PH-2102_Lecture Notes 8/29/2013

Simple Heterocyclics CHEMISTRY OF FURAN

Five Membered Heterocyclics with Single Heteroatom
Sources & Occurrence
Aromatic
ring O N S
H Chemical Synthesis
systems Furan Thiophene
Pyrrole

Partially Structure & Aromaticity

unsaturated ring N S
O
systems
Dihydrofuran
H
Pyrroline Dihydrothiophene O Chemical Properties

Pharmaceutical Applications
Fully saturated
ring systems O N S
H
Tetrahydrofuran Pyrrolidine Tetrahydrothiphene Summary

Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 1 Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 2

Sources & Occurrence of Furan Synthesis of Furan

Natural Sources General Principle of Heterocyclic Synthesis

Retrosynthetic Chemistry – Retrosynthesis

The name is derived from the term “furfur” – A name
given to the carbohydrate derivative “furfural”.
What is Retrosynthesis?
Working backward from the target heterocyclic ring, by

Rice bran – Carbohydrates – Ribo sugars, a systematic bond disconnection approach, to find a
Furanosides etc. simple, easily available chemical template, known as
chemical precursor(s).

Vitamin C – Ascorbic acid
Strategies used:

Starting from aliphatic precursors

Nucleic acids – RNA and DNA – Which contain
Cyclisation, cycloaddition reactions
deoxy or ribo-furanoside ring systems
Starting from aromatic precursors

Conversion of one ring to another heterocyclic ring
Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 3 Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 4

Synthesis of Furan Synthesis of Furan

1. Dry distillation of mucic acid 4. Dehydration of succinic dialdehyde

COOH Dry Distillation
Heat H2SO4 P2O5
(CHOH)4
- CO2 O COOH OHC CHO HC CH
CH2OH
-CO2 O
- 3H2O -CO2
O O Heat
O
Furan
H H Furan
2. Decarboxylation of furoic acid
5. Fiest Benary synthesis
(O)
Heat
O
O CHO O COOH O O
-CO2 C2H5O CH3
Furan Cl R Pyridine
C2H5O
3. Decarboxylation of furfural + H3C O CH3
Ag2O/ Steam H3C O
O CH3
O
O CHO -CO
Furan

Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 5 Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 6

A S Raja, Dept. of Pharma, IIT (BHU) 1

PH-2102_Lecture Notes 8/29/2013

Synthesis of Furan STRUCTURE & AROMATICITY

6. Paal Synthesis
Furan is planar and it possess resonance

energy.
P2O5
R R
It contains “oxygen” as a heteroatom which has
O O H2SO4 R O R an un-hybridized “p” orbital O

Mechanism!!
There are four carbons and an oxygen, together
forms a ring of sextet containing 6 pi electrons

Structurally resembling to cyclopentadienyl

carbanion (pi excesseive system)

Replacement of a “CH” with “oxygen” gives a

neutral, aromatic compound, Furan

Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 7 Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 8

STRUCTURE & AROMATICITY Chemical Properties of Furan

Aromaticity A. Electrophilic Aromatic Substitution Reactions

Thus, furan fulfills the criteria of aromaticity O HgCl O NO2

HgCl2

O
HNO3

The lone pair of unhybridized p orbital on the Ac2O
oxygen atom contributes to the pi electron
system of the ring and thus completes the sextet nBuLi SO3

form. O Li O Pyridine O SO3H

Cl2/-40 deg
C6H5N2Cl

It has a resonance energy of 16 kcal/mol BF3
O deg Ac2O

Furan is the least aromatic when compared with Cl O Cl

N
other five membered heterocyclics such as O N C6H5
Thiophene (RE : 29 kcal/mol) and Pyrrole (RE :
COCH3
22 kcal/mol) O

Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 9 Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 10

Chemical Properties of Furan Chemical Properties of Furan

8. Reaction with ammonia - - - Pyrrolidine 11. Diels-Alder reaction with Maleic anhydride - - - Cyclic Adduct

9. Reaction with HCl - - - Tetramethylene chlorohydrin

12. Reduction with Ni - - - THF

10. Ring opening reaction with MeOH - - Diacetal of succinic aldehyde

13. Basicity of furan - - - Protonated furan - - - Brown resin

Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 11 Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 12

A S Raja, Dept. of Pharma, IIT (BHU) 2

PH-2102_Lecture Notes 8/29/2013

Pharmaceutical Applications of Furan Pharmaceutical Applications of Furan

Nitrofurantoin Furosemide Ranitidine
Nitrofurazone
O COOH
H CH3 HC NO2
O N
O N S CH3
O2N C N N NH2 O2N C N N NH H3C O N N
O H H O H H H
SO2NH2
O Cl
Bacteriocidal drug Urinary antiseptic – against E Coli, Diuretic – Tabs, Caps Anti-Ulcer Drug – Tabs (Renitab, Torrentin
Klebsila, Aerobacter etc. T/t of odema associated with CHF For the management of ZES and GERD
Mangement of HT
Furazolidone Rofecoxib Ascarbic acid
Diloxanide furoate O
O S CH3
HO OH
CH3 Cl
O2N C N N O
O H O N C Cl
O H HO O O
O O H
O OH
O O
Anti-Protozoal,
Antibacterial drug Diuretic – Tabs, Caps
For the treatment of Amoebic NSAIDS – Super Aspirin drug
dysentery – Tablets along with Antiinflammatory drug T/t of odema associated with CHF
metronidazole Rhumaetoid Arthritis Mangement of HT

Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 13 Senthil Raja A, Department of Pharmaceutics, IIT (BHU), Varanasi 29 August 2013 14

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