Esters 3-keto, reaction with anilines

Loev and co-workers152 prepared the unsubstituted lH-2,l-benzothia-zine 2,2-dioxide (239) by the route of Scheme 11. Methyl chlorosulfonyl-acetate was converted into the sulfonanilide (235) by reaction with aniline. Hydrolysis of the ester group in 235 gave 236 which, with polyphosphoric acid, cyclized to 1 H-2,l-benzothiazin-4-one (237). Spectral data indicated that 237 existed in the keto form. Ketone 237 was converted to the tosylhydra-zone 238 which, by a Bamford-Stevens reaction, afforded 239 in good overall yield. The iV-methyl analog of 239 was also prepared by the above reaction sequence using N-methylaniline. 

The dibeta-keto ester 7 readily undergoes acid-catalyzed reactions with aniline and other aromatic amines to form 2,5-diarylamino-3,6-dihydroterephthalates 9 in excellent yieldsl . The structure of 9 was established on the basis of its elemental analysis, chemical behavior, and IR and NMR spectral. ... 

If a 3-diketone is used rather than a 3-keto ester, the result is a 4-alkylquinoline in what is known as the Combes quinoline synthesis. Reaction of aniline with acetyl acetonate (2,5-pentanedione), for example, generated enamine 258, which is in equilibrium with the imine (259). Enolization to 260 in the presence of HE was followed by cyclization to give the quinoline (261) in 96% yield.l57,l56a... 

The condensation reaction of aniline with alkoxy-methylenemalonic esters, followed by cyclization to 4-hydroxy-3-carbalkoxy quinolines, is described as the Gould-Jacobs reaction. The reaction can use various derivatives of methylene malonic ester such as keto-malonic esters, malonitriles, malonamides, and Meldrum acid. 

Such a reaction course dependence has also been observed in the case of the Rh- or Cu-catalysed three-component reaction of diazoacetates (60) with anilines and p,y-unsaturated a-keto esters (61) (Scheme 8). Depending on the electronic nature of (60) and to a lesser extent on the metal nature of the catalyst (Rh or Cu), the three-component reaction can be directed selectively towards acyclic products (62) or cyclic products (63). The observed regioselectivity has been attributed to the inherent reactivity of the intermediate ammonium ylides (64) according to HSAB principles. 

Highly regioselective, three-component reactions of diazoacetates with anilines and p,y-unsaturated a-keto esters 1,2-addition versus 1,4-addition. (c)X. Zhang, J. Ji, Y. Zhu, C. Jing, M. Li, W. Hu, Org. Biomol. Chem. 2012,10, 2133-2138. A highly diastereoselective three-component tandem l,4-conJugated addition-cychzation reaction to multisubstituted pyrrolidines. 

Scheme 2.28 Three-component reaction of diazoacetophenones with anilines, and p,y-unsaturated a-keto esters.

The KlO-catalyzed reaction of aniline with 3-keto esters gives enamines chemoselectively, avoiding the competing formation of anilide observed with other acidic catalysts. ... 

Conra.d-Limpa.ch-KnorrSynthesis. When a P-keto ester is the carbonyl component of these pathways, two products are possible, and the regiochemistry can be optimized. Aniline reacts with ethyl acetoacetate below 100°C to form 3-anilinocrotonate (14), which is converted to 4-hydroxy-2-methylquinoline [607-67-0] by placing it in a preheated environment at 250°C. If the initial reaction takes place at 160°C, acetoacetanilide (15) forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoline [607-66-9] (49). This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents (see Chemotherapeuticsanticancer). 

The proposed mechanism for the Conrad-Limpach reaction is shown below. Condensation of an aniline with a 3-keto-ester (i.e., ethyl acetoacetate 5) with loss of water provides enamino-ester 6. Enolization furnishes 10 which undergoes thermal cyclization, analogous to the Gould-Jacobs reaction, via 6n electrocyclization to yield intermediate 11. Compound 11 suffers loss of alcohol followed by tautomerization to give 4-hydroxy-2-methylquinoline 7. An alternative to the proposed formation of 10 is ejection of alcohol from 6 furnishing ketene 13, which then undergoes 671 electrocyclization to provide 12. 

General Conditions for each step and selectivity of m-substituted anilines As previously mentioned, Hauser and Reynolds reported on factors governing the first step of the Conrad-Limpach reaction but they tvere by no means exhaustive. Other than the conditions reported above for the first step, HClAleOH, CHCI3 or CHCI2 (neat or with acid catalyst), PhMe or PhH with removal of water with or without acid catalyst, or EtOH/AcOH/CaS04 were reported to provide the desired enamino-ester from an aryl amine and 3-keto-ester. Hauser and Reynolds also noted that o-nitroaniline and o-nitro-p-methoxyaniline failed to form the desired enamino-ester under conditions which they reported. 

The Conrad-Limpach reaction has been applied as a key step in the formation of pyrido[4,3-b]quinoline. Condensation of 3 different anilines 55 (R = H, Br, OMe) with keto-ester 56 provided the enamino-esters 57 in acceptable yields. Cyclization gave the desired quinolones 58 in good to moderate yield. ... 

The aniline nitrogen is then converted to the para-toluenesulfonamide (4-3). Reaction of this intermediate with ethyl co-chlorobutyrate in the presence of potassium carbonate then gives the alkylation product (4-4). Potassium tert-butoxide-catalyzed Claisen condensation of this diester leads to azepinone (4-5) as a mixture of methyl and ethyl esters resulting from alternate cyclization routes. A strong acid leads to the transient keto-acid, which then decarboxylates the toluensulfonyl group is lost under reaction conditions as well as affording the benzazepinone (4-6). This last intermediate is then acylated with the benzoyl chloride (4-7) to afford amide (4-8). 

Amines also react with P-keto-esters to give the corresponding amino acid derivative. When 1.133 was treated with ethylamine in reaction 4, ethyl 3-(N-ethyl-amino)-3-phenylprop-2-enoate (1.134) was obtained. Several other 3-aryl derivatives (piperonyl, p-bromophenyl, p-methylphenyl, and p-nitrophenyl) were prepared by this method. The use of different amines (methylamine, isopropylamine, benzyl-amine, allylamine, aniline) led to several different N-substituted derivatives. ... 

Although the above route was successful in providing an easy access to the aryl acetic acid 7, it was still plagued by the use of p-(p-cyanophenyl)aniline (5), which is a suspected carcinogen. Thus it was decided to use a different p-substituted aniline and later extend it via a Pd mediated process. Commercially available and inexpensive p-bromo aniline was the compound of first choice. Condensation with dimethoxy tetrahydrofuran followed by Vilsmeier/Friedel-Crafls reaction sequence resulted in die formation of the required aldehyde 35. However, the decarbonylation of this aldehyde proved to be extremely difficult. With fewer options available, we decided to convert the bromide to the boronate ester 37 by reacting with bis(pinacolato)diboron 36. To our surprise, the boronate ester 37 underwent decarbonylation readily with Pd/alumina to give the keto ester 38. The keto group was reduced by treatment with either Ra-Ni or Pd-... 

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