Deals with Simple Heterocyclic Compounds Preparation and properties. Classification, Nomenclature,

1. Chemistryof Heterocyclic
Compounds
Dr. S. Sreenivasa M.Phil., Ph.D., D.Sc.
Associate Professor and Coordinator
Department of Studies and Research in Organic
Chemistry, Tumkur University, Tumkur – 572 103

2. Course Summary

3. Introduction
• Heterocycles
contain
one or more heteroatoms
in
a ring
Z
X X X
Y Y
carbocycl
e
heterocycle
s
X, Y, Z are usually O, N or S
•
•
•
•
Aromatic, or partially or
fully
saturated – this course will focus on aromatic
systems
Heterocycles are important and a large proportion of natural products contain
them
Many pharmaceuticals and agrochemicals contain at least one heterocyclic unit
Heterocyclic systems are important building-blocks for new materials
possessing interesting electronic, mechanical or biological properties

4. Classification – Aromatic Six-Membered
HeterocyclesIsoelectronic carbocycle
4 4
3
2
5
6
3
2
5
61
ON
1
pyridine
X
pyrylium
4
N
4 4
3
2
5
6
3
2
5
6
3
2
5
6
N
N
N N N
1
pyridazine
1
pyrimidine
1
pyrazine
4 5 4 5
3
2
6
7
3 6
72 N
N
1 8 1 8
quinoline isoquinoline

5. Classification – Aromatic Five-Membered
HeterocyclesIsoelectronic carbocycle
3 4 3 4 3 4
2 1
N
5 2 5 2 5
O
1
furan
S
1
thiophene
H
pyrrole
3 4 3 4 3 4
N N N
2 1
N
5 2 5 2 5
O
1
oxazole
S
1
thiazole
H
imidazole
3 4 3 4 3 4
2 1
N
5 2 5 2 5N N N
O
1
isoxazole
S
1
isothiazole
H
pyrazole
4
53
6
2 1
N 7
H
indole

6. Classification
Unsaturated
– Unsaturated / Saturated
O O
aromatic dipolar resonance form
O O
4( )-pyrone
N
H
O N
H
O N OH
2-pyridone
Saturated
O
O
O O N H
pyrrolidine
O
ethylene oxide THF 1,4-dioxan dihydropyran

7. Functional Group Chemistry
Imine Formation
R3
R3
O R3
NH2
N NH
R1
R2
R1
R2
R1
R2
H3O
H H
H
R3
N
H 3
H R HH
OHO R3
N NOH2
R1
R2
R1
R2
R1
R2
R1
R2
• Removal of water is usually required to drive the reaction to completion
• If a dialkylamine is used, the iminium ion that is formed can’t lose a proton
enamine is formed
and an

8. Functional Group
Enols and Enolates
Chemistry
O OH O O OB
H
R1
R1
R1
R1
R1
E H
R2
R2
enol form
R2
R2
R2
keto form enolate
• The enol form is favoured by a conjugating group R2 e.g. CO2R, COR, CN, NO2 etc.
• Avoid confusing enols (generated under neutral/acidic conditions) with enolates
(generated under basic conditions)
• Enolates are nucleophilic through C or O but react with C electrophiles through C
Enol Ethers R3
O OR3
R1
R3
OH
R3
R2
acetalOR3
O
R1
R1
H
R2
R2
OH2Oenol ether
R1
R2

9. Functional Group Chemistry
Enamines
R3
R3
R3
R3
R3
R3
N
H
NO N
H H
R1
R1
R1
H
R2
R2
R2
iminium ion
(Schiff base)
enamine
R3
R3
R3
R3
N N OH2O
E E
R1
R1
R1
E
R2
R2
R2
• Analogues of enols but are more nucleophilic and can function as enolate equivalents
• Removal of water (e.g. by distillation or trapping) drives reaction to completion
• Enamines react readily with carbon nucleophiles at carbon
• Reaction at N is possible but usually reverses

