Aromatic Heterocyclic Chemistry

Aromatic Heterocyclic
Chemistry
David T. Davies
-"
-"eN
Oll'OlD ICII~CI
.... ,
'UILICATIOHl '
ZENECA
Aromatic Heterocyclic
Chemistry
David T. Davies
SmrthKline Beecham Pharmaceuticafs, Hariow, Essex
OXFORD
VNIVERSITY PRBSS
Contents
2
Introduction
Pyrroles, thiophenes, and furans
1
10
Oxazoles, imidazoles, and thiazoles
20
Isoxazoles, pyrazoles, and isothiazoles
28
5
6
7
8
9
Pyridines
35
Quinolines and isoquinolines
46
Indoles
53
Five-membered ring heterocyc1es with three or foUr heteroatoms
61
Six-membered ring heterocycles containing one oxygen atom
67
10
Pyrimidines
73
II
Answers to problems
78
Index
87
1. Introduction
1.1 Heterocyclic chemistry

Heterocyclic chemistry is a large and important branch of organic chemistry.
Heterocyc1es occur in nature, for instance in nuc1eic acids (see Chapter 10)
and indole aIkaloids (see Chapter 7). Synthetic heterocyc1es have widespread
uses as herbicides (e.g. 1.1), fungicides (e.g. 1.2), insecticides (e.g. 1.3), dyes
(e.g. 1.4), organic conductors (e.g. 1.5), and, of course, pharmaceutcal
products such as the anti-u1cer drug 1.6.
el
N~N
H I~ 11 H
EtN ~ N /'--- NEt
1.1
1.3
[ s>-=<s ]
1.5
1.6
1.2 Aromaticity and heteroaromaticity

"
Any ring system containing at least one heteroatom (i.e. an atoro other than
carbon - typically nitro gen, oxygen, or sulphur) can be described as
heterocyc1ic. This broad definition encompasses both aromatic heterocyc1es
. (such as pyridine 5.1) aild their non-aromatic counterparts (piperidine 1.7).
5.1
1.7
Aromatic heterocyc1es are described as being heteroaromatic, and we shall

concentrate on these systems in this book at the expense of more saturated
systems. Let us now consider the concept of aromaticity with regard to
benzene.
The compound numbering system

in this chapter is not as odd as it
might seem. For more on
compound 5.1 see Chapter 5, etc .
2 Introduction
H
[ )~XH
H
H
1.Sa
lOo
H*H 1 H*H
H
.4
H
1.9
l.8b
I
I
The earbon atoms in benzene are sp2 hybridised, and the hydrogen atoms
are in the same plane as the earbon atoms. The remaining six p orbital s are at
~ghLanglest()the plane of the rin.g and c~oniai~~~1X1telecftollf. Benzene
fulfils the HckeIcrltena for aromatidtyasapplieirtocyclic poI yenes
containing 4n + 2 electrons (where n=l in this case) in filled p orbital s
eapable of overlap.
Although two mesomeric representations 1.8a,b can be drawn for benzene,
this does not imply two rapidly-interconverting forros. Rather, the six 1t
eleetrons are deloealised in molecular orbitals resulting in an annular electron
cIoud aboye and below the plane of the ringo Benzene can also be represented
by structure 1.9, which emphasises the cyclical arrangement of electrons. In
agreementvvitllthistheory, the car~n-carbon bond lengths are all equivalent
~ (0.14~nm) and intermediate between that o a~single(Oj54Iii !lri(rao~~l~~~
. (Oj33 nm) carbon-:earboIl bn~~.The extra~ theriiidYIJ.amic stabiIisation'
imparted to benzene by this phenomenon of electron delocalisation, called
'resonance', can be determined indirectly. Real, delocalised benzene is
thermodynamically more stable than a theoretical cyclohexatriene molecule
(i.e. non-delocalised structure 1.8a) by around 150 kJ mol-l.
How does this concept of aromaticity apply to typical heterocycIes such as
pyridine 5.1 and pyrrole 2.1? Pyridine can formally be derived from benzene
by replacement of a eH unit by an sp2 hybridised nitrogen atom.
Consequently, pyridine has a lone pair of electrons instead of a hydrogen
atom. However the six 1t electrons are essentially unchanged, and the pyridine
is a relatively 3.romatic heterocycIe.
.0
N
H
5.1
:U
A difficulty arises with five-membered heterocycles such as pyrrole, which

at first sight would appear to have only four 1t electrons, two short of the 4n
+ 2 Hckel criteria for aromaticity. The nitrogen atom is sp2 hybridised and
formally contains a lone pair of electrons in the remaining p orbital at right
angles to the ringo However, the system is delocalised, as shown below.
eO~eO~Oel
eN
H
eN
H
eN
H
Ii
1
I
f~
r
j
'1
I
Aromatic heterocyclic chemistry 3

Thus, delocalisation of the nitrogen lone pair completes the sextet of
electrons required for aromaticity. These two examples illustrate the point
that certain heterocycles (closely analogous to benzene and naphthalene) such
as pyridine 5.1, pyrimidine 10.1, and quinoline 6.1 are aromati~Q-y right'
whereas other heterocyc1es s~ch as pyrrole 2.1, imidazole 3.2, and triazole
8.7 have to 'earn' aromaticity by delocalisation of a lone pair of electrons
from the heteroatom.
.
o es
N
5.1
10.1
(~
N
2.1
3.2
N
H
6.1
r~\
tz_,N ,N
H
8.7
What are the consequences of this concept of lone pair delocalisation for a
related series of heterocycles such as pyrrole 2.1, thiophene 2.2, and furan
2.3? As delocalisationresults in electron 10ss from the h~teroatom concerned,
the xtelltordelociUIsation (andhence aromaticity) will vary withthe
electronegativiW of the heteroatom. The highly electronegative oxygen atom
in furaI holds on to electron density more strongly than the heteroatom in
thiophene or pyrrole. Furan is generally considered to have a non-aromatic
electron distribution fairly close to that depicted by structure 2.3.
1[)
s
2.1
2.2
2.3
N
H
In fact the thorny problem as'to how aromatic is a particular heterocyc1e or

series of heterocycles has been a preoccupation of physical organic chemists
for 'so~e time. Bond lengths, heats of combustion, spectroscopic dati; and
theoretica11y-calculated resonance energies have a11 been invoked, but an
absolute measure of aromaticity remains elusive. Nevertheless, trends
regarding relative aromaticity will be alluded to in this text as they arise.
1.3 Synthesis of heterocycles

