Of heteroaromatic N-imines

Tamura, Y., Ikeda, M., Advances in the Chemistry of Heteroaromatic N-Imines and N-Aminoazonium Salts, 29, 71. 

Volume 29 consists of six contributions. Three of these deal with specific groups of compounds and update previous contributions in this publication on the same type of compounds. Thus, R. K. Smalley, who writes on The Chemistry of Indoxazenes and Anthranils 1966-1979, updates the article by Wunsch and Boulton published in 1967 in Volume 8. Raymond Bonnett and Stephanie A. North, writing on The Chemistry of the Isoindoles, update the contribution by White and Mann, published in Volume 10, in 1969, and Richard M. Scrowston, with his review entitled, Recent Advances in the Chemistry of Benzo[fe]-thiophenes, updates that by himself and Iddon in Volume II, published in 1970. The chemistry of Furoxans and Benzofuroxans is covered by A. Gasco and A. J. Boulton. This and the subject of Mononuclear Heterocyclic Rearrangements reviewed by Michele Ruccia, Nicolb Vivona, and Domenico Spinelli, are both topics close to the hearts of the Editors of this volume. Finally, Yasumitsu Tamura and Masazumi Ikeda have summarized Advances in the Chemistry of Heteroaromatic N-Imines and N-Aminoazonium Salts. Although this subject was reviewed as recently as 1974, in Volume 17 of Advances, its growth since then has been so dramatic that this further review is very timely. 

The mechanism of attack of 1,3-dipolar reagents on fluoroalkenes can be considered to be either stepwise or concerted. Heteroaromatic N-imines react by a stepwise 1,3 addition to perfluoroalkenes and -alkynes to give fluorinated pyrazolo[l,5-a]pyridines [82JCS(P1)1593]. Pyridinium /-butoxycarbonylmethylide with fluoroalkenes gave pyrrolo[l,2-a]pyri-dines [86JCS(P 1) 1769] and indolizines (22) are obtained with pyridinium phenacylide [91JFC(51)407]. 

Heteroaromatic N-Imines H.-J. Timpe, Adv. Heterocycl. Chem., 1974,17, 213-255. Chemistry of the Heterocyclic N-Oxides , A. R. Katritzky and J. M. Lagowski, Academic Press, New York, 1971. 

It is interesting to compare the endo selectivities of two closely related types of dipoles. The ylides 47, derived by an imine-azomethine ylide tautomerism of the imines of a-amino esters (Section II,C), are typical dipoles that exhibit high endo selectivity in cycloadditions to cyclic olefins. On the other hand, N-substituted derivatives 79, derived by the deprotonation route (Section II,D) from N-substituted a-amino esters and aldehydes, are very poor in endo selectivity. The N-unsubstituted dipoles 47 are involved in the cycloadditions as ( , )-ylides (or syn-ylides), while the N-substituted dipoles 79 as ( ,Z)-ylidic forms (or anti -ylides). However, the difference in ylide geometry is not the only reason for the lowered endo selectivity of 79, since the anti forms of heteroaromatic N-ylides undergo exclusive endo-selective cycloadditions with cyclic cis-olefins (83H1907 84CL465 85BCJ3137). 

The ultraviolet (UV) absorption spectra of the heteroaromatic N-imines are dependent upon many factors, such as the nature of the parent heterocycles, substituents on the imino nitrogen, and solvent used. Usually pyridine N-acylimines show two intense absorption maxima at 230-235 and 330-360 nm in aprotic solvents such as dioxane, benzene, or chloroform, the latter band of which disappears by addition of acid.13,20,21,75,77 In protic solvents such as alcohol or water a hypsochromic shift and a hypochromic effect of the long-wavelength absorption are observed for example, pyridine N-benzoylimine shows a maximum at 352 nm (e 9700) in dioxane but at 313 nm (e 4650) in ethanol. 13,21 The long-wavelength absorption of pyridine N-ethoxycarbonylimine has been ascribed to a n-n transition on the basis of a Pariser-Parr-Pople (PPP) calculation and measurements of the absorption spectra of preoriented pyridine N-imines in polarized UV light.125... 

Heteroaromatic N-imines and IV-aminoazonium salts show a variety of reactivities, depending on the nature of the heteroaromatic ring and the substituents on the imino or amino nitrogen. The most important types of the reactions are (i) reactions with electrophiles at the imino or amino nitrogen, (ii) reactions with nucleophiles on the heteroaromatic ring, (iii) 1,3-dipolar cycloaddition, (in) 671-electrocyclic reaction of 1,5-dipoles (mainly thermal reaction), (n) 47t-electrocyclic reaction (mainly photochemical reaction), and (vi) N—N bond cleavage (by thermolysis, photolysis, oxidation, and reduction). 

In general, the reaction of heteroaromatic JV-imines with a,/ -unsaturated carbonyl compounds gives cycloaddition products as described later (Section IV,C). However, in some cases they can act as nucleophiles. Thus, pyridine N-ethoxycarbonylimine, in the presence of silicic acid, reacts with fumarate, maleic anhydride, (V-phenylmaleimide, p-benzoquinone, and a-naphthoquinone to give the corresponding enamines in good yields (Eq. 23).176 Pyridine JV-imine also reacts with dimethyl maleate to give dimethyl aminofumarate.164... 

