2. • Unsaturation is often introduced by elimination e.g. dehydration, dehydrohalogenation
General Strategies for Heterocycle Synthesis
Manipulation of Oxidation State
X
X
X, Y = O, S, NR
conjugate addition
+ +
+
Ring Construction
• Cyclisation – 5- and 6-membered rings are the easiest to form
• CX bond formation requires a heteroatom nucleophile to react with a C electrophile
Y Y
X
hexahydro
[O]
H2 H2
[O]
X
X X
tetrahydro dihydro
H2
[O]
X
aromatic
or
3. 14
General Strategies for Heterocycle Synthesis
O O
NH3
N
H
NH3
N
N
H
O O
N
H
2H2O 2H2O
X X
Common Strategies
“4+1” Strategy
X X
• Strategy can be adapted to incorporate more than one heteroatom
“5+1” Strategy
• 1,5-Dicarbonyl compounds can be prepared by Michael addition of enones
O O
NH3
H
N N
H
H2
[O]
2H2O
5. Less stable than pyrrole & thiophene
less reactive than pyrrole towards E+
Aromatic as lone pair of e participate in Pi cloud, follow Huckel’s rule of
aromaticity 4n + 2π
O and 4 C SP2 hybridised & lie in same plane
6. Synthesis of Furan: 1) From carbohydrate:
Polysaccharide (Oat)
Acid
hydrolysis
Furfuraldehyde
2-furoic acid
Decarboxylation
Furan
9. 4) Synthesis of furan by Paal –Knorr method: Ring closure mtd. Subst. open
chain compd (1,4 diketone) cyclize by acid to give furan
Mechanism via mono enol formation.
Sterically hindered diketone do not cyclize to furan
10. Chemical reactions of furan:
1) Reaction with acid: F can be hydrolysed easily by acid to give aldehyde. Mild
conditions shd be used otherwise protonated F undergoes polymerization.
F with EWD more stabile to acids
12. Chemical reactions of furan:
2) Electrophilic aromatic substitution: more reactive than benzene.
2 position more reactive. Conditions need to be controlled.
A) Halogenation: proceeds quickly to give mix of either mono and poly subs or
resin
% of 2 subst product can be increased by using less amt of Cl2
2- Bromo can be obtd by Br2 in dioxane
13. Chemical reactions of furan:
2) Electrophilic aromatic substitution:
B) Nitration: Mild nitrating agents used acetyl nitrate (acetic anhydride
+ HNO3
14. Chemical reactions of furan:
2) Electrophilic aromatic substitution:
C) Sulfonation: Mild sulfonating agents used Pyridine- SO3 complex
If H2SO4 used, it gives resin
15. Chemical reactions of furan:
2) Electrophilic aromatic substitution:
D) Friedel Crafts reaction: Anhydride and acyl halide need Lewis catalyst.
But reactive anhydride like (CF3CO)2O work without catalyst.
Alkylation not successful, polymerization.
F containing EWD can be alkylated.
16. Chemical reactions of furan:
3) Carbene and nitrene: Cabene add across 2,3 C db.
There is not much report of reactions of nitrene with furan
17. Chemical reactions of furan:
4) Reaction with reducing agents: dependent on catalyst, solvent & temp
18. Chemical reactions of furan:
5) Reaction with oxidizing agents: F is O2/air sensitive, 1,4 addition to diene system
19. Chemical reactions of furan:
6) DA Reaction : Furan as a diene reacts with dienophiles to give DA adduct.
But due to aromatic character and ring strain in cycloadduct it is thermolabile,
revert to SM.
22. O
furan
O CH=O
O Br
O HgCl O I
1. HCN, HCl
2. H2O
Br2
dioxane
HgCl2
CH3CO2Na
I2
CH3COCl
O C
O
CH3
Extra
23. Thipohene
Have two pairs of nonbonding e
but only 1 pair is in the
unhybridized p orbital and is able
to overlap with the C of the ring.
