Dimethyl azodicarboxylate

A novel pyrolytic method of generating nitrile ylides in situ was reported by Burger [44] (equation 45) Such nitrile ylides react with various dipolarophiles alkynes [44] (equation 46), nitriles [45] (equation 47), dimethyl azodicarboxylate [45], aldehydes [45], and nitroso compounds [46]... 

When other acceptor systems such as tetracyanoethylene, ethyl propiolate, dibenzoylacetylene, or dimethyl azodicarboxylate were reacted with 41, no additional products were formed. Accordingly, the scope of the reaction for the nucleophilic addition of 41 to electron-poor alkenes, alkynes, and diazo compounds is quite narrow. 

The cycloadducts 257 of esters of azodicarboxylic acid to 2,7-dimethyloxepin undergo a spontaneous Claisen rearrangement to form the dihydrocyclopropapyridazines 258 (equation 139)132. Homofulvenes 259 (R1, R2 = HorMe) react with dimethyl azodicarboxylate to form rearranged adducts 260 (equation 140)133. 

The (3-lactone is obtained in 47% yield by reaction of N-(benzyloxycarbonyl)-L-serine with triphenylphosphine and dimethyl azodicarboxylate in THF. It is stable to air at 25° and can be stored for some time it is rapidly hydrolyzed by aqueous base. 

Some hetero double bond systems have been shown to enter [3 + 2] cycloaddition reactions with the mesoionic 1,3-dithiolones. Thus, the mesoionic 1,3-dithiolones (2) react with formaldehyde, prepared in situ by depolymerization of paraformaldehyde, with regiospecific formation of the 2-oxa-6,7-dithiabicyclo[2.2.1]heptanone derivatives (131). The corresponding reaction of (2) with the N=N double bond of dimethyl azodicarboxylate proceeds via cycloaddition yielding (132), and a similar reaction takes place between (2) and 4-phenyl-l,2,4-triazoline-3,5-dione (78CB3171). 

The synthesis of BENZYL ISOCYANIDE from benzaldehyde via reductive amination with 5-aminotetrazole followed by oxidation of the resultant amine with sodium hypobromite provides a general method for the synthesis of isocyanides. The preparation of BIS(2,2,2-TRICHLOROETHYL) AZODICARBOXYLATE makes available an alternative to dimethyl azodicarboxylate that is not only more reactive in Diels-Alder reactions but whose ester groups can be removed under neutral conditions. 

Mono-benzoyldiimides such as 177 behave in a relatively normal manner, reaction with the pyrrolidine enamine of cyclohexanone (or cyclopentanone) giving the oxadiazine 178355 (Scheme 181). Reaction of dimethyl azodicarboxylate with / -disubstituted aldehyde enamines is reported to give the 1,2-diazetidine 179 and hence the aldehyde 180 on hydrolysis356", dibenzoyldiimide gives the oxadiazine 1813566 (Scheme 181). The ethoxycarbonyl aroyl diimide 182 reacts to give oxadiazine 183 exclusively357 (Scheme 182). 

All the reactions described so far have mobilised six electrons, but other numbers are possible, notably a few [8 + 2] and [6 + 4] cycloadditions involving 10 electrons in the cyclic transition structure. A conjugated system of eight electrons would normally have the two ends of the conjugated system far apart, but there are a few molecules in which the two ends are held close enough to participate in cycloadditions to a double or triple bond. Thus, the tetraene 6.17 reacts with dimethyl azodicarboxylate 6.18 to give the [8 + 2] adduct 6.19, and tropone 6.20 adds as a 6-electron component to the 4-electron component cyclopentadiene to give the adduct 6.21. 

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. 

The ene reaction of an azodicarboxylate ester was first observed in 196218-19 as a process competing with cycloaddition to dienes, but little additional work has been done on the ene reaction with simple alkenes. An elegant study in 1976 provided evidence for a concerted, suprafacial reaction between dimethyl azodicarboxylate and (S)-(Z)-l-deutero-4-methyl-l-phenyl-2-pentene (15) based on the direction and high level of chirality transfer observed20. 

