Diethyl azodicarboxylate mechanisms

A variety of reagents can function as the electrophile E+ in the general mechanism. The most useful synthetic procedures for preparation of halides are based on the halogens, positive halogens sources, and diethyl azodicarboxylate. A 1 1 adduct formed from triphenylphosphine and bromine converts alcohols to bromides.15 The alcohol displaces bromide ion from the pentavalent adduct, giving an alkoxyphosphonium intermediate. The phosphonium ion intermediate then undergoes nucleophilic attack by bromide ion, forming triphenylphosphine oxide. 

In a 1-1., three-necked, round-bottomed flask equipped with a constant-pressure dropping funnel, a mechanical stirrer, and a reflux condenser is placed 174 g. (1.0 mole) of ethyl azodicarbox-ylate in 150 ml. of ether. Freshly prepared cyclopentadiene (70 g., 1.06 moles) is added dropwise over a 1-hour period to the stirred ethereal solution of diethyl azodicarboxylate. During the addition a gentle reflux is maintained by external cooling with an ice-water bath as needed. When the addition is complete, the reaction mixture is allowed to stand for 4 hours, or less if the yellow color of the azodicarboxylic acid ester disappears. I he dropping funnel and condenser are replaced by a glass stoj)pcr and a short distillation head, respectively. The ether and unreactcd diene are distilled off on a steam bath and the... 

A wide variety of species can function as the electrophile E+ in the general mechanism. The most useful synthetic procedures for preparation of halides are based on the halogens, positive halogen sources, and diethyl azodicarboxylate. 

The oxidation of hydrazine derivatives with diethyl azodicarboxylate is of particular interest because it involves direct hydrogen abstraction. The oxidation of keto hydrazones with lead tetraacetate leads to azoacetates, presumably by a free radical mechanism. 

Macrolactonization can also be achieved by the Mitsunobu reaction [44] with inversion of the configuration of the alcohol. The reaction principle and mechanism are demonstrated in Scheme 24. Addition of triphenylphosphine to diethyl azodicarboxylate (DEAD, 73) forms a quaternary phosphonium salt 74, which is protonated by hydroxy acid 11, followed by phosphorus transfer from nitrogen to oxygen yielding the alkoxyphosphonium salt 76 and diethyl hydrazinedicarboxy-late 75. Then, an intramolecular Sn2 displacement of the important intermediate 76 results in the formation of the lactone 15 and triphenylphosphine oxide. 

The observed range of solvent effects (less than a factor of four) for the ene reaction between 3-phenyl-l-7 -tolylpropene-(l) and diethyl azodicarboxylate, given in Eq. (5-45), is best explained by a concerted mechanism involving an isopolar six-centre transition state [136]. 

The reaction mechanism is believed to proceed according to the following outline Triphenylphosphine reacts with the diethyl azodicarboxylate to give an intermediate, which is then protonated by the carboxylic acid to form a neutral salt. This salt then reacts with the alcohol to form dicarboethoxyhy-drazine and a new salt. This salt then reacts further to give a triphenylphos-... 

An example of an alcohol activation method is the Mitsunobu reaction. This reaction is performed by slow addition of the seco-acid alcohol to a mixture of diethyl azodicarboxylate (DEAD) and PPhs in toluene or THF. In the mechanism, the key intermediate is an alkoxyphosphonium cation, which is formed by DEAD and PPhs in situ. The macrolactone is formed by an intramolecular Sn2 reaction of this intermediate via an attack of the carboxylate moiety and therefore the reaction proceeds with inversion of the configuration at C-co. 

This method is unusually mild, using neutral conditions and low temperatures (20 °C and less). It tolerates a number of functional groups in the components (e.g. acetals, esters, alkenes, etc.)- The alcohol, the carboxylic acid and triphenylphosphine are treated dropwise in an inert solvent (dichloromethane, THF, ether) with diethyl azodicarboxylate (DEAD). The ester is formed rapidly. However, tedious chromatography is frequently required to remove the by-products, triphenylphosphane oxide and hydrazo ester. The main value of the reaction lies in the clean inversion of configuration at a secondary carbinol center and in its selectivity towards primary hydroxy groups (vide infra). Inversions are usually performed with benzoic or p-nitrobenzoic acid. The benzoates are purified and saponified with aqueous base to furnish the inverted alcohols in overall yields of ca. 50%. Elimination is the main side reaction. Thus, from (44) 75% of the desired Sn2 product (45) is formed, along with 25% of the elimination product (46) (equation 19). The mechanism of the reaction has been clarified to the point that betaine (47) is the pri-... 

Grochowski, E., Hilton, B. D., Kupper, R. J., Michejda, C. J. Mechanism of the triphenylphosphine and diethyl azodicarboxylate induced dehydration reactions (Mitsunobu reaction). The central role of pentavalent phosphorus intermediates. J. Am. Chem. Soc. 1982,104, 6876-6877. 

Alkoxythiazoles (68) give an abnormal Diels-Alder reaction with highly reactive dienophiles such as 4-phenyl-3//-l,2,4-triazole-3,5(4/0-dione (PTAD), diethyl azodicarboxylate (dead), or diethyl oxomalonate. As an example, the reaction of (68) with PTAD (69) is illustrated in Equation (17). The product of the reaction (70) is the formal [3-1-2] cycloadduct between (69) and the corresponding nitrile ylide derived by the opening of thiazole ring system. For this abnormal Diels-Alder reaction of thiazoles a stepwise mechanism has been proposed <92BCJ3315>. 

Nucleophilic Attack at Other Atoms. The mechanism of reactions involving alcohols (or phenols) with the triphenylphosphine-diethyl azodicarboxylate (DAD) reagent (the Mitsunobu reaction) has now been reconsidered in the light of a number of spectroscopic and preparative studies in the past year. In an... 

Only the corresponding dibenzo derivatives have been reported. Benzocinnolinium salts (480 R = Ph, OEt) react easily with diethyl azodicarboxylate via the corresponding azomethine imines by a 1,3-dipolar cycloaddition mechanism to give (481) (Equation (76)) <74RRC1507,76RRC1203>. 

Fig. 19 Mechanism and synthesis of photohealable metallosupramolecular polymers, (a) Proposed optical healing of a metallosupramolecular, phase separated network, (b) Synthesis of macromonomer 3 and polymerizatiMi by addition of Zn(NTf2)2. DEAD, diethyl azodicarboxylate. Reproduced with ptamission from 75]...

Other useful reagents such as formaldehyde, diethyl azodicarboxylate, selenium dioxide, and simple olefins, just to name a few. A number of mechanistic and labeling studies employing MA as a reagent has shed considerable light on the mechanism. In this section, therefore, we will limit the discussion to mechanisms as studied with MA, and, where applicable, highlight the studies with other reagents. 

Suggest a mechanism for the formation of 85 from 84. Provide the structure of the intermediate in the conversion of 85 86. Provide the structure of an unproductive cycloadduct obtained from the reaction of 85 with diethyl azodicarboxylate. (Unnatural Products-14)... 

Dealkylation of Amines. Treatment of a secondary or tertiary amine with diethyl azodicarboxylate in nonpolar solvents followed by acidic hydrolysis leads to the formation of mon-odealkylated amines. The mechanism of this reaction is believed to involve the formation of a triaza adduct (by Michael addition) followed by a two-step ylide rearrangement yielding an alkyl-substituted hydrazocarboxylate. Research on unsymmetrically substituted amines suggests that benzyl groups are more easily removed than alkyl groups methyl groups are the hardest to remove except in cyclic amines like iV-methylpiperidine (eq 3). The Al-dealkylation of imines has also 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... 

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