Mayer 1882
Coal tar, pt and animal metabolite
24. Synthesis of Thiophene:
1) Using Na-Succinate
Classical mtd Phos. trisulfide ( Red P +S)
Industrial mtd use hydrocarbon (butane/butene/1,3-butadiene and elemental S
600 0C
25. Synthesis of Thiophene:
2) Ring closure Mtd
A) From unsaturated compds/ Fiesselmann mtd:
Condensation Rxn
27. Synthesis of Thiophene:
2) Ring closure Mtd
C) Hinsberg Mtd: 1,2 dicarbonyl compound diethylthiodiacetate in
presence of st base
involved 2 aldol condensation betn reactant and forms half ester
28. Chemical reactions of thiophene:
1) Reaction with acid: T stable to acid.
V. st acid can cause polymerization. Orthophosphoric acid under mild condition
gives trimer.
30. Chemical reactions of Thiophene:
2) Electrophilic aromatic substitution: more reactive than benzene.
Pyrrole>furan>Thiophene>Benzene
2 position more reactive.
A) Halogenation: Rxn with NBS gives 2- bromo T
31. Chemical reactions of Thiophene:
2) Electrophilic aromatic substitution: more reactive than benzene.
Pyrrole>furan>Thiophene>Benzene
2 position more reactive.
B) Nitration:
32. Chemical reactions of Thiophene:
2) Electrophilic aromatic substitution:
C) Sulfonation: 95% H2SO4 used at rt readily occurs
33. Chemical reactions of Thiophene:
2) Electrophilic aromatic substitution:
D) Friedel Crafts reaction: wide variety of choices available
34. •Chemical reactions of Thiophene:
3) Reaction with carbene & Nitrene: caboethoxy carbene adds to C2-C3 bond to
give cyclopropane compd, which can be opened with acid to give thiophene Beta-
acetic ester
R=C:
R–N: acts as E+
36. •Chemical reactions of Thiophene:
4) Reaction with Nu: Every positional combination of Nitro and Halo T actiavate
system towards SN rxn
Seems like normal displacement Rxn
37. Chemical reactions of Thiophene:
5) Reaction with free radicals/ Gomberg Bachmann rxn:
1 of the best & simple mtd for synthesis of aryl thiophenes
38. •Chemical reactions of Thiophene:
6) Reaction with oxidising agents:
Resistant to mild oxidising agents.
HNO3 breaks ring to maleic acid and oxalic acid.
Peracid (perbenzoic acid attacks S atom)
Initial sulfoxide ca not be isolated due to dimerization &
further oxidation to
Thiophene 1,1’ dioxide/ Thiolane can form it’s also reactive but isolable
40. •Chemical reactions of Thiophene:
8) Diels-Alder reaction: Acetylenic dienophiles. Chelotropic expulsion
of S from unstable intermediate, which gives benzene derivative
44. The Knorr Synthesis:
Imp & widely used mtd
Condensation of Alfa amino ketone with another dicarbonyl compound
with active methylene grp in presence of acetic acid
45. Hantzch synthesis of pyrrole:
Alfa halo ketone/aldehyde react with beta keto ester (Beta chloro ketone)
In presence of N containing base (NH3 or amine) which acts as base as well as solvent.
Yield moderate to good.
46. The Paal Knorr Synthesis of Pyrrole:
General mtd
Condensation of 1,4 diketone with NH3 or primary amine.
47. The Piloty Robinsons Synthesis:
Monocyclic version of Fischer indole synthesis.
Ketazine with st acid to give pyrrole through [3,3] sigmatropic rearrangement
of tautomeric divinyl hydrazine
48. Chemical reactions of Pyrrole:
1) Reaction with acid:
H attached at N undergoes rapid exchange in acid & alkali
Similar exchange also possible for H at C under more acidic condition
Exchange rate of α proton is double than that of β proton
Isolation of trimer of pyrrole could be achieved by controlled addition of acid
49. Chemical reactions of Pyrrole:
2) Reaction with base:
pKa 17.5 which is larger than imidazole so pyrrole is wk acid than imidazole.
Weaker than phenol but equal to EtOH
It reacts with K to liberate H2 and form salt
Acidity of P can be increased by putting EWG at position 3 which stabilizes
anion by resonance
51. Mono-C-alkylation of pyrroles cannot be achieved by direct reaction
with simple alkyl halides, either alone or with a Lewis-acid catalyst,
e.g. pyrrole does not react with methyl iodide even above about 150
°C, gives further heating leads to a complex mixture made up
mostly of polymeric material together with some poly-methylated
pyrroles.
