Ethyl azodicarboxylate

ETHYL AZODICARBOXYLATE (Formic acid, azobis-, diethyl ester) 

Ethyl hydrazodicarboxylate. In a 2-1. three-necked flask, equipped with a mechanical stirrer, two 500-ml. dropping funnels, and a thermometer (Note 1), is placed a solution of 59 g. (1 mole) of 85% hydrazine hydrate in 500 ml. of 95% ethanol. The reaction flask is cooled by means of an ice bath. When the temperature of the solution has dropped to 10°, 217 g. (2 moles) of ethyl chloroformate is added dropwise with stirring at a rate sufficient to maintain the temperature between 15° and 20°. After one-half of the ethyl chloroformate has been introduced, a solution of 106 g. (1 mole) of sodiiun carbonate in 500 ml. of water is added dropwise simultaneously with the remaining ethyl chloroformate. The addition of these two reactants is regulated so that the temperature does not rise above 20° and so that the addition of the chloroformate is completed slightly in advance of the sodium carbonate in order to ensure a slight excess of ethyl chloroformate in the reaction mixture at all times. 

After all the reactants have been added, the precipitate on the upper walls of the flask is washed down with 200 ml. of water and the reaction mixture is allowed to stir for an additional 30-minute period. The precipitate is then collected on a Buchner funnel, washed well with a total of 800 ml. of water, and dried in an oven at 80°. There is obtained 145-150 g. (82-85%) of ethyl 

Ethyl azodicarboxylate. A mixture of 100 g. (0.57 mole) of ethyl hydrazodicarboxylate, 500 ml. of benzene, and 500 ml. of water is placed in 2-1. three-necked flask equipped with a mechanical stirrer and a gas inlet tube. The flask and contents are tared, the flask is placed in an ice bath, and a slow stream of chlorine is bubbled into the mixture with stirring. The temperature is maintained below 15°, and chlorine is introduced until the increase in weight amounts to 50-55 g. (Note 3). The flow of chlorine is stopped and the reaction mixture is stirred imtil a clear, orange-colored benzene layer forms when the mixture is allowed to settle. 

The layers are separated, and the water layer is extracted once with benzene. The benzene solutions are combined and washed twice with 100-ml. portions of water, then with 100-ml. portions of 10% sodium bicarbonate solution until neutral (usually four to six washes are required), twice more with water, and then are dried over anhydrous sodium sulfate. The benzene is removed under reduced pressure on a steam bath, and the residue is distilled in vacuum through a short indented column. After a small fore-run, the main fraction is collected at 107-111°/15 mm. There is obtained 80-82 g. (81-83%) of ethyl azodicarboxylate. 

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In a similar manner the addition of ethyl azodicarboxylate to the morpholine enamine of cyclohexanone furnished the less substituted isomer (34) with the substituent in the axial orientation (2, 26). 

It would be pertinent to point out (25,27) that the trisubstituted isomer of the enamine of 2-aIkylcyclohexanone reacts in a quantitative manner with ethyl azodicarboxylate to give the addition product (35). This reaction in Conjunction with NMR spectroscopy can thus be employed for the determination of the amount of the trisubstituted isomer. According to the authors, hydrolysis of 35 furnishes the corresponding cw-2,6-disubstituted cyclohexanone (36) this seems unlikely since it would involve the stereo-electronically unfavored equatorial protonation of the enamine. 

The reaction of morpholine enamines of cyclic ketones with ethyl azodicarboxylate has also been demonstrated 56,136). The enamine (113) on reaction with ethyl azodicarboxylate can give the 2- or 2,6-bis(N,N di-carboxyhydrazino)cyclohexanones 199 and 200, respectively, on hydrolysis. 

All attempts to prepare other [2 + 4] cycloadducts of sulfoxides 115 with dienophiles such as maleic anhydride, ethyl azodicarboxylate, etc., have failed60. A method for preparing ordinary alkyl-substituted thiirene oxides (e.g. 18 R1 = R2 = alkyl) is still lacking. 

A derivative of benzylhydrazine, procarbazine (8), exhibits antineoplastic activity. In an interesting insertion-type sequence, reaction of the p-toluamide (5) with ethyl azodicarboxylate leads directly to the substituted hydrazine (6). It is not unlikely that the first mole of the diazo compound... 

H- 1,4-Thiazines and benzothiazines undergo oxidation to dehydro dimers (83) and (84) which are of considerable interest as they are the parent chromophores of the trichosiderin (trichochrome) pigments which occur in mammalian red hair and in the feathers of some birds (74T2781). In the case of monocyclic thiazines, reagents such as nitrobenzene or picric acid are required, but air oxidation is sufficient in the bicyclic series. It is curious that whereas aerial oxidation of the ester (85) gives both the dehydro dimers (86) and (87), ethyl azodicarboxylate only yields the tautomer (87) <70AC(R)35l). 

The reaction of ethyl azodicarboxylate with indolizines has been reported to give substituted products such as 137 in high yield.203 This type of reaction has also been reviewed.204... 

