Gould–Jacobs reaction
The Gould–Jacobs reaction is an organic synthesis for the preparation of quinolines and 4‐hydroxyquinoline derivatives. The Gould-Jacobs reaction is a series of reactions. The series of reactions begins with the condensation/substitution of an aniline with alkoxy methylenemalonic ester or acyl malonic ester, producing anilidomethylenemalonic ester. Then through a 6 electron cyclization process, 4-hydroxy-3-carboalkoxyquinoline is formed, which exist mostly in the 4-oxo form. Saponification results in the formation of an acid. This step is followed by decarboxylation to give 4-hydroxyquinoline.[1] The Gould-Jacobs reaction is effective for anilines with electron‐donating groups at the meta‐position.[2]
Specifically, 4-quinolinol can be synthesized.[3] In this reaction aniline or an aniline derivative first reacts with malonic acid derivative ethyl ethoxymethylenemalonate with substitution of the ethoxy group by nitrogen. A benzannulation takes place by application of heat to a quinoline. The ester group is hydrolysed by sodium hydroxide to the carboxylic acid and decarboxylation again by application of heat to 4-hydroxyquinoline.
Gould–Jacobs reaction
Extension of the Gould-Jacobs approach can prepare unsubstituted parent heterocycles with fused pyridine ring of Skraup type (see Skraup reaction).[1]
Mechanism
The mechanism for the Gould–Jacobs reaction begins with a nucleophilic attack from the amine nitrogen follows by the loss of ethanol to form the condensation product. A 6 electron cyclization reaction with the loss of another ethanol molecule forms a quinoline (ethyl 4-oxo-4,4a-dihydroquinoline-3-carboxylate). The enol form can be represented from the keto form through keto-enol tautomerism. Protonation of the nitrogen forms ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate.
Examples and applications
An example is the synthesis of 4,7-dichloroquinoline.[7]
- Floctafenine and glafenine are a pair of fenamate NSAIDs whose syntheses rely on the Gould–Jacobs reaction.[8]
- Several quinolone antibiotic structures such as rosoxacin, oxolinic acid, droxacin, etc.
Another example is in the synthesis of antimalarials as aminoalkylamino derivatives of 2,3-dihydrofuroquinolines[9]
The Gould reaction is also used to convert 5-aminoindole to quinolines for the purpose of synthesizing pyrazolo[4,3-c]pyrrolo[3,2-f]quinolin-3-one derivatives as modified pyrazoloquinolinone analogs. These compounds have the potential to act as antagonists at central benzodiazepine receptors (BZRs) in Xenopus laevis oocytes.[10]
![Conversion of 5-aminoindole to quinolines by the Gould-Jacobs reaction for the purpose of synthesizing pyrazolo[4,3-c]pyrrolo[3,2-f]quinolin-3-one derivatives](/wiki/File:Gould-Jacobs_reaction_on_5-aminoindole.png)
The Gould‐Jacobs reaction has also been used both conventionally with condensation steps and acyclic intermediated and with single step microwave irradiation to synthesize ethyl 4‐oxo‐8,10‐substituted‐4,8‐dihydropyrimido[1,2‐c]pyrrolo[3,2‐e]pyrimidine‐3‐carboxylates.[11]
![Conventional and microwave radiation approach to synthesize ethyl 4‐oxo‐8,10‐substituted‐4,8‐dihydropyrimido[1,2‐c]pyrrolo[3,2‐e]pyrimidine‐3‐carboxylates by the Gould-Jacobs reaction](/wiki/File:Synthesis_of_ethyl_4%E2%80%90oxo%E2%80%908,10%E2%80%90substituted%E2%80%904,8%E2%80%90dihydropyrimido(1,2%E2%80%90c)pyrrolo(3,2%E2%80%90e)pyrimidine%E2%80%903%E2%80%90carboxylates_by_the_Gould-Jacobs_reaction.png)
References
- ^ a b Li, Jie Jack (2006). "Gould–Jacobs reaction". Name Reactions: A Collection of Detailed Reaction Mechanisms. Berlin, Heidelberg: Springer. pp. 289–290. ISBN 978-3-540-30030-4.
- ^ Wang, Zerong (2010). "Gould‐Jacobs Reaction". Comprehensive Organic Name Reactions and Reagents. John Wiley & Sons, Inc. ISBN 9780471704508.
- ^ Gould, R. Gordon; Jacobs, Walter A. (1939). "The Synthesis of Certain Substituted Quinolines and 5,6-Benzoquinolines". J. Am. Chem. Soc. 61 (10): 2890–2895. doi:10.1021/ja01265a088.
- ^ Li, Jie Jack (2009). "Gould–Jacobs reaction". Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications (4th ed.). Springer-Verlag. pp. 263–265. doi:10.1007/978-3-642-01053-8_113. ISBN 9783642010538.
- ^ Lengyel, László Csaba; Sipos, Gellért; Sipőcz, Tamás; Vágó, Teréz; Dormán, György; Gerencsér, János; Makara, Gergely; Darvas, Ferenc (2015). "Synthesis of Condensed Heterocycles by the Gould–Jacobs Reaction in a Novel Three-Mode Pyrolysis Reactor". Org. Process Res. Dev. 19 (3): 399–409. doi:10.1021/op500354z.
- ^ "Gould-Jacobs Reaction". Gould–Jacobs Reaction. Vol. 276. 2010. pp. 1252–1255. doi:10.1002/9780470638859.conrr276. ISBN 9780470638859.
{{cite book}}:|journal=ignored (help) - ^ Price, Charles C.; Roberts, Royston M. (1948). "4,7-Dichloroquinoline (Quinoline, 4,7-dichloro-)". Organic Syntheses. 28: 38. doi:10.15227/orgsyn.028.0038; Collected Volumes, vol. 3, p. 272.
- ^ Tsoung, Jennifer; Bogdan, Andrew; Kantor, Stanislaw; Wang, Ying; Charaschanya, Manwika; Djuric, Stevan (2017). "Synthesis of Fused Pyrimidinone and Quinolone Derivatives in an Automated High-Temperature and High-Pressure Flow Reactor". Journal of Organic Chemistry. 82 (2): 1073–84. doi:10.1021/acs.joc.6b02520. PMID 28001397.
- ^ Cruickshank, Philip A. (1970). "Antimalarials. 1. Aminoalkylamino derivatives of 2,3-dihydrofuroquinolines". Journal of Medicinal Chemistry. 13 (6): 1110–1114. doi:10.1021/jm00300a022. PMID 5479851.
- ^ Ferlin, Maria Grazia (2005). "Novel anellated pyrazoloquinolin-3-ones: synthesis and in vitro BZR activity". Bioorganic & Medicinal Chemistry. 13 (10): 3531–3541. doi:10.1016/j.bmc.2005.02.042. PMID 15848766.
- ^ Desai, Nirmal D. (2009). "The gould‐jacob type of reaction for the synthesis of novel pyrimidopyrrolopyrimidines: A comparison of classical heating vs solvent free microwave irradiation". Journal of Heterocyclic Chemistry. 43 (5): 1343–1348. doi:10.1002/jhet.5570430530.
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