Lectures in Heterocyclic Chemistry

Chem. 4239
Collected and organized by

Prof. Dr. Adel Awadallah

Islamic University of Gaza
(2011)

N
N

N
Pyridine

quinoline
O

Isoquinoline
O

O
-pyrone
H
N

1H-pyrrole

-pyrone
O

furan

thiophene

Lectures in Heterocyclic Chemistry

(Collected and organized by Prof. Dr. Adel Awadallah)

Text Book
Heterocyclic Chemistry, T. L. Gilchrist
Other Books and References
* Heterocyclic Chemistry, R. Gupta, M. Kumar, V. Gupta
* Heterocyclic Chemistry, J. A. Joule, G. F. Smith
* An Introduction to the chemistry of Heterocyclic compounds, R.
M. Acheson
* Comprehensive Heterocyclic Chemistry, edited by: A. R. Katritzky
and C. W. Rees
* Journals in organic and heterocyclic chemistry such as
J. Heterocyclic Chem.
Heterocycles
Molecules
Synthetic communications
J. Organic Chemistry

Nomenclature of Heterocyclic Compounds

Systematic Nomenclature system:

(Hantzsch-Widman System)

Heterocycles with recognized trivial names

Naming Heteromonocycles
Prefix (heterotoms, number, positions)

Stem (ring size + saturation)

Examples: Name the following compounds

N

OH

O N

CN

H3C

Ac

CH3

Ph

N N

CHO

Et

N
N

N
N

O
N

NO2

N
N
O
isoxazole

O
Oxazole

N
S

thiazole

isothiazole

Cl

Indication of saturated positions

1 position (H)
2 positions (dihydro)
3 positions (dihydro + H)
4 posit ions (tetrahydro)
5 positions (tetrahydro + H)
Saturated positions receive the lower number
Examples:
H
N

N
H

N
H

O
N

H
N N

H
N

N N

N
HN

O
N

Compounds containing exocyclic C=O and C=S

H3C
N
S
N

Ph
N

N N
O

N
N

H3C

H2N
4-amino-6-oxo-1-phenyl-1,4,5,6-tetrahydro1,2,4-triazine
4-amino-1-phenyl-1,4,5,6-tetrahydro1,2,4-triazin-6-one

1,4-dihydro-1,4-dimethyl-5H-tetrazol-5-thione

Me

Ph

OH
N

2,5-Dihydro-1-hydroxy-3-methyl4-phenyl-1H-pyrrole-2-one
2,5-Dihydro-1-hydroxy-3-methyl4-phenylpyrrole-2-(1H)-one

3H-pyrazin-2-one
Pyrazin-2(3H)-one

Nomenclature of fused ring systems

Prefix(O)

Base component
N
O

Benzoxazole

Base Component
1) One ring only contains N, Choose it
N
O
Benzoxazole

2) No, Nitrogen, oxa , thia, aza

S

O
Thieno[ ]furane

3) One consists of two or more rings, choose it

NH
N
H
pyrrolo[

]indole

4) Two rings of different size, choose the larger

N

N
H

pyrrolo[ ]pyridine

5) Choose the one with more heteroatoms

H
N
N
N
H
pyrrolo[ ]pyrrazole

6) Same number of heteroatoms, choose oxa > thia > aza

H
N

imidazo[ ]oxazole

7) Same number of heteroatoms, same oxa, thia, aza, then

choose lower numbering
O

H
N

N
H
imidazo[ ]pyrrazole

O
oxazolo[ ]isoxazole

Indicate the fusion by giving letters to the base components and

numbers to the prefix (go in the same direction)

O
N

H
N

a d 4 3
b c 5 12

c
oxazolo[5,4-d]isoxazole

imidazo[

10

N
H
]pyrrazole

Examples:
H
N

S
N
H

N
S

H
N

NH

H
N
N

N
H

O
N
H

O
N
N
H

N
N

11

Numbering substituents on fused rings:

