Azodicarboxylates, reactions with enamines

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. 

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). 

Enamines derived from ketones undergo some of the same reactions described for enol ethers, for example with arenesulfonyloxy carbamates as in Eq. 96120 121 3" and with ethyl azidoformate as in Eq. 98.302 303 The reaction with activated azo compounds occurs readily at room temperature or below and diamination often cannot be avoided with the more electrophilic reagents (Eq. lOl).400,401 The proline-catalyzed reaction of ketones with azodicarboxylic esters, which proceeds by way of the enamines, has been mentioned above (Eq. 91). 

In 2003, a proline-catalyzed enamine-enamine activation sequence was used to develop a three-component reaction leading to functionalized P-amino alcohols 35 [29, 30]. The reaction used both ketones (specifically, acetone) and aldehydes 33 as donors, together with azodicarboxylate 34 (Scheme 42.9) [30]. The first step is the pro line-catalyzed amination of aldehydes [31], leading to intermediate 36, which represents the electrophiUc substrate for the subsequent aldol reaction with acetone. Both intermolecular steps proceed under enamine catalysis by proline 1. A key factor in the high level of chemoselectivity observed was the much higher reactivity of aldehyde over ketone in the proline-catalyzed a-amination reaction, which selectively forms 36. 

Silyloxyproline 25 (10 mol%) was able to catalyzed the reaction of several cyclic and acychc ketones with dibenzylic azodicarboxylate (18b). In order to achieve high yields and enantioselectivities, nine equivalents of water were added to the reaction mixture, although this addition retards the reaction [33]. When these conditions were applied to the reaction with cyclopentanone, the major product was the a,a -diaminated cyclopentanone in 46% yield and 99% ee. In this process, contrary to that observed for the case of aldehydes, a linear correlation between the enantiomeric excess of the product versus the catalyst was found. Quantum mechanical calculations suggested that the most stable transition state was that in which the anti-conflgured enamine reacts with the azodicarboxylate in the trans configuration. 

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 conversion of (—)-apomorphine into (+)-apomorphine has been achieved.56 The O-dealkylation of 10,11-dimethoxyaporphine, using sodium thioethoxide in dimethylformamide, has been reported.57 The reactions of the enamine dehydro-nuciferine with dimethyl acetylenedicarboxylate, methyl propiolate, methyl acrylate, and diethyl azodicarboxylate have been investigated, and have resulted in the preparation of a novel series of 7-substituted aporphines.58... 

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. 

In 2011, Moreau, Greek and coworkers reported a multicatalytic process [6] merging two consecutive enamine catalytic cycles based on a Michael addition/a-amination cascade reaction [7]. The Michael addition of aldehydes to p-nitrostyrene followed by the electrophilic amination were catalyzed, respectively, by the diphenylprolinol silylether 5 and the 9-amino-(9-deoxy)-cpf-cinchonine 6 (Scheme 12.4), both previously described by Hayashi and coworkers [8] and Melchiorre and coworkers [9]. One interesting feature of this reaction is that diphenylprolinol silylether 5 can specifically catalyze the Michael addition, while 9-amino-(9-deoxy)-ep/-cinchonine 6 is required to promote the electrophilic amination. The Michael addition of propionaldehyde to p-nitrostyrene was achieved by using only 5 mol% of catalyst 5 in chloroform at 0 C. After completion of the reaction, dibenzyl azodicarboxylate (DEAD, 1.5 equiv), trifluoroacetic acid (15 mol%) and the second catalyst 6 (5 mol%) were added. The expected product 7 was obtained as a single diastereomer in good yield (80%) and with excellent enantioselectivity (ee 96%). Various nitroalkenes bearing electron-rich and electron-deficient aryl... 

Marigo et al. developed a multicomponent domino-conjugated nucleophilic thiol addition-electrophilic amination reaction that gave access to 1,2-aminothiol derivatives with >99% ee in a one-pot process using 128 as a catalyst (Scheme 1.72) [ 114]. The soft sulfur nucleophile 168 first reacted with the iminium ion intermediate, followed by addition of the enamine intermediate to the azodicarboxylates 169. In situ reduction and cyclization resulted in the formation of highly functionalized oxazolid-inones 170 in nearly enantiopure form. 

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