Heterocyclic enamines rearrangement

A similar sequence of reactions takes place with the enamlnes of cyclic ketones (55-57) the initially formed unstable cyclobutene rearranges with insertion of two carbon atoms into the ring. A wide variety of cyclic ketones have been allowed to react in this way. For instance, the enamine (75) gave 76 on reaction with dimethyl acetylenedicarboxylate in refluxing toluene (55) and the heterocyclic enamine (77) obtained from dihydro-3-(2H)-... 

Cope rearrangement involving enamines has been found in the case of a-(3-butenyl)-enamines . Heterocyclic enamine 123 rearranges almost quantitatively to product 124, which tautomerizes rapidly to the isomer 125 at 220-245 "C (equation 25). On the other hand, only partial rearrangement of the five-membered analogue 126a-126b has been found (equation 26), The difference between 123 and 126 is attributed to the different... 

From the addition reaetions of acrolein- to aldehyde-derived enamines, aminotetrahydropyrans have been obtained. On heating, these products rearranged to enaminoaldehydes in examples where the initial enamine was disubstituted (320,321). The addition of acrolein to ketone derived enamines has been applied to syntheses of heterocyclic and bridged bieyclic compounds (301,321-323). 

Since tautomeric rearrangement is not possible when secondary amines react with acetylene, the intermediate enamines can be isolated.312,314 Vinylation with acetylene of heterocyclic nitrogen bases, such as pyrrole, indole, carbazole, was achieved in this way.312,315 However, when terminal alkynes react with secondary amines,... 

The problems involved are exemplified here by Knorr s pyrrole synthesis (A. Gossauer, 1974). It has been known for almost a century that a-aminoketones (C2N components) react with 1,3-dioxo compounds (C2 components) to form pyrroles (C4N-heterocycles). A side-reaction is the cyclodimerization of the a-aminoketones to yield dihydropyrazines (C4Nj), but this can be minimized by keeping the concentration of the ar-aminoketone low relative to the 1,3-dioxo compound. The first step in Knorr s pyrrole synthesis is the formation of an imine. This depends critically on the pH of the solution. The nucleophilicity of the amine is lost on protonation, whereas the carbonyl groups are activated by protons. An optimum is found around pH 5, where yields of about 60% can be reached. At pH 4 or 6 the yield of the pyrrole may approach zero. The ester groups of /7-keto esters do not react with the amine under these conditions. If a more reactive 1,3-diketone is used, it has to be symmetrical, otherwise mixtures of two different imines are obtained. The imine formed rearranges to an enamine, which cyclizes and dehydrates to yield a 3-acylpyrrole as the normal Knorr product (A. Gossauer, 1974 G.W. Kenner, 1973 B). 

Similar enamine cyclization processes occur in several other successful heterocycle syntheses, e.g. in the Fischer indole synthesis. In this case, however, a labile N—N bond of a l-aryl-2-vinylhydrazine is cleaved in a [3,3]-sigmatropic rearrangement, followed by cyclization and elimination of ammonia to yield the indole (B. Robinson, 1963, 1969 R. J. Sundberg, 1970). Regioselectivity is only observed if R2 contains no enolizable hydrogen, otherwise two structurally isomeric indoles are obtained. Other related cyclization reactions are found in the Pechmann synthesis of triazoles (T.L. Gilchrist, 1974) and in G. Bredereck s (1939) imidazole synthesis (M.R. Grimmett, 1970). 

Aminoquinolines 62 have been prepared in a two-step, one-pot, three-component reaction of 2-azidobenzophenones, secondary amines and arylac-etaldehydes [110]. The microwave-assisted reaction proceeded via the initial formation of enamines 59. Subsequent addition of 2-azidobenzophenones 60 afforded the triazoline intermediates 61, which underwent thermal rearrangement and cyclocondensation to furnish 2-aminoquinolines 62 (Scheme 41). Direct comparison with conventional thermal conditions demonstrated the superiority of microwave dielectric heating in terms of yields (73% vs. 31% of heterocycle 63 after 10 min at 180 °C). Furthermore, the formation of by-products due to decomposition of azide 60 was diminished in the microwave-assisted synthesis. Purification of the products was achieved using solid-phase extraction techniques. 

The two-carbon ring expansion which involves the [2 + 2] cycloaddition of enamines of cyclic ketones with electron-deficient acetylenes followed by thermal rearrangement of the resulting fused cyclobutenes (see Section II.E) has been successfully used in the synthesis of medium-size heterocycles. Examples include the preparation of compounds 407246, 408247 and 409248. 

The 26 chapters, written by experts from 14 countries, cover a wide spectrum of topics related to the chemistry of enamines, including theory, structural chemistry, spectral properties, formation, reactions and stereochemistry, acidities, rearrangements, oxidation and reduction, as well as other topics. In two chapters, the material related to enamines was meagre. Hence, the chapter on radiation chemistry also deals with compounds with non-conjugated C=C and amino groups, and the chapter on synthesis and uses of isotopically labelled enamines includes enamines in which the nitrogen is part of a heterocyclic system. 

Enamines 39a and b, derived from tetrahydrothiophene and tetrahydrofuran, respectively, rearranged to give the corresponding six-membered ring heterocycles 41. °... 

Scheme 193). On heating the mixture, preferably in the absence of triethylamine, the hexahydro-a-quinolone 185 was obtained directly, together with the enamide 184 and amide 186. Since the enamide could not be cyclized to the hexahydro-a-quinalone under thermal or acid-catalysed conditions, then clearly the enamide is not an intermediate in the formation of the heterocycle which must therefore arise by. /V-acylation of the enamine tautomer, followed by a [3,3]sigmatropic rearrangement and cyclization of the ketene intermediate (Scheme 194). Significantly vide infra), when the imine of 2-methylcyclohexanone was used, the rearrangement to the ketene occurred at the more substituted Cj position. 

While most classical enamines and open-chain enamino esters2 are obtained by condensation, e.g., of a secondary amine with a keto compound, heterocyclic /3-enamino esters can be obtained only by special reactions as, e.g., rearrangement or direct syntheses. Some of these are depicted in this section. 

Claisen rearrangements, in nitrogen heterocyclic systems, 8, 143 Complex metal hydrides, reduction of nitrogen heterocycles with, 5, 45 Covalent hydration, in heteroaromatic compounds, 4, 1, 43 Cyclic enamines and iinines, 6,147 Cyclic hydroxamic acids, 10, 199 Cyclic peroxides, 8, 165... 

Acylotropic intramolecular rearrangements of keto enamines of benzo [l)]-annulated heterocycles 12KGS112. 

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