which then undergoes a 1,2-shift with ring-expansion. Thus, reaction of 6/2-40 with Rh2(OAc)4 led to a 72 28 mixture of 6/2-41 and 6/2-42 in 85 % yield. Cu(acac)2 can also be used with even better yields, but lower selectivity (65 35). 

Scheme 6/2.7. Three-component reaction of a a-diazoester, an imine and an alkene.

Cyclopropanation reactions can be promoted using copper or rhodium catalysts or indeed systems based on other metals. As early as 1965 Nozaki showed that chiral copper complexes could promote asymmetric addition of a carbenoid species (derived from a diazoester) to an alkene. This pioneering study was embroidered by Aratani and co-workers who showed a highly enantioselective process could be obtained by modifying the chiral copper... 

The seminal report of an asymmetric homogeneous metal-catalyzed reaction described the copper-catalyzed group-transfer reaction from a diazoester to an alkene, Eq. 3 (2). This article provided experimental verification of the intervention of copper carbenoid olefin complexes in the catalytic decomposition of diazo com-... 

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. 

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. 

Some examples of transformations involving carbonyl ylides are listed in Table 4.20. Entry 1 illustrates the conversion of P-acyloxy-a-diazoesters into a-acyloxyacrylates by ring fission of a cyclic carbonyl ylide [978]. This reaction has been used for the synthesis of the natural aldonic acid KDO (3-deoxy-Z)-manno-2-octulosonic acid), which is an essential component of the cell wall lipopolysaccharide of gram-negative bacteria (Figure 4.15). 

Diazoesters 22 have an electronically unique a-carbon atom. (Scheme 9) They are commonly used for the formation of aziridines 23 from imines 24. The intermediate (25) resulting from the addition of a-diazoesters 22 to the latter (24) can undergo elimination of the proton at the a-position prior to extrusion of molecular nitrogen. This interrupted aza-Darzens reaction allows for the direct alkylation of diazoesters 22 via cleavage of a carbon-hydrogen bond. 

Scheme 9 Mechanism of a Friedel-Crafts-type alkylation of a-diazoesters...

In conjunction with their Friedel-Crafts alkylation, Terada et al. found phosphoric acid (R)-3m (2 mol%, R = 9-anthryl) bearing a bulky 9-anthryl group to mediate the asymmetric Friedel-Crafts-type reaction of a-diazoester 22a with iV-acylated aldimines 26 (Scheme 10). a-Diazo-P-amino esters 27 were obtained in moderate yields (62-89%) and very good enantioselectivities (91-97% ee) [20],... 

A closely related reaction employs a-diazoesters or y-diazoketones.23 With these compounds, molecular nitrogen acts as the leaving group in the migration step. The best results are achieved using dialkylchloroboranes or monoalkyldichloroboranes. 

Exploiting the Lewis basic phosphoryl oxygen of Im, Terada reported the direct alkylation of a-diazoesters with N-acyl imines to afford P-amino-a-diazoesters in high yields and ee s (Scheme 5.12) [23]. Earlier, Johnston had observed that catalytic TfOH promoted aziridine formation (Aza-Darzens reaction) between diazoacetates and N-benzyl imines [24]. The authors propose that aziridine formation is circumvented through C—H bond cleavage by the phosphoryl oxygen of 1 (Intermediate A). However, as noted by the authors, the low nucleophilicity of N-acyl imines might also be considered as the cause of this selective transformation. 

Huisgen, Szeimies, and Mobius have studied the addition reactions of aryl azides to a,/S-unsaturated esters and nitriles.1 4 Methyl acrylate (73) reacts with aryl azides to form l-aryl-4-carbomethoxy-A -triazolines in agreement with the orientation rule based on electronic effects. These A -triazolines are completely converted by base catalysis into the ring-opened isomer. Thus l-phenyl-4-carbomethoxy-A2-triazo ine (74) gives, in the presence of triethylamine at room temperature, methyl 3-aniline-2-diazopropionate (75). The A2-triazolines as well as the a-diazoesters are thermolabile. 74 is converted into l-phenyl-2-carbomethoxyaziridine (76) and 75 gives methyl 3-anilinoacrylate (77) as thermolysis product.262... 

Some a-diazoesters are obtained directly from the addition reaction when a long reaction time is required. Dimethyl fumarate, for example, reacts only very slowly with phenyl azide at 25°. After 60 days the a-diazoester is obtained in 90% yield. 

The fluorophenol could be converted into 56 in four good steps but the insertion of the vinyl group to give 57 by formylation and a Wittig reaction went in only 18% and the cyclo-propanation with a diazoester and Cu(I) (chapter 30) gave poor selectivity in favour of the cis isomer of 57. Worse still, it was necessary to protect the phenol as a methyl ether and the removal of the methyl group, the last step, went in only 52% yield, wasting nearly half of all the material. 

Table 6.28 Bransted acid-catalyzed direct alkylations of a-diazoesters.

Bronsted Acid-Catalyzed Direct Alkylations of a-Diazoesters [21] (p. 228)... 

Lo and Fu have developed a Cu(ii) catalyst based on chiral bidentate N,N-ligands that effects an enantioselective ring expansion of oxonium ylides derived from oxetanes and a-diazoesters of type 53 (Equation 98) <2001T2621>. 

Transition metal-catalyzed decomposition of a-diazoesters of type 60 result in the formation of a benzo[intramolecular Diels-Alder reaction with a tethered vinyl group followed by spontaneous N-assisted opening of the endoxide bridge to yield 11-azasteroid analogs (Scheme 92) <1999J(P1)59>. 

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... 

The second cyclopropanation occurs at the only remaining alkene with a carbene generated a diazoester. The stereoselectivity comes from attack on the opposite side of the ring to the r membered ring already present. 

How would you attempt to make the starting material The original workers used ar carbene reaction - the Cu(l)-catalysed insertion of a diazoester into bis trimethylsilyl acett kr... 

---