This document discusses strategies for synthesizing three, four, five, and six-membered heterocyclic rings. It outlines three strategies for each ring size, including the Gabriel ring closure and Hassner synthesis for aziridines, pyrolysis of cyclopropyl azides and photocycloaddition for azetines, the Paal-Knorr and Hantzsch syntheses for pyrroles, and the Hantzsch synthesis and reactions with maleic anhydride for pyridines and pyridazines. A variety of heterocyclic compounds are derived from carbocyclic precursors by replacing carbon atoms with heteroatoms like nitrogen, oxygen, or sulfur.

1. Presented To- Ms.Gul Naz Fatima
Sr. Asst. Professor, BBDNIIT, Lucknow
Presented By- Sachin Kumar Vishwakarma
M.Pharm. 1st year
(Pharmaceutical Chemistry)
STRATEGIES FOR SYNTHESIS OF
THREE, FOUR, FIVE AND SIX-
MEMBERED RINGS

2. Classification of Organic Compounds
Organic
compounds
Cyclic
compounds
Homocyclic
compounds
Heterocyclic
compounds
Open chain
compounds
Straight chain
compounds
Branched
compounds
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3. Heterocyclic compounds
Greek word “heteros” means different .
Heterocyclic compounds are those where one or more
atom(s) of the ring are heteroatoms, for example, N, O, S, P,
As, Se, B, and so on.
More than half of the known organic compounds are
heterocyclic compounds .
For example- nucleic acid bases, hemoglobin, chlorophyll,
vitamins, amino acids, alkaloids, carbohydrates etc.
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4. Structures of some heterocycles
Aziridine
Pyrimidine
Pyrrole Pyridine
Oxetene Oxazole
NH
O
NH
N
O
N
N
N
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5. Three membered heterocycles
Formally derived from cyclopropane by replacing a carbon
atom with a hetero atom.
Such a change widely affects the physical and chemical
properties of the resulting heterocyclic rings.
Three membered saturated heterocyclic compounds
containing a N, O, and S as the hetero atom are known as
aziridine, oxirane, and thiirane respectively .
Chemically they are most stable than cyclopropane
derivatives .
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6. Strategies for synthesis
Strategy-1, The Gabriel ring closure –The aziridine was first
obtained in 1888 by heating β-bromomethylamine in presence of
KOH.
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7. The Gabriel ring closure mechanism do not follow
the following reaction :-
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8. Strategies for
synthesis
Strategy-2,
The Hassner
synthesis for
aziridine
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9. Strategies for synthesis
Strategy-3, Synthesis of Diaziridines from Schiff’s base
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10. Four membered heterocycles
Heterocyclic analogues of cyclobutane .
Relatively less strained than the three membered
heterocyclic rings .
Some examples are as follows :-
HN
Azitidine
O
Oxetane
S
Thietane
HN
2-Azetine
N
Azete
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11. Strategies for synthesis
Strategy-1,Pyrolysis of Cyclopropylazides –A useful route to
azetines involve pyrolysis of cyclopropyl azides .
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12. Strategies for synthesis
Strategy-2, Photocycloaddtion
12
-azetin

13. Strategies for synthesis
Strategy-3, Oxetane synthesis by Cyclization reactions
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14. Five membered heterocycles
The simplest of the five- membered heterocyclic compounds
are pyrrole, furan, and thiophene .
Characterized by high degree of reactivity towards
substitution by electrophilic reagents rather than addition .
From molecular orbital standpoint these molecules are
described as consisting of planar pentagon with sp2 hybridized
carbon atom.
ON
H
N
H
S
Pyrrole Furan Thiophene Oxazole 1H-imidazole
N
O
N
N
H
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15. Strategies for synthesis
Strategy-1, The Paal-Knorr synthesis of pyrrole
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16. Strategies for synthesis
Strategy-2, The Hantzsch synthesis of Pyrrole
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17. Strategies for synthesis
Strategy-3, Simmons-Smith reaction for Thiophene synthesis
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18. Six membered heterocycles
The methane (-CH=) group in a benzene ring can be replaced
by a heteroatom to generate six membered heterocyclic
compounds .
 The departure from perfectly regular hexagonal geometry
caused by the presence of the heteroatom .
 A strong permanent dipole, traceable to the greater
electronegativity of nitrogen compared with carbon.
N O S
Pyridine Pyrrone Thiopyran
N
N
N
N
Pyrazine Pyrimidine 18

19. Strategies for synthesis
Strategy-1, The Hantzsch synthesis of Pyridine
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20. Strategies for synthesis
The Hantzsch synthesis of Pyridine- Mechanism
Step-1
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21. Contd.
Step-2
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22. Strategies for synthesis
Strategy-2, Synthesis of Pyridine from other ring systems
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23. Strategies for synthesis
Strategy-3, Pyridazines synthesis from Maleic anhydride
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24. References
1.Bansal, R.K.; ‘‘Heterocyclic Chemistry’’; Third edition; New
Age International Publishers; New Delhi, 2002.
2.Joule, J.A.; Mills, K.; ‘‘Heterocyclic Chemistry’’; Fifth
edition; John Wiley & Sons Ltd.; United Kingdom, 2010.
3.Morrison, R.T.; Boyd, N.B.; Bhattacharjee, S.K.; ‘‘Organic
Chemistry’’; Seventh edition; Dorling Kindersley Pvt. Ltd.;
New Delhi, 2013.
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