Azadienes isomerization

Aza-Diels-Alder reaction between the lactim ether 49, as azadiene, and 3-methyleneoxindole, as dienophile, resulted in an isomeric mixture of the aza-Diels-Alder products 55 and 56 (Equation 4) <20030L3205>. 

The oxime derived from 2-furfural has been used for the first time as an electron-rich 1-azadiene by Kusurkar and Bhosale (91TL3199) (Scheme 16). Thus, 2-furfuraldoxime 60 undergoes at 120°C [4 + 2] cycloaddition to acrylonitrile, acrylic acid esters, and maleic anhydride to give stereoiso-meric cycloadducts 61 and 62. The isomeric fused pyridines obtained were not separated, but dehydrogenated to the corresponding furo[2,3-c]pyridine N-oxide derivatives. 

This method has been applied to the synthesis of other 2-azadienes. The corresponding non-silylated /V-allylimine is not formed and does not isomerize into the azadiene under the conditions of the reaction. The stereochemistry (E/Z E/E) of the diene depends on... 

Primary enamines 115 have been obtained by flash thermolysis of adducts 116 at 600 °C in vacuo. A retro-Diels-Alder reaction occurs to give vinylamine (R = R1 = R2 = H). These primary enamines have been identified by their spectroscopic properties at — 80 °C. At temperatures > 80 °C isomerization to the imine occurs as well as self-condensation to various nitrogen heterocycles or acyclic azadienes. 

Imines derived from benzylamine and a,3-unsaturated ketones which represent 1-azadiene systems can be isomerized to the corresponding 2-azadienes with potassium t-butoxide. Addition of r-butyl-lithium occurs smoothly to afford simple imine anions that undergo alkylation in the usual fashion. 3S The two examples provided in Scheme 17 illustrate the power of this method to provide either a,a- or a,a -substitution. On the other hand, reaction of similar 1-azadiene systems with Grignard reagents results in addition to form the imine anion directly (equation 44). This example represents one of the early contributions to asymmetric induction in this area and will be elaborated in Section 4.1.3.5. 

The 1-azadiene and the dienophilic character of 2-alkenyl-5,6-dihydro-4//-l,3,4-oxadiazines (150 Section 6.17.6.2) have been explored (Scheme 21) <93TL457>. Attempts to effect cycloaddition with DMAD, dimethyl fumarate, and acrylonitrile failed, whereas with maleic anhydride and A-methylmaleimide unexpected noncyclic adducts (e.g. 151) are obtained. The alkenyl oxadiazines also fail to give cycloadducts with l-methoxy-3-trimethylsilyloxy-l,3-butadiene with or without the presence of a Lewis acid catalyst. However, with methyl penta-2,4-dienoate mixtures of diastereo-isomeric products (e.g. 152) are formed, albeit slowly, by [4 + 2] cycloaddition at the alkenyl side chain, rather than at the C2—N3 imine bond. 

C.V. Azadienes. Azadienes such as 163 and 164 are useful diene partners that can be used for the preparation of many heterocycles and alkaloids.The utility of 1-azadienes in the Diels-Alder reaction is limited by the fact that isomerization occurs to give a conjugated imine, probably via a proton transfer. An example is the equilibration of 187 and 188. Addition of maleic anhydride to this mixture gave the Diels-Alder adduct derived from aminobutadiene (187), and the cycloadduct 189.1 2 Even when isomerization is prevented, the aminobutadiene is relatively unreactive and the yields can be poor. An important side reaction is a competitive [2+2]-cycloaddition (sec. 11.10.A), which often leads to poor yields of the [4+2]-cycloadduct. 1 3494 incorporation of tertiary alkyl substituents are also used to stabilize the 1-azadiene. 

Thermal isomerization of amino-substitued 2i/-azirines (e.g. 183 -> 184) results in the formation of 2-azadienes. They react with activated alkynes, e.g. with acetylenedicarboxylic ester (ADE), in a hetero-Diels-Alder reaction, giving dihydropyridines (e.g. 185), which aromatize with elimination of amine yielding pyridine-3,4-dicarboxylic esters (e.g. 186). 

The gas-phase fluorination of substituted pyrimidine 117 (Rf = CF(CF3)2) over C0F3 leads to the selective and high-yield formation of azadiene 118, however, unsubstituted F-pyrimidine under similar conditions forms the dimer 119. On the other hand, the reaction of isomeric F-pyridazine with C0F3 is straightforward leading to azadiene 120 (Fig. 9.36). Detailed discussion on the radical cation mechanism... 

The treatment of 125 ( = 1) with CI2 orMel leads to compounds 126 and 127 in decent yields and the alkylation of 125 ( = 2) with fluorinated alkyl trifluor-osulfonates results in the formation of amines 128 (Fig. 9.38). Isomeric azadienes 129 and 130 both produce stable unsaturated azaanion 131 upon treatment with CsF in polar media. The reaction of 129 with Mel leads to the formation of unsaturated heterocycle 132 and the treatment with boron trifluoride results in the mixture of dienes 129 and 130 " (Fig. 9.39). 

FIGURE 9.45 Photochemical isomerization of perfluorinated cyclic azadienes. 

In sharp contrast to heterocycles, containing only one double bond, poly-fluorinated cyclic azadienes undergo photochemical isomerizations. The outcome of the reaction depends on the structure of starting material. For example, irradiation of 129 results in high-yield formation of cyclobutene 148 (Fig. 9.45). 

More recently (2004), Joule proposed a novel synthetic route to access the akuammiline scaffold with reports from his group s synthetic efforts toward realizing this plan. Retrosynthetically, they envisioned akuammiline (1) to result from late stage imine formation of ketone 247 (Scheme 32). The functionality at position 16 would then be elaborated from a carbonyl contained in diketone 248, which in turn was planned to be obtained via an intramolecular Claisen condensation and double bond isomerization of enamine 249, the latter the product of an aza-Diels—Alder cycloaddition involving cyclic 1-aza-1,3-diene 250 and an acrylate 251. To access azadiene 250 they planned an oxidative ring opening of bicyclic pyrrole 252. 

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