10. Functional
Common Building-Blocks
O
Group Chemistry
O NH
R R R
OH
carboxylic acids
NH2 NH2
amidinesamides
O NH O O O O
1 R2 1 2
H2N NH2 H2N NH2 R R OR
-keto estersurea guanidine -diketones
Building-Blocks for Sulfur-Containing Heterocycles
O S
P2S5
1 2
R RR SH
S
R1
R2
R1
R2
thioketones thiols thioethers
• Heterocycle synthesis requires:
C O or C N bond formation using imines, enamines, acetals, enols, enol ethers
C C bond formation using enols, enolates, enamines
• During heterocycle synthesis, equilibrium is driven to the product side because of
removal of water, crystallisation of product and product stability (aromaticity)

11. General Strategies for Heterocycle Synthesis
Ring Construction
• Cyclisation – 5- and 6-membered rings are the easiest to form
• C X bond formation requires a heteroatom nucleophile to react with a C electrophile
Y Y
+ + conjugate addition
+X
X
X, Y = O, S, NR
Manipulation of Oxidation State
[O] [O] [O]
or
H2 H2 H2
X
hexahydro
X
tetrahydro
X X X
aromaticdihydro
• Unsaturation is often introduced by elimination e.g. dehydration, dehydrohalogenation

12. General Strategies for
Common Strategies
Heterocycle Synthesis
“4+1” Strategy
X X
H
NN
NH3 NH3
2H2O 2H2O
N
H
N
H
O O O O
• Strategy can be adapted to incorporate more than one heteroatom
“5+1” Strategy
X X
H
[O]NH3
2H2O H2
NN
H
O O
• 1,5-Dicarbonyl compounds can be prepared by Michael addition of enones

13. General
“3+2” Strategy
Strategies for Heterocycle Synthesis
“3+3” Strategy
oror
XX X X X X
Examples
X H2N H2N O H2N OH
O +
+
X H2N O OH
+ Hal+
O Hal = Cl, Br, I
+
O
O
E E
NH2 NH2 OH OH
+

14. Bioactive Quinolines/IsoquinolinesH
NEt2
Me
HO
N HN
H
MeO MeO
N
quinine
• Quinine is an anti-malarial
N
chloroquine
the bark of the Cinchona treenatural product isolated from
• Chloroquine is a completely synthetic anti-malarial drug
found in quinine – parasite resistance is now a problem
MeO
that has the quinoline system
N
MeO
OMe
OMe
papaverine
• Papaverine is an alkaloid isolated from the opium poppy and is a smooth muscle
relaxant and a coronary vasodilator

15. Quinolines – Synthesis
Structure
N
N
• pKa values (4.9 and 5.4) are similar to that of pyridine
• Possess aspects of pyridine
ammonium salts
and naphthalene reactivity e.g. form N-oxides and
Combes Synthesis
MeO
(“3+3”)
O Me MeMeO MeOO
O O
Me Me
H2O
NH2 N Me N
H
Me
MeO MeO MeO
c-H2SO4,
MeMeO HMeO Me MeO Me OH
O
H2O
N
H
MeN Me N
H
Me
MeOMeO MeO
23%

16. Quinolines
Conrad-Limpach-Knorr Synthesis (“3+3”)
– Synthesis
OEt OH OO O
O
Me OEt 270 °C
rt, H2O
NH2 N
H
Me N Me N
H
Me
70%
• Very similar to the Combes synthesis by a -keto ester is used instead of a -diketone
• Altering the reaction conditions can completely alter the regiochemical outcome
Me Me MeO O
O
250 °C, H2OMe OEt
140 °C,
NH2
H2O
N
H
O N
50% H
O N OH

17. Quinolines – Synthesis
Skraup Synthesis (“3+3”)
OH
H H
H
H
O O
130 °C, H2SO4
NH2 N
H
N
H
H OH
[O] (e.g. I2) H2O
N N
H
N
H85%
• Acrolein can be generated in situ by treatment of glycerol with conc. sulfuric acid
dihydroquinoline• A mild oxidant is required to form the fully aromatic system from the
MeO1.
Me Me
Me
ZnCl2 or FeCl3,
NH2 EtOH, reflux
2. [O]
N
65%