There are many syntheses of the major heterocycles and they are often
complementary irt that they afford different substitution patterns on the ringo
Most of the synthetic inethods we shall examine are fairly classical (indeed
some are decidedly ancieiit!) although many of the specific examples are quite
modern. Many classical syntheses of hete,rocyc1es revolve around the
condensl;ltion reaction in its various guises. Let us consider the mechanism of
a simple acid-cataIysed condensation, that of generalised ketone 1.10 and
amine 1.11 to give imine 1.12.
Protonation of the l\etone oxygen atom activates the ketone to
nucleophilic attack by the amine. Lbss of a proton from 1.13 produces
neutral intermediate 1.14. A second protonation, once again on the oxygen
atom affords 1.15, which on 10ss of a water molecule and a proton gives the
For a review on the concept of

heterocyclic aromaticity see
Katritzky et al (1991).
4 In troductio n
imine 1.12. AH these steps are 'reversible, but in practice if water can be
removed from the equilibrium (for instance by azeotropic distillation) then
such reactions can be forced to completion. This type of reaction occurs
many times in this text, but in future wj~l not be presented in such detail.
The student is strongly advised to work through, using pen and paper, the
mechanism shown below and the many subsequent mechanisms. Confidence
with reaction mechanisms will facilitate understanding of heterocyclic
chemistry and organic chernistry in general.
RJ
1.10
'F 0
Rl
~+He
~e
-H2O
1.11
..
Rl
=N-R2
Rl
1.12
R1,O-H
~
><~~H
Rl
H 2N-R2
I 'H
Rz ,
1.13
O-H
l(N,H
Rl I
R2
RIX~
N ... H
Rl
Rz
I
I
1.15
1.14
,!
1,
H,e H
+H
,
I
,i
~-H20
_He
-H
Rl Cf/H
Rl
cataIytic He
H2N-R2
The disconnection approach to synthesis essentiaHy involves working

backwards from a target compound in a logical manner (so-called
retrosynthesis), so that a number of possible routes and starting materials are
suggested. This approach has been applied mainly to alicyclic, carbocyclic.
and saturated heterocyclic systems. Retrosynthetic analyses are presented in
this text not as an all-embracing answer to synthetic problems, but rather as
an aid to understanding the actual construction of unsaturated heterocycles.
Returning to the condensation presented above, this leads to an important
disconnection. The imine-like linkage present in' several heterocycles
(generalised structure 1.16) can arise from cyclisation of 1.17, containing
amino and carbonyl functionalities.
The symbol
denotes a
dlsconnection. an analytical
process in which a structure is
transformed into a suitable
precursor
1,.
I
I
Now consider condensation of ammonia with ketoester 1.18. The isolated

product i8 not imine 1.19 but the thermodynamically more stable enarnine
tautomer 1.2.0 which has' a. conjugated doubl~ boIlrl system and a strong
intramolecular hydrogen...bond. Although not a heterocyclic example, 1.20 '
illustrates thatan~enamiD.e:me linkage, as in generalised heterocyc1e 1.21, is
also accessible by a condensatio,n reaction.
'
,
.....
OEt
~C02Et
O
1.18
~C02Et
NH
1.19 ,
..
r<?
~N, ... H
H
1.20
r
1
1
f
,i
In a retrosynthetic sense, formal hydrolysis of the carbon-nitrogen bond of

1.21 reveals enoll.22 which would exist as the more stable ketone tautomer
1.23. Note that in the hydrolytic disconnection step the carbon becomes
attached to a hydroxy group and the nitro gen to a hydrogen atom - there is no
change in the oxidation levels of carbon or nitrogen.
>
1.22
1.23
Unlike our initial imine disconnection which is restricted to nitro gen

heterocycles (with one or two specific exceptions such as pyrylium salts, see
Chapter 9), the heteroatom in the enamine or enamine-like disconnection
could be divalent. Therefore this disconnection is also applicable to oxygenand sulphur-containing heterocycles, typified by 1.24 and 1.25.
RO
RO
>
1.24
R'o-SH
>
1.25
Let us see how this disconnection approach can rationalize the synthesis of
pyrrole 2.16.
~
N
-0r-
-0r-
OH NH2
2.16
Retrosynthetic analysis suggests a double condensation between diketone

1.26 and arnmonia. Pyrrole 2.16 can actually be prepared if this way - see
Chapter 2.2.
Anpther aid to understanding heterocyclic synthesis in general is the fact
that a large number of five- and six-membered heterocycles.can be constructed
from various combinations of small acyclic molecules by complementary
matching of nucleophilic and electrophilic functionality.
-rr,
1.26
!Be
e-e,
e!B
'l-ze)
NH
Returning to the synthesis of pyrrole 2.16, dl.ketone 1.26 can be regarded as a

four-carbon bis-electropb,ilic fragment and ammonia, in this instance, as a
bis-nucleophilic nitro gen fragrnent. Arnmonia can form up to three bonds in
a nucleophilic manner.
OH
NH3
~--nrO O
1.26
6 Introduction
In this particular instance the correct oxidation level autornatically results

from the condensation reaction, giving pyrrole 2.16 directly. In other cases
cyclisation does not afford the correct oxidation level and an unsaturated
systern has to be oXldised to achieve arornaticity. For instance, 1,5-diketones
1.27 react with ammonia to give dihydropyridines 1.28 which can be oxidised
to pyridines 1.29.
[O]
R)lNJl. R
-2H
Do
I /.
N
1.1.7
1.28
1
i
H H
NH3
1.1.9
Examples of this cyclisation-oxidation strategy include the synthesis of

pyridotriazine 5.32 (page 42) and syntheses of quinolines and isoquinolines
(Chapter 6). Sorne examples of nucleophilic and electrophilic fragments are
shown in Table 1.1. Several points arlse from the tableo
Consider acylating species such as acid chlorides. Acylation of diamine
1.30 initialIy gives amide 1.31 which undergoes a condensation to produce
benzirnidazole 1.32. The carbonyl rnoiety is acting exclusively as an
electrophilic centre.
I!
~NH2' __R_)l
__a~
..
~NH2
'1
1.30
f
However, deJocalisation of the nitro gen Jone pair in the arnide linkage (see
rnesom~ric representations 1.33a,b) produces a nucJeophilic oxygen atorn
which can react with electrophiles as shown.
..
.
I
I
1
R1'NAR
,
..
EEB
Rl....NJt: R
,'-'
H 1.33b
t.33a
Ojo
06
Rl....N
EB R
..
o-E
RIEB
'NI
R2
H
r
1

Nucleopbilic fragments
No. oC ring atolOS
1
NH3 , HzO ,HzS
(see Chapters 2 and 5)
H2N- NH2 ,H2N- OH
(see pyrazole and isoxazole syntMsis, Chapter4)
.'
(see thiazole syntMsi~, Chapter 3, and pyrimidine syntMsis, Chapter 10)

(see quinoline syntMsls, Chapter 6)
((1
NH2
(see benzimido.zole syntMsis, Chapter 1)
NH
2
Vl
(see isoqulnoline syntMsis, Chapter 6)
NH2
Electrophilic fragmenfs
No. oC ring atolOS
O
(X = leaving group. ego CI- see benziml%ole syntMsis. Chapter 1
RAX
and isoquinoline syntMsis. Chapter 6)
~~R
(see thiazole syntMsis, Chapter 3)
Rl~R2
(~ (see quinoline syntMsis, Chapter 6)
"--.R. R2 = alkyl or O-a/kyl

(see pyrazole and isoxazole syntMsis. Chapter4, and pyrimidine syntMsis, Chapter 10)
R~R
(see pyrrole. thiopMne. andfuran syntheses. Chapter 2)
Nucleophilic LElectrophilic fragments

No. Qf.rlrrg atoms
O~
(see Chapter 1 and oxazole synthesis. Chapter 3)

