Chem. 4239
Collected and organized by
N
N
N
Pyridine
quinoline
O
Isoquinoline
O
O
-pyrone
H
N
1H-pyrrole
-pyrone
O
furan
thiophene
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
(Hantzsch-Widman System)
Naming Heteromonocycles
Prefix (heterotoms, number, positions)
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
N
H
N
H
O
N
H
N N
H
N
N N
N
HN
O
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
Base component
N
O
Benzoxazole
Base Component
1) One ring only contains N, Choose it
N
O
Benzoxazole
O
Thieno[ ]furane
]indole
N
H
pyrrolo[ ]pyridine
H
N
N
N
H
pyrrolo[ ]pyrrazole
imidazo[ ]oxazole
H
N
N
H
imidazo[ ]pyrrazole
O
oxazolo[ ]isoxazole
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
14
13
15
12
16
11
17
10
5'
N
N
9
7
8
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
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
base
+
EtO2C
EtO2C
CO2Et
24
CO2Et
CH3
O
N
H
Strong base
R
R
N
H
heat
25
26
Br
N
H
+
NH2
N
H
Indole
NH2
NH
Cl
R
N
R
Isoquinoline
27
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
29
30
31
R
O
EtO
NH2 - OH
R
O
HO N
H
32
O
O N
H
33
34
35
36
37
38
R
O
EtO
NH2 - OH
R
O
HO N
H
39
O
O N
H
40
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
46
More Examples:
47
48
49
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
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.
53
Nitrenes
Formation
Nitrenes are very reactive and not isolated as such. They are
formed as reactive intermediates in the reactions:
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)
54
NO2
LTA
O
O
N
NH2
55
56
57
Examples:
58
59
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
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.
Nitrenes
Formation
Nitrenes are very reactive and not isolated as such. They are
formed as reactive intermediates in the reactions:
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)
65
NO2
LTA
O
O
N
NH2
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.
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
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
LUMO
LUMO
HOMO
HOMO
orbitals of a 1,3-dipole
orbitals of a dipolarophile
79
+
Y
.
X
.
z
R
R
+
R
R
Regiochemistry
80
R
R
Generation of 1,3-Dipoles
Nitrile oxides
Nitrile Sulfides
Examples
81
82
83
84
Hetero-Diels-Alder Reactions
Reaction between cyclopentadiene and diethyl azodicarboxylate
R
COOEt
COOEt
COOEt
COOEt
+
R
electron withdrawing
electron releasing
COOEt
COOEt
R
+
COOEt
electron releasing
COOEt
electron withdrawing
85
86
87
88
2 + 2 Cycloaddition
89
Paterno-Buechi Reaction
90
Cheletropic Reaction
91
Heterocyclic Synthesis
Pyridine
: N
H N
Pyrrole
Pyridine
CH3
Picolines
COOH
COOH
N
nicotinic acid
isonicotinic acid
H
N
N
CH3
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
Ar
MeO2C
H3C
CO2Me
NH2 O
CH3
Ar
CO2Me
MeO2C
H3C
N
H
93
CH3
NH2
enone
O
Ar
Cl
MeO2C
H3C
CO2Me
Ar
NH2 O
MeO2C
H3C
Ar
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
ChiChibabin Reaction
Amination of pyridine and related heterocycles at the 2-position by sodamide
NaNH2
-NaH
H
N
Na+
NH2
98
NH2
4' 4
7
8
8' N
1
5 4'
N2
8'
Isoquinoline
Quinoline
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
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
103
Heterocyclic Synthesis
Pyrylium Salts
O
2H-Pyran-2-one
O
O
-pyrone
O
4H-pyran-4-one
pyrone
OHN
SO3
O O
O
ClO4-
Na+
104
Synthesis of -Pyrones
105
-Pyrone
O
O
CH3
H3C
EtONa
+
OEt
EtO2C
EtO2C
OEt
HCl
0 oC
O O
CO2Et
EtO2C
CO2Et
CO2Et
HCl / Cu
160 oC
O
+
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
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]
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
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
EtO2C
EtO2C
+
H3C
RNH2
H3C
Cl
NH
R
EtO2C
CH3
H3C
N
R
References
1.
2.
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
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
115
CHCl3
N
ether
Cl
N
CHO
+
N
K
Ring Expansion
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
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
121
Cycloaddition Reactions
Diels-Alder reaction with maleic anhydride
O
O
O
O
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.
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
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).
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]
126
Reactions of Thiophene
Electrophilic Substitution
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.
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