18. Quinolines
Synthesis (“4+2”)
– Synthesis
Friedlander
PhPh PhO
H
Me MeOMe
O Me H2O
c-H2SO4, AcOH
heatNH2 N
H
Me N Me
88%
Ph PhOPh
OMe
Me H2OO
KOH aq., EtOH
0 °C N N
71%NH2
H Me MeOH
• The starting acyl aniline can be difficult to prepare
• Acidic and basic conditions deliver regioisomeric products in good yields

19. Isoquinolines
Pomeranz-Fritsch Synthesis (“3+3”)
– Synthesis
EtO OEt
OEt
OEtH2N H , EtOH
H2OO N N
H
Bischler-Napieralski Synthesis (“5+1”)
MeCOCl P4O10, heat Pd-C, 190 °C
NH N NNH2
O
Me Me
93%Me
• Cyclisation can be accomplished using POCl3 or PCl5
• Oxidation of the dihydroisoquinoline can be performed using a mild oxidant

20. Isoquinolines
Synthesis (“5+1”)
– Synthesis
Pictet Spengler
MeOMeO MeO
HCHO 20% aq. 20% HCl aq.
heat 100 °C NNH2 N
H
MeO MeO MeO
[O]
N NH NH
80% H
• An electron-donating substituent on the carboaromatic ring is required
• A tetrahydroisoquinoline is produced and subsequent oxidation is required to give the
fully aromatic isoquinoline

21. Quinolines/Isoquinolines
Electrophilic Reactions
–
*
Regiochemistry
N
N H
H
*
• Under strongly acidic conditions, reaction occurs via the ammonium
• Attack occurs at the benzo- rather than hetero-ring
salt
• Reactions are faster than those of pyridine but slower than those of naphthalene
NO2
Nitration
fuming HNO3,
cH2SO4, 0 °CN N N
72% 8%
NO2
• In the case of quinoline, equal amounts of the 5- and 8-isomer are produced

22. Quinolines/Isoquinolines
Electrophilic Reactions
–
Sulfonation
HO3S
30% oleum3, >250 °C
90 °C
N N N
thermodynamic productSO3H 54%
• Halogenation is also possible but product distribution is highly dependent on conditions
• It is possible to introduce halogens into the hetero-ring under the correct conditions
• Friedel-Crafts alkylation/acylation is not usually possible

23. Quinolines/Isoquinolines
Nucleophilic Reactions
–
Regiochemistry
N
N
• Attack occurs at hetero- rather than benzo-ring
• They are enerally more reactive than pyridines to nucleophilic attack
Carbon Nucleophiles
2-MeOC6H4Li H2O
Et2O, rt H OMe H OMe
N N N
H
Li
[O]
N
MeO

24. Quinolines/Isoquinolines
Nucleophilic Reactions
–
n-BuLi H2O [O]
benzene, rtN N NH N
Li
H n-Bu
required to regenerate aromaticity
H n-Bu n-Bu
• Oxidation is
Amination H NH2
KNH2, NH3 (l) > 45 °C
65 °C H
N N
K
N
K
NH2
KMnO4, 65 °C KMnO4, 40 °C
NH2
N
50%
NH2 N
60%
thermodynamic product

25. Quinolines/Isoquinolines –
Nucleophilic Substitution
Displacement of Halogen
NaOEt, EtOH
reflux Cl
N Cl N N OEt
OEt
OMe
Cl
NaOMe, MeOH
OMe
Cl
DMSO 100 °CN N N
87%

26. Quinolines/Isoquinolines –
The Reissert Reaction
PhCOCl KCN
H
N N N
CN
CN
O Ph O Ph
base, MeI
NaOH aq.
Me Me
N Me N N
CN CN
HO Ph O Ph
O
• The proton adjacent to the cyano group is extremely acidic
• The reaction works best with highly reactive alkyl halides

