Ketene aminals heterocyclics

The cycloaddition between a nitrilimine 319 and an aroyl substituted heterocyclic ketene aminal 318 has been found to be stepwise, involving an initial nucleophilic addition of 318 to 319 followed by intramolecular cyclocondensation of the intermediate 320 providing fully substituted pyrazole 321 (Eq. 36) [92]. When Ar was the 2,4-dinitrophenyl group, the intermediate 320 was isolable and required forcing conditions (xylene, reflux, 10 h) to undergo cyclization ... 

New heterocyclic ketene aminals have been obtained in yields ranging from 60 to 94% [89] starting from ethyl lff-perimidine-2-acetate or acetonitrile and isocyanates (Scheme 8.63). 

The aroyl-substituted heterocyclic ketene aminals 482 react with 4-chlorophenyl azide to give polysubstituted 1,2,3-triazoles 483 and imidazo[ 1. Z-r 1.2,4]triazoles 39 (Equation 112) <2000HAC387>. Polysubstituted 1,2,4-triazoles are formed by the nucleophilic attack of the ct-carbon of the azide. Then, through the cyclocondensation and aromatization sequences, the fused heterocycles resulted by a 1,3-dipolar addition at first, and then through a Dimroth rearrangement and deamination of chloroaniline <1992JOC184>. 

An interesting pyrrolo[l,2-tf]pyrimidine was described as the product of the reaction of the heterocyclic ketene-aminals 236 that was synthesized by cyclocondensation of ketene dithioacetals 237 and 1,3-diamino propane. These compounds reacted with diethyl oxomalonate that behaves as an hetero-enophile, yielding the corresponding products 238 in acceptable to good yield (Scheme 31). A mechanism that involves an aza-ene reaction, via adduct 239 which isomerizes to ketene aminal 240 to produce the lactam ring of 238, has been proposed <1999J(P1)321>. 

The reaction of 2,4-dinitrohalobenzenes (F,Cl,Br,I) with the anions of heterocyclic ketene aminals was reported to give arylated products by the S l mechanism. This proposal was based on ESR spectroscopy, ESR spin trapping with nitroso-/-butane and the inhibition of the reaction by FeCl3182. 

The hetero-Diels-Alder reaction is amongst the most efficient processes for the synthesis of six-membered heterocyclic ring systems. Solvent-free conditions have been used to improve reactions of heterodienophiles and heterodynes with low reactivities. Cado et al. (1997) have described the hetero-Diels-Alder reaction of ethyl lH-perimidine-2-acetate as heterocyclic ketene aminal with ethyl propiolate nnder solvent-free conditions with focused microwave irradiation. The new fused perimi-dines (23) were obtained in good yields (67-98%). 

The aza-ene reaction recently found application in the synthesis of imidazo[1,2-a]pyridine and imidazo[1,2,3- y][1,8]naphthyridine derivatives in the laboratory of Z.-T. Huang.The reaction of heterocyclic ketene aminals with enones such as MVK proceeded via an aza-ene addition, followed by intramolecular cyclization to afford the products. The aroyl-substituted heterocyclic ketene aminals (Ar=Ph, 2-furyl, 2-thienyl) underwent two subsequent aza-ene reactions when excess MVK was used. 

Zhang, J.-H., Wang, M.-X., Huang, Z.-T. The aza-ene reaction of heterocyclic ketene aminals with enones an unusual and efficient... 

The (2 + 2)-cycloaddition reactions of ketenes with heterocycles via an endocyclic imino group have contributed substantially to the synthesis of penicillin (92a) and cephalosporin C (93a) antibiotics and structurally related heterobicyclic /Mactams.7 11 Reactions with relatively stable ketenes, e.g., diphenylketene, have been reported as well as reactions of heterocycles with mixtures of acid chlorides and tertiary amines. 

Heterocyclic ketene aminals (78) react smoothly with ethyl bromoacetate, and pyrroloimidazoles (79) are obtained by further cyclocondensation of alkylation products <89CB95>. Another procedure is based on reaction of 1,2-ethylenediamine and ethyl levulinate (80) under microwave irradiation giving (81) <92SL219>. Compound (80) also reacts with glycinamides, and alaninamides <93JMC4214> to give the corresponding pyrrolo[l,2-a]imidazolone derivatives (82). These reactions are shown in Scheme 13. 