14
13

15

12

16

11

17

10

5'
N

N
9

7
8

1) Use rectangular coordinates

2) As many rings as possible lie in a horizontal row
3) A maximum number of rings are in the upper right quadrant
4) The system is numbered in a clockwise direction
commencing with that atom which is not engaged in the ring
fusion and is furthest to the left:
in the uppermost ring or
in the ring furthest to the right in the upper row
5) C atoms which belong to more than one ring are omitted
6) Heteroatoms in such positions are, however, included
7) If there are several possible orientations in the coordinate
system,
12

a))) the one in which the heteroatoms bear the lowest

locants is valid,,,,,,
b))) or the one in which the C atom that belongs to more
than one ring has the lowest locant

8
N

a))))

b))))

not

7
N

3'

1
N

1
N

7
2

2
N 3

not

13

4'

2
3

Examples:
1
O

9
8

O
2

H3C

7
6

indeno[1,2-b]pyran-2(5H)-one

S
N

Br

CH3

Ac

14

15

16

17

18

Chapter 4
Ring Synthesis
Cyclization Reactions
transformation

Cycloaddition Reactions

Ring

Ring enlargement
E
Nu

ring contraction

19

1) Displacement at saturated carbons

NH2

NH2

NH2

Br

NH2
Br

Br

Br

H
N

H
N

NH

NH

Br

Examples
20

H H
R

RNH2

Br Br
Feist-Benary Furane Synthesis
O

CO2Et

R1

+
Cl
-Haloketone

R1
Pyridine

HO
Cl

CO2Et
R

R1
HO
Cl

CO2Et
R
O -

-Ketoester

CO2Et
R1

R
O

21

22

More Examples

23

Intramolecular Nucleophilic Addition to Carbonyl Groups

Hinzberg Synthesis of Thiophene
(Carbon nucleophile)
R

base

+
EtO2C

EtO2C

CO2Et

Pall-Knorr Synthesis of Furane

Pall-Knorr Synthesis of Pyrrole

24

CO2Et

CH3
O
N
H

Strong base
R

R
N
H

heat

25

26

Cyclization onto the ortho position of a phenyl ring

A free ortho position act as a nucleophilic center
R

Br

N
H

+
NH2

N
H
Indole

NH2

NH

Cl
R

N
R
Isoquinoline

27

Shaker Youssif, Mohamed Assy, J. Chem. Res. (s), 1996, 442-443

O

HN

+
N

PhNH2

Cl

CH3

DMF

HN
N
CH3

N
H

HN
O

POCl3

N
H

CH3

NH2NH2
O
HN

HN
N

CH3

NHNH2

CH3
O

Ph

Ph
benzil

O
O

HN
O

Ph

O
Ph

N
CH3

N N
H

Ph
Ph

HN
N

CH3

28

N
H

Intramolecular Nucleophilic Addition to Other double bonds

(C=S, C=N, C=C)

29

30

Cyclization onto triple bonds

31

R
O
EtO

NH2 - OH

R
O

HO N
H

32

O
O N
H

Cyclization onto nitriles (CN)

33

Cyclization onto Isonitriles (R-NC)

34

35

36

37

Cyclization onto triple bonds

38

R
O
EtO

NH2 - OH

R
O

HO N
H

39

O
O N
H

Cyclization onto nitriles (CN)

40

Cyclization onto Isonitriles (R-NC)

41

42

43

44

Radical Cyclization
Five- and six-membered rings are most commonly formed by
preferential exo-cyclization.

Kinds of Radicals:
Neutral (generated by tributyltin hydride for carbon radicals,
or by photolysis of N-Cl bond).
This radical is very reactive and unselective.
Protonated radicals(add efficiently to many types of double
bonds, mainly C=C)
Radicals complexed to metal ions (moderate reactivity)
Neutral aminyl radical

45

Neutral carbon radical

46

Protonated aminyl radical

Radicals complexed to metal ions

More Examples:

47

48

49

Carbene and nitrene cyclization

Carbenes are uncharged, electron deficient molecular species
that contain a divalent carbon atom surrounded by a sextet of
electrons.
Nitrenes are uncharged, electron deficient molecular species
that contain a monovalent nitrogen atom surrounded by a
sextet of electrons.