27. Isoquinolines – Synthesis of a Natural Product
Synthesis of Papaverine
O O O
MeO
Me2CH(CH2)2ONO,
MeOMeO
Me ZnCl2, HCl, rt
NaOEt, EtOH, rt N NH2
Cl
MeO MeOMeO OH
75% O
KOH aq., rt
OMeOH OH
OMeMeO MeO
Na-Hg, H2O, 50 °C
MeO
P4H10,
xylene, heat NH NHN O O
MeO MeOMeO
30% 60%
OMe OMe OMe
MeO MeO MeO
• Cyclisation is
reaction
achieved by the Pictet-Grams reaction cf. the Bischler-Napieralski

28. Bioactive Furans, Pyrroles and Thiophenes
NO2
Me2N S
O
NHMe
N
ranitidine
• Ranitidine (Zantac®, GSK) is one of the biggest
H2-receptor antagonist and lowers stomach acid
H
selling drugs in history. It is an
levels – used to treat stomach ulcers
O
CO2H
N
Ph
ketorolac
• Ketorolac (Toradol®, Roche) is an analgesic and anti-inflammatory drug
Me
N
S
N
banminth
• Pyrantel (Banminth®, Phibro) is an anthelminthic agent and is used to treat worms in
livestock

29. Furans, Pyrroles and Thiophenes – Structure
Structure
SO N
H
X
..
• 6 electrons, planar, aromatic, isoelectronic with cyclopentadienyl anion
Resonance Structures
etc.
X
+
X
..
X X
• Electron donation into the ring by resonance but inductive electron
1.42 Å
withdrawal
1.44 Å 1.43 Å
1.35 Å 1.37 Å 1.37 Å
0.71 D 1.55 D 0.52 D
1.37 Å 1.38 Å 1.71 Å SO N
H
1.68 D 1.57 D 1.87 D
SO N
H
• O and S are more electronegative than N and so inductive effects dominate

30. Furans – Synthesis
Paal Knorr Synthesis
R1
R2
R1
R2
R1
R2
O
OH
O O O O
HH H
heatH
H
H
1 2 1 2 1 2
R R R R R R
O O O
OH2
• The reaction is usually reversible and can be used to convert furans into 1,4-diketones
• A trace of acid is required – usually TsOH (p-MeC6H4SO3H)

31. Furans
Feist-Benary Synthesis (“3+2”)
– Synthesis
Me O
EtO2C O + Me EtO2C O Me EtO2C
+ Cl
Me O Cl Me O Cl Me O
NaOH aq., rt
OH Me
H
OH
MeMeEtO2C EtO2C
EtO C ClOH 2
H2O
Me Me
O O
isolable
Me O
• The product prior to dehydration can be isolated under certain circumstances
• Reaction can be tuned by changing the reaction conditions

32. Furans – Synthesis
Modified Feist-Benary
I
EtO2C O + Me EtO2C Me EtO2C Me
+ O O
Me O Cl
I
Me O Me O
NaI, NaOEt,
EtOH
EtO
EtO C
HEtO2C EtO2C
Me2
H2O
Me
OH
O
Me Me Me
Me OO O
• Iodide is a better leaving group than Cl and the carbon becomes more
• The Paal Knorr sequence is followed from the 1,4-diketone onwards
electrophilic
• The regiochemical outcome of the reaction is completely altered by addition of iodide

33. Thiophenes – Synthesis
Synthesis of Thiophenes by Paal Knorr type reaction (“4+1”)
Me
Me Me
Me Ph
P4S10 S O
Me Ph
Me Me Ph
SO O
Me Ph
O S
• Reaction might occur via the 1,4-bis-thioketone

34. Pyrroles
(“4+1”)
– Synthesis
Paal Knorr Synthesis
Me Me Me Me Me Me
O O O HN O H2N
NH3, C6H6,
heat
H
H
1 2 1 2
Me Me R R R R
N
H
N
H
N
OH H
• Ammonia or a primary amine can be used to give the pyrrole or N-alkyl pyrrole

