Named reactions Advanced Organic Chemistry.Debus radziszewski.Knorr pyrimidine.Combes synthesis.Pinneer pyrimidine.e.pdf

This presentation provides a detailed overview of four major named reactions used in Heterocyclic Chemistry, specifically focusing on the synthesis of pharmaceutically important heterocyclic rings. SLIDESHARE SUMMARY: Organic Named Reactions
Slide 1: Title & Introduction

Title: Heterocyclic Chemistry: Organic Named Reactions, Mechanism, and Applications


Presenter: Sajna K S, 1
st
Sem M.Pharm, Department of Pharmaceutical Chemistry


Focus: Core synthetic methodologies for imidazole, pyrazole, pyrimidine, and quinoline rings.

Slide 2: Contents

Debus-Radziszewski Imidazole Synthesis


Knorr Pyrazole Synthesis


Pinner Pyrimidine Synthesis


Combes Quinoline Synthesis

1. Debus-Radziszewski Imidazole Synthesis

Reaction: A multicomponent condensation of a dicarbonyl compound (like glyoxal, diketones), an aldehyde, and ammonia.



Product: Substituted Imidazole.



Key Mechanism: The dicarbonyl and ammonia first condense to form a diimine, which then cyclizes with the aldehyde.

Pharmaceutical Applications:

Synthesis of the antibiotic Metronidazole.

Synthesis of Ornidazole.

2. Knorr Pyrazole Synthesis

Reaction: Conversion of a hydrazine or its derivatives with a 1,3-dicarbonyl compound.


Catalysis: Uses an acid catalyst.


Product: Substituted Pyrazole.

Pharmaceutical Applications:

Synthesis of Antipyrine (used to treat ear infections).

Synthesis of the NSAID Celecoxib.

3. Pinner Pyrimidine Synthesis

Reaction: Condensation of 1,3-dicarbonyl compounds with amidines.


Catalysis: Catalyzed by acids or bases.


Product: Substituted Pyrimidine derivatives.


Key Mechanism: Involves protonation, nucleophilic attack by the amidine, cyclization, and final dehydration.

Pharmaceutical Applications:

Synthesis of the antibiotic Trimethoprim (used for UTI).

Synthesis of the antibiotic Sulfamerazine.

4. Combes-Quinoline Synthesis

Reaction: Condensation of unsubstituted anilines with β-diketones.


Product: Substituted Quinolines.


Key Mechanism: Formation of an intermediate Schiff base followed by an acid-catalyzed ring closure.

Pharmaceutical Applications:

Synthesis of the antimalarial drugs Chloroquine.

Synthesis of Hydroxychloroquine.

1. HETEROCYCLIC
CHEMISTRY
ORGANIC NAMED REACTIONS,
MECHANISM AND APPLICATIONS
PRESENTED BY
SAJNA K S
1
st
SEM M.PHARM
DEPARTMENT OF PHARMACEUTICAL
CHEMISTRY
ST. JAMES COLLEGE OF
PHARMACEUTICAL SCIENCES
1

2. CONTENTS
•DEBUS-RADZISZEWSKI IMIDAZOLE SYNTHESIS
•KNORR PYRAZOLE SYNTHESIS
•PINNER PYRIMIDINE SYNTHESIS
•COMBES QUINOLINE SYNTHESIS
•CONCLUSION
•REFERENCES
2

3. DEBUS-RADZISZEWSKI IMIDAZOLE
SYNTHESIS
•Consists of condensing a dicarbonyl compound such as
glyoxal, ketoaldehydes or diketones with an aldehyde
in the presence of ammonia.
•The reaction is named after Heinrich Debus and
Bronistaw Leonard Radziszewski's discovery.
32
N
3
N
H
1
5
4
Dicarbonyl Ammonia Aldehyde

4. •The method is used commercially to produce several imidazoles.
•The process is an example of a multicomponent reaction.
4
dicarbonyl and ammonia condenses to give a diimineStep 1
DICARBONYL
Ammonia
Diimine

5. .

5
Diimine condenses with the aldehyde and gives imidazole.Step 2
Diimine Aldehyde
Imidazole

6. O
O
R
1
R
2
O
–
O
–
R
1
R
2
+
N
H
H
H
N
H
H
H
O
–
O
–
R
1
R
2
NH
3
+
NH
3
+
O
–
O
–
NH
3
+
NH
3
+
R
1
R
2
OH
OH
NH
2
NH
2
R
1
R
2
OH
2
NH
NH
R
1
R
2 6
STEP 1:
PROTON
TRANSFER
Nucleophilic attack
-H20
DIIMINE

7. NH
NH
R
1
R
2
+
O
R
3
H
NH
NH
R
1
R
2
+
O
R
3
H
R
2
R
1
N
N
R
3
H
R
1
R
2
NH
NH R
3
R
1
R
2
N
NH R
3 7
STEP 2:
-2H20
IMIDAZOLE