Generally there are two types of carbenes; singlet or triplet carbenes.

Singlet carbenes have a pair of electrons and an sp2 hybrid structure.
Triplet carbenes have two unpaired electrons. They may be either sp 2
hybrid or linear sp hybrid. Most carbenes have a nonlinear triplet ground
state

Carbenes are called singlet or triplet depending on the electronic spins

they possess. Triplet carbenes are paramagnetic and may be observed
by electron spin resonance spectroscopy if they persist long enough.
The total spin of singlet carbenes is zero while that of triplet carbenes
is one (in units of ). Bond angles are 125-140 for triplet methylene
and 102 for singlet methylene (as determined by EPR). Triplet
carbenes are generally stable in the gaseous state, while singlet
carbenes occur more often in aqueous media.
For simple hydrocarbons, triplet carbenes usually have energies 8
kcal/mol (33 kJ/mol) lower than singlet carbenes (see also Hund's rule
of Maximum Multiplicity), thus, in general, triplet is the more stable
state (the ground state) and singlet is the excited state species.

50

Formation Reactions of
Carbenes

51

Reactions of Carbenes
1) Addition to multiple bonds
Singlet carbenes generally participate in cheletropic reactions as
either electrophiles or nucleophiles. Singlet carbene with its
unfilled p-orbital should be electrophilic. Triplet carbenes should
be considered to be diradicals, and participate in stepwise radical
additions. Triplet carbenes have to go through an intermediate
with two unpaired electrons whereas singlet carbene can react in
a single concerted step. Addition of singlet carbenes to olefinic
double bonds is more stereoselective than that of triplet
carbenes. Addition reactions with alkenes can be used to
determine whether the singlet or triplet carbene is involved.
Reactions of singlet methylene are stereospecific while those of
triplet methylene are not. For instance the reaction of methylene
generated from photolysis of diazomethane with cis-2-butene
and trans-2-butene is stereospecific which proves that in this
reaction methylene is a singlet.[4]

52

Insertions are another common type of carbene

reactions.
The carbene basically interposes itself into an existing bond. The order of
preference is commonly: 1. X-H bonds where X is not carbon 2. C-H bond
3. C-C bond. Insertions may or may not occur in single step.

Carbene insertion
Intramolecular insertion reactions present new synthetic solutions.
Generally, rigid structures favor such insertions to happen. When an
intramolecular insertion is possible, no intermolecular insertions are
seen. In flexible structures, five-membered ring formation is preferred
to six-membered ring formation.

Carbene intramolecular reaction

Carbene intermolecular reaction

53

Nitrenes

Formation
Nitrenes are very reactive and not isolated as such. They are
formed as reactive intermediates in the reactions:

1) from thermolysis or photolysis of azides with

expulsion of nitrogen gas, analogues to the formation of
carbenes from diazo compounds.
_
R N N N
+

a)

R=alkyl,aryl,H
b)

R SO2

h
or

R N + N2

_
N N N
+

h
or

R=alkyl,aryl
c)

d)

_
RO C N N N
O
R=alkyl,aryl
+

h
or

RO C NH O SO2
O
base
_
RO C N O SO2
O

R SO2 N + N2

RO C N + N 2
O

NO2

NO2

_
RO C N + O SO2
O
(nosylate)

2) from isocyanates, with expulsion of carbon

monoxide, analogues to carbene formation from ketenes
R-N=C=O gives R-N

54

NO2

3) From N-amino heterocycles

O
O
N

LTA

O
O
N

NH2

4) From photolysis of Sulfilimines:

55

56

57

Examples:

58

59

Carbene and nitrene cyclization

Carbenes are uncharged, electron deficient molecular species
that contain a divalent carbon atom surrounded by a sextet of
electrons.
Nitrenes are uncharged, electron deficient molecular species
that contain a monovalent nitrogen atom surrounded by a
sextet of electrons.

Generally there are two types of carbenes; singlet or triplet carbenes.

