Indoles with azodicarboxylate

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

The Mitsunobu reaction was also applied to the synthesis of [ 1,2,4]triaz-ino[4,5-n]indoles (84AG517). Thus, reaction of the 2-acylindoles 127 with sodium borohydride in methanol or with lithium aluminium hydride in tetrahydrofuran gave the corresponding alcohols 128. Their cyclization with diethyl azodicarboxylate in the presence of triphenyl-phosphine gave the triazinoindoles 129. Acid treatment of the latter afforded 130 (Scheme 30). 

Cyclization of indol-2-yl acyclo C-nucleosides that carry acid-sensitive O-protective groups such as 11 has been successfully achieved without affecting these groups by dehydration with triphenylphosphine-diethyl azodicarboxylate-iodine a mixture of anomeric C-nucleosides (12) was usually produced [94CL265 95JAP(K)95/118268] (Scheme 4). 

Whereas 2-formylthiophene and 3-formyl indole react with diethyl azodicarboxylate to give products arising from radical reactions at their respective formyl groups, 2-formylfuran gives a product derived from an initial 4+2 cycloaddition (Scheme 8) <9719313>. 

Finally, there is also a relevant example of an intermolecular conjugate Friedel-Crafts/electrophilic amination cascade developed very recently by Melchiorre in which 2-methyl-IH-indole reacted with a variety of a,p-unsatu-rated aldehydes and dialkyl azodicarboxylates in the presence of a primary amine catalyst, leading to the formation of a family of products containing two contiguous stereocenters, one of them a quaternary one (Scheme 7.43). This reaction started with the conjugate addition of 2-methyl-lH-indole to the enal... 

SCHEME 2.29 Organocascade catalysis with combination of azodicarboxylate and either indole or thiol derivatives. 

Diels-Alder [4 + 2] Cycloadditions. Except as noted below, diethyl azodicarboxylate reacts with conjugated dienes to yield [4 + 2] cycloadducts. When the diene moiety is a vinyl aromatic, cycloaddition with DAD is a powerful route for the preparation of annulated tetrahydropyridazine derivatives. Thus the indole derivative (4) reacts with DAD at rt to afford cycloadduct (5) (eq 8). ... 

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