Azines electrophiles

When 7r-deficient thiadiazoles are fused to an azine, electrophilic substitution is possible only in the presence of strongly electron-donating substituents (74BCJ2813) (Scheme 56). Some [l,3,4]thiadiazolo[3,2-a]pyrimidin-5-ones were brominated next to the oxo group (90DOK743). 

Thiadiazoles like oxadiazoles are 7r-electron deficient systems. When fused to azines, electrophilic substitution on carbon is only to be expected in the presence of strongly electron-donating substituents. Thus the lactams (666) and (667) are activated for electrophilic substitution (74BCJ2813), whereas in the absence of an activating substituent the electrophile may attack an aromatic side-chain as in the case of (668) (70JOC1965). 

Abstract The chapter reviews the classic Reissert reaction, the keystone of a broad family of multicomponent reactions involving azines, electrophilic reagents and nucleophiles to yield A,a-disubstituted dihydroazine adducts. The first sections deal with the standard nucleophilic attack upon activated azines, including asymmetric transformations. Section 5 focuses on the generation of dipolar intermediates by azine activation, and on their subsequent transformation chiefly in cycloadditions. Lastly, Sect. 6 is primarily devoted to a special branch of this chemistry involving isocyanides. It also covers the reactivity of dihydroazines and reviews the mechanistic proposals for related reactions. 

The factors in carboaromatic nucleophilic displacements summarized in this section are likely to be characteristic of heteroaromatic reactions and can be used to rationalize the behavior of azine derivatives. The effect of hydrogen bonding and of complexing with metal compounds in providing various degrees of electrophilic catalysis (cf. Section II, C) would be expected to be more extensive in heteroaromatics. 

There are conflicting generalizations in the heterocyclic literature as to the relative reactivity of a- and y-positions in azines toward nucleophiles. Variations in the relative reactivity are attributed in this and subsequent sections to specific factors operating in addition to activation by azine-nitrogen. Another possible source of variation may be a decrease in selectivity with increasing reactivity of one or both reagents, an effect established in electrophilic aromatic... 

One significant difference between nitrocarboaromatics and aromatic azines is the tendency of the activating center of the latter to react with electrophiles or compounds capable of hydrogen bonding, thereby accelerating nucleophilic substitution. 

The azinones and their reaction characteristics are discussed in some detail in Section II, E. Because of their dual electrophilic-nucleophilic nature, the azinones may be bifunctional catalysts in their own formation (cf. discussion of autocatalysis below) or act as catalysts for the desired reaction from which they arise as byproducts. The uniquely effective catalysis of nucleophilic substitution of azines has been noted for 2-pyridone. 

Amination of the deactivated carbanion of 4-benzylpyridine formed with excess sodamide presumably proceeds because the strong indirect deactivation is overcome by electrophilic attack by Na+ at the partially anionic azine-nitrogen and by concerted nucleophilic attack by H2N at the 2-position via a 6-membered cyclic transition state (75). However, in simple nucleophilic displacement a carbanion will be more deactivating than the corresponding alkyl group, as is true in general for anionic substituents and their non-ionic counterparts. 

Quinone diazides can also be obtained by the diazo group transfer reaction of 4-tosyl azide. For example, 9-diazo-10-anthrone (2.55) is formed from anthrone (2.54) if the reaction is carried out in an ethanol-piperidine mixture. On the other hand, if ethanol is replaced by pyridine, dimerization with loss of molecular nitrogen takes place and the azine 2.56 is isolated (Scheme 2-32 Regitz, 1964 Cauquis et al., 1965). In the preceding discussion tosyl azide was shown to be an electrophilic reagent. It therefore seems likely that it is not the anthrone 2.54 but its conjugate base which reacts with tosyl azide. 

Jug and co-workers investigated the mechanism of cycloaddition reactions of indolizines to give substituted cycl[3,2,2]azines <1998JPO201>. Intermediates in this reaction are not isolated, giving evidence for a concerted [8+2] cycloaddition, which was consistent with results of previous theoretical calculations <1984CHEC(4)443>. Calculations were performed for a number of substituted ethenes <1998JPO201>. For methyl acrylate, acrylonitrile, and ethene, the concerted [8+2] mechanism seems favored. However, from both ab initio and semi-empirical calculations of transition states they concluded that reaction with nitroethene proceeded via a two-step intermolecular electrophilic addition/cyclization route, and dimethylaminoethene via an unprecedented two-step nucleophilic addition/cyclization mechanism (Equation 1). 

The formation of a second ring, based on the generation of a six-membered carbanion followed by alkylation with a difunctional electrophile and further cyclization, was also exploited in the synthesis of hexahydropyrrolo[l,2-tf]pyr-azine-l,4-dione 235 starting from alkoxycarbonyl piperazine-2,5-dione 233. When the key precursor was treated with 2equiv of NaH and 1,3-dibromopropane, the bicyclic compound 234 was obtained in acceptable yield and further transformed into compound 235 by deprotection and decarboxylation (Scheme 30) <2005T8722>. 

Terminal alkynes readily react with coordinatively unsaturated transition metal complexes to yield vinylidene complexes. If the vinylidene complex is sufficiently electrophilic, nucleophiles such as amides, alcohols or water can add to the a-carbon atom to yield heteroatom-substituted carbene complexes (Figure 2.10) [129 -135]. If the nucleophile is bound to the alkyne, intramolecular addition to the intermediate vinylidene will lead to the formation of heterocyclic carbene complexes [136-141]. Vinylidene complexes can further undergo [2 -i- 2] cycloadditions with imines, forming azetidin-2-ylidene complexes [142,143]. Cycloaddition to azines leads to the formation of pyrazolidin-3-ylidene complexes [143] (Table 2.7). 

Azoles or azines with an amino group at C-2 have also been used as bis(nucleophiles) to prepare a variety of fused heterocychc systems. In these cases, the geometry of the bis(nucleophile) permits reaction with both electrophilic centers of the oxazolone. Thus, initial Michael reaction and subsequent ring... 

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