Singlet carbenes have a pair of electrons and an sp2 hybrid structure.
Triplet carbenes have two unpaired electrons. They may be either sp 2
60

hybrid or linear sp hybrid. Most carbenes have a nonlinear triplet ground

state

Carbenes are called singlet or triplet depending on the electronic spins

they possess. Triplet carbenes are paramagnetic and may be observed
by electron spin resonance spectroscopy if they persist long enough.
The total spin of singlet carbenes is zero while that of triplet carbenes
is one (in units of ). Bond angles are 125-140 for triplet methylene
and 102 for singlet methylene (as determined by EPR). Triplet
carbenes are generally stable in the gaseous state, while singlet
carbenes occur more often in aqueous media.
For simple hydrocarbons, triplet carbenes usually have energies 8
kcal/mol (33 kJ/mol) lower than singlet carbenes (see also Hund's rule
of Maximum Multiplicity), thus, in general, triplet is the more stable
state (the ground state) and singlet is the excited state species.

61

Formation Reactions of
Carbenes

62

Reactions of Carbenes
1) Addition to multiple bonds
Singlet carbenes generally participate in cheletropic reactions as
either electrophiles or nucleophiles. Singlet carbene with its
unfilled p-orbital should be electrophilic. Triplet carbenes should
be considered to be diradicals, and participate in stepwise radical
additions. Triplet carbenes have to go through an intermediate
with two unpaired electrons whereas singlet carbene can react in
a single concerted step. Addition of singlet carbenes to olefinic
double bonds is more stereoselective than that of triplet
carbenes. Addition reactions with alkenes can be used to
determine whether the singlet or triplet carbene is involved.
Reactions of singlet methylene are stereospecific while those of
triplet methylene are not. For instance the reaction of methylene
generated from photolysis of diazomethane with cis-2-butene
and trans-2-butene is stereospecific which proves that in this
reaction methylene is a singlet.[4]

63

Insertions are another common type of carbene

reactions.
The carbene basically interposes itself into an existing bond. The order of
preference is commonly: 1. X-H bonds where X is not carbon 2. C-H bond
3. C-C bond. Insertions may or may not occur in single step.

Carbene insertion
Intramolecular insertion reactions present new synthetic solutions.
Generally, rigid structures favor such insertions to happen. When an
intramolecular insertion is possible, no intermolecular insertions are
seen. In flexible structures, five-membered ring formation is preferred
to six-membered ring formation.

Carbene intramolecular reaction

Carbene intermolecular reaction

64

Nitrenes

Formation
Nitrenes are very reactive and not isolated as such. They are
formed as reactive intermediates in the reactions:

1) from thermolysis or photolysis of azides with

expulsion of nitrogen gas, analogues to the formation of
carbenes from diazo compounds.
_
R N N N
+

a)

R=alkyl,aryl,H
b)

R SO2

h
or

R N + N2

_
N N N
+

h
or

R=alkyl,aryl
c)

d)

_
RO C N N N
O
R=alkyl,aryl
+

h
or

RO C NH O SO2
O
base
_
RO C N O SO2
O

R SO2 N + N2

RO C N + N 2
O

NO2

NO2

_
RO C N + O SO2
O
(nosylate)

2) from isocyanates, with expulsion of carbon

monoxide, analogues to carbene formation from ketenes
R-N=C=O gives R-N

65

NO2

3) From N-amino heterocycles

O
O
N

LTA

O
O
N

NH2

4) From photolysis of Sulfilimines:

66

Liquidphaseexperiment
_ H3C
CH3
R N N N +
C C
H
H
+

N
+

CH3
H3 C
H
H
CH3
H
cistrans
(predominantaziridineproduct)
(minoraziridineproduct)
H3C
H

PointofInformation:Whenaninertsolventisaddedtothereactionmixture,moretrans
productisobtainedattheexpenseofthecisproduct.

