Jacobs-Gould reactions

The Gould-Jacobs reaction is a sequence of the following reactions (1) condensation of an arylamine 1 with either alkoxy methylenemalonic ester or acyl malonic ester 2 providing the anilidomethylenemalonic ester 3 (2) cyclization of 3 to the 4-hydroxy-3-carboalkoxyquinoline 4 (3) saponification to form acid 5, and (4) decarboxylation to give the 4-hydroxyquinoline 6. All steps of this process will be described herein with emphasis on the formation of intermediates like 3 and 4. 

The first reaction can be conducted using various derivatives of methylenemalonic ester, such as malononitriles 7, malonamides 8, P-keto-esters 9 or Meldrum s acid 10. Substitutions of the aryl ring (including fused rings) and within the aryl ring are well tolerated for this reaction. 

In 1885, Just reported the reaction of sodium diethylmalonate with Af-phenylbenzimino chloride to provide 11. Thermal cyclization provided 12. This work was virtually untouched for several decades, but laid the groundwork for further development. 

In 1939, Gould and Jacobs reported the condensation of aniline with acetyl malonic ester (AME) and ethoxymethylenemalonate (EMME), respectively, followed by cyclization of anilinomethylenemalonic ester 13 and 14 in mineral oil to afford the esters 15 and 16. Saponification of the esters gave the known acids 17 and 18, respectively. 

In order to expand the utility of the reaction, modification of the route to anilidomethylene malonic ester equivalents was developed. Simple condensation of triethyl orthoformate with cyanoacetic ester, acetoacetic ester, or malonic ester in the 

Horvath, G., Hermecz, 1., Gorvath, A., Pongor-Csakvari, M., Pusztay, L. J. Hetero-cycl. Chem. 1985, 22, 481. 

Suzuki, N., Tanaka, Y., Dohmori, R. Chem. Pharm. Bull. 1979, 27, 1. 

Curran, T. T. Gould-Jacobs REaction in Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 423-436. (Review). 

The Gould-Jacobs reaction is a sequence of the following reactions  

u Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 113, Springer-Verlag Berlin Heidelberg 2009 

Example 3, Mierowave-assisted Gould-Jaeobs reaetiom 

Jacobs, W. A. J. Am. Chem. Soc. 1939, 61, 2890-2895. R. Gordon Gould was bom in Chicago in 1909. He earned his Ph.D. at Harvard University in 1933. After serving as an instmctor at Harvard and Iowa, Gould worked at Rockefel- 

Elguero J., Marzin C., Katritzky A. R., Linda P., The Tautomerism of Heterocycles, Academic Press, New York, 1976, pp 87—102. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 121, Springer International Publishing Switzerland 2014 

Example 3, Microwave-assisted Gould-Jacobs reaction  

Milata, V. Claramimt, R. M. Elguero, J. Zalupsky, P. Targets in Heterocyclic Systems 2000, 4,167-203. (Review). 

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. 

The reaction mechanism is postulated to involve initial conjugate addition of aniline derivative to methylene malonate and elimination of the alcohol providing P-anilinoacrylate. Heating the reaction mixture at 180-320 °C promotes the second alcohol elimination, producing what is believed to be an imino-ketene, which readily undergoes a 67t-electrocyclization to afford the desired 4-hydroxy-3-carbalkoxy quinoline derivative after 

The antiprotozoal spectum of activity is apparently changed by replacing alkoxy substituents with alkyl or amino groups. Thus, by using the appropriate substituted anilines in a Gould-Jacobs reaction, a series of 

4-Hydroxy-quinoline carboxylates, prepared using the Could-Jacobs reaction, have also been frequently used as precursors for the synthesis of biologically interesting quinoline compounds. For example, the syndiesis of 

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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. 

Several high-boiling, inert solvents have been reported in various steps of the Gould-Jacobs reaction. Dowtherm, f Ph20, cumene, tetraglyme, diphenyl methane, ... 

Alternative techniques, such as flash vacuum pyrolysis vide infra-, 30 —> 33), have been applied to the Gould-Jacobs reaction. Use of microwave has in some cases provided an... 

