Gould–Jacobs reaction explained

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.

Extension of the Gould-Jacobs approach can prepare unsubstituted parent heterocycles with fused pyridine ring of Skraup type (see Skraup reaction).

Further reading:[4] [5] [6]

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.

Another example is in the synthesis of antimalarials as aminoalkylamino derivatives of 2,3-dihydrofuroquinolines[8]

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.[9]

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.[10]

Notes and References

  1. Book: Li, Jie Jack. Name Reactions: A Collection of Detailed Reaction Mechanisms. Springer. 2006. 978-3-540-30030-4. Berlin, Heidelberg. 289–290. Gould–Jacobs reaction.
  2. Book: Wang, Zerong. Comprehensive Organic Name Reactions and Reagents. John Wiley & Sons, Inc.. 2010. 9780471704508. Gould-Jacobs Reaction.
  3. The Synthesis of Certain Substituted Quinolines and 5,6-Benzoquinolines. R. Gordon. Gould. Walter A.. Jacobs. Walter Abraham Jacobs. J. Am. Chem. Soc.. 1939. 61. 10. 2890–2895. 10.1021/ja01265a088.
  4. Book: Li. Jie Jack. Name Reactions . Gould–Jacobs reaction . 2009. 263–265. 10.1007/978-3-642-01053-8_113. 4th. Springer-Verlag. 9783642010538. https://books.google.com/books?id=Ff1DAAAAQBAJ&pg=PA263.
  5. Lengyel. László Csaba. Sipos. Gellért. Sipőcz. Tamás. Vágó. Teréz. Dormán. György. Gerencsér. János. Makara. Gergely. Darvas. Ferenc. Synthesis of Condensed Heterocycles by the Gould - Jacobs Reaction in a Novel Three-Mode Pyrolysis Reactor. Org. Process Res. Dev.. 19. 3. 2015. 399–409. 10.1021/op500354z.
  6. Book: Gould - Jacobs Reaction. Gould-Jacobs Reaction. 2010. 10.1002/9780470638859.conrr276. Comprehensive Organic Name Reactions and Reagents. 276. 1252–1255. 9780470638859.
  7. 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 . 10.1021/acs.joc.6b02520 . 28001397 .
  8. Cruickshank. Philip A.. 1970. Antimalarials. 1. Aminoalkylamino derivatives of 2,3-dihydrofuroquinolines. Journal of Medicinal Chemistry. 13. 6. 1110–1114. 10.1021/jm00300a022. 5479851.
  9. Ferlin. Maria Grazia. 2005. Novel anellated pyrazoloquinolin-3-ones: synthesis and in vitro BZR activity. Bioorganic & Medicinal Chemistry. 13. 10. 3531–3541. 10.1016/j.bmc.2005.02.042. 15848766.
  10. 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. 10.1002/jhet.5570430530. free.