Evidence of Singlet Nitrene C-H Insertion Selectivity

R N + alkane
(singlet)

alkaneinsertionproducts
Relativereactivities

Alkane
CH3 CH 3
H3 C C
C CH 3
H

R N

CH3 CH 3
CH 3 CH 3
H3 C C
C CH 3 + H 3 C C
C CH 2 NH

NH R

67.0:1.0
H H
H 3 C C C CH3
H H

R N

H H
H H
+
H 3 C C C CH2 NH
H 3 C C C CH 3
H H
R
H NH R
9.0:1.0

SingletnitreneCHinsertionselectivity:

tertiaryCH>secondaryCH>primaryCH

67

Examples:

68

69

70

Electrocyclic Reactions
Formation of a -bond at the termini of a fully
conjugated -system by heat or light.

71

Examples

72

73

More Examples

74

75

76

Cycloaddition Reactions

1,3-Dipolar Cycloaddition Reactions

Resonance Structures of 1,3-Dipoles

Each molecule has at least one resonance structure which indicates separation of
opposite charges in 1,3-relationship.

77

Mechanism of Cycloaddition:
1,3-Dipolar cycloaddition reactions were found to be stereoselective. Most of them are
regioselective.
2 -electrons of the dipolarophile and 4 electrons of the dipolar compound participate in a concerted,
pericyclic shift. The addition is stereoconservative

78

1) Concerted Mechanism (suggested by R. Huisgen)

LUMO

LUMO

HOMO

HOMO

orbitals of a 1,3-dipole

orbitals of a dipolarophile

79

2) Biradical mechanism (Stepwise mechanism by Firestone)

+
Y

.
X

.
z

R
R

+
R

R
Regiochemistry

80

R
R

Generation of 1,3-Dipoles
Nitrile oxides

Nitrile Sulfides

Nitrile Imides (Nitrilimines)

Examples

81

82

83

84

Hetero-Diels-Alder Reactions
Reaction between cyclopentadiene and diethyl azodicarboxylate

Normal Diels-Alder Reaction

R

R
COOEt

COOEt

COOEt

COOEt

+
R

electron withdrawing

electron releasing

Inverse electron demand Diels-Alder Reaction

COOEt

COOEt
R

+
COOEt

electron releasing

COOEt

electron withdrawing

85

Diens and Dienophiles

86

87

88

2 + 2 Cycloaddition

89

Paterno-Buechi Reaction

90

Cheletropic Reaction

91

Heterocyclic Synthesis

Pyridine

: N

H N
Pyrrole

Pyridine

Pyridine is a water -miscible liquid, b. p. 115 oC with an unpleasant odour

An Excelent polar solvent

A base (pka = 5.23)
Pyrrole is less basic than pyridine becuase the lone pair of electrons
in pyrrole is part of the aromatic ring, while that in pyridine is free.
********************************************************************
CH3
CH3
N

CH3

Picolines

COOH
COOH
N

nicotinic acid

isonicotinic acid

H
N
N

CH3

Tobacco alkaloid (nicotine)

Alkaloide (alkali like)

92

Ring Synthesis
1) The Hantzsch Synthesis
1,3-dicarbonyl compound + ammonia + aldehyde

CO2Me

MeO2C
O

H3C

CH3
Ar

NH3

H
O

Ar
MeO2C
enamine
H3C

NH2

CO2Me

enone
CH3

Conjugate addition (1,4-addition)

Ar
MeO2C
H3C

CO2Me
NH2 O

CH3

Ar
CO2Me

MeO2C
H3C

N
H

93

CH3

Unsymetrical pyridine can be prepared from

different enamines and enones
Cl
MeO2C
enamine
H3C

NH2

enone
O

Ar

Conjugate addition (1,4-addition)

