Diazoacetate, ethyl

ETHYL DIAZOACETATE (Acetic acid, diazo-, ethyl ester) 

Submitted by Ennis D. Womack and A. B. Nelson. Checked by R. L. Shriner and C. H. Tilford. 

three-necked round-bottomed flask is fitted with a 50-ml. separatory funnel and a mechanical stirrer sealed with a well-lubricated rubber collar. A stopper in the third neck of the flask carries a glass tube that reaches to the bottom of the flask, enters the top of a 1-1. separatory funnel, and extends down to the stopcock. 

A solution of 140 g. (1 mole) of glycine ethyl ester hydrochloride 1 and 3 g. of sodium acetate in 150 ml. of water is added to the flask and cooled to 2° by means of an ice-salt bath. A cold solution of 80 g. (1.15 moles) of sodium nitrite in 100 ml. of water is added, and the mixture is stirred until the temperature has fallen to 0°. The temperature is maintained below 2°, and stirring is continued throughout all the following operations. To the cold mixture are added 80 ml. of cold, alcohol-free ethyl ether (Note 1) and 3 ml. of cold 10% sulfuric acid. After 5 minutes, the reaction mixture is blown over into the 1-1. separatory funnel by application of air pressure. The lower aqueous layer is quickly sucked back into the reaction flask. The ether layer is removed and immediately washed with 50 ml. of cold 10% sodium carbonate solution. This ether solution should be neutral to moist litmus paper if not, the washing with sodium carbonate is repeated. The ether solution is finally dried over 10 g. of anhydrous sodium sulfate. 

A second portion of 80 ml. of alcohol-free ether is then added to the reaction mixture with stirring, followed by 15 ml. of cold 10% sulfuric acid over a period of 5 minutes. After 3 minutes contact (Note 2), the ether layer is removed as before, washed immediately with 50 ml. of fresh 10% sodium carbonate solution, and dried over 10 g. of sodium sulfate. This procedure is repeated (about 6 or 7 times) until the ether layer is no longer yellow. 

The kinetics of hydrolysis of ethyl diazoacetate has been studied most thoroughly. The equation 

In the presence of halide ions, an additional term involving the first power of the halide concentration occurs in the rate equation, viz. 

Equation (47) was suggested for the first time by Bredig and Ripley [202]. In order to establish it unambiguously, it is necessary to carry out experiments at a constant ionic strength since feH and kHX are influenced by salt effects. Studies in the presence of halides at a constant ionic strength have never been done. Other approaches have been used instead. Albery and Bell [200] measured hydrolysis rates of ethyl diazoacetate in moderately concentrated perchloric acid and hydrochloric acid solutions. Rates in hydrochloric acid were faster than those in perchloric acid at the same stoichiometric concentration. In order to verify the dependence on the chloride ion concentration, it was assumed that rates of the reaction without participation of chloride (first term in eqn. (47)) are the same in perchloric acid and hydrochloric acid if the H0 values are equal. Activity coefficients were introduced in eqn. (47) as follows  

Activity coefficient ratios in the second term were approximated by known values of the square of the mean activity coefficient of HC1, and it was shown that the rate increase in hydrochloric acid (in comparison to perchloric acid at the same h0) depends on the first power of the chloride ion concentration. 

More recently, Albery et al. [203] carried out an improved analysis of experimental data for dilute acidic solutions which was based on an extension of McCauley and King s treatment [204] of kinetic data for the reaction of diazoacetone with water and halide ions. Albery et al. determined rate coefficients as well as product ratios, p - (moles ethyl halogenoacetate formed)/(moles ethyl glycollate formed), with the aid of UV spectrophotometric and gas—liquid chromatographic methods. In eqn. (48), the logarithms of the activity coefficient ratios were considered to be linearly dependent on the ionic strength, viz. 

For further reactions of the aliphatic diazo-compounds see ethyl diazoacetate (below). 

Recrystallization from benzene affords a product that has superior storage qualities. A liter dissolves 5-6 g. at the boiling point. 

The product turns pink, and eventually gray, if exposed to air for an extended period. It should be stored under nitrogen.  

The submitters indicate that N,N-diethylselenourea may be prepared similarly, using diethylcyanamide. In this case, a solution of 50 ml. each of concentrated aqueous ammonium hydroxide and ethanol is used as a solvent. The reaction is carried out at 60°, the solvent being replenished as needed by a solution containing 80 ml. of ethanol and 20 ml. of concentrated ammonium hydroxide. The yield of crude material is 65-80%. Recrystallization from benzene gives a white product, m.p. 117-118°. 

The procedure gives a commensurate yield when carried out on twice the scale. 

Iron selenide can be obtained from the Canadian Copper Refiners Ltd., Montreal, Quebec. 

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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). 

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. 

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],... 

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... 

Compounds containing the neutral (formally zwitterionic) group =N2 attached by one atom to carbon are named by adding the prefix diazo- to the name of the parent compound (Rule 931.4), e.g., diazomethane, ethyl diazoacetate. Diazo is a so-called characteristic group appearing only as a prefix in substitutive nomenclature. Chemical Abstracts and Beilstein indexing of diazo compounds is analogous to that mentioned above for diazonium ions and salts, but Diazo compounds is not... 

The premier example of this process in an ylide transformation designed for [2,3]-sigmatropic rearrangement is reported in Eq. 15 [107]. The threo product 47 is dominant with the use of the chiral Rh2(MEOX)4 catalysts but is the minor product with Rh2(OAc)4. That this process occurs through the metal-stabilized ylide rather than a chiral free ylide was shown from asymmetric induction using allyl iodide and ethyl diazoacetate [107]. Somewhat lower enantioselectivities have been observed in other systems [108]. 

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