Aldehydes formation, azodicarboxylate

C-Nucleophiles have recently been added asymmetrically to azodicarboxylates as Michael-acceptors, resulting in a-amination of the nucleophilic component. Examples of this type of reaction, which is based on activation of the aldehyde or ketone component by enamine formation, are summarized in Scheme 4.27. Please note that this type of reaction is covered in more detail in chapter 7 of this book. 

Extension of this proline-catalyzed a-amination to the use of aldehydes as starting materials has been described independently by the Jorgensen and List groups [6, 7]. The principle of the reaction and some representative examples are shown in Scheme 7.4. The practicability is high - comparable with that of the analogous reaction with ketones described above. For example, in the presence of 5 mol% L-proline as catalyst propanal reacts with azodicarboxylate 3a at room temperature in dichloromethane with formation of the a-aminated product 5a in 87% yield and with 91% ee [7]. Good yields and high enantioselectivity can be also obtained by use of other types of solvent, e.g. toluene and acetonitrile. The products of type 5 were isolated simply by addition of water, extraction with ether, and subsequent evaporation. 

The photochemical addition of 2H-azirines to the carbonyl group of aldehydes, ketones and esters is completely regiospecific (77H143). Besides the formation of the isomeric oxazolines 18 from 3 and ethyl cyanoformate, there is also formed the imidazole 19 from addition to the C = N in the expected regioselective manner. Thioesters lead to thiazolines 20, while isocyanates and ketenes produce heterocycles 21 (Scheme 4). The photocycloaddition of arylazirines with a variety of multiple bonds proceeds in high yield and provides a convenient route for the synthesis of five-membered heterocyclic rings. Some of the dipolarophiles include azodicarboxylates, acid chlorides, vinylphospho-nium salts and p-quinones. 

As adenosine antagonists, a great number of 8-substituted xanthines with varying substitution patterns in the 1- and 3-position have been prepared. As starting materials, l,3-dialkyl-5,6-di-aminouracils are used, which are transformed to the 1,3,8-trisubstituted xanthines by one of three methods. The first consists of condensing diaminouracil with an aldehyde to form the imine which is oxidatively cyclized by treatment with diethyl azodicarboxylate (DEAD) in a modification of a reported general procedureto give the appropriate xanthine derivative, e.g. formation of 10. 

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... 

A more complex process was the multicomponent reaction [9u, 21] between acetone (3a), benzyl azodicarboxylate (6) and enolizable aldehydes 5 (Scheme 4.2) [22] catalyzed by substoichiometric amounts of (S)-proline (1). The higher reactivity of the aldehydes over acetone (about 100-fold) towards the azodicarboxylate, led to the formation of an a-amino aldehyde derivative which was the electrophilic partner for the fnrther aldol reaction. The low diastereomeric ratio (ca. 1 1) of the products 7 was attributed to the easy and fast racemization of the initial formed a-amino aldehyde, compare to its reaction with acetone. Notwithstanding, this strategy has been used in the synthesis of a rennin inhibitor. 

Purine Synthesis. Aminopyrimidines and aminouracil derivatives can be converted into purines with diethyl azodicarboxylate in a number of closely related synthetic methods. Treatment of compound (1) with an aldehyde leads to the formation of imine (2), which is converted to purine (3) with DAD (eq 4). A number of researchers have applied variations of this approach. Treatment of 6-aminouracils or 6-aminopyrimidines (unsubstituted at the 5-position) with DAD leads to the initial formation of hydrazino Michael adducts. Treatment of these adducts with excess DAD leads to cyclization (eq 5). 

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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