Cl
MeO2C
H3C

CO2Me
Ar
NH2 O

MeO2C
H3C

Ar

2) Reaction of Ammonia + 1,5-diketone

NH3
O O

Oxidation
N

N
H

94

3) Diels-Alder Reaction
X
N

-H2O

R
CO2H

CO2H

+
CO2H

N
Ph

Ph

Ph

CO2H

CF3

CF3

400 oC

-H2

Ph

Ph
Ph
O

+N

Ph

Ph

Ph

heat
- CO

Ph

Ph

Ph

COOR

CF3

heat

COOR
N

Tos

4) Kroehnke Synthesis

95

Tos

[O]
N

96

Chemistry of Pyridine
a) Reaction at nitrogen
CH3I

I-

CH3
N

Cl

Cl-

N
A good acylating agent

Use of N-Oxides
O
R

OOH

PX3

ONHO3

H2 / Pd

PX3

+
N

O-

O-

NO2

NO2

NH2

PX3
NH2

97

Electrophilic Substitution
Pyridine is million times less reactive than benzene

Nitration (less than 5%, Chlorination in moderate yield, Bromination in a good

yield)
3-position is usually attacked preferably

ChiChibabin Reaction
Amination of pyridine and related heterocycles at the 2-position by sodamide

NaNH2

-NaH
H

N
Na+

NH2

98

NH2

Quinoline and Isoquinoline

5
6

4' 4

7
8

8' N
1

5 4'

N2

8'

Isoquinoline

Quinoline

Quinoline Skraup Synthesis

Aniline

Glecerol

H2SO4

quinoline
O

O
NH2

N
H

Doebner-von Millar
O
O
NH2

N
H

Combes Synthesis
R
O
NH2

R
N
O

99

Friedlaender Synthesis
O
H

NO2

1) Base

R2

2) Reduction

R2

Isoquinoline Synthesis
Bischler-Napierlaski
O
MeO

Cl

NH2

MeO

MeO

POCl3

MeO

NH

MeO
N

MeO
R

R
Pd

MeO
N

MeO
R

Pictet-Spengler Synthesis
O
R

H+

NH2

N
R

100

MeO
NH

MeO
R

Pomeranz-Fritsch Synthysis
OEt

EtO
H2NCH2CH(OEt)2
O

OR

OR

H
H2SO4

OR

Chemistry of Quinoline and Isoquinoline

Nucleophilic Substitution (ChiChibabin Reaction)
NaNH2
N

NH2

N
NaNH2
N

N
NH2

101

N
H
-H2

KOH
o

225 C

OH

N
K+

KOH
N

225 C

OK

N
-H2

N K+

OH

N
OK

NH
O

102

Electrophilic Substitution
Occurs at the 5- or 8-positions, or both

Quinoline N-Oxides can be nitrated at the 4-position or

photoisomerize as follows

103

Heterocyclic Synthesis
Pyrylium Salts
O

2H-Pyran-2-one
O

O
-pyrone

O
4H-pyran-4-one
pyrone

Preparation of Pyrylium Salts

HClO4

OHN
SO3

O O

O
ClO4-

Na+

Reactions of Pyrylium Salts

104

Synthesis of -Pyrones

105

Diels-Alder Reactions of -Pyrones

-Pyrone
O

O
CH3

H3C

EtONa

+
OEt
EtO2C

EtO2C

OEt

HCl
0 oC
O O

CO2Et

EtO2C

CO2Et

CO2Et

HCl / Cu
160 oC
O

Cliasen Condensation of Ethylpropiolate with Acetone

O
OEt
Ph

+
O

H2SO4

EtONa

Me

Ph

Me

106

Me

Ph

Me

Pyrrole
b. p. 129

Porphobilinnogen

Insect pheromone

Pyrrolnitrin

(s)-proline

107

Pyoluteorin

Nicotine

Porphyrin

haemin

Haem (iron (II) complex)

uroporphyrinogen

Chlorophyll

108

Bilirubin

Vitamin B12

109

Synthesis of pyrrole
Knorr Synthesis
L. Knorr, Ber. 17, 1635 (1884); Ann. 236, 290 (1886); L. Knorr, H. Lange, Ber. 35, 2998
(1902).