35. Pyrroles
Synthesis (“3+2”)
– Synthesis
Knorr Pyrrole
MeEtO2C
EtO2C O Me
KOH aq.
HO2C
N
H
53%
MeO2C O NH2
Me NH2N O Me
N MeMe O NH2
• Use of a free amino ketone is problematic – dimerisation gives a dihydropyrazine
HO Me
MeEtO2C
EtO2C O Me EtO2C
via
EtO2C O Me
NaOH aq.
or
NH2EtO2C
N
H
EtO2C O NH3 Cl EtO2C EtO2CO N
H
• Problem can be overcome by storing amino carbonyl compound in a protected form
• Reactive methylene partner required so that pyrrole formation occurs more rapidly
than dimer formation

36. Pyrroles – Synthesis
Liberation of an Amino Ketone in situ by Oxime Reduction
MeEtO2C
EtO2C O Me
Zn, AcOH
or Na2S2O4 aq.
(sodium dithionite)
Me
N
H
Me O N
OH
Preparation of -Keto Oximes
O
from
O
-Dicarbonyl Compounds
H
O ONaNO2, H
(HNO2)
OEt OEt
H2O N O
O O O O
H
OEt OEt
N N
OOH

37. Pyrroles – Synthesis
One-Pot Oxime Reduction and Pyrrole Formation
O
CO2EtO O
EtO2C CO2Et
OEt
Zn, AcOH EtO C2 N
HN
CO2EtOH
Hantzsch Synthesis of Pyrroles (“3+2”)
EtO2C
Cl
H
EtO2C O + Me Me EtO2C Me
+ O O
Me O Cl Me NH2 Me NH
NH3 aq.
rt to 60 °C
EtO2C EtO2C
EtO C Me2
H2O
Me
OH
O
NH2
Me Me Me
N
H
41%
N
H
Me
• A modified version of the Feist-Benary synthesis and using the same starting materials:
an -halo carbonyl compound and a -keto ester

38. Furans, Pyrroles Thiophenes –
Electrophilic
Substitution – Regioselectivity
Substitution
Electrophilic
H
E E E
E
X X X X XH H HE
E E E
H HE
H
X X X X
• Pyrrole > furan > thiophene > benzene
• Thiophene is the most aromatic in character and undergoes the slowest reaction
• Pyrrole and furan react under very mild conditions
• -Substitution favoured over -substitution more resonance forms for intermediate and
so the charge is less localised (also applies to the transition state)
• Some -substitution usually observed – depends on X and substituents
NO2
AcONO2
NO2X X X
X = NH 4:1
X = O 6:1

39. Furans – Electrophilic Substitution
Nitration of Furans
AcONO2,
NO2
H
AcO NO2
H N
<0 °C
(Ac2O, HNO3)O O O
isolable
H
NO2 AcO
pyridine, heat
AcOH
NO2
H
NO2O O
• Nitration can occur by an addition-elimination process
• When NO2BF4 is used as a nitrating agent, the reaction follows usual mechanism
Bromination of Furans
Br2, dioxan, HBr
Br Br Br0 °C
Br
O O O O
80%
Br H H H
Br
Br
• Furan reacts vigorously with Br2 or Cl2 at room temp. to give polyhalogenated products
• It is possible to obtain 2-bromofuran by careful control of temperature

40. Furans – Electrophilic Substitution
Friedel-Crafts Acylation of Furan
O
Me
Ac2O, SnCl4, Ac2O, SnCl4,
O
150 °CH3PO4 cat., 20 °C
Me Me Me Me
O O O O
Me
: 6800:1 77%
acylation• Blocking groups at the positions and high temperatures required to give
Vilsmeier Formylation of Furan
Me Me
Me2NCO, POCl3,
O
0 to 100 °C
O O
H
76%
Mannich Reaction of Furans
CH2O,
Me2NH.HCl
NMe2CH2 NMe2O O O O
66%
H
NMe2