RyX
O
"k"
O
(see Chapter 1 and coumarin synthesis. Chapter 9)
rt
NH2
(see oxazole synthesis, Chapter 3. and Knorr pyrrole

synthesis, Chapter 2)
8lntroduction
The reaction of an acylating species
with a nucleophile is shown below.
Amides can eyc1ize in this manner as, for example, in the aeylation of amino
acids 1.34 to afford oxazolidinones 1.35.
(o O
Rl)f~AR2
excess
R2
Cl
~
R100H
NH2
R100
~
H ....~yO
1.34
N~
R2
R2
1.35
Aeylating speeies are thus

ineluded in both electrophilic and
nuc1eophilie/electrophilic eategories in Table 1.1. For a related example see
the synthesis of oxazoles in Chapter 3.
1,3-Dicarbonyl compounds, such as malonate derivatives, can also be
c1assified under two eategories. As well as reacting simply as a thtee-atom
bis-electrophilic fragment (as in the synthesis of barbiturate 10.25 (page 77),
an alternative reaetivity is available. Condensation (by nuc1eophilic attaek)
of the active methylene earbon and electrophilic reaetion at just one of the
carbonyI groups is a two-atom nuc1eophilic/electrophilie profile, as seen in
the preparation of coumarin 9.16.
For the.slke of simplicity in this fext
the two-stage process is abbreviated
Ihus:
Br':
I
~
OH
+
EtO
"Jl-OEt
~~
- H20
-EtOH
Br'(JC(
~ I -..;::
C0 2Et
9.16
These eoncepts of retrosynthesis and heterocycle construction will help put

the syntheses encountered in the following chapters into a broader
perspective.
1.4 References
Textbooks
Aeheson, R.M. (1967). An introduction to the chemistry 01 heterocyclic
compounds, (2nd edn). Wiley, New York.
Paquette, L.A. (1966). PrincipIes 01 modern heterocyclic chemistry.
Benjamin, New York.
Joule, J.A. and Smith, G.F. (1979). Heterocyclic chemistry, (2nd edn).
Van Nostrand Reinhold, New York.
GiIchrist, T.L. (1985). Heterocyclic chemistry. Longrnan, Harlow.
i
f
.)
r1
1
1;
!
'J

The first two (Acheson and Paquette) are still very good texts even today. Of
the more recent pair, both are warmly recommended. Joule and Smith is
possibly a more introductory text than Gilchrist, which contains many
joumal references and is pitched at the advanced undergraduate/postgraduate
leve!. See Gilchrist for discussion of the nuc1eophilic/electrophilic
fragment approach to heterocyclic synthesis.
Warren, S. (1978). Designing organic syntheses, p.l50-172. Wiley,

Chichester.
Warren S. (1982). Organic synthesis - the disconnection approach, p.
3260-345. Wiley, Chichester.
Reference books and series
Coffey, S. (ed.) (1973 - 1986). Heterocyclic compounds (Vols. 4A - 4K of
Rodd's chemistry of carbon compounds). EIsevier, Amsterdam.
Elderfield, R.C. (ed.) (1950 - 1967). Heterocyclic chemistry, Vols. 1 - 9.
Wiley, New York.
Katritzky, A.R. and Boulton, A.J. (ed.) (1963 - 1989). Advances in
heterocyclic chemistry, Vols. 1 - 45. Academic Press, Orlando.
Katritzky, A.R. and Rees, C.W. (ed.) (1984). Comprehensive heterocyclic
chemistry, Vols. 1 - 8. Pergamon Press, Oxford.
Katritzky, A.R. et al, (1991). Heterocycles, 32, 127-161.
Sammes, P.G. (ed.) (1979). Heterocyclic chemistry (Vol. 4 of
Comprehensive organic chemstry, ed. D. Barton and W.D. Ollis).
Pergamon Press, Oxford.
Weissburger, A. and Taylor, E.C. (ed.) (1950 - 1990). The chemistry of
'heterocyclic compounds. Wiley Interscience, New York.
AH of these sources contain exceHent reviews on virtuaHy every aspect of
heterocyclic chemistry. In particular, Katritzky and Rees is a thoroughly
comprehensive work. For those particularly interested in the synthesis of
heterocyc1es as pharrnaceutical agents see:
Lednicer, D. and Mitscher, L.A. (1977, 1980, 1984, and 1990). Organic
chemistry of drug synthesis, Vols. 1 - 4. Wiley, New York.
Experimental references
In this introductory text there is Hule detail regarding solvents, yields,
workup procedures, etc. However, several chapters reference a relevant
experimental procedure (taken from Organic syntheses or Vogel) which the
student is strongly encouraged to read. For an excellent selection of
experimental procedures for the synthesis of heterocycles see:
Fumiss, B.S., Hannaford, A.J., Smith, P.W.G., and TatcheH, A.R. (1989).
Vogel's textbook of practical organic chemistry (5th edn),
pp. 1127 - 1194. Longman, Harlow.
2. Pyrroles, thiophenes, and,

furans
2.1 Introduction
<1
The numbering of heterocycles 11
generally starts at the heteroatom
aH
Ne H
Under extreme conditions of

acidity pyrrole is protonated, but
at the C2 position.
Pyrrole 2.1, thiophene 2.2, and furan 2.3, are five-membered ring
heteroaromatic compounds containing one heteroatom. They derive their
aromaticity from delocalisation of a lone pair of electrons from the
heteroatom. Consequently the lone pair is not available for protonation and
hence these heterocycles are not basic.
4-~,?
S~ __ )
NI
H
2.1
Th~ basis and extent of their aromaticity is discussed 'in Chapter 1. In

summary, the capacity for the lone pair on a particular heteroatom to be
deloc3.1.ised is inversely related_t() the. electronegativity of the heteroatom. For,
instace~ . furan is the least aroma tic of tbe .trio 'because--oxygenhas the
greatest electronegativity and hence ~esomeric representations 2.4b-e make
relatively less of a contribution to the electronic structure of furan than they
do in ~e cases of pyrrole and thiophene. The order of aromaticity is furan <
pyrrole < thiophene. We shall see later how this variaton in aromaticity
affects the reactivities of these tbree related heterocycles.
~ ~
X
El)
Note that protonation of the

pyrrole nitrogen would lead to a
non-aromatic cation.
2.4b
2.4a
X=NH,S,O
2.4c
2.4d
y]
Me
A small number of simple pyrroles such as 2.5 and 2.6 occur naturally.
Far more important are the tetramic pyrrole derivatives (porphyrins) such as
chlor.ophyll-a 2.7 and haem 2.8.
2.5
2.8
Acetylenic thiophene 2.9, found in sorne species of higher plnts, is one

of the few naturalIy-occurring thiophenes. However, the thiophene ring is
used in several important pharmaceutical products, such as the penicillin
antibiotic 2.10.
Chlorophyll-a Is a plant pigment

Involved in the crucial
photosynthetic process in which
the energy 01 sunlight is
harnessed to incorporate carbon
dioxide into plant metabolism.
Haem, however, is lundamental to
mammalian biology, belng the
oxygen-binding component 01
haemoglobin. Oxygen absorbed
Irom the air is transported around
the body whlle tmporarily coordinated to the iron atom of
haemoglobin, whlch occurs in the
red blood ceUs.
2.9
2.10
In contrast to the pyrrole and thiophene series, the furan nucleus occurs in
many plant-derived terpenes such as 2.11. The most important furancontaining drug is 2.12, which reduces gastric acid secretion and is important
in the treatment of ulcers.
NO
NHMe
N~S~NM~
H
O
2.12
I
"
2.2. Synthesis of pyrroles, thiophenes, and furans

