Disubstituted azodicarboxylate

Sn2 inversion of an alcohol by a nucleophile using disubstituted azodicarboxylates (originally, diethyl diazodicarboxylate, or DEAD) and trisubstituted phosphines (originally, triphenylphosphine). 

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. 

This class of compound is represented by 2,3-disubstituted-l,2,3-benzoxadiazoles and new caged structures. 2,3-Disubstituted-l,2,3-benzoxadiazoles 128 were prepared in high yield when the Huisgen zwitterion, formed between dialkyl azodicarboxylates 127 and triphenylphosphine, was reacted with 3-methoxy 4,6-disubstituted-l,2-benzoqui-nones 126 (Equation 23 Table 6) <20050L5139>. 

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). 

Carbodlimides. Diethyl azodicarboxylate (1) reacts with N,N -disubstituted thioureas (2) in THF at room temperature overnight to form a I I adduct (3) [an N, N -disubstituted-S-(N ,N4-biscarboethoxy)hydrazinoisothiourea], which on treat ment with triphenylphosphine at room temperature affords the corresponding carbo. ... 

Additions to compounds with activated double or triple bonds are known. Compound 406 (R = Me) gives 427 with acrylonitrile(405 does not react ), and 401 reacts with diethyl azodicarboxylate and maleic anhydride to give 428 and 429, respectively. The 2,6-dimethyl derivative of 396 undergoes addition to dimethyl acetylenedicarboxyl-ate at C-5 (position a. Scheme 18), but tetracyanoethylene gives both C-5 and C-7 (a and b) products, the latter predominating. Reid had earlier reported that 396 reacts with bulky electrophiles to give mixtures of products and disubstituted derivatives. 

It is possible to trap the 2-substituted lithium derivatives produced by organometalUc addition with electrophiles for example the use of di-f-butyl azodicarboxylate leads, after a simple aerial oxidative re-aromatisation, to 2,5-disubstituted pyridines. ... 

Although the result is not clearly stated in the paper, the tricyclic 4,5-disubstituted isoindole 24 appears to give the cycloadduct with dimethyl azodicarboxylate.37 4,5,6,7-Tetrachloroisoindole gives the disubstitution product 84 however.34... 

Reaction of 4,6-disubstituted-3-methoxy-l,2-benzoquinones with dialkyl azodicarboxylates and triphenylphosphine gives dihydro-1,2,3-benzoxadiazoles 99 in good yield (64—94%) (Scheme 25). A multistep mechanism leading to the zwitterionic intermediates 98, which then cyclise to the products 99, has been proposed (05OL5139). An N,N-diphenyl-2,3-dihydro-l,2,3-benzoxadiazole has been obtained (40% yield) by reaction of 3,5-di-f-butyl-l,2-benzoquinone with W-phenyliminophosphorane (PhN - PPhg) (see also Section 3.1.3.2) (02SC2779). 

Additional examples of oxidations at a nitrogen center inciude the foiiowing the PhI(OAc)2-induced oxidation of aromatic amines to imines appiied for deprotection of protected amino diois [512], N-acylation of 1,3-disubstituted thioureas using PhI(OAc)2 [513], PhI(OAc)2-promoted oxidation of 1,2-dicarbethoxyhydrazine to diethyl azodicarboxylate as a key step in an organocatalytic Mitsunobu... 

Melchiorre and co-workers [55] demonstrated the efficiency of the TEA salt of 9-amino-(9-deoxy)-epi-hydroquinine 21 in promoting an iminium/enamine cascade sequence including a sulfa-Michael followed by an amination reaction (Figure 14.6). The reaction of a,(3-disubstituted enals with t-butyl or benzyl mercaptan and di-t-butoxycarbonyl azodicarboxylate enabled the formation, in excellent levels of enantioselectivity, of valuable precursors of a-amino acids containing two contiguous stereocenters, one of which is quaternary (Scheme 14.19). The diastereomeric ratio of products was also satisfactory. 

Ma has developed a three-component allene carboamination reaction for the stereoselective synthesis of 2,5-as-disubstituted pyrrolidine derivatives [54]. A representative transformation involving allene 58, 4-iodoanisole, and imine 59 that generates 60 in 90% yield is shown below (Eq. (1.28)). The reaction is believed to proceed through the intermediate Jt-allylpalladium complex 62, which is formed by carbopalladation of the alkene to give 61 followed by addition of the malonate anion to the activated imine. Intramolecular capture of the allylpalladium moiety by the pendant nitrogen nucleophile affords the pyrrolidine product. A related asymmetric synthesis of pyrazolidines that employs azodicarboxylates as one of the electrophilic components has also been reported [55]. The pyrazolidine products are obtained with up to 84% ee when chiral bis oxazolines are employed as ligands. 

Barbas has significantly expanded the a-amination method to include the formation of a,a-disubstituted amino acids [90, 91]. Treatment of aldehyde 112 with azodicarboxylate 113 in the presence of 20 mol% e t-107 furnishes 114 in 96% yield and >99% ee, permitting a facile synthesis of the glutamate receptor ligand AIDA (115, Scheme 10.19) [91]. 

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