8. O
O
+ NH
3+
CH
3
O
H
acetaldehyde
ammonia
oxaldehyde
N NH
CH
3
2-methyl-1H-imidazole
N NH
CH
3
NO
2
N N
CH
3
NO
2
OH
OH
OH
ethane-1,2-diol 8
APPLICATIONS
SYNTHESIS OF METRONIDAZOLE:
Metronidazole
HNO3/H2SO4
2
Glyoxal
USE:
ANTIBIOTIC
Debus Radiszewski
synthesis

9. APPLICATIONS
•Synthesis of Ornidazole
9O
O
+ NH
3+
CH
3
O
H
acetaldehyde
ammonia
oxaldehyde
N NH
CH
3
2-methyl-1H-imidazole
N NH
CH
3
NO
2
N N
CH
3
NO
2
Cl
OH
O
Cl
2
HNO3/H2SO4
Ornidazole
Glyoxal
Debus Radiszewski
synthesis

10. KNORR PYRAZOLE SYNTHESIS
•Organic reaction used to convert a hydrazine or its derivatives and a
1,3-dicarbonyl compound to a pyrazole using an acid catalyst.
10
Hydrazine
1,3 dicarbonyl
compound
PyrazoleN
2
3
N
H
1
5
4

11. MECHANISM
11
IMINE
Protonation
of oxygen
Proton shift
Protonation
of oxygen
Nucleophilic
attack
Nucleophilic
attackProton shift
Removal of
proton

12. APPLICATIONS
•Synthesis of antipyrine from phenyl hydrazine
12
USE:
TREAT EAR INFECTION
Knorr pyrazole
synthesis

13. •Synthesis of celecoxib
13
CelecoxibO
CH
3
1-phenylethan-1-one1-phenylethan-1-one
+
F
F
F
O
O CH
3
ethyl trifluoroacetate
CH
3
O
O
F
F
F
+
SO O
NH
2
NH
NH
2
4-hydrazinylbenzene-1-sulfonamide
N
N
F
F
F
CH
3
S
O
O
NH
2
NSAID
Knorr pyrazole
synthesis

14. PINNER PYRIMIDINE SYNTHESIS
•The condensation of 1,3-dicarbonyl compounds with amidines
catalysed by acids or bases to give pyrimidine derivatives.
14N
1
2
6
N
3
5
4

15. MECHANISM
15
Protonation Attack by amidine
Proton transfer
DehydrationProton transfer
Nucleophile attack/
cyclization
Dehydration
Deprotonation
protonation

16. •Synthesis of trimethoprim
16Trimethoprim
POCl3NH
2
O CH
3
O O
ethyl 3-amino-3-oxopropanoate
+
NH
2
NH
2
NH
guanidine
N
NH NH
2
NH
2
O
N
NCl
NH
2
NH
2
CH
3
O
O
O
CH3
CH3
CH3
1,2,3-trimethoxy-4-methylbenzene
N
N
NH
2
NH
2
OH
O
O
CH
3
CH
3
APPLICATIONS
USE:
ANTIBIOTIC (UTI)

17. APPLICATIONS
•Synthesis of sulfamerazine
17
USE:
ANTIBIOTIC

18. COMBES-QUINOLINE SYNTHESIS
•It involves the condensation of unsubstituted anilines (1) with β-
diketones (2) to form substituted quinolines (4) after an acid-catalyzed
ring closure of an intermediate Schiff base (3).
18
Aniline Intermediate
Quinolines
Diketones2
3
N
1
4
10
5
7
6
8
9

19. MECHANISM
19
Protonation of
oxygen
Nucleophilic
attachment of
aniline
-H2O
Formation
of schiffs
base

20. MECHANISM
20
Cyclisation
-H+
-H20

21. Synthesis of 4,7-dichloroquinoline
21

22. 1.Synthesis of chloroquine
22
Chloroquine
USE:
ANTIMALARIAL

23. 2. Synthesis of Hydroxychloroquine
23
Hydroxychloroquine
4-[ethyl(2-hydroxymethyl)amino]-
1-methyl butylamine
USE:
ANTIMALARIAL

24. 24
1.July A Hernandez Munoz, Joel J Junior, Flavia Martins da Silva. Radziszewski
reaction: an elegant, easy, simple and efficient method to synthesise imidazoles
Current Organic Synthesis.2014; 11 (6):824-834.
2.Mahfoudh M, Abderrahim R, Leclerc E, Campagne JM. Recent approaches to
the synthesis of pyrimidine derivatives. Eur J Org Chem. 2017;(20):2856-2865.
3.Hill MD, Movassaghi M. New strategies for the synthesis of pyrimidine
derivatives. Chemistry. 2008;14(23):6836-6844.
4.Jie Jack Li. Knorr pyrazole synthesis. In: Name Reactions: A Collection of
Detailed Reaction Mechanisms.2006:331-334.
5.Dalal M. A textbook of organic chemistry - volume 1. Dalal Institute;2019:233-
244.
6.SA Yamashkin, LG Yudin, AN Kost. Closure of the pyridine ring in the combes
quinoline synthesis. Chemistry of Heterocyclic compounds.1992; 28 (8):845-
855.
REFERENCES

25. THANK YOU
25