Azodicarboxylate esters formation

In common with other azodicarboxylic acid derivatives, the uses of 4-phenyl-l,2,4-triazoline-3,5-dione are many. It undergoes a Diels-Alder reaction with most dienes11-14 and is, in fact, the most reactive dienophile so far reported.15 16 As with the formation of all Diels-Alder adducts the reaction is reversible, and in the case of the adduct with 3-j3-acetoxy-17-cyano-5,14,16-androstatriene, the reverse reaction can be made to proceed under especially mild conditions.14 An instance has also been reported of the dione photochemically catalyzing other retro Diels-Alder reactions.17 Along with the proven use of azodicarboxylic ester,18-18 the dione should be potentially important in the preparation of strained ring compounds. 

Interaction of the mesoionic thiadiazolium salt (299 Ar = Ph) with hydrazine led to the formation of l,4-dihydro-6-hydrazino-l,2,4,5-tetrazine (300) (76KGS713). The reaction of salts (299) with azodicarboxylate esters was at one time thought to provide the mesomeric... 

As l,2,4-triazole-3,5-dione (PTAD) is a stronger dienophile than acetylenic esters, more facile formation of the Diels-Alder cycloadducts was expected. But because it cannot behave as a diene in a reaction with alkynes such as diethyl azodicarboxylate, the formation of dihydrooxadia-zines is excluded. In spite of these characteristics, no Diels-Alder adducts were obtained in the reaction of l-phenyl-4-vinylpyrazole with PTAD in acetone at -80°C and 2,2-dimethyl-4(l-phenylpyrazol-4-yl)-8-phenyl-l,6,8-triaza-3-oxabicyclo[4.3.0]nona-7,9-dione 277 was obtained as a major product. The isolation of the tetrahydrooxadiazine 277 indicates that the 1,4-dipole 278 was formed and trapped with acetone. 

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. 

The mechanism of the Mitsunobu reaction is proving to be more complex than previously recognised. Evidence has been presented for the irreversibility of betaine formation between triphenylphosphine and azodicarboxyl ate esters. The course of the subsequent reaction of the betaine with m-chloroperoxybenzoic... 

A modified Mitsunobu procedure in which 63 is first treated with the preformed complex 68 (prepared by reaction of triphenylphosphine and diisopropyl azodicarboxylate) and then cesium thioacetate leads to significant racemization [17]. However, if the free acid is reacted instead with an appropriate thioacid (rather than the ester and a cesium salt), optical yields improve significantly. Thus, thioacetylation of (S)-l can be accomplished by treating it with 68 followed by the addition of thioacetic acid in THF to provide in 48% yield (5)-2-(acet-ylthio)-2-phenylacetic acid (69) with 84% ee after recrystallization. The low yield is due in part to the unavoidable formation to the extent of at least 50% of a viscous, polymeric material. The reaction is complete in minutes, however, and proceeds with retention of configuration. Presumably this is a result of a double inversion mechanism that passes through an a-lactone. Interestingly, the corresponding reaction with lactic acid does occur with inversion [18]. 

However, epimerization could be achieved using the Mitsonobu procedure by treatment with diethyl azodicarboxylate (DEAD), PhaP, and formic acid followed of careful hydrolysis of the resulting formate ester to give compound 48. The conversion of compound 48 into erivanin (50) was simply a repetition of the previous sequence. 

In recent years, the Mitsunobu reaction has been studied extensively in solution and has found many useful applications. In an effort to overcome many of the problems associated with solution synthesis, the use of highly loaded triphenylphosphine polystyrene-derived resin represents a simple solution to the problem of purification. Thus, reaction of a series of alcohols of type 67 with carboxylic acids in the presence of diethyl azodicarboxylate (DEAD) and PS-PPhj in THF between 0°C and room temperature resulted in the clean formation of the expected esters of type 68. 5 Filtration through a plug of AljO, gave the essentially pure products in high yields (70-90%). 

This reaction was first reported by Mitsunobu in 1967. It is the alkylation of compounds with active protons by using primary or secondary alcohols as the alkylating agents in combination with triphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), to form molecules like esters, ethers, thioethers, and amines. Therefore, this reaction is generally known as the Mitsunobu reaction or Mitsunobu coupling. In addition, the specific reaction for forming esters by means of DEAD (or DIAD) and PPhs is generally referred to as the Mitsunobu esterification." Occasionally, the Mitsunobu reaction is also called the Mitsunobu transformation (for the conversion of alcohol into amines) or Mitsunobu cyclizafion (for the formation of cyclic compounds). Because of its intrinsic features of stereospecificity, as well as its occurrence in neutral media and at room temperature without a prerequisite activation of alcohol, this reaction has been extensively studied and used to synthesize a variety of compounds since 1970. 

Next, the three building blocks were connected sequentially. Initial esterification was attempted via standard Mitsunobu conditions, which afforded poor results due to the formation of the undesired 2,4-phthahde. Nevertheless, esterification was achieved by the use of trifuryl phosphine and di/so-propyl azodicarboxylate, providing benzoic ester 545. The ensuing addition of previously lithiated dithiane 541 led to the open chain precursor 546. RCM under application of the Grubbs II catalyst 547 was successfully used to create the macrohde 548. Removal of the dithiane and cleavage of the methyl ethers as well as subsequent regioselective aromatic chlorination completed this total synthesis of radicicol (478) (Scheme 9.10). 

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