This document discusses three heterocyclic organic reactions: the Debus-Radziszewski imidazole synthesis, the Knorr pyrazole synthesis, and the Combes quinoline synthesis. The Debus-Radziszewski reaction synthesizes imidazoles from a dicarbonyl, aldehyde, and ammonia. The Knorr reaction synthesizes pyrazoles from hydrazines and 1,3-dicarbonyl compounds using an acid catalyst. The Combes reaction synthesizes quinolines by condensing unsubstituted anilines with β-diketones followed by an acid-catalyzed ring closure.

1. HETEROCYCLIC
ORGANIC
REACTIONS
(Advanced Organic Chemistry)
PRESENTED BY
VISHAL DADARAO DAKHALE
M.PHARM (SEM I)
PHARMACEUTICAL CHEMISTRY DEPARTMENT

2. CONTENTS :
Debus - Radziszewski Imidazole Synthesis
Knorr Pyrazole Synthesis
Combos Quinoline Synthesis

3. Debus - Radziszewski Imidazole Synthesis :
 The Debus - Radiszewski Imidazole Synthesis is an organic reaction used for the
synthesis of Imidazole from a dicarbonyl, an aldehyde and ammonia.
 The reaction is named after Heinrich Debus and Bronistaw Leonard Radziszewski
discovery.
 The dicarbonyl component is commonly glyoxal, but can also include various 1,2-
diketones and ketoaldehydes.
 It consists of condensing a dicarbonyl compound such as glyoxal, -keto
aldehydes or -diketones with an aldehyde in the presence of ammonia.
 Benzil, for instance, with benzaldehyde and two moleules of ammonia reacts to
yield 2, 4, 5-triphenylimidazole.
 Formamide often proves a convenient substitution for ammonia.
 The method is used commercially to produced several imidazoles.
 The process is an example of a multicomponent reaction.

4. Mechanism of Synthesis :
 The reaction can be occurring in two stages –
 In the first stage, the dicarbonyl and ammonia condense and give an diimine.
 In second stage, this diimine condenses with the aldehyde.

5. Knorr Pyrazole Synthesis :
 The Knorr pyrazole synthesis is an organic reaction used to convert a hydrazine
or its derivatives and a 1,3-dicarbonyl compound to a pyrazole using an acid
catalyst.
 The mechanism begins with an acid catalyzed imine formation, where in the
case of hydrazine derivatives the attack can happen on either carbonyl carbon
and result in two possible products.
 The other nitrogen of the hydrazine derivative then attacks the other carbonyl
group which has also been protonated by the acid and forms a second imine
group.
 This diimine compound gets deprotonated to regenerate the acid catalyst and
provide the final pyrazole product.

6. Mechanism :
 The Knorr pyrazole synthesis is the synthesis of pyrazole derivatives by the reaction
between β-diketones and hydrazine derivative.
 Thus, in above reaction, a mixture of isomeric pyrazoles may be obtained. Contrary
to general opinion, the product is only one of the isomers, e.g., benzoylactone and
phenylhydrazine from only 3-methyl-1,5-diphenylpyrazole.
 The mechanism of these condensation is uncertain.

7.  A possible pathway is as follows :
 Since the phenyl group ca conjugate with an adjacent carbonyl group more than methyl
group, nucleophilic attack at the PhCO carbonyl group is decredsed.
 In some cases, two isomers have been isolated.
 For example 3- -benzoylacetyl-1,5-diphenylpyrazole (1) reacts with phenylhydrazine to
produced a mixture of 11’,5,5’-tetraphenyl-3,5-bipyrazole (2) and 1,1’,3’,5-tetrapphenyl-3,5’-
bipyrazole (3).
 In this case conjugation can occure at either end.

8.  Instead of β-diketones, β-ketoaldehydes in the form of their vinyl ethers (enol
ethers) can also be used.
 In this also, a mixture of isomers may be obtained.
 If β-keto-esters are used then pyrazolones are formed.
 For example, hydrazine and ethylactoacetate from 3-methylpyrazole-5-one.
 Similarly, ethylacetoactate on reaction with phenyl hydrazine gives 3-methyl-1-
phenylpyrazole-5-one.
 This on methylation, yields 2,3-dimethyl-1-phenylpyrazole-5-one (antipyrine).

10. Combos Quinoline Synthesis :
 The Combes quinoline synthesis is a chemical reaction, which was first reported
by Combes in 1888.
 It involves the condensation of unsubstituted anilines(1) with β-diketones (2) to
form substituted quinolones (4) after an acid-catalyzed ring closure of an
intermediate Schiff base (3).
 The Combes quinoline synthesis is often used to prepare the 2,4-
substituted quinoline backbone and is unique in that it uses a β-
diketone substrate, which is different from other quinoline preparations, such as
the Conrad-Limpach synthesis and the Doebner reaction.

11. Mechanism :

12.  The reaction mechanism undergoes three major steps –
 The first one being the protonation of the oxygen on the carbonyl in the β-diketone,
which then undergoes a nucleophilic addition reaction with the aniline.
 An intramolecular proton transfer is followed by an E2 mechanism, which causes a
molecule of water to leave.
 Deprotonation at the nitrogen atom generates a Schiff base, which tautomerizes to
form an enamine that gets protonated via the acid catalyst, which is commonly
concentrated sulfuric acid (H2SO4).
 The second major step, which is also the rate-determining step, is the annulation of
the molecule.
 Immediately following the annulation, there is a proton transfer, which eliminates
the positive formal charge on the nitrogen atom.
 In the third step, the alcohol is then protonated, followed by the dehydration of the
molecule, resulting in the end product of a substituted Quinoline.

13. Importance of Quinoline Synthesis :
 There are multiple ways to synthesize quinoline, one of which is the
Combes quinoline synthesis.
 The synthesis of quinoline derivatives has been prevalent in biomedical studies due
to the efficiency of the synthetic methods as well as the relative low-cost production
of these compounds, which can also be produced in large scales.
 Quinoline is an important heterocyclic derivative that serves as a building block for
many pharmacological synthetic compounds.
 Quinoline and its derivatives are commonly used in antimalarial drugs, fungicides,
antibiotics, dyes, and flavoring agents.

14.  Quinoline and its derivatives also have important roles in other biological
compounds that are involved in cardiovascular, anticancer, and anti-inflammatory
activities.
 Additionally, researchers, such as Luo Zai-gang et al., recently looked at the synthesis
and use of quinoline derivatives as HIV-1 integraseinhibitors.
 They also looked at how the substituent placement on the quinoline derivatives
affected the primary anti-HIV inhibitory activity.