Azodicarboxylates Diels-Alder reactions

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. 

Thieno[2,3(3,2)-/]indolizines such as 50 undergo Diels-Alder reactions with diethyl azodicarboxylate (DEAD) to give the tetracyclic system 51 (Equation 6) <1995TL83>. 

Jimenez et al. studied the asymmetric Diels-Alder reactions of 1-aryl-1,2-diaza-l,3-butadienes 114, heterodienes derived from sugars, with diethyl azodicarboxylate (115), a heterodienophile [85]. The reactions were performed without solvent in a focused microwave reactor for periods of a few hours. The reaction is stereoselective... 

Azo compounds are reactive dienophiles. Indeed, one of the very first Diels-Alder reactions was the addition of diethyl azodicarboxylate to cyclopentadiene (equation 134)128 129. Other early examples of the reaction are the formation of tetrahydropyridazines from indazolone 252 and phthalazinedione 253 (equations 135 and 136)130. 

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. 

The stereoselective normal electron demand Diels-Alder reaction of chiral 13-diaza-13-butadienes 42, derived from acyclic carbohydrates, with diethyl azodicarboxylate 2 yields the corresponding functionalized l,23,6-tetrahydro-133,4-tetrazines 43. The observed stereoselectivity is markedly dependent on the relative stereochemistry at C-1 3 - Reactions proceed slowly in benzene solution at room temperature, but are greatly accelerated by microwave irradiation <99JOC6297>. 

Avalos et al. has reported the microwave-assisted synthesis of tetrazine derivatives by a hetero Diels-Alder reaction of homochiral 1,2-diaza-l,3-butadienes with diethyl azodicarboxylate (Scheme 3.40)65. Under conventional conditions, reactions could be performed in benzene solution at room temperature. However, under microwave heating conditions, the reaction was significantly accelerated (by a factor of 1000) when carried out solvent free. The observed stereoselectivity was identical for the hetero Diels-Alder reaction under both microwave-heated and conventional conditions. 

Avalos, M., Babiano, R., Cintas, P., Clemente, F.R., Jimenz, J.L., Palacios, J.C. and Sanchez, J.B., Hetero-Diels-Alder reactions ofhomochiral 1,2-diaza-1,3-butadienes with diethyl azodicarboxylate under microwave irradiation. Theoretical rationale of the stereochemical outcome, /. Org. Chem., 1999,64, 6297-6305. 

Ten years later, the synthesis of alkyl-substituted thiirene sulfoxide 140 was reported (Scheme 69), making use of a Diels-Alder reaction between thiirano-radialene sulfoxide 138 and the highly reactive dienophilic 4-substituted 1,2,4-triazoline-3,5-diones 139 (TAD) [132]. The fact that other classical reactive di-enophiles, including maleic anhydride and ethyl azodicarboxylate, do not react with sulfinyldiene 138, reveals its low reactivity. 

Macrocyclic azodicarboxylates containing a steroid skeleton were also synthe-tized using a similar synthetic route [52]. These compounds were trapped by Diels-Alder reaction with cyclopentadiene. 

The acetate ofthis alcohol is used in a Diels-Alder reaction with the interesting dienophile DEAD (diethyl azodicarboxylate—in orange). 

The synthesis of BENZYL ISOCYANIDE from benzaldehyde via reductive amination with 5-aminotetrazole followed by oxidation of the resultant amine with sodium hypobromite provides a general method for the synthesis of isocyanides. The preparation of BIS(2,2,2-TRICHLOROETHYL) AZODICARBOXYLATE makes available an alternative to dimethyl azodicarboxylate that is not only more reactive in Diels-Alder reactions but whose ester groups can be removed under neutral conditions. 

Formyl and 2-acetylfuran underwent an unusual reaction with ethyl azodicarboxylate to form adducts 285 and 286, respectively, as depicted in Equation (177) <1997T9313, 1999J(P1)73>. Computational studies of the reaction suggested an initial Diels-Alder reaction between the furan and azodicarboxylate, followed by rearrangement of the cycloadducts. A similar transformation was observed for the reaction between furfurals and 1,4-phthalazinedione in the presence of Pb(OAc)4, as shown in Equation (178) <20020L773>. 