The Knorr pyrrole synthesis is a widely used chemical reaction that synthesizes substituted
pyrroles (3).[1][2][3] The method involves the reaction of an -amino-ketone (1) and a compound
containing a methylene group - to (bonded to the next carbon to) a carbonyl group (2).[4]

The original Knorr synthesis employed two equivalents of ethyl acetoacetate,

one of which was converted to ethyl 2-oximinoacetoacetate by dissolving it in
glacial acetic acid, and slowly adding one equivalent of saturated aqueous
sodium nitrite, under external cooling. Zinc dust was then stirred in, reducing
the oxime group to the amine. This reduction consumes two equivalents of zinc
and four equivalents of acetic acid.
Modern practice is to add the oxime solution resulting from the nitrosation and
the zinc dust gradually to a well-stirred solution of ethyl acetoacetate in glacial
acetic acid. The reaction is exothermic, and the mixture can reach the boiling
point, if external cooling is not applied. The resulting product, diethyl 3,5dimethylpyrrole-2,4-dicarboxylate, has been called Knorr's Pyrrole ever since.
In the Scheme above, R2 = COOEt, and R1 = R3 = Me represent this original
reaction.

H3C

H3C

EtO2C

NaNO2
AcOH

EtO2C

H3C

Zn
AcOH

EtO2C

OH

H3C
EtO2C

+
NH2

H3C

CO2Et
O

EtO2C

CH3

110

CO2Et
N

CH3

O
NH2

Paal-Knorr Pyrrole Synthesis

The Paal-Knorr Pyrrole Synthesis is the condensation of a 1,4dicarbonyl compound with an excess of a primary amine or
ammonia to give a pyrrole.

111

The Hantzsch pyrrole synthesis

The Hantzsch pyrrole synthesis, named for Arthur Rudolf
Hantzsch, is the chemical reaction of -ketoesters (1) with
ammonia (or primary amines) and -haloketones (2) to give
substituted pyrroles (3).[1][2]
Note: direct reaction of -ketoesters (1) with -haloketones (2)
gives furan [Fiest-Benary furan synthesis], and this can be a
troublesome side reaction.

EtO2C

EtO2C

+
H3C

RNH2

H3C

Cl
NH
R

EtO2C
CH3

H3C

N
R

References
1.
2.

^ Hantzsch, A. Ber. 1890, 23, 1474.

^ Feist, F. Ber. 1902, 35, 1538.

112

CH3

Reactions of Pyrrole
Substitution at nitrogen
A) Metallation of Pyrrole
NaNH2, or KNH2

N
H

NH3 Liq

NNa+ (K+)
ionic

Na, or K

N
H

innert solvent

NNa+ (K+)
ionic

EtMgBr / ether

N
H

MgBr
covalent

RLi

N
H

N
Li
covalent

113

B) Formation of N-substituted pyrrole

N-substituted products are normally isolated only from reaction of pyrrole anions with
electrophiles

MeI/ NH3 Liq

N

NK

Me

MeI/ HMPA
N

95%

hexamethylphosphorousamide

Me

98%

MgBr

CH3COCl

MgBr

Ac

PhCOCl
NK

toluene / 110 oC

114

Ph

N
H

Ac

Electrophilic Substitution

Intermediates in the electrophilic substitution of pyrrole

115

The Vilsmeier Haack reaction

Cycloaddition Reactions with dichlorocarbene

Reimer-Tieman Reaction

CHCl3
N

ether

Cl
N

CHO

+
N

K
Ring Expansion

Diels-Alder Reactions of pyrrole

Pyrroles normally do not undergo DA reactions
Exception
CO2Me
O
N
+
OEt
CO2Me
N-Ethoxycarbonylpyrrole

Dimethyl acetylenedicarboxylate

[2 +2] Cycloaddition

116

CO2Et
N
CO2Me
CO2Me

117

Furan
b.p. = 31 oC
Natural products containing furane

Rosefuran

Ascorbic

O
O
H
Furfural (Furan-2-carboxaldehyde)

NO2

Me2N

S
O

N
H

NHMe

H
Ranitidine ( a successful drug for the treatment of peptic ulcer)