The more reactive allyl bromide reacts with pyrrole at room
temperature, but mixtures of mono- to tetra-allyl-pyrroles together
with oligomers and polymers are obtained.
Chemical reactions of Pyrrole:
3) Alkylation:
52. Chemical reactions of Pyrrole:
3) Electrophilic Aromatic substitution: π e density is more as
compared to benzene.
ES Rxn occurs similar to benzenoid system
Occurs at 2 position
if blocked to other position
Max resonance max stability/probability
2 position
Followed by 3
53. Chemical reactions of Pyrrole:
3) Electrophilic Aromatic substitution:
A) Halogenation: Extremely reactive
Chlorination (SO2Cl2)
Bromination (Br2 CH3COOH)
Iodination (I2/KI3)
All these gives tetra halo derivatives
Hard to get mono halo derivative
Halo-pyrroles are v. unstable, decompose in air & light
54. Chemical reactions of Pyrrole:
3) Electrophilic Aromatic substitution:
B) Nitration: Extremely reactive
55. Chemical reactions of Pyrrole:
2) Electrophilic aromatic substitution:
C) Sulfonation: If H2SO4 used at rt forms polymer
So mild sulfonating agent (Pyridine sulfur trioxide complex) used
56. Chemical reactions of Pyrrole:
4) Reaction with oxidising agents:
Easy
Autoxidation by air, light red brown colour.
Ozonolysis at low temp breakdown of ring.
If ring does survive it forms maleinimide
deri.
With H2O2 also it gives similar prodt
57. Chemical reactions of Pyrrole:
5) Reaction with reducing agents:
P won’t respond to rxn with LAH, Na/Liq NH3
But reduction is possible in acidic media
Species under attack protonated
70. Reaction of imidazole with acid & base
Base and form crystalline salt with acid.
More acidic than pyrroles and thus forms salts of the following type with Grignard
reagent or metal ions.
71. Reaction of imidazole with oxidising agents:
stable to auto oxidation and to the action of chromic acid
Can be oxidised by KmnO4 .
H2O2 Readily opens the ring to form oxamide
N
N
H
NH
N
H
O2 / MeOH
O
MeO
MeO
Oxygen in the presence of a sensitizer (single oxygen) reaction gives an
imidazolidine derivative
72. Reactions of imidazole -Electrophilic substitution Rxn:
E + would attack the unshared electron pair on N-3, but not that on the
‘pyrrole’ nitrogen since it is the part of the aromatic sextet.
It is more susceptible to E + attack than thiazole, furan and thiophene.
Attack takes place at the 4th and 5th position
76. Catalysis role of imidazole - Ester Hydrolysis.
Inspired by evidence that the imidazole ring of histidine residues present in various
hydrolytic enzymes is responsible for their proteolytic activities,
imidazole itself has been shown to be an excellent catalyst of ester hydrolysis
In intramolecular transesterifications and hydrolyses of 2-hydroxymethylbenzoic acid derivatives,
the accelerating role of imidazole is due to its ability to act as a proton transfer catalyst rather
than as a nucleophile.
77. Indole:
abundant in nature
tryptophan, indole-3-acetic acid,
serotonin, natural products, drugs
Isolated industrially from coal tar
Biosynthesis of tryptophan
Isoelectronic with naphthalene
Very weakly basic: pKa of protonated indole: 2.4
Protonation occurs at C–3 preferentially
Easily oxidized (atmospheric oxygen) very e rich
Electrophilic attack occurs at C–3 (site of most
electron density)
C–3 is more reactive to electrophilic attack than benzene
83. Reissert indole synthesis:
Basic condensation of o-nitrotoluene with oxalic ester to o-
nitrophenylpyruvic ester, reduction of the nitro group to an amino group,
cyclization to indole-2-carboxylic acid and final decarboxylation
![• Unsaturation is often introduced by elimination e.g. dehydration, dehydrohalogenation
General Strategies for Heterocycle Synthesis
Manipulation of Oxidation State
X
X
X, Y = O, S, NR
conjugate addition
+ +
+
Ring Construction
• Cyclisation – 5- and 6-membered rings are the easiest to form
• CX bond formation requires a heteroatom nucleophile to react with a C electrophile
Y Y
X
hexahydro
[O]
H2 H2
[O]
X
X X
tetrahydro dihydro
H2
[O]
X
aromatic
or](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)