41. Thiophenes –
Nitration of Thiophenes
Electrophilic Substitution
NO2
AcONO2
NO2S S S
• Reagent AcONO2 generated in situ from c-HNO3 and Ac2O
Halogenation of Thiophenes
Br2, Et2O, Br2, Et2O,
48% HBr, 48% HBr,
Br Br Br10 10 °C 25 5 °CS S S
• Occurs readily at room temperature and even at 30 °C
• Careful control or reaction conditions is required to ensure mono-bromination

42. Pyrroles –
Nitration of Pyrroles
Electrophilic Substitution
NO2
AcONO2
AcOH, 10 °C
NO2N
H
N
H
51%
N
H
13%
• Mild conditions are required (c-HNO3 and c-H2SO4 gives decomposition)
Vilsmeier Formylation of Pyrroles
Me O Me OPCl2 Me Cl
POCl3
N N N
Me H Me H Me H
K2CO3 aq.H
H H
Cl
N
H
Cl Me N
H
N
H
N
H
83%
NMe2 NMe2 ON
H Me

43. Pyrroles – Porphyrin Formation
OH
OH OH2
R1
R2
N
H
N
H
N
H R2
R2
R1
R1
H R2
N
H
N
H
N
H
N
H
N
H N
H
R1
R1
R2
R1
R2
R1
, R2
= H
NH HN NH HN NH N
HN N HNNH HN NH
no extended aromaticity 18 -electron system
• The extended aromatic 18 -electron system is more stable than that having four
isolated aromatic pyrroles

44. Porphyrin Natural Products
CO2H
HO2CN N N N
Fe Mg
N
H
N N N N
H N2
porphobilinogen
MeO2C O
OHO2C CO2H
O
haem chlorophyll-aC20H39
• The pigment haem is found in the oxygen carrier haemoglobin
• Chlorophyll-a is responsible for photosynthesis in plants
• Both haem and chlorophyll-a are synthesised in cells from porphobilinogen

45. Furans, Pyrroles Thiophenes
Deprotonation
–
Metallation
n-BuLi
H LiX X
>>
Bu
X = O
X = NR
X = S
pKa (THF)
pKa (THF)
pKa (THF)
35.6
39.5
33.0
Deprotonation of Pyrroles
R M M
H
pKa (THF) 39.5
MNN N N
H
pKa (THF) 17.5
• Free pyrroles can undergo N or
M
C deprotonation
• Large cations and polar solvents favour N substitution
• A temporary blocking group on N can be used to obtain the C-substituted compound

46. Furans, Pyrroles Thiophenes
Directed Metallation
Regioselectivity in Deprotonation
–
Control of
Y Li YY
n-BuLi Bu
Li
H
X XX
Common directing groups: CO2H(Li), CH2OMe, CONR2, CH(OR)2
Synthesis of , ’-Disubstituted Systems
Y Y Y
n-BuLi n-BuLi
E1
E2
1 2 1
E E E
X X X
Use of a Trialkylsilyl
Y
Blocking Group
Y Y Y
n-BuLi n-BuLi F
Me3SiCl E
SiMe3 E SiMe3 E
X X X X

47. Furans – Synthesis of a Drug
Ranitidine (Zantac®) Using a Mannich ReactionPreparation of
Me2NH.HCl,
Me2N
CH2O, rt
O OO
OH OHO
furfural
HS(CH2)2NH2,
c-HCl, heatNO2
NO2 MeS NHMe
Me2N S Me2N S
O O
NHMe
N NH2
ranitidine H
• Furfural is produced very cheaply from waste vegetable matter and can be reduced to
give the commercially available compound furfuryl alcohol
• The second chain is introduced using a Mannich reaction which allows selective
substitution at the 5-position
• The final step involves conjugate addition of the amine to the
compound and then elimination of methane thiol
, -unsaturated nitro

