Diazoacetates 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). 

The reaction of cyclohexene with the diazopyruvate 25 gives unexpectedly ethyl 3-cyclohexenyl malonate (26), involving Wolff rearrangement. No cyclo-propanation takes place[28]. 1,3-Dipolar cycloaddition takes place by the reaction of acrylonitrile with diazoacetate to afford the oxazole derivative 27[29]. Bis(trimethylstannyl)diazomethane (28) undergoes Pd(0)-catalyzed rearrangement to give the A -stannylcarbodiimide 29 under mild conditions[30]. 

From Diazo Compounds via 1,3-Dipolar Cycloaddition. This method has been utilized widely in heterocychc chemistry. Pyrazohne (57) has been synthesized by reaction of ethyl diazoacetate (58) with a,P-unsaturated ester in the presence of pyridine (eq. 12) (42). 

Azulene (2) A mixture of 2-isopropyl-4,7-climethylindane 1 (200 g, 1.91 mol) and ethyl diazoacetate (50 g, 0.5 mol] was heated for 1 h at 130°C. Vacuum distillation and recovery ol 1 (160 g) gave a brown residue which was heated with 40% NaOH (40 mL) and EtOH (200 mL). The unreacled ester was extracted with Et20 and the aqueous solution was acidified to obtain crude 2, which after distillation afforded 24 g ol 2(52%), bp t60-185°C/ 2mm. 

Higher temperatures should be avoided because of the explosive character of ethyl diazoacetate. The product should be placed in dark brown bottles and kept in a cool place. It should be used as soon as possible. 

Etliyl diazoacetate has been prepared from sodium nitrite luid ethyl glycinatc hydrochloride in the presence of diethyl filler. The present [irocedure utilizes the unique ability of... 

By choice of fluorinating agent, either hydrofluorination [6, 98, 99] or halo fluorination [6, 99] of ethyl diazoacetate is realized (equation 26)... 

Alkyl diethylphosphononuoroacetates have been used extensively in ol fi-nanon procedures [69], principally forming the ffJ-a-fluoro-a.P-unsaturated esters with very high stereoselectivity [70] (equation 61) (Table 22). Preparation of the ethyl diethylphosphonofluoroacetate from ethyl fluoroacetate has obviated the necessity to prepare ethyl bromofluoroacetate from bromine fluoride and ethyl diazoacetate [71],... 

The copper-catalyzed decomposition of diazoacetic ester in the presence of pyrrole was first described in 1899 and later investigated in more detail by Nenitzescu and Solomonica. Ethyl pyrrole-2-acetate (13), the normal product of electrophilic substitution, was obtained in 50% yield and was degraded to 2-methylpyrrole. Similarly iV -methylpyrrole with two moles of diazoacetic ester gave, after hydrolysis, the 2,5-diacetic acid (14) while 2,3,5-trimethylpyrrole gave, after degradation, 2,3,4,5-tetramethylpyrrole by substitution of ethoxycarbonylcarbene at the less favored )3-position. Nenitzescu and Solomonica also successfully treated pyrroles with phenyl-... 

Ethyl diazoacetate adds endo to Me3Si(C=C)2SiMe3 to give 3-ethoxycarbonyl-4-trimethylsilylethynyl-5-trimethylsilylpyrazole (88JOM247). 

Catalytic, enantioselective cyclopropanation enjoys the unique distinction of being the first example of asymmetric catalysis with a transition metal complex. The landmark 1966 report by Nozaki et al. [1] of decomposition of ethyl diazoacetate 3 with a chiral copper (II) salicylamine complex 1 (Scheme 3.1) in the presence of styrene gave birth to a field of endeavor which still today represents one of the major enterprises in chemistry. In view of the enormous growth in the field of asymmetric catalysis over the past four decades, it is somewhat ironic that significant advances in cyclopropanation have only emerged in the past ten years. 

The normal electron-demand principle of activation of 1,3-dipolar cycloaddition reactions of nitrones has also been tested for the 1,3-dipolar cycloaddition reaction of alkenes with diazoalkanes [71]. The reaction of ethyl diazoacetate 33 with 19b in the presence of a TiCl2-TADDOLate catalyst 23a afforded the 1,3-dipolar cycloaddition product 34 in good yield and with 30-40% ee (Scheme 6.26). 

Incorporation of the phenethyl moiety into a carbocyclic ring was at first sight compatible with amphetamine-like activity. Clinical experience with one of these agents, tranylcypromine (79), revealed the interesting fact that this drug in fact possessed considerable activity as a monamine oxidase inhibitor and as such was useful in the treatment of depression. Decomposition of ethyl diazoacetate in the presence of styrene affords a mixture of cyclopropanes in which the trans isomer predominates. Saponification gives acid 77. Conversion to the acid chloride followed by treatment with sodium azide leads to the isocyanate, 78, via Curtius rearrangement. Saponification of 78 affords tranylcypromine (79). 