Nearly every substitution of the aromatic ring has been tolerated for the cyclization step using thermal conditions, while acid-promoted conditions limited the functionality utilized. Substituents included halogens, esters, nitriles, nitro, thio-ethers, tertiary amines, alkyl, ethers, acetates, ketals, and amides. Primary and secondary amines are not well tolerated and poor yield resulted in the cyclization containing a free phenol. The Gould-Jacobs reaction has been applied to heterocycles attached and fused to the aniline. 

Although regio-isomers have been reported in some cases as being problematic, due to the wide range of substituents that withstand the cyclization, the Gould-Jacobs reaction is one of the more general methods used to prepare quinolines. 

As previously described, the Gould-Jacobs reaction has been applied to heterocycles fused to anilines, and to some amino-substituted heterocycles. Selectivity of N- and C-cyclization of 2-aminopyridino-methylene malonates has been mentioned (51 and 56). The normal mode of cyclization of 2-aminopyridino-methylene malonates is on the nitrogen to form a pyridopyrimidine. If an electron-donating group (EDG) is in the 6-... 

The Knorr quinoline synthesis refers to the formation of a-hydroxyquinolines 4 from P-ketoesters 2 and aryl amines 1. The reaction usually requires heating well above 100°C. However, some cases do exist when the cyclization takes place in the presence of a catalytic amount of mineral acid at temperatures as low as -10 °C. The intermediate anilide 3 undergoes cyclization by dehydration with concentrated sulfuric acid. The reaction is conceptually close to the Doebner-Miller and Gould-Jacobs reactions. ... 

The relative ease of preparation of condensed thiazole derivatives is a consequence of facile thiazole ring closure, and therefore also benzothiazole amines with an amino group on the benzene ring (except for the weakly regioselective nitration of benzothiazoles) are very easily accessible and useful substrates for the Gould-Jacobs reaction. 

Another approach involves utilization of the amines for addition of a fused pyridine ring to the benzothiadiazole skeleton. The Gould-Jacobs reaction of 4-amino-2,l,3-benzothiadiazole 60 with diethyl ethoxymethylenemalonate gave the substitution product, and, after thermal cyclization in diphenyl ether, afforded the... 

The applied Gould-Jacobs reaction is very often used to prepare angularly annelated pyridine-ring-substituted imidazoquinolines in inert media under conditions of thermal cyclocondensation, for example at temperatures above 250°C. 

Pefloxacin (33) is the N-methyl analogue of norfloxacin (58) and is at least partly converted to it by metabolic enzymes in vivo. It has been launched in France for the treatment of a number of infections including those caused by sensitive strains of Pseudomonas aeruginosa. It can be synthesized starting with the Gould-Jacobs reaction of 3-chloro-4-fluoroaniline (28) and diethyl ethoxymethylenemalonate in an addition-elimination sequence leading to 29 which undergoes... 

Although there is versatility in the synthetic methodologies of each individual quinolone antibacterial, two different methods are utilized to synthesize the basic skeleton of l,4-dihydro-4-oxoquinoline-3-carboxylic acid. The first method is based on the Gould-Jacobs reaction [9] using appropriately substituted aniline derivatives and diethyl ethoxymalonate, which results in the formation of the intermediate anilinomethylenemalonate. Further thermal cyclization of this intermediate followed by hydrolysis gives rise to the targeted l,4-dihydro-4-oxoquinoline-3-carboxylic acid, according to Scheme 1. 

The thermal ring closure of Af-(het)arylaminomethylenemalonates gave bi- or polycondensed 4-hydroxypyridine-3-carboxy lates. This type of reaction is named the Gould-Jacobs reaction. (The reaction is illustrated in Scheme 40). The cyclized products may exhibit oxo-enol tautomerism. In this review, the hydroxy form is generally depicted. This type of tautomerism was discussed in an excellent review (76MI1). 

The Skraup, Doebner-Miller, and Gould-Jacobs reactions for the syntheses of quinolines, quinaldines, and 4-hydroxyquinolines, respectively, were applied to 5-aminotropolone derivatives (e.g., 208, Scheme 50) to get pyridotropolones 209-211 (59NKZ75 68NKZ620) and other derivatives [52CI(L)471 60NKZ295]. These reactions illustrate the behavior of 5-aminotropolones as typical aromatic amines (55CRV9,... 

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