Azodicarboxylate reagents

In summary the Mitsunobu reaction can be described as a condensation of an alcohol 1 and a nucleophile—NuH—11, where the reagent triphenylphosphine is oxidized to triphenylphosphine oxide and the azodicarboxylate reagent 12 is reduced to a hydrazine derivative 13 ... 

One of the first attempts in this field refers to a multicomponent intermolecular sulfa-Michael/amination cascade process in which an a,p-unsatu-rated aldehyde and a thiol were reacted in the presence of a dialkyl azodicarboxylate reagent, giving access to p-amino-y-thioalcohol derivatives with excellent yields and enantioselectivities. Isolation of the final products was accomplished by in situ reduction followed by base-promoted cyclization (Scheme 7.48). 0-Trimethylsilyl diarylprolinol 31c was identified as the best... 

A further development of the method by immobilization of DEAD effects an easily separable (insoluble) and non-explosive reagent in Mitsunobu reactions. The methyl azodicarboxylate reagent immobilized on polystyrene 1742 functions well in Mitsunobu reactions and gives yields comparable to those obtained with soluble DEAD [1279]. Diphenylcarbodiimide was obtained in 41% yield. 

Cydization of P-hydroxy-a-amino esters under Mitsunobu reaction conditions is an alternative approach to aziridine-2-carboxylic esters [6b, 13-16], In this case the P-hydroxy group is activated by a phosphorus reagent. Treatment of Boc-a-Me-D-Ser-OMe 13 (Scheme 3.5) with triphenylphosphine and diethyl azodicarboxylate (DEAD), for example, gave a-methyl aziridinecarboxylic acid methyl ester 14 in 85% yield [15]. In addition to PPh3/DEAD [13b, 15], several other reagent combi-... 

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. 

Silylated primary allylic amines, e.g. CH2=CHCH2N(SiMe3)2, are produced from allylic chlorides and the mixed reagent AgI/LiN(SiMe3)2205. The formation of allylic amines from olefins by the ene reaction is shown in equation 77. The ene adducts 205 from bis(2,2,2-trichloroethyl) azodicarboxylate are converted into 206 by zinc dust in acetone/acetic acid206. 

Since diimide exists as a transient intermediate and cannot be isolated under normal conditions, procedures for reduction by diimide necessarily involve generation of the reagent in situ1 1 11. Diimide can be generated by (i) oxidation of hydrazine, (ii) acid decomposition of azodicarboxylate salts and (iii) thermal or base-catalyzed decomposition of substituted benzenesulfonyl hydrazides. 

The hydroxymethyl and carboxyl group of Ser can participate in pyrazole-ring formation, as shown in the transformation of A -protected L-Ser with the Mitsunobu reagent into a /3-lactone which afforded the N-protected serine hydrazide upon treatment with methyl hydrazine. Cyclization to 25 was achieved by diisopropyl azodicarboxylate (DIAD) and TPP [90H(31)79]. 

The reaction of -protected aminomalonate with the Mitsunobu reagent (TPP and DIAD) gave a mixture of a triazoline as the main product and 53 (31%). This compound was formed by the attack of the azodicarboxylate oxygen rather than nitrogen during the cyclization step (88TL4661). 

A variety of 2,4-oxazolidinedione moieties have been prepared as precursors to A-acyliminium ions. These, in turn, have been used in synthetic approaches to 13-aza-16-oxasteroids, interesting and novel heterocycles, " and natural products such as ( )-p-conhydrine, 294b, ( )-6>-methylpaUidinine, 297, 4-oxa-2-aza-podophyllotoxin, 299, and morphine, 302. Introduction of the 2,4-oxazolidinedione can be achieved by conventional alkylation. However, it is normally introduced through Mitsunobu chemistry using diisopropyl azodicar-boxylate or diethyl azodicarboxylate. " The former reagent is favored by... 

The general conclusion to be drawn from the experience reported with these various oxidative methods is that with increasing reactivity of the oxidizing agents more side reactions are to be expected at sensitive amino acid residues, in particular at Met, Trp, and Tyr. In this context, the azodicarboxylic acid derivatives could represent a valid alternative 54,55 since these reagents are devoid of any side reaction at these sensitive residues 56 The reaction of di-ferf-butyl azodicarboxylate (1) with a peptide cysteine thiol leads to the intermediate formation of a sulfenohydrazide adduct 2 that reacts with the second thiol to generate the... 

Bifunctional reagents have recently been used to facilitate separations in the Mitsunobu reaction.39 Mitsunobu products are often hard to separate from excess reagents and byproducts, including phosphines and phosphine oxides. The tagged phosphine 21 and azodicarboxylate 22 and the byproducts formed from these are converted to the carboxylic acid forms by treatment with trifluoroacetic acid (TFA) at the end of the reaction. The excess reagents and byproducts could then be captured on an ion exchange resin for convenient removal. 

Stereochemical inversion of a 6-lactone.1 The 0-lactone 2, obtained by standard lactonization of 1, was inverted to 4 by hydrolysis to the hydroxy acid 3 followed by laclonizalion with triphenylphosphine and diethyl azodicarboxylate. This method evidently involves activation of the hydroxyl group followed by an intramolecular Sn2 attack by the carboxyl group. Two other reagents can he used for this purpose ... 

Much work has been done on configuration and conformation, e.g. of 2-methoxy-2-oxo-4,5-diphenyl-l,3,2-dioxaphospholanes with 170 and lsO labelled reagents (81CC245). A large number of 2-dimethylamino-l,3,2-dioxaphospholanes or 3-methoxy-2-methyl-l,3,2,-oxazaphospholanes are mentioned in a recent publication, in which spiro compounds of the general structure (108) were prepared by addition to diethyl azodicarboxylate (equation (69)) (80PS(8)147>. 

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). 

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