We shaH first examine a general synthesis applicable to aH three
heterocycles, then consider two specific syntheses of pyrroles.
Retrosynthetic cleavage of a carbon-heteroatom bond in 2.13gives enol
2.14 which is equivalent to ketone 2.15. Repeating the process gives us a
l,4-dicarbonyl compound and the heteroatom-containing fragment such as a
primary amine or hydrogen sulphide.
Terpenes are plant-derived

natural products constructed of
multiples of the five-carbon
hydrocarbon isoprene.
12 Pyrroles, thiophenes, andfurans

R;z
R3
~Rl~R4'
O O
+ RNH2,H2S,H20
2.13
The forward process is known as the Paal-Knorr synthesis. Tbis is a ver':!

straightforward synthesis limited only by the accessibility' of the 1,4-CiIcarbonyl precuisors.
The mechanism is illustrated by
the preparation of 2,5-dimethyl
pyrrole 2.16 and is simply.two
consecutive condensations.
-~O
. . -(}O
1l
H
~H ......_ _
1)H
HCl
.~
Ph
S
2.17
P2SS
Ph-i)-Ph
O O
...
Ph
~
S
Ph
-h-
P2SS
...
Ph~C02Me
H2S
HCl
O O
JO---Ph
2.19
C02Me
2.20
EB,.o~o
n
J!..J>.....- ~_/<,
-H20 ! / \ / H
Ph
Ph
~ Ph~ ~ H O ( ) If9
-+- Ph
OH
-cJ
-01=Q \.. /\
Y'f'"
SH
....-Ph4-_ 1(HEB
SO
2.17
However, the situation is slight1y difierent when phosphorus (V)

sulphide is used. This reagent converts ketones to thioketones, by exchange
of a phosphorus-sulphur double bond with a carbon-oxygen double bond.
1
j
When hydrogen sulphide' is the heteroatom source the mechanism is

similar to the pyrrole case.
HS--..
S
2J8
O O
Ph-O-O O
1
f
The Paal-Knorr synthesis can similarly be applied to thiophenes, e.g.

compounds 2.17 - 2.20.
PhD-O O
I
1
2.16
H2S
1I
1
1
ft
I
!
.1

For instance, in the synthesis of 2.19, the 1,4-diketone is converted into
the corresponding 1,4-dithioketone followed by 10ss of hydrogen su1phide.
Ph~
/-Ph
\.
}>2SS
- - - . Ph~
O O
H2S
tT-Ph
S S
Ph
--fJS
The mechanism 01 the cyclisation

step is similar to that of thiophene
2.17.
Ph
2.19
Our retrosynthetic ana1ysis of the Paa1-Knorr.synthesis leads to a prob1em

when applied to furan, as it implies addition of a water molecule, followed by
elimination of two water molecules. In practice, simple dehydration of a 1,4dicarbonyl compound leads to furans as in the preparation of 2.21.
Returning again to pyrr01es, probably the most widely-used method for

their preparation is the Knorr pyrrole synthesis, which is the condensation of
a ketone 2.22 with an et-aminoketone 2.23 to give pyrrole 2.13, via enamine
2.24. A reasonl;l.b1e mechanism is shown below, although none of the
inter:rrlecliates is isolated.
(i
2.22
R2
R3
W"
R-1!...N)-.. R4
H
2.13
The a.-aminoketones are often prepared by nitrosation of an active

methylene group followed by reduction of the oxime to the amine (e.g. 2.25
to 2.26 to 2.27).
H~o
~C02Et
2.25
~
~
AcOH
~C02Et
-.
o
.. N,
..
- CsHuOH
<><C02Et
O
El)
HUNH
~C02Et
~CsHll
As a.-aminoketones are prone to se1f-condensation (see page 22 for a

dlSCusswnofa=:amiokeioIlesJ, tue Ini til condensadonstepis fadlifited by ...
--.R2iil2~2roein7f-anelectiri~witndiawing group.-This enhnces the
-e.lectrophilc llatureof ihe ketone carhonyl g"oup thereby increasing the rate
of the desired reaction, and favours enamine tautomer 2.24 over the imino
N .... OH
2.26
~C02Et
..
AcOH
Zn
NH2
2.27
14 Pyrroles, thiophenes, ami furans

tautomer because of conjugation with the electron-withdrawing group. A
selection of Knorr pyrrole syntheses, showing the key intermediate enamines'l
is shown below.
C",..l'
~NX:O
0
C1- :(
CO.)Et
,lo
The Knorr pyrrole synthesis
consists of a ketone and amine
condensing to give an enamine,
followed by intramolecular
cyclisation of this enamine onto
the remaining ketone.
H2N
CO.)Et
Ph:t
2.3
HlN'
Ph
lL X
N
H
Ph
'
1
J
N
H
K-
N
COlEt H
C02Et
--E
COlEt C,Hl1
~
I 0J:C,Hl1
~
Ph
N
H
CO Et
HlN
~ ~
Et
N
H
)0
COlEt
Note that pyrrole reacts with

electrophiles on carbon, lika an
enamine.
O~,Hll
c0.2Et
C02Et
~j
,lo
0y
~ ~
N
COlEt H
Ph
Ph
Ph
___t_
b(
N
H
Ph
Ph
Electrophilic substitution of pyrrofe, thiophene,

and furan
AH three heterocycles undergo aromatic substitution reactions, though their

reactivities vary considerably. Let us consider a generalised mechanism and
how the stability of the two possible intermediates affects the position of
substitution.
COj:'[OE~
eO~ rrfLE
t}
XH
)'
0-.
U
X=NH,S,O
XH
2.28a
H E
2.298
XH
2.28b
Ji: O-E
2.28c
E
-H
-.
2.29b
The intermediate derived from attack at the e2 position has greater

delocalisation of the positive charge (mesomeric forms 2.28a,b,c) than that
derived from attack at the e3 position (mesomeric forms 2.29a,b). As the
charge is more extensively delocalised in the former, this intermediate is at
lower energy. This in turn is reflected in a lower activation energy for this
pathway and manifested in a selectivity for electrophlic substitution at the
e2 position over the e3 position. The 'actual isomer ratio depends on the
heterocycle, the electrophile, and the precise conditions,aUhoughin many
cases such reactions are virtuaHy regiospecific, and only the e2 substitution
1
1
I
~
I!
r
~
ji
g
~
li
~
:;
.~
,
~~
Aromalle hel",ocyelie eheml.<try 15
products are isolated. Very reactive electrophiles (such as the nitronium ion
N02+) exhibt low~r selectivity because they tend to be less discriminating
, as to where they attack the heteroaromatic nucleus.
Thi': ease of electrophilic substitution is pyrrole > furan > thiophene >
benzene.
,
pyrrole is extremely reactive towards electrophiles wmle thiophene, the
most aromatlc of the trio, is much less reactive. At a very rough
approximation, the reactivity of thiophene is of the order of a heteroatomsubstituted benzene derivative such as phenol. Despite large differences in
. the rates of electrophilic substitutions there are some important aromatic
substitution reactions common to all three heterocycles.
The Vilsmeier reaction is the formylation of reactive aromatic compounds
by using a combination of phosphorus oxychloride and N ,NdimethyIformamide, followed by a hydrolytic workup.
o
X
X=NH,S,O
T.o give a quantitative feel for

these oifferences in reactivity,
data for the bromination of three
representative derivatives are
shown below.
Oyo
H
The reaction proceeds by formation of the electrophilic Vilsmeier complex