Preparative Methods (1) is easily made by cy clization of commercially available A-Cbz-r-serine (4) under modified Mit-sunobu conditions, using a preformed complex of dimethyl azodicarboxylate (DMAD) and Triphenylphosphine (eq 1). The reaction proceeds via hydroxy group activation, and labeling studies show that the 3-hydroxy group is lost in a 4-exo-tet cyclization mechanism. The p-lactone must be separated quickly from the reaction mixture, and a slight excess of DMAD improves the yield because unreacted triphenylphosphine can cause polymerization. The Boc (f-butoxycarbonyl) analog (2) is prepared similarly, and the p-toluenesulfonate (tosylate) salt (3) is synthesized from (2) by acidic cleavage. ... 

Dimethyl azodicarboxylate (164) has been reported to undergo a [ 4 + 2] photocycloaddition to the diene (165) to give the 2,3-diazabicyclo[2.2.2]octene (166). An analogous solid-state addition has been described in the ox-azolone (167) to give the photodimer (IbS), and oxidation of the photoadduct derived from 1-oxoanhydromethylberberine and nitrosobenzene has been used in a synthesis of ring C-substituted benzo[c]phenanthridines. ... 

A strong indication that this is indeed the reaction course is provided by the construction of compounds VIII-X from the addition of I to dimethyl acetylene dicarboxylate, dimethyl azodicarboxylate, and 4-phenyl-2,4-triazoline-3,5-dione, respectively. ... 

Imino ethers and 2-alkoxybenzthiazolium salts prepared from chiral alcohols react with carboxylic acids to give the esters of the corresponding inverted rdcohols (Scheme 39).7ic.72d,73,75a reaction of a chiral alcohol with a carboxylic acid, DEAD and PhsP affords the ester of the inverted alcohol (Scheme 44). 2 Diisopropyl or dimethyl azodicarboxylate can be used instead of DEAD. Little difference between these reagents has been reported. ... 

Silylated (and germylated) hydrazines have been prepared by the addition of Ph3SiH, and similarly substituted silanes, to the N=N bond of diethyl and dimethyl azodicarboxylates. Spectroscopic data support formulations (5) and (6), and a radical mechanism could be substantiated for hydro-silylation whereas the addition of germanes proceeded via polar intermediates.72... 

Dimethylaziridiiie, mesa- and dl-, 741 Dimethyl azodicarboxylate, 850 Dimethyl azulene-l,2-dicarboxylate, 272... 

DEAD = diethyl azodicarboxylate DMAD = dimethyl azodicarboxylate ... 

Similarly, starting from the partially reduced dimethyl azodicarboxylate 6,6-dimethylfulvene adduct 17 and removing the alkylidene group by ozonolysis, it was possible to elaborate a whole series of 5-substituted bicyclo[2.1.0]pentanes including 5-hydroxybicyclo[2.1.0]pen-tane. Alternatively, derivatives in the highly unstable 5-alkylidenebicyclo[2.1.0]pen-tane series were made via hydroboration of the 5,6-double bond of the dimethyl azodicarboxylate 6-bromofulvene adduct 18 including 5-deuteromethylene-2-methoxybicyclo[2.1.0]pen-tane (19). °... 

With the hetero dienophile dimethyl azodicarboxylate, 1,2-diazetidines (e.g, 15) are formed. ... 

The temperature of the solution should be about -75°C before dimethyl azodicarboxylate is added. 

Dimethyl azodicarboxylate (manufactured by Tokyo Kasel Kogyo Co., Japan) was purchased from CTC Organic, 792 Windsor Street, Atlanta, GA 30315. Overheating of dimethyl azodicarboxylate should be avoided because of the danger of explosion. Distillation should be conducted from a temperature-controlled bath in the hood behind a safety shield. The material used distilled at 71-72°C (2 mm), at a bath temperature of 84-86°C. It is important that the addition of this compound to the reaction mixture be carried out at a constant rats without Interruption because it tends to freeze in the syringe needle. The checkers explored the use of diethyl azodicarboxylate because of its lower cost and wider availability. However, the corresponding hydrazine derivative Is more difficult to separate from the -lactone product of this step. 

---