Five-membered heterocycles

1
 Pyrroles - Synthesis
• Knorr pyrrole synthesis

2
Paal-Knorr Synthesis

3
Mechanism

4
5
6
Hantzsch pyrrole synthesis

7
Mechanism

8
Piloty-Robinson synthesis

9
Barton-Zard reaction

10
11
Van Leusen reaction

12
Thermal cycloaddition methods

13
Heterocyclization

15
 Reactions of pyrrole
• Reactions with bases: pka = 17.5

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Reactions of deprotonated pyrrole

17
N-arylation

18
Reactions with electrophiles

19
20
Reactions - halogenation

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Acylation

22
General mechanism

23
Reactions with carbenes

24
Diels Alder reaction

25
Pyrrole reduction

26
Pyrrole Oxidation – Polypyrrole Synthesis

n C4H4NH + 2 FeCl3 → (C4H2NH)n + 2 FeCl2 + 2 HCl

27
 Electropolymerization

The Nobel Prize in Chemistry was awarded in 2000 for work on conductive polymers including
polypyrrole

28
Pyrrolic macrocycles - Porphyrins

29
 Furan
• Synthetic methods
Paal-Knorr synthesis

30
Mechanism

31
32
Fiest-Benary synthesis

33
Heterocyclizations

34
Reactions of furans

35
36
Ring opening with strong acid

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Reaction with electrophiles

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39
40
Reaction of halo-furans

41
 Thiophenes
• Synthesis
Paal-Knorr Thiophene Synthesis

42
Mechanism

43
44
Lawesson’s reagent

45
Hinsberg thiophene synthesis

46
Mechanism

47
Thiophene halogen dance

48
Benzoin condensation

49
Reaction with carbenes

50
Diels Alder reaction

51
 Practice Problems
a) Bn b) c) d)
1) MeI CuI/MeLi SH COCl2 NH 1) NaNO2/HCl
N
2) NaH -10 oC, THF pyridine 2) LiALH4
O OH

e) f) S g)
NaH, THF MeO2C CO2Me TiCl4.Zn
O OO
THF
reflux
OH N reflux
Bn
h) 1) nBuLi i) Sn, HCl j) Zn/Cu CH2I2
S 2) O
O NO2
O

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a) Ph
O b) Ph P2S5
S-Buli O
-78 oC, THF O
O

c) Ph Ph
d)
heat O
1) NaBH4
O -CO2
2) H3O+
O O
O

e) TsOH, reflux f) S AlCl3

O
O
O

53
 1) NH2NH2
2) PhCOCl, py H Me 1) DMF-POCl3
MW heating N Zn/HCl (aq.) N 2) NaOH, heat
a) ? b) ? c) ?
Ph CH2CHO
COCH3

OTs 1) PhLi, THF

e) 2) 3,4-dimethyl f) S
? 1) nBuLi-THF ?
furan
Br 3) H3O+ 2) CuI-THF
2) methacrolein

S 1) DMF-POCl3
g) ?
2) NaOH, heat
3) ethanolic KCN

54
O
N 1) NaH, THF
Ph 2)
NO2

S MeO2C CO2Me i) excess PhMgBr

heating Ph

NOH
O 1) nBuLi j)
2) HCHO SH COCl2
3) c. H2SO4
Ph OH

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 1) N3CO2Et
a) Ph 2) H+/ EtOH
1) POCl3-DMF
H3C ? 2) aq. NaOH, ?
i)
N
HCl Me
b) O
?
?
S
O S c. HNO3
f)
?

1) ?
2) ?
NMe ?
NOH
Ph

l) 1) NaH, THF
BrCH2COOEt ?
Br 2) c. H2SO4
1) ? OH
2) ?
Ph S Br Ph S SiMe3
Ph Lawesson's reagent
g) ?
O

O
1) nBuLi 1) NaNO2/HCl
h) NH 2) MCPBA
e) O ? ?
2) O

i) O CO2Me

g) O 1) excs Na, pentanol NO2 reflux ?

N 2) TsCl, py
3) NaOEt ?
56