2.30, followed by electrophilic substitution of the heterocycle. The formyl
group is generated in the hydrolytic workup. Pyrrole, thiophene, and furan all
undergo this formylation which is highly selective for the e2 position.
Relativo Rato
s
O
1.2 x lOZ
NH
5.6x 108
Cl
H~NM~
ele
2.30
El)
..
-HNM~
QyO
H
AH three heterocycles undergo sulphonation with the pyridine-sulphur

trioxide complexo This behaves like a mild source of sulphur trioxide,
enabling the sulphonation to be carried out under essentially neutral
conditions.
o
X
X=NH,S,O
Furan and pyrrole are not stable to mineral acids, but acetyl nitrate can be
used for the nitration of all three heterocycles.
:.~::::~~ a~d
:::::::::
furans Whilst!he meohanism shown above applies to pyrrole and !hiophene,!he

ntration of furan with acetyl nitrate gives the 2,5-addition product 2.32, j
V
arising from attack of acetate ion on the intermediate cation 2.31. Treatment i
()f~,"-~g _withI'yridine eliminates the elements of acetic acid proaucing J
nitrofur!l!!_b33.-----i
be intercepted to give 2.32. This
O
O
~, !,~'.
important theoretical point:
because furan is not very aromatic
and the driving force to 'rearomatise' by loss of a proton is
not very strong cation 2.31 c~n
behaviour is not observed with

pyrrole and thiophene.
11
O
O
eo"'~"'O~
~
~ UNO~H~N02_ACOH..
( ' ~ ES H
Ac~ O H
2.3
Aod'
2.31
232
Ca
Ji
lf:JO
N0
233
Thiophene, alkyI-substituted furans, and especially pyrrole, undergo

Mannich reactions.
o
o
N
H
CH1O/HNEt1
AcOH
..
CH1O/HNM~
..
HCl
--O
CH1O/HNMez
AcOH
~NEtl
N
H
~NMel
S
. ~NM~
O
This involves condensation of the heterocycle, formaldehyde, and an amine

(usually a secondary amine) to give an aminomethyl derivative.
Me1NH+CHzO
AcOH
~NM~
X
The Friedel-Crafts acylation and aIkylation reactions are fundamental

processes in aromatic chemistry. Pyrroles and furans are not stable to the
Lewis acids necessary for these reactions, but thiophenes are stable to Lewis
acids, and do undergo Friedel-Crafts acylation and alkylation.
PhCOCIAlCl3
..
~O
Observe that electrophilic

substitution occurs at the e3
position when both the C2 and CS
positions are blocked.
f?y0
Ph
O
EtBr
ES
CH;:=. NMel
..
~
s
1,

The reactivity of all three heterocyles is considerably reduced when
electron-withdrawing groups are present on the ringo This is important in the
synthesis of l'yrrole_~Ii.vatives a~Kad(Is~ ~l!emicaI stability to the ring;
~1:l~ir~~~I1"~t~~e~erformed inthepresence of Lewis~.cias.
.
The regochemstry of these

reactons s easily explaned by
ratoilalsatons from classcal
benzene chemstry, Le. electronwthdrawng groups drect meta.
---fJS
CHzO
COZMe
HCI
"
AcONOz
NO z
2.4 Anion chemistry of pyrroles, thiophenes, and

furans
Pyrrole has a weakly acidic hydrogen atom attached to the nitrogen (pKa=
17.5) and can be deprotonated by strong bases. The sodium and potassium
salts are ionie in character and the naked anion tends to react on nitrogen as in
the preparation of N-methyI pyrrole 2.34. The corresponding magnesium
derivative 2.35 has more covalent character and tends to react more on carbon
than nitrogen, as in the preparation of pyrrole aldel:\yde 2.36
NaNH2
po
2.1
O
N
H
2.1
Oe
N
N
H
MeI
po
OEt
Do
Cr:
MgBr
2.35
2.34
N
Me
Na$
r:- J?~
O~
po
~H~
N H
Qyo
H
2.36
N-methyl pyrrole 2.34, thiophene, and furan can be metallated at the C2

position with alkyl lithium reagents. This position is more activated to
deprotonation than the C3 position because of the electron-withdrawing
inductive effect of the heteroatom. The nucleophilic 2-lithio species can then
be reacted. with various electrophiles, as in the preparation
of 2.37, 2.38,
.
.j
18 Pyrroles, thiophenes, and furans
and 2.39. Let us see how this methodology can be applied to the synthesis of J
2.42, a furan-containing mimic of a long-chain fatty acid. Deprotonation of
furan and alkylation produces 2.39. A second deprotonation.at the e5 J
position and alkylation gives bromide 2.40. Displacement of -fue bromide
affords nitrile 2.41, and acidic hydrolysis yields the target furan 2 . 4 2 . i
n-BuLi
..
Me
The precise nature of the carbonlithium bond is beyond the scope

of this book. Organolithium
intermediates are here
represented as carbanion and
catlon to emphasise differences in
properties and reactivities as
compared with tull covalent bonds.
Me
Me
n-BuLi
..
Li lB
CIP(O)(O:t)2
2.2
2.37
~ ,,0
S
~""OEt
2.38
OEt
I
I
I
The alkyl group at the C2 position

is not deprotonated in the second
alkylation.
2.40
2.39
2.3
.,
Note the use of -CN as a synthon
tor -C02H.
2.41
2.42.
2.5 Problems
1.
M~cOs
ii
H
2.43
Tricyclic pyrrole derivative 2.43 is a drug currently under development for

the treatment of schizophrenia. It is prepared by a Knorr pyrrole synthesis.
What are the structures of the two starting materials required, and that of the
intermediate enamine?
2. Why is pyrrole aldehyde 2.44 less reactive to nucleophiles than, say,
benzaldehyde? Why is pyrrole alcohol 2.45 readily polymerised on exposure
to acid?
QyO
H
2.44
~OH
N
H
2.4S
I
I