48. Indoles – Bioactive Indoles
O
H
Me
X N
CO2H NMe2 H
O OH
NH2 S
MeNH
N N N
lysergic acidX = OH
X = NEt2
H
tryptophan
H
sumatriptan
H
lysergic acid diethyamide (LSD)
• Tryptophan is one of the essential
• Sumatriptan (Imigran®, GSK) is a
for 5-HT receptors for in the CNS
amino acids
drug used to
and a constituent of most proteins
treat migraine and works as an agonist
• LSD is a potent psychoactive compound which is prepared from lysergic acid, an
alkaloid natural product of the ergot fungus
NH2
HO
N
H
5-hydroxytryptamine (serotonin)

49. Indoles
O
– Synthesis
R1Fischer Synthesis
R1
R2
R1
H or
2
R Lewis acid
R2
H2O NH3NH2 N
NN
H
N
H
H
Ph
ZnCl2, 170 °C
Ph
N
NN
H
H76%
H
H
Ph
Ph
NH
N NH3N
H
H
H
Ph Ph Ph
[3,3]
NH2 NH2 NH2
N
H
NH NH2
H
• A protic acid or a Lewis acid can be used to promote the reaction

50. Indoles – Synthesis
Bischler Synthesis
H Me
O Me O Me
H2Opolyphosphoric
acid (PPA), 120 °C KOH aq.
NN N
64% H
O CF3 O CF3
• An -arylaminoketone is cyclised under acidic conditions
• The reaction also works with acetals of aldehydes
Me EtO OEt Me
(CF3CO)2O,
CF3CO2H, heat
NN
CF3
O CF3 93% O

51. Indoles – Electrophilic
Nitration of Indoles
O2N
Substitution
NO2
c-H2SO4, c-HNO3 PhCO2NO2, 0 °C
MeMe Me
0 °C
NN N
H84% H
• Polymerisation occurs when there is
H 35%
no substituent at the 2-position
• Halogenation is possible, but the products tend to be unstable
Acylation of Indoles O O
Me Me
Ac2O, AcOH, heat NaOH aq., rt
N N
-product!
Me
N
H 60% H
O
Ac2O, AcONa Ac2O, AcOH, heat
N
O
Me
• Acylation occurs at C before N because the N-acylated product does not react

52. Indoles – Electrophilic Substitution
Mannich Reaction
NMe2
CH2O, Me2NH, H2O, heat 93%
H2O, 0 °C or AcOH, rt 68%
N N N
H H
NMe2
H2C NMe2 (preformed) 95%
• A very useful reaction for the synthesis of 3-substituted indoles
• The product (gramine) can be used to access a variety of other 3-substituted indoles
Synthesis of Tryptophan from Gramine
EtO2C CO2H
CO2Et
NMe2 EtO2C CO2Et
NHAc
NaOH aq. then
NH2
Na
NHAc
PhMe, heat H2SO4, heat
N N N
H 90% H 80% H

53. Indoles – Electrophilic Substitution
Synthesis of Other 3-Substituted Indoles from Gramine
MeSO4 NMe3 CNCN
NaCN aq., 70 °C
N N N
H2O H HH2O 100% H
• The nitrile group can be modified to give other useful functionality
CN CO2H
NH2
LiAlH4 acid/base hydrolysis
N N N
H H H

54. Indoles – Synthesis of a Drug
Synthesis of Ondansetron (Zofran®, GSK) using the Fischer Indole Synthesis
O O
O O
ZnCl2, heat
H2O NH
NNHNH2 N
H H
N
Me
MeI, K2CO3
N Me3N I
OO ON
Me
N
H Me2NH.HCl, CH2O
then MeI
NN N
MeMe Me
• Ondansetron is a selective 5-HT antagonist used as an antiemetic in cancer
chemotherapy and radiotherapy
• Introduction of the imidazole occurs via the
elimination of the ammonium salt
, -unsaturated ketone resulting from

55. ReferenceBooks
•
•
•
Heterocyclic Chemistry – J. A. Joule, K. Mills and G.
F. Smith
Heterocyclic Chemistry (Oxford Primer Series) – T.
Gilchrist
Aromatic Heterocyclic Chemistry – D. T. Davies