A solution containing 167 grams of stabilized styrene and 183 grams of ethyl diazoacetate is cooled to 0°C and dropped into 83.5 grams of styrene with stirring, in a dry nitrogen atmosphere, at 125° to 135°C, This produced the ester ethyl 2-phenylcyclopropanecar-boxylate. 

Ethyl-1 -(3-cyano-3,3-diphenylpropyl)-4-phenylisonipecotate HCI Difenoxime Ethyl diazoacetate... 

The catalytic asymmetric cyclopropanation of an alkene, a reaction which was studied as early as 1966 by Nozaki and Noyori,63 is used in a commercial synthesis of ethyl (+)-(lS)-2,2-dimethylcyclo-propanecarboxylate (18) by the Sumitomo Chemical Company (see Scheme 5).64 In Aratani s Sumitomo Process, ethyl diazoacetate is decomposed in the presence of isobutene (16) and a catalytic amount of the dimeric chiral copper complex 17. Compound 18, produced in 92 % ee, is a key intermediate in Merck s commercial synthesis of cilastatin (19). The latter compound is a reversible... 

The thermal decomposition of ethyl diazoacetate in 9//-indcno[2,l -6]pyridine (3) effects expansion of the pyridine ring to give ethyl indeno[l,2-Z>]azepine-3-carboxylate (4), the first example of the indeno[l,2-Z>]azepine system.56... 

Ethyl 2,4,7-triaryl-l,3-oxazepine-6-carboxylates 15 are formed in modest yield by the reaction of ethyl diazoacetate with 1,3-oxazinium perchlorates 14.13... 

A stirred solution of 2,4,6-triphenyl-l,3-oxazinium perchlorate (3.06 g, 7.5mmol) in MeCN (100 mL) was treated with ethyl diazoacetate (1.80 mL, 17.2 mmol) followed by i-Pr2NEt (0.64 mL, 3.75 mmol). After ca. 30 min the theoretical amount of N2 had been evolved. The solution was stirred for 15 h, aq NaHC03 was added and the mixture was extracted with CHC13. The dried (K2C03) extract was concentrated and the residue was chromatographed (silica gel, benzene) yield 1.10 g (38%) mp 161 C. 

The only known fully unsaturated 1,3-thiazepines are ethyl 2,4,7-triaryl-l,3-thiazepine-6-car-boxylates 2, which are formed in moderate yield by the action of ethyl diazoacetate on 2,4,6-triaryl-l,3-thiazinium perchlorates 1 in a reaction analogous to that of oxazinium salts the preparative procedure is analogous to that given for ethyl 2,4,7-triaryl-l,3-oxazepine-6-car-boxylates (see Section 4.1.1.2.1.1.).13... 

Cyclization of the diazo compounds 1 a or 1 b, obtained from 2,4,6-trimethylpyrylium tetra-fluoroborate and ethyl diazoacetate or dimethyl diazomethanephosphonate, respectively, thus gives 1//-1,2-diazepines 2, which are stabilized by hydrogen bonding.71... 

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-... 

The most successful approach in this reaction category has been the use of chiral boron Lewis acid catalysts, in the addition of ethyl diazoacetate to imines reported by Wulff (Scheme 1.33) [59-60]. 

Reactions between imines and a-diazo carboxylates afford aziridine-2-carboxylates [55]. An asymmetric version of this reaction using chiral nonracemic catalysts has been described [53, 56-58]. As an example, catalytic aziridination of inline 44 (Scheme 3.14) with ethyl diazoacetate in the presence of 10% catalyst generated... 

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]. 

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],... 

Probably the most widely applicable asymmetric imine aziridination reaction reported to date is that of Wulff et al. These workers approached the reaction from a different perspective, utilizing the so-called vaulted , axially chiral boron Lewis acids VANOL and VAPOL [35] to mediate reactions between ethyl diazoacetate and N-benzhydrylimines (Scheme 4.29) [36]. The reactions proceed with impressive enantiocontrol, but there is a requirement that the benzhydryl substituent be present since this group is not an aziridine activator there is, therefore, a need for deprotection and attachment of a suitable activating group. Nonetheless, this method is a powerful one, with great potential for synthesis, as shown by the rapid synthesis of chloroamphenicol by the methodology [37]. 

Ethyl benzoylacetate has been prepared by the condensation (by means of sodium ethylate) of ethyl acetate with ethyl benzoate,1 acetophenone with ethyl carbonate,2 and acetophenone with ethyl oxalate, with subsequent heating 3 by treatment of ethyl phenylpropiolate4 or a-bromocinnamic acid 5 with concentrated sulfuric acid, and of ethyl diazoacetate with benzalde-hyde 6 by the condensation of benzene with the monoethyl ester of malonyl monoacid chloride and aluminum chloride,7 of benzoyl chloride with the product of the reaction of magnesium and ethyl chloroacetate in ether,8 of alcohol on benzoylacetimino ethyl... 

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