3. Nitration of furan with nitronium tetrafluoroborate produces nitrofuran
2.33 directly. Contrast this result to the two stage reaction necessary with
acetyI nitrate, page 16. Explain these observations.
![JO
N0
2.33
2.2
4. What is the mechanism of this reaction?
o
S
2.2
PhCOCI
Phyf)
O
2.6 References
Dean, F.M. (1982). Adv. heterocyclic chem., 30, 167; 31, 237
(furans).
Gronowitz, S. (ed.) (1985). In ThiOphene and its derivatives (The
chemistry 01 heterocyclic compounds red. A,. Weissburger and E.e. Taylor],
Vol. 44). Wiley Interscience, New York.
Fumiss, B.S., Hannaford, A.J., Smith, P.W.G, and Tatchell, A.R. (1989).
Vogel's textbook 01 practical organic chemistry (5th edn), p.1148
(preparation ofpyrrole 2.16). Longman, Harlow.
.
Jackson, A.H. (1979). In Heterocyclic chemistry (ed. P.G. Sammes)
(Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D.
Ollis) (pyrroles). Pergamon Press, Oxford.
Jones, R.A. (ed.) (1990). In Pyrroles (The chemistry 01 heterocyclic
compounds red. A. Weissburger and E.C. Taylor], Vol 48, Part 1). Wiley
Interscience, New Yorlc
Jones, R.A. and Bean, G.P. (1977). The chemistry 01 pyrroles. Academic
Press, London.
Jones, E. and Moodie, I.M. (1970). Org. syn., 50, 104 (C2 metallation of
thiophene).
Katritzky, A.R. and Rees, C.W. (ed.) (1984). Comprehensive heterocyclic
chemistry, Vot 4, part 3 (five-membered rings with one heteroatom).
Meth-Cohn, O. (1979). In Heterocyclic chemistry (ed. P.G. Sammes)
Ollis), p.737 (thiophenes). Pergamon Press, Oxford.
Sargent, M.V. (1979). In Heterocyclic chemistry (ed. P.G. Sammes)
(Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and
W.D. Ollis), p.693 (furans). Pergamon Press, Oxford.
Silverstein, R.M., Ryskiewicz, E.E., and Willard, C. (1963). Organic
syntheses, Coll. Vol. IV, 831 (Vilsmeier forrnylation of pyrrole):
1
3. Oxazoles, imidazoles, and
thiazoles
~
3.1 Introduction
g;
Oxazole 3.1, imidazole 3.2, and thiazole 3.3 are the parent structures of a
related series of 1,3-azoles containing a nitrogen atom plus a second
heteraatom in a five-membered ringo
3
'~!2
'
They are isomeric with the 1,2-azoles isoxazole, pyrazole, and isothiazole
(see Chapter 4). Their aromaticity derives from delocaliSation of a lone pair
from the second heteroatom, 3.4a-e.
(v
XJ
....-... (~
x
EIl
3.4a
3.4b
()
x
e(~
x
EB
EIl
3.4c
3.4d .
'
C)e
I
X
i
EB
3.4e
The imidazole ring occurs naturalIy in histamine 3.5, an important

mediator of inflarnmation and gastric acid secretion. A quatemised thiazole
ring is found in the essential vitamin thiamin 3.6. There are few naturalIY
occurring oxazoles, apart frm some secondary metabolites fram plant and
fungal sources,
NH2
~1
!
4;
!
t
'1
N
H
3.5
l.,':,
X=O,NH,S
The biosynthesis of histamine

involves decarboxylation of the
amino acid histidine.
'1! 2
'~f2
4J
1:
1,'
3.6
Oxazole, imidazole, and thiazole can be formal1y derived from furan,

pyrrole, and thiophene respectively by replacement of a CH graup by a
nitro gen atom at the 3 position. The presence of this pyridine-like nitrogen
deactivates the 1,3-azoles towards electrophilic attack and increases their
susceptibility towards nucIeophilic attack (see later). These 1,3-azoles can be
viewed as hybrids between furan, pyrrole, or thiophene, and pyridine.
1
r
,t
I
I
I
j

Imidazole (pK a=7.0) is more basic than oxazole (pKa=O.8) or thiazole
(pKa=2.5). This increased basicity arises from the greater electron-releasing
capacity of two nitrogen atoms relative to a combination of nitrogen and a
heteroatom of higher electronegativity. AIso note that a symmetrical
resonance-stabilised cation 3.7a,b is formed.
He
(~
-.
N
H
3.7a
3.Th
Furthermore, certain substituted imidazoles can exist in two tautomeric

forms.
fr~
N
H
3.8
3.9
For instance, the imidazole shown aboye exists as a rapidly equilibrating

mixture of 4-methyI 3.8 and 5-methyI 3.9 tautomers, and is referred to as
4(5)-methylimidazole. It must again be stressed that tautomerisation and
resonance are totally different. Mesomeric representations 3.7a,b are not
interconverting Iike tautomers 3.8 and 3.9; this is simply a means to describe
an intermediate hybrid structure.
3.2 Synthesis of oxazoles

R,etrosynthetic cleavage of the carbon-oxygen bond in generalised oxazole
3.10 produces iminoalcohol 3.11 (better represented in the arnide form
R2
R2
}[N
Rl
O"-R3
.{-N
Rl /
OH
::>-
3.11
3.10
R2
NHl
Rl
3.15
Ax
3.14
OH
~
~
Rl-<- N'(R
OH
O 3.12
1~
2Ji
R1-t .1r- R3
O O
R
O
R3
R3
3.13
3.12). Similar tautomerisation of the enol group gives an actual

intermediate 3.13, and disconnection of the amide lnkage reveals
arninoketone 3.15 and an acylating species 3.14 such as an acid chloride. The
, forward process, cyclocondensation of arnides 3.13 to yield oxazoles 3.10, is
known as the Robinson-Gabriel synthesis.
The statement lhat oxazole has a

pK a of 0.8 means that the
protonated form of oxazole is a
very strong acid.
Therefore oxazole (as the free
base) is a very weak base indeed.
22 Oxazoles, imidazoles, and thiazoles
Base
3.10
3.13
In practice the dehydratloh can be achieved with a broad range of acids or

acid anhydrides, such as phosphoric acid, phosphorus oxychloride, phosgene
(CQCI2), and thionyl chloride. An example of the mechanism is shown
below for thionyI chloride and involves activation of the amide to imidolyl
halide 3.16 then intramolecular attack by the enolic form of the ketone.
R~~R3
;I~ea
O ('S"O
e0
p~Br
~.1'
PhO
3.17
Ph
~2
)::.0 el
3.16
Ph
NaN3
N3
--
Ph
0~C02;
3.23
Drugs which reduce inflammation

are often used to treat the
symptoms of arthritis.
l.NaOH
2.Hel
yNy R3~
-"... O
p~NH2.Ha
~Pb lE:::~.)
el
Ph)[N
TIte aminoketones themselves can be prepared by a number of methods. A

typical ro)Jte is illustrated by the synthesis of anti-inflamm~tory drug 3.23.
Ph
.J.~
C02Et
1,'
J
~
Ph.J!....O~~Et
3.22
3.21
Btomination ofketone 3.17 gives 3.18 which can be conveited to azide 3.19.
Hydrogenation of 3.19 in the presence of hydrochloric acid affords
aminoketone hydrochloride salt 3.20. Such aminoketones are oiten isolated as
the corresponding salts because. the free aminoketones are prone to
dimerisation, having both nucleophilic and electrophilic centres. (For a
common altemative preparation of aminoketones, s~e the Knorr pyrrole
synthesis, Chapter 2.) Liberation of the free base of 3.20,in the presence of
ttIe acid chloride affords amide 3.21 which is cyclised to oxazole 3.22. Ester .
hydrolysis then affords the biologicalIy-active carboxylic acid 3.23.
3.3 Synthesis of imidazoles

Although there are several ways of preparing imidazoles, there is no one
outstanding method. Qne useful synthesis is the condensation of lj. 1,~-
I
i.
t
f
I
I
f
r
tl
.~
dicarbo~yl
c0r,np.o und with arnmonium acetate and an aldehyde, as in the

preparatlon of lml(lazole 3.25.
~~
'
MeO
I~
H~
e e
"
MeO
NH4 0Ac
MeO
A reasonable rationalisation is a cyc1ocondensation type of process to give

3.24.followed by 'irreversible tautomerisation to 3.25.
3.4 Synthesis of thiazoles
.'jit'
:
;1
1i
y
f,
Retrosynthetic discoJlllection of the nitrogen-<:arbn bond in thiazole 3.26

leads fonnally to enol 3.27 which is equivalent to ketone 3.28. This can be
derived from haloketone 3.29 and thioamide 3.30.
,
, )[~
R
3.26
1;
R)(OH
~
R3
RJ
2X
R
~
~
Rl
::>
S;RJ
3.27
3.28
RXO
Rl
NH2
SAR3
3.30
X=CI,Br,I
The forward p'focess is the Hantzsch synthesis of thiazoles which, despite

its antiquity (it is around 100 years old), is still very widely used.
-HCl
Heat
(~
S
3.31
The mechanism fOf the fonnation of thiazole 3.31 involves initia!