Recently, Li and cowoilcers developed the multicomponent solvent-free domino heteroannulation of heterocyclic ketene aminals for the synthesis of benzo[Y]imidazo[l,2-a] quinolinediones [69]. This scaffold is found in diverse natural products and pharmaceuticals with important biological activities ranging from antinucrobial to cytotoxicity. 

L.-R. Wen, Q.-C. Sun, H.-L. Zhang, M. Li, Org. Biomol. Chem. 2013, 11, 781-786. A new rapid multicomponent domino heteroannulation of heterocyclic ketene aminals solvent-free regioselective synthesis of functionalized benzo[g] imidazo [ 1,2-a] quinolinediones. 

Heterocyclic ketene aminals have been found to be good aza-ene compounds which can undergo hetero-ene reactions readily with activated carbonyl compounds and enones " to provide novel and efficient synthetic routes to y-lactam-fused diaza-heterocycles and fused di- and tri-heterocycles, respectively. Such aminals bearing a secondary enamine moiety have been found to undergo an efficient aza-ene reaction with 4-phenyl-l,2,4-triazoline-3,5-dione under very mild conditions. The regio- and diastero-selectivity of the ene reaction of 4-phenyl-l,2,4-triazoline-3,5-dione with chiral allylic alcohols and their derivatives have been studied, " while Singleton and Hang have proposed a new mechanism for the ene reactions of triazolinediones which involves an open biradical as the key intermediate. This biradical is assumed either to form the ene product or to form reversibly an intermediate aziridinium imide which would be a shunt off the main ene mechanistic pathway. 

It is well known that heterocyclic ketene aminals are versatile compounds for the synthesis of a wide variety of heterocycles [64,65]. Reaction of heterocyclic ketene aminals with 1,3-dipoles such as azides opens the avenue to prepare original polysubstitued triazoles [66, 67]. 

Condensation of heterocyclic ketene aminals 78 with 2,3,4,6-tetra-O-acetyl-p-D-glucopyranosyl azide 79 in anhydrous 1,2-dichloroethane at room temperature gave glucosylated 1,2,3-triazole derivatives 80 in very good yields (Scheme 25). Activity screening showed that glycosylated triazole 80 possessed antimmor and antiviral activities. 

The cyclopropenium system m y combine with a large number of donor groups, mainly heterocyclic and carbocyclic systems to give cyclopropenium cyanines. En-amines or ketene acetals of appropriate basicity, e.g. Fischer Base (135) or 134, can be easily cyclopropenylated by the ethoxy cyclopropenium cation 75 as well as 2- or 4-alkylsubstituted heterocyclic quartemary salts of pyridine, quinoline, and benzothiazol in the presence of a tertiary base76,10s ... 

Abstract The basic principles of the oxidative carbonylation reaction together with its synthetic applications are reviewed. In the first section, an overview of oxidative carbonylation is presented, and the general mechanisms followed by different substrates (alkenes, dienes, allenes, alkynes, ketones, ketenes, aromatic hydrocarbons, aliphatic hydrocarbons, alcohols, phenols, amines) leading to a variety of carbonyl compounds are discussed. The second section is focused on processes catalyzed by Pdl2-based systems, and on their ability to promote different kind of oxidative carbonylations under mild conditions to afford important carbonyl derivatives with high selectivity and efficiency. In particular, the recent developments towards the one-step synthesis of new heterocyclic derivatives are described. 

Photolysis or thermolysis of heteroatom-substituted chromium carbene complexes can lead to the formation of ketene-like intermediates (cf. Sections 2.2.3 and 2.2.5). The reaction of these intermediates with tertiary amines can yield ammonium ylides, which can undergo Stevens rearrangement [294,365,366] (see also Entry 6, Table 2.14 and Experimental Procedure 2.2.1). This reaction sequence has been used to prepare pyrrolidones and other nitrogen-containing heterocycles. Examples of such reactions are given in Figure 2.31 and Table 2.21. 

Nucleophiles other than hydride can be added to support-bound imines to yield amines. These include C,H-acidic compounds, alkynes, electron-rich heterocycles, organometallic compounds, boronic acids, and ketene acetals (Table 10.9). When basic reaction conditions are used, stoichiometric amounts of the imine must be prepared on the support (Entries 1-3, Table 10.9). Alternatively, if the carbon nucleophile is stable under acidic conditions, imines or iminium salts might be generated in situ, as, for instance, in the Mannich reaction. Few examples have been reported of Mannich reactions on insoluble supports, and most of these have been based on alkynes as C-nucleophiles. 