Since Huisgen et al. first demonstrated the 1,3-dipolar character of pyridine N-imine in 1962,182 the 1,3-dipolar cycloaddition reactions of the heteroaromatic JV-imines have been explored extensively. The reactivity stems from the azomethine structure of the JV-imines.183 The cycloaddition of a variety of activated alkynes and alkenes to the JV-imines yields fused dihydro-pyrazoles and tetrahydropyrazoles, respectively. However, the aromaticity of the heteroaromatic ring is destroyed at this stage, so that such primary cycloadducts usually undergo further reaction to achieve stabilization in various ways as shown in Scheme 4 (i) aromatization, (ii) hydrogen transfer, (iii) rearomatization by rearrangement, and (iv) rearomatization by N—N... 

Since the JV-imines are generally unstable, the reaction is usually carried out by treating the JV-aminoazonium salts with base in the presence of 1,3-dipolarophiles. The versatility of this reaction is demonstrated by application to a wide range of the six-membered heteroaromatic N-imines which include substituted pyridine JV-imines,187 di-JV-imines of 2,2 -bipyridyl and... 

The major reaction of five-membered heteroaromatic N-imines (1-alkyl-l, 2,4-triazole 4-acylimines254 and 4-arylimines,255 2-phenylbenzotriazole 1-cyanoimine,97 thiazole JV-acetylimine,239 and 1-alkybenzimidazole 3-acylimines122) is N—N bond fission, with a few exceptions. In the case of 1-methylbenzimidazole JV-ethoxycarbony limine, a 1,2-migration of the ethoxycarbonylamino group has been observed.122... 

Unlike some aliphatic amine N-imines,6 heteroaromatic N-imines are always alkylated at the nitrogen atom of the imino group,11 1214 34 37 72 - 86 - 87 [Eq. (10)] although mesomerism also affords other points of attack (see Section III,A). The alkylation of unsubstituted pyridine N-imines with polynitrohalobenzenes yields N-(polynitroarylimines) (see Section II, A,4). 

The earlier reviews described a number of synthetic approaches to this system. The most generally useful, however, were observed to be those starting with A -aminopyridinium derivatives and constructing the five-membered ring. The chemistry of A -aminoazonium salts, and heteroaromatic N-imines in general, has been reviewed <81AHC(29)73>. Syntheses reported since the publication of the first edition continue to reflect the above-mentioned observation. 

The synthetically important methods can be classified into the following three categories (i) direct iV-amination of the heteroaromatic bases, (ii) cyclization of monohydrazone derivatives, and (Hi) iV-alkylation of N-aminoazoles. In addition, there are several special methods that have been used for the preparation of some particular heteroaromatic iV-imines and iV-aminoazonium salts. 

Nitrenes generated photochemically or thermally from arenesulfonyl azides and alkoxycarbonyl azides add to the nitrogen atom of heteroaromatic bases to give the corresponding N-(substituted imines).20,21,50,64-69 However, the yields are usually low and the scope is severely limited. 

The stereochemistry of the 1,3-dipolar cycloaddition of the heteroaromatic iV-imines has been investigated in some detail by using the reaction of phenanthridine N-benzoylimine with a series of activated olefins such as JV-methylmaleimide, maleic anhydride, diethyl maleate, methyl acrylate, methyl methacrylate, and methyl trans-crotonate (e.g., Eq. 30).202 The adducts from the former three have the all-cis stereochemistry. These results are rationalized in terms of secondary molecular orbital interactions. With acrylates such stereospecificity is lost, suggesting that this effect is of lesser importance in these cases (see Table II). 

Amino-1,2,4-triazoles (50) or their derivatives are usually starting material for the synthesis. They are readily available and already contain the exocyclic N-N bond required for heteroaromatic A-imines. 4-Amino-1,2,4-triazoles can be quaternized by alkyl halides or tosylates at the N-l atom to give the salt 52.79-82 (Scheme 5) The orientation of quatemization is proved by the reactions in Scheme 6 for the example of the quaternary acylamino salts 52. Quaternary salts of the type 52 can also be prepared by reaction of 1,3,4-oxadiazolium salts (51)83 with aryl hydrazines84 and from aryl hydrazine hydrohalides and orthoesters.86 With alkali, the 1-alkyl-s-triazole-4-imines8(7-82 86 can be obtained in the normal manner from these salts (Scheme 5). The free A-imines are all stable except the A-unsubstituted compound itself.87 Recently, other structures were tentatively reported 88 for the deprotonation products of analogous quaternary salts (52) with hydrazine. 

Heteroaromatic A-imines are photochemically active compounds (see Table III) On irradiation they generally yield products of (a) N-N bond cleavage, (b) ring enlargement, (c) rearrangement. However, the available data do not permit definition of the conditions necessary for selective reactions. Apparently unimportant changes in the substituents and the solvent may lead to different results. Therefore, the photochemical reactions will be discussed separately for the individual A-imines. 

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