118

Synthesis of Furan
Paal-Knorr Synthesis

Feist-Benary Furane Synthesis

O

CO2Et

R1

+
Cl
-Haloketone

R1
Pyridine

HO

Cl

CO2Et
R

R1
HO
Cl

CO2Et
R
O -

-Ketoester

CO2Et
R1

R
O

119

Reactions of Furan
a) Protonation
b) Electrophilic aromatic substitution

Bromination of furane:
Br2
O

DMF

Br

120

Nitration of Furane

Vilsmeier-Haack reaction produces 2-formylfuran

121

Cycloaddition Reactions
Diels-Alder reaction with maleic anhydride

O
O

O
O

Reaction with Acrylonitrile

CN
O

CN

39 % (5 weeks) r.t.
55% (4h) 15,000 atm
100% (48 h) Lewis acid ZnI2 (48 h)
Reaction with dimethylacetylendicarboxylate

122

Thiophene
o

b. p. 84 C
from coal tar
electron rich aromatic compound which is more aromatic than benzene.

Pyrantal 49, is a broad spectrum anthelmintic agent ( ) effective

against pinworm and hookworm
Bioten (Vitamin H), 50, occurs in yeast and egg
Thiophene also occurs in organic conducting polymers
heat

S
O

123

SO2

Ring Synthesis
a) The Pall Synthesis
b) The Hinzberg Synthesis
c) The Gewald Synthesis
Lawesson's reagent can be used also in the first synthesis.

Simple carbonyl compounds can be used in the third synthesis in the presence of elemental
sulfur

124

Lawesson's reagent
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Lawesson's reagent

IUPAC
name
Other names

[show]

Lawesson's reagent,
LR

Lawesson's reagent, or LR, is a chemical compound used in organic synthesis as a thiation

agent. Lawesson's reagent was first made popular by Sven-Olov Lawesson, who did not,
however, invent it. Lawesson's reagent was first made in 1956 during a systematic study
of the reactions of arenes with P4S10.[1]

Preparation
Lawesson's reagent is commercially available. It can also be conveniently prepared in
the laboratory by heating a mixture of anisole with phosphorus pentasulfide until the
mixture is clear and no more hydrogen sulfide is formed,[2] then recrystallized from
toluene or xylene.
As Lawesson's reagent has a strong and unpleasant smell, it is best to prepare the
compound within a fume-hood and to treat all glassware used with a decontamination
solution before taking the glassware outside the fume-hood. One common and effective
method of destroying the foul smelling residues is to use an excess of sodium
hypochlorite (chlorine bleach).

[edit] Mechanism of action

125

Lawesson's reagent has a four membered ring of alternating sulfur and phosphorus
atoms. With heating, the central phosphorus/sulfur four-membered ring can open to
form two reactive dithiophosphine ylides (R-PS2). Much of the chemistry of Lawessons's
reagent is in fact the chemistry of these reactive intermediates.

In general, the more electron rich a carbonyl is, the faster the carbonyl group will be
converted into the corresponding thiocarbonyl by Lawesson's reagent.

[edit] Applications
The chemistry of Lawesson's reagent and related substances has been reviewed by
several groups.[3][4][5][6] The main use of Lawesson's reagent is the thionation of carbonyl
compounds. For instance, Lawesson's reagent will convert a carbonyl into a
thiocarbonyl.[7] Additionally, Lawesson's reagent has been used to thionate enones,
esters[8], lactones[9], amides, lactams[10], and quinones.

In one study, reaction of maltol with LR results in a selective oxygen replacement in two
positions.[11]

A combination of silver perchlorate and Lawesson's reagent is able to act as an oxophilic

Lewis acid with the ability to catalyze the Diels-Alder reaction of dienes with ,unsaturated aldehydes.

126

Reactions of Thiophene
Electrophilic Substitution

Substitution takes place at the 2- position

Reactivity
pyrrole >> furan > thiophene > benzene
Thiophene tends to undergo substitution rather than addition reactions and it is not so readily
cleaved by acids as is furan.

Substitution of 2-substituted thiophene

S

Me

electron releasing

O2N
nitration

Me

CHO

O2N

CHO

electron withdrawing

O2N

3 :1 ratio

127

CHO

Nucleophilic Substitution

Cycloaddition Reaction
Thiophene is a poor diene
O
S

O
O

O
O

128

129