Azodicarboxylates

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). 

An oxidative cyclization, (151) -> (152), with azodicarboxylate (78CC764) is balanced by the synthesis of 5-deazaalloxazines from aryl bis(6-aminouracilyl)methanes, which involves azodicarboxylate in an intermediate electrophilic capacity (153 -> 154) (79CPB2507). Other methods involve reductive cyclizations (72AP751). 

Similarly, no systematic study of the IR spectra of the pyridopyridazines has been recorded, but the spectra of the [2,3-d] derivatives have been discussed <68AJCl29l). The diones of this series have also been studied <69MI21501), and IR used to distinguish between the structure (303) and the possible isomeric formulation (304) <74JHC35l). The IR spectra of some of the azodicarboxylic ester adducts <79X2027) have been recorded, whilst in the benzo fused systems some problems with the structure of acyl derivatives in the pyridazino[4,5-6]quinoline series have been resolved with the help of IR spectroscopy <71BSF906, 72BSF1588). 

Amongst miscellaneous UV spectra recorded are those of alkylthio adducts of pyrido[3,2-c]pyridazine (78KGS1272), various pyrido[3,4-d]pyridazines (57AC(R)728) and several vinyl-pyridine-azodicarboxylic ester adducts (79T2027, 79KGS639). 

The other main source of various pyridopyridazines from pyridines are the [4 + 2] cycloaddition reactions, already mentioned (Section 2.15.8.3), between vinylpyridines and azodicarboxylic esters (79T2027, 79KGS639) or triazolidinediones e.g. 78KGS651). 2-Vinyl-pyridines gave reduced pyrido[3,2-c]pyridazines (370), 4-vinylpyridines gave [3,4-c] analogues, whilst 2-methyl-5-vinylpyridine furnishes a mixture of the [2,3-c] and [4,3-c] compounds. Yields are low, however, and these remain curiosities for practical synthetic purposes. 

Cycloaddition reactions of aziridines with a wide assortment of dipolarophiles have been studied. The reaction of dialkyl azodicarboxylates with the cf5-aziridine (27) is stereospecific... 

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, vinylphosphonium salts and p-quinones. 

U. Oiethyl azodicarboxyl ate 1s purchased from Aldrich Chemical Company, Inc., and is used without further purification. 

A novel pyrolytic method of generating nitrile ylides in situ was reported by Burger [44] (equation 45) Such nitrile ylides react with various dipolarophiles alkynes [44] (equation 46), nitriles [45] (equation 47), dimethyl azodicarboxylate [45], aldehydes [45], and nitroso compounds [46]... 

In a similar manner the addition of ethyl azodicarboxylate to the morpholine enamine of cyclohexanone furnished the less substituted isomer (34) with the substituent in the axial orientation (2, 26). 

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 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. 

The Mitsunobu reaction is usually used to introduce an ester with inversion of configuration. The use of this methodology on an anomeric hydroxyl was found to give only the /3-benzoate, whereas other methods gave mixtures of anomers. Improved yields are obtained in the Mitsunobu esterification when p-nitrobenzoic acid is used as the nucleophile/ Bis(dimethylamino) azodicarboxylate as an activating agent was... 

To prepare fervenulin 4-oxides 12 or toxoflavine 4-oxides 146, it is convenient to use the reaction of l,3-dimethyl-2,4-dioxopyrimidin-6-yl hydrazone 147 or N-(3-methyl-2,4-dioxopyiimidin-6-yl) iV-methylhydrazone 148 with potassium nitrate in acetic acid [75CPB1885,76CPB338,76JCS(CC)658,82JHC1309,93CPB362]. Diethyl azodicarboxylate can be used instead of potassium nitrate [76JCS(P1 )713]. 

When Diels and Alder published their famous paper in 1928, Diels had been working with related reactions for several years [6]. In 1925, Diels reported the reaction of azodicarboxylic ester (Et0C(0)2CN=NCC(0)0Et) with compounds containing a conjugated diene system. He found that addition of the azodicarboxylic ester occurs at the 1,4-position of the conjugated system as with cyclopentadiene and with butadiene. This work probably led to the famous Diels-Alder reaction. In 1927, Diels and his student Alder published a paper on the reaction of azodicarboxylic ester with styrene. 

The mechanistic pathway" " can be divided into three steps 1. formation of the activating agent from triphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) 2. activation of the substrate alcohol 1 3. a bimolecular nucleophilic substitution (Sn2) at the activated carbon center. 

In an initial step triphenylphosphine adds to diethyl azodicarboxylate 5 to give the zwitterionic adduct 6, which is protonated by the carboxylic acid 2 to give intermediate salt 7. The alcohol reacts with 7 to the alkoxyphosphonium salt 8 and the hydrazine derivative 9, and is thus activated for a SN2-reaction ... 

In summary the Mitsunobu reaction can be described as a condensation of an alcohol 1 and a nucleophile—NuH—11, where the reagent triphenylphosphine is oxidized to triphenylphosphine oxide and the azodicarboxylate reagent 12 is reduced to a hydrazine derivative 13 ... 

The conversion of an alcohol to an amine can be achieved in a one-pot reaction the alcohol 1 is treated with hydrazoic azid (HN3), excess triphenylphosphine and diethyl azodicarboxylate (DEAD). The initial Mitsunobu product, the azide 14, further reacts with excess triphenylphosphine to give an iminophosphorane 15. Subsequent hydrolytic cleavage of 15 yields the amine—e.g. as hydrochloride 16 ... 

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