nucleophilic attack by sulphur followed by a cyc1ocondensation.
Thiocarbonyl compounds are

much more nucleophilic than '
carbonyl compounds,because
of the lower electronegativity
of sulphur as comparad to
oxygen.
.~.
240xazbles, imidazoles, and thiazoles

ffJ
, H
yO H
"7:\
o~ N~H
Q '
HO~N
--- H~~~ ~_~ I
::)~,r ~ ~~
fcr:
S~
S
HO
\;-N
S;I
3.31
The thioamides themselves are convenientIy prepared from the corresponding '~
ainides by treatment with phosphorus (V) sulphide (see the Paal-Knort
synthesis of thiophenes, Chapter 2, for this type of conversion). A variationJ.
of the Hantzsch reaction utilises thioureas, where R3 in 3.30 is a nitrogen
and not a carbon substituent. For instance, thiourea itself is used in the ,~
preparatin of 2-aminothiazoles such as 3.32.
I
t
:rO
!i
Heat
3.32
J"
3.5 Electrophilic substitution reactions of oxazoles,

imidazoles, and thiazoles
As with pyridine, not only does
the electronegative nitrogen atom
wlthdraw electro n density from
the ring, but under the acidic
conditions of many electrophilic
reactions the azole nitrogen is
protonated. The azolium callon is
relatively inert tq further attack by
a positively charged electrophile.
The 1,3-azoles are not very reactive towards electrophilic attack due to the
deactivating effect of the pyridine-like nitro gen. However, electron-donating
groups can facilitate electrophilic attack, as in the preparation of oxazoles
3.34 and 3.35. Dimethylamino oxazole 3.33 is essentially functioning like
an enamine in this reaction.
1:
~
I
i
'i
't
1
~
ffJ
- H
N
) [ \\
NOz
S /"'--.OMe
3.35
Imidazole can be nitrated under forcing conditions, nitration remarkably

occurring on the imidazolium cation 3.7a,b, giving nitroimidazole 3.36 after
loss of two protons.
1
f
I,
j
i
1
\
Heat
3.6 Anion chemistry of oxazoles, imidazoles, and

thiazoles
The C2 position of 1,3-azoles is particularly electron-deficient because of the
e1ectron-withdrawing effect of the adja:cent heteroatorns. The acidity of the
protons at this position is such that deprotonation can be achieved with
strong bases to give nuc1eophilic carbanions 3.37 which can be quenched
with electrophiles producing substituted 1,3-azoles 3.38.
(~
X
l/N
~_;>8
n-BuU
Ea
l/N
~ _~
LiEa
X 3.37
3.38
E
Sirnilarly, aIkyl groups at the C2 positions (but not the C4 or e5 positions)

can be deprotonated giving carbanions 3.39a,b which can also be quenched
with electrophiles to afford 1,3-azoles 3.40.
[~
. [[N.Ea
I/N8 . Ea] Ea
~-BuLlp
~ ~Ll ~ ~_\..U
~ [~N~E
X
X=O,NR,S
X~
3.39a
3.39b
3.40
Sorne examples of both the aboye types of reactivity are given below
[~
N
1. n-BuLi
CPh3
(~
S
Ph
;rN
Ph
O~
1. n-BuLi
~
2.CH3CHO
3.HO/H2O
1. n-BuU
2.P~CO
r.~
OH
Ph
;rN
~
Ph
OH
~ ~Ph
O
Ph
3.HO/H2O
[~
N
Me
(~
S
1. n-BuLi
2.PhCHO ~
3.HO/H2O
1. n-BuLi
2.MeI
\lO
f.V
. l:'f
Me
't.~
RO~8
08
RO~
~~O
2M"lNCHO
There is a useful analogy

between resonance-stabilised
anion 3.39a,b and an ester
enolate anion. Note that in both
cases the negative charge can be
delocalised onto a heteroatom.
Ph
260xazoles, imidazoles, and thiazoles
3.7 Nucleophilic aromatic substitution of oxazoles,

imidazoles, and thiazoles
We have previously discussed the redl,lced reactivity to electrophiles of :I~

oxazole, imidazole, and thiazole, as compared to furan, pyrrole, and .'
thiophene, which results from the presence of the pyridine-like nitrogen
atom. This behaviour is paralleled by increased reactivity to nucleophiles. _
Nuc1eophilic attack on furan, pyrrole, and thiophene derivatives only occurs !j
when an additional activating group is present, as in the displacement
.reaction giving thiophene 3 . 4 1 ' i !
j,'.,,".'
1
-;
- HBr
3.41
Once again this reactivity parallels

certain features of carbonyl
chemistry. Compare the reaclion of
aniline with chloroformates, below.
(o
The nitro group plays a key role as an electron-acceptor in this reaction, t

which a1so illustrates the fact that imidazole is a good nucleophile. However, f
no activation is necessary with 2-halo-l,3-azoles, which can react with
nucleophiles, as shown by the preparations of 3.42 and 3.43.
Ph
Ro~Q
H 2NPh
RO~NPh
H
It
Ph
e)
Ph
Ph
)[~
~ Ph )[)<~
=-L Ph )[~
o
o NHPh
o NHPh
~Cl
3.42
[~ ~ (~~ L
S
eOMe
'1
H2NPh
s~Br
I
t
OMe
<
3.8 Problems
1. Suggest a synthesis of oxazole 3.33.
3.33
2. A less general synthesis of oxazoles is the condensation of bromoketones

with amides. What is the mechanism for the formation of oxazole 3.44? How
does 3.44 relate to the oxazole which might be prepared from the same
bromoketone by conversion to the corresponding aminoketone, Nformylation, and cyclocondensation?
o
Ph
Ph~
Br
Heat
1[,
O
3.44

3. Carboxylic acid 3.46 has been extensively used in the preparation of
semi-synthetic penicillins and cephalosporins. Devise a synthesis of 3.46
from es ter 3.45.
COzEt
MeO'N~O
3A5
3.9 References
Campbell, M.M. (1979). In Heterocyclic chemistry (ed. p.a. Sammes)
Ollis), p. 962 (oxazoles) and p. 967 (thiazoles). Pergamon Press, Oxford.
Furniss, B.S., Hannaford, A.J., Smith, P.W.G., and Tatc~ell, A.R. (1989).
Vogel's textbook oi practical organic chemistry (5th edn), p.1153
(preparation of aminothiazole 3.32). Longman, Harlow.
Grirnmett, M.R. (1970). Adv. heterocyelic chem., 12, 103 (imidazoles).
Grimmett, M.R. (1979). In Heterocyclic chemistry (ed. p.a. Sammes)
(Vol. 4 of Comprehensive organic chemistry, ed. D.Barton and W.D.
Ollis), p.357 (imidazoles). Pergamon Press, Oxford.
Grirnmett, M.R. (1980). Adv. heterocyclic chem., 27, 241 (imidazoles).
Lakhan, R. and Ternai, B. (1974). Adv. heterocyclic chem., 17, 99
(oxazoles).
Metzger, J.V. (1979). In Thiazole and its derivatives (The chemistry oi
heterocyclic compounds red. A. Weissburger and E.C. Taylor], Vol. 34).
Wiley Interscience, New York.
Turchi, !.J. (1986). In Oxazoles (The chemistry oi heterocyclic compounds
red. A. Weissburger and E.C. Taylor], Vol. 45). Wiley Interscience, New
York.
Turchi, I.J. and Dewar, M.J.S. (1975). Chem. rev. ,7S, 389 (oxazoles).
'iffW
ffF. --
w"'nm:wm-gm
775 G7
4. Isoxazoles, pyrazoles, and