Other syntheses involve the preparation from the monoacetate of the enolic form of nitrosuccindialdehyde/ or the dibenzoyldioxime of maleic aldehyde/ or by dehydrogenation of l-tosyl-l,4-dihydro-pyridazine. From 2,5-diacetoxy- or 2,5-dimethoxy-2,5-dihydro-furan pyridazine can be obtained in high yield. Maleic aldehyde has been obtained also when decomposing the adduct obtained in the Diels-Alder reaction between furan and diethyl azodicarboxylate and straightforward condensation with hydrazine afforded pyridazine in 55% yield.Another direct reaction involving maleic aldehyde... 

Azodicarboxylates are recognized for their ability to participate as 2ir components of HOMOdi e-con-trolled Diels-Alder reactions with dienes and for their participation in ene reactions with reactive al-kenes. 489 j, addition, electron-rich or reactive simple alkenes that do not contain a reactive allylic hydrogen atom have been shown to participate in competitive [2 + 2] and [4 + 2] cycloaddition reactions with azodicarboxylates in which the observed course of the reaction is dependent upon the solvent polarity and nucleophilic character of the alkene (Table 13). As may be anticipated, alkoxycarbonyl-aroyldiimides (4), diaroyldiimides (5), and aiylaroyldiimides (6) participate with increasing selectivity as 4tr components of [4 + 2] cycloaddition reactions. 

The Diels-Alder reaction of diethyl azodicarboxylate with a 20-acetoxypregna-16,20-d iene (116) gave the heterocyclic der i vati ves (117 predominantly 16a), which were hydrolysed to the corresponding ketones (118). ... 

In the gas phase, 2 is a thermally very stable compound up to 850 °C. Pyrolysis at 880°C/10 Torr generates styrene (55-62%) and o-xylene (6%) along with small amounts of phenylacetylene, benzene, toluene and unidentified hydrocarbons. Cycloaddition reactions with dienophiles were among the first reactivity studies on 2 they were of course driven by the expectation to generate a cyclobutadiene structure by a twofold (4 + 2) cycloaddition. However, while 2 reacts readily with electron-deficient alkenes such as TCNE, A -phenyhnalermide, 4-phenyl-l,2,4-triazolinedione and diethyl azodicarboxylate to form 1 1 adducts 115, a second Diels-Alder reaction... 

Alternatively, the 5,6-double bond in the initial adduct can be elaborated via Diels-Alder reactions with cyclopentadiene derivatives and this provides an entry to the tetracy-clo[5.2.1.0 0 ]decane series. Hence reaction of the diethyl azodicarboxylate adduct with hexachlorocyclopentadiene gave the adduct 13 which was elaborated to give endo,syn-l,7,8,9,10,10-hexachlorotetracyclo[5.2.1.0 0 ]dec-8-ene (14). Similar syntheses yield derivatives with a variety of substituents at CIO and in this series it was found that sulfuric acid hydrolysis of the carbamates gave a better yield than sodium hydroxide in methanol. The... 

The homolog of prismane, quadricyclane (29) was obtained through the homo-Diels-Alder reaction between diethyl azodicarboxylate and norborna-2,5-diene, ° although the deazetization has to be carried out photochemically. Thermal deazetization of the diazene 28 (and of closely related diazenes ) results in a reversion to the homodiene. 

Alkoxythiazoles (68) give an abnormal Diels-Alder reaction with highly reactive dienophiles such as 4-phenyl-3//-l,2,4-triazole-3,5(4/0-dione (PTAD), diethyl azodicarboxylate (dead), or diethyl oxomalonate. As an example, the reaction of (68) with PTAD (69) is illustrated in Equation (17). The product of the reaction (70) is the formal [3-1-2] cycloadduct between (69) and the corresponding nitrile ylide derived by the opening of thiazole ring system. For this abnormal Diels-Alder reaction of thiazoles a stepwise mechanism has been proposed <92BCJ3315>. 

Two of the double bonds of ethyl azepine-I-carboxylate can take part in a Diels-Alder reaction for example, with heterodieneophiles sudi as diethyl azodicarboxylate or 4-phenyl-1,2,4-triazole-3,S dione, the addition proceeds at ambient temperature over 12 weeks. 

Strictly speaking, these variants are no more ene reactions than the cycloaddition reaction of dimethyl azodicarboxylate with 1,3-butadiene is a Diels-Alder reaction. Indeed, the reaction of a carbonyl group, specifically formaldehyde, is separately known as the Prins reaction. The overall characterization of the reaction as a process that fundamentally effects the change illustrated in the basic ene reaction, regardless of the specific atoms involved, is nonetheless useful and will be discussed here. 

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