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The Gould–Jacobs reaction is an
organic synthesis Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one o ...
for the preparation of
quinoline Quinoline is a heterocyclic aromatic organic compound with the chemical formula C9H7N. It is a colorless hygroscopic liquid with a strong odor. Aged samples, especially if exposed to light, become yellow and later brown. Quinoline is only ...
s 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. The Gould-Jacobs reaction is effective for anilines with electron‐donating groups at the ''meta''‐position. Specifically, 4-quinolinol can be synthesized. In this reaction
aniline Aniline is an organic compound with the formula C6 H5 NH2. Consisting of a phenyl group attached to an amino group, aniline is the simplest aromatic amine. It is an industrially significant commodity chemical, as well as a versatile start ...
or an aniline derivative first reacts with
malonic acid Malonic acid (IUPAC systematic name: propanedioic acid) is a dicarboxylic acid with structure CH2(COOH)2. The ionized form of malonic acid, as well as its esters and salts, are known as malonates. For example, diethyl malonate is malonic aci ...
derivative ''ethyl ethoxymethylenemalonate'' with substitution of the ethoxy group by nitrogen. A
benzannulation In organic chemistry annulation (from the Latin ''anellus'' for "little ring"; occasionally annelation) is a chemical reaction in which a new ring is constructed on a molecule. : Examples are the Robinson annulation, Danheiser annulation and cert ...
takes place by application of heat to a quinoline. The
ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...
group is hydrolysed by
sodium hydroxide Sodium hydroxide, also known as lye and caustic soda, is an inorganic compound with the formula NaOH. It is a white solid ionic compound consisting of sodium cations and hydroxide anions . Sodium hydroxide is a highly caustic base and alkal ...
to the
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyl ...
and
decarboxylation Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...
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 The Skraup synthesis is a chemical reaction used to synthesize quinolines. It is named after the Czech chemist Zdenko Hans Skraup (1850-1910). In the archetypal Skraup reaction, aniline is heated with sulfuric acid, glycerol, and an oxidizing agen ...
). Further reading:


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. *
Floctafenine Floctafenine is a nonsteroidal anti-inflammatory drug (NSAID). Synthesis Floctafenine can be synthesized beginning with the conversion of ''ortho''-trifluoromethyl aniline (1) to a quinolol. The compound is then condensed with ethoxy methyle ...
and
glafenine Glafenine is a nonsteroidal anti-inflammatory drug (NSAID). Use of glafenine is limited due to the risk of anaphylaxis and acute kidney failure Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in ki ...
are a pair of
fenamate Fenamic acid is an organic compound, which, especially in its ester form, is called fenamate. serves as a parent structure for several nonsteroidal anti-inflammatory drugs (NSAIDs), including mefenamic acid, tolfenamic acid, flufenamic acid, and ...
NSAIDs whose syntheses rely on the Gould–Jacobs reaction. *Several
quinolone antibiotic A quinolone antibiotic is a member of a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the substance 4-quinolone. They are used in human and veterinary medicine to treat bacterial infections, as wel ...
structures such as
rosoxacin Rosoxacin (also known as acrosoxacin, tradename Eradacil) is a quinolone antibiotic indicated for the treatment of urinary tract infections and certain sexually transmitted diseases. Rosoxacin is not available in the United States. It was deve ...
,
oxolinic acid Oxolinic acid is a quinolone antibiotic developed in Japan in the 1970s.JP Patent 49138244 Dosages 12–20 mg/kg orally administered for five to ten days. The antibiotic works by inhibiting the enzyme DNA gyrase. It also acts as a dopamine ...
, droxacin, etc. Another example is in the synthesis of antimalarials as aminoalkylamino derivatives of 2,3-dihydrofuroquinolines The Gould reaction is also used to convert 5-aminoindole to quinolines for the purpose of synthesizing pyrazolo ,3-''c''yrrolo
,2-''f'' The comma is a punctuation mark that appears in several variants in different languages. It has the same shape as an apostrophe or single closing quotation mark () in many typefaces, but it differs from them in being placed on the baseline o ...
uinolin-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. 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
,2‐c The comma is a punctuation mark that appears in several variants in different languages. It has the same shape as an apostrophe or single closing quotation mark () in many typefaces, but it differs from them in being placed on the baseline o ...
yrrolo
,2‐e The comma is a punctuation mark that appears in several variants in different languages. It has the same shape as an apostrophe or single closing quotation mark () in many typefaces, but it differs from them in being placed on the baseline (t ...
yrimidine‐3‐carboxylates.


References

Quinoline forming reactions Name reactions {{reaction-stub