Ten years later, the synthesis of alkyl-substituted thiirene sulfoxide 140 was reported (Scheme 69), making use of a Diels-Alder reaction between thiirano-radialene sulfoxide 138 and the highly reactive dienophilic 4-substituted 1,2,4-triazoline-3,5-diones 139 (TAD) [132]. The fact that other classical reactive di-enophiles, including maleic anhydride and ethyl azodicarboxylate, do not react with sulfinyldiene 138, reveals its low reactivity. 

Linear thieno[c J]benzothiadiazoles dimerize by linking at the carbocyclic peri positions <75ACR139>. While most [c] fused heterocycles add dienophiles across the heterocyclic ring, the thieno[l,2-c 4,5-c ]benzisothiazole (21) added ethyl azodicarboxylate across the benzenoid ring <86CB3158>. 

Formyl and 2-acetylfuran underwent an unusual reaction with ethyl azodicarboxylate to form adducts 285 and 286, respectively, as depicted in Equation (177) <1997T9313, 1999J(P1)73>. Computational studies of the reaction suggested an initial Diels-Alder reaction between the furan and azodicarboxylate, followed by rearrangement of the cycloadducts. A similar transformation was observed for the reaction between furfurals and 1,4-phthalazinedione in the presence of Pb(OAc)4, as shown in Equation (178) <20020L773>. 

It is again strongly recommended that distillation of methyl or ethyl azodicarboxylate be carried out from a thermally controlled bath, not an electrically heated mantle, for the latter may overheat the material being distilled. The bath should have a thermometer in it to keep track of the bath temperature, which should not be allowed to go higher than 130°C. The bath should be lowered at the end of the distillation. The distillation should be shielded on all sides by fixed shielding, as described in "Prudent Practices for Handling Hazardous Chemicals in Laboratories", National Academy Press, Washington, DC (1981), pp. 170-171 see also Org. Synth., Coll. Vol. VIin 993, p. vi. 

Tests show that either methyl or ethyl azodicarboxylate can be detonated by shock or heat (C. S. Sheppard, H. N. Schack, and O. L. Mageli, U.S. Patent 3, 347, 845 [1967]), Methyl azodicarboxylate is far more easily detonated than the ethyl ester. Hence, since the chemical properties of the two esters are similar, ethyl azodicarboxylate is almost always the preferred reagent. 

Sheppard, Schack and Mageli have shown that the presence of a shock-stable solvent, e.g., methylene chloride or benzene in the proportion by weight of 30% solvent to 70% methyl or ethyl azodicarboxylate, gives solutions that are stable to shock or heat. It is recommended that either of these azodicarboxylates be stored only as such a solution. 

It has been suggested that, as an additional safety measure, methyl and ethyl azodicarboxylates be distilled at 0.1 -0.5 mm with a maximum oil bath temperature of 80°C. (S. C. Blackstock, Vanderbilt Department of Chemistry). Blackstock reports b.p 35-36oC/0.1 mm for dimethyl azodicarboxylate. Extreme care should be taken to maintain the pressure at or below that specified throughout the distillation. The receiver should be chilled in an ice bath. In addiiton, the drying step should be carried out very carefully since residual moisture will lead to hydrolysis during the distillation giving rise to diimide and carbon dioxide. 

We know of no instances of explosions with t-butyl azodicarboxylate [Org. Synth., Coll. Vol. V. 1973, 1601 or bis(2,2,2-trichloroethyl) azodicarboxylate [Org. Synth., Coll. Vol. VI11990, 56], which would be expected to be less prone to explosion than the methyl or ethyl azodicarboxylates because of their higher molecular weights. Nevertheless, for safety they too should be prepared and handled behind good shielding and, if they are to be kept for a long time, stored in a shock-stable solvent as described above. 

Aliphatic hydrazines of the type RiC(CN)NHNHC(CN)Rj are prepared by the interaction of ketone cyanohydrins and hydrazine. These compounds can be oxidized to azonitriles with hypobromous acid in methanol. In a similar manner, ethyl azodicarboxylate, CjH50jCN=NC0jCiHj, is synthesized by the action of hypochlorous acid on ethyl hydrazodicar-boxylate (83%)- ... 

ISOCYANIDES Triphenylphosphine-Di-ethyl azodicarboxylate. ISOCYANATOQUINONES Oxalyl chloride. 

A larger excess of chlorine causes the formation of higher-hoiling materials and lowers the yield of ethyl azodicarboxylate. 

Ethyl azodicarboxylate can be prepared by treating ethyl hydrazodicarboxylate with concentrated nitric acid or a mixture of concentrated and fuming nitric acid. ... 

New Diels-Alder adducts of thebaine with aromatic nitroso-compounds of structure (118 R = H, Me, Cl) have been prepared. These are unstable and can be hydrolysed to 14-aryIhydroxylaminocodeinones (119), which can be reduced to derivatives of the hitherto inaccessible 14-aminodihydrocodeinone (120). The base (119 R = H) is susceptible to base-catalysed displacement of the oxide bridge, the product being the 5,14-bridged thebainone derivative (121). ° The reaction between thebaine and excess of ethyl azodicarboxylate involves Diels-Alder addition and addition of the N-CH3 group to a second molecule of azo-ester. The primary product (122) has not been isolated pure, but yields ethyl hydrazodicarboxylate and the substituted codeinone (123) on hydrolysis. ... 

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