Wolff rearrangement of /)-diazenyl-a -diazo ketone 83 in the presence of water, methanol (or even with primary and secondary amines) under varied reaction conditions comes with surprise Instead of the expected homologous acid 89, methyl ester 90 (or the respective amide), 2-phenylcinnolin-3(2E0-one (91) is the only product indicative of the anticipated in situ formation of ketene intermediate 88 (Scheme 22). Obviously, the apparent 67r-electrocyclization reaction prevails forming the isolated heterocyclic product 91, a so far unknown compound. 

Reactions of 4-aryl-5(2f/)-isoxazolones with 1,2-dibromoethane in acetonitrile in the presence of 1 equiv of triethyl-amine gave 2-bromoalkyl-4-aryl-5(2/f)-isoxazolones as major products that were converted to heterocyclic ketene AjO-acetals by treatment with sodium methoxide in boiling methanol <1997T10433>. The preparation of quinoline derivatives was achieved by catalytic hydrogenation of 2-(2-formylaryl)-5(2//)-isoxazolones <2003T9887>. 

By electrolysis of 2-bromoamides in DMF the aminal esters (492 Scheme 89) are accessible. In the reaction of benzoylphenyl ketene with the isoquinolinedione (493) the heterocyclic aminal ester (494) is formed. Another heterocyclic aminal ester (496) was obtained from a hydrazinoyl chloride and a benzoxazine derivative (495). ... 

In Table II 13C-NMR data are given for a number of 4,5-dihydrofurans (Scheme 16).62 Schemes 17 and 18 present more 13C-NMR data of additional heterocyclic /J-enamino esters, which are, however, limited to unsaturated atoms C-2 and C-3.63 All of the enamino esters 68a-d, 69-72 show the common feature of a strongly electron deficient C-2, as in an amidine-C or a ketene-S, N-(-0,N-)aminal,65 while C-3 does not appear as an olefinic carbon... 

Photfrfysis of a-Diazo Carbonyl Compounds - Some recent advances in the matrix photochemistry of diazoketones, including some heterocyclic species, have been reviewed. Flash photolysis of 10-diazo-9(10//)-phenanthrenone (35) in aqueous solution led to the detection of two transient species on the pathway to the final product, fluorene-9-carboxylic acid. These were identified, from solvent isotope effects and the nature of the observed acid-base catalysis, as fluorenylideneketene (36, X = CO) and the enol of fluorene-9-carboxylic acid (36, X = C(0H)2), formed by hydration of the ketene. In related studies, fluorenylideneketene was found to react with amines to give ylides as intermediates on the route to the amide final products. The product distribution from the photochemical reactions of 2-diazo-3-oxo-5,10,15,20-tetraphenylchlorins with alcohols strongly depends on the central metal ion of the irradiated diazoketones. ... 

Michael/Henry/dehydration/aromatisation reaction of 2-(2-oxoethyl) benzal-dehydes and nitroalkenes mediated by pyrrolidine to obtain polysubstituted naphthalene derivatives. DBU catalysed the conjugate additions of alcohols to ot,p-unsaturated nitriles, esters and ketones. Perhaps more important are the aza-Michael addition reactions of amines to a,p-unsaturated ketones, nitriles and esters. Recently, Costa, Vilarrasa and coworkers described the addition of lactams, imides, 2-pyridone, pyrimidine-2,4-diones and inosines to methyl propiolate and other similar compounds, DABCO and DMAP being the best catalysts. As mentioned before, tertiary amines give zwitterionic species with activated allynes. It was as early as 1932 when Diels and Alder used the reaction of pyridine with dimethyl acetylenedicarbojylate (DMAD) for the synthesis of heterocycles. The interception of the corresponding intermediate with Al-tosylimines and activated olefins provided access to l-azadienes ° and highly substituted butadienes (Scheme 2.6). When the quenching species of the zwitterionic intermediate is a 1,2-diketone, dibenzoyl maleates or cyclopentenedione derivatives could be obtained (Scheme 2.6). The interception of the zwitterionic species of N-methyl imidazole (NMI) and DMAD with ketenes to obtain unsaturated esters has also been shown. ... 

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