isothiazoles
Isoxazole 4.1, pyrazole 4.2, and isothiazole 4.3 are the parent struetures of
the 1,2-azole family of heterocycIes, having a nitrogen atom plus one other
heteroatom in a 1,2-relationship in a five-membered ringo
4
5eN 2
o
"',
5C:('l2
NI
4.1
4.2
4.3
The aromatie sextet is eompleted by deloealisation of the lone pair from the
seeond heteroatom, 4.4a-e. Consequently, as in pyridine, the nitrogen atoms',
of the 1,2-azoles have a lone pair available for protonation. However the 1,2- I
azoles are signifieantly less basic than the 1,3-azoles because of the electronwithdrawing effeet of the adjaeent heteroatom. Isoxazole and isothiazole are.
essentially non-basie heteroeycles (pKas <O), and even pyrazole (pKa=2.5) is f
a much weaker base than the corresponding 1,3-azole imidazole (pKa=7).
f
i
ICN
x~
ICJ
x
ES
4.4a
4.4b
e
~
eN
x
4~Je
x
ES
4.4c
eeN
x~
ES
ES
4.4d
4.4e
".
X=O,NH,S
As with substituted imidazoles, substituted pyrazoles may exist as a

mixture of tautomers. 5-Methyl pyrazole 4.5 and 3-methyI pyrazole 4.6 exist
as a rapidly equilibrating mixture in soIution.
4
3~NHl
~'N)
2
4.6
Although there are a few examples of naturally-oceurring 1,2-azoles, many

totally synthetie derivatives have found pharmaeeutieal application.
lI
1.
1
.~I
I: R):;)
d:
4.1 Synthesis
~
;;
f isoxazoles and pyrazoles
. Retrosynthetic disconnection of generalised 1,2-azole 4.7 gives initially 4.8

which wold exist as ketone 4.9. This in turn is clearly derived from 1,3-
"fj
tone
:~10. ~
Rz
Rl
R3
l:!:N
OH
~
~
Rl
O N,XH
Rl
X=O,NH,S
This ana1ysis suggests that condensation of 4.10 with hydroxylamine 4.11,

hydrazine 4.12, or thiohydroxylamine 4.13 should give tbe corresponding
1,2-azole. This approacl represents an important route to isoxazoles and
pyrazoles, but thiohydroxylamine 4.13, although known, is far too unstable
for synthetic purposes. The synthesis of isotbiazoles will be mentioned latero
The mechanism of the forward process is illustrated by the preparation of
isoxazole 4.14 and is simply two consecutive condensations.
He
O
O)
GH
~--.~
HzN-OH
~r-(
~~r-.
O
OH
4.11
H2NOH
4.12
4.13
HzNNHz
HzNSH
4.10
4.9
4.8
4.7
r;
R
R3
In practice hydr'xylamine and

hydrazine are very reactive
nucleophiles, far more so than
might be expected from
conslderation of simple physical
parameters. The inceased
nucleophilicity of a heteroalom
when bonded to a second
hereoatom is ~no"Vn as the a
effect. For a theoretical
rationalislion of the a effeet in
terms of frontier obitals see
Fleming, 1976.
~
O
4.14
Note tbat ifhydroxylarnine or a substituted hydrazine is condensed with an

unsymmetricaI diketone (4.10, where RI and R3 are different) tben a
regioisomeric mixture of isoxazoles or. pyrazoles may result. However a
single regioisomer may predominate where there is an inherent bias.
O
Jl~Jl'R
HzNOH
3
Rz
+
For instance, the preparation of isoxazole 4.17 is virtualIy regiospecific
because the reaction cornmences with tbe more nucIeophilic heteroatom (i.e.
nitrogen) attacking tbe more electrophilic ketone (activated by tbe electronwitbdrawing inductive effect of the adjacent ester group). The reader is
encouraged to consider tbe regiochemical bias in the preparation of isoxazole
4.15 and pyrazole 4.16.
The general reactions of H2NOH

and H2NNHR with unsymmetrical
diketones are shown here.
30 Isoxazoles, pyrazoles, and isothiazoles
o
~
MeO
MeO
4.15
HO,
O
N
~C02Et
4.17
The other important isoxazole synthesis involves the concerted [3+2]

cycloaddition reaction of nitrile oxides 4.18 with either alkynes 4.19 or
alkyne equivalents 4.20.
<""
4.19
Rz
\1\
R3
R2
R3
~W) - + )J
Rl'--
eO
4.18
Rl
X=OAc,NM~,N02
A wide range of nitrile oxides is known (R3 = H, aryl, alkyI, es ter, halide,
etc). The method of choice for the preparation of simple nitrile oxides (R3 =
alkyI, aryl) is oxidation of the corresponding oxime:
(-2H)
4.18
Several oxidising agents can be used (lead tetraacetate, N~

bromosuccinimide, chlorine, etc). A mechanism 'is illustrated 1:elow for
alkaline sodium hypochlorite.
t;t
fa''H
N~
N~ reOH
Y..~--+
R,
~H
Cl-OH
R3
---...
Cl
4.18
Let us now consider the synthesis of isoxazole 4.28, a drug for the
treatment of bronchial asthma. The most direct preparation of isoxazolyl
ketone 4.24 is the cycloaddition of unstable bromonitrile oxide 4.22
(prepared in situ by dehydrobromination of 4.21) with acetylenic ketone 4.23.
Observe the regioselectivity of this reaction. Both electron~donating and
electron~withdrawing groups on the acetylenic components in such
cycloadditions tend to occur at the es position in the final isoxazole and not
at C4. Bromination of ketone 4.24 affords bromoketone 4.25 which is
Br
,1,
N$
o
=--4.~
4.23
Br~
NI \
---...
, 'o
4.21
4.24
Br
~n
"o?)rBr
4.25
4.22
NaBHI
Br
Br
H2N-t-Bu
"O~NH-t-Bu
~'o~
OH
Br
N'O~Br,
4.28
OH
4.27
4.26
reduced with sodium borohydride to give bromohydrin 4.26. Treatment with a

strong base produces epoxide 4.27 :via the intermediate alkoxide, and
nucleophilic opening of this epoxide a,t the least sterically hindered position
affords the target drug 4.28.
4.2 Synthesis 01 isothiazoles

Isothiazoles are usually prepared by routes involving formation of the
nitrogen-sulphur bond in the cyclisation step. This is often set up by
oxidation of the ,sulphur atom, as in the conversion of thioamide 4.29 to
isothiazole 4.30. '
J-l
N:)\'NH
4.30
2
il
1
'J
l
]
.J
~N'H
w" '-...A
C;
-HCl
f,
r'},
1'/ / '
/'
4.3 Electrophilic substitution of isoxazoles,

pyrazoles, and isothiazoles
'
The presence of a pyridine-like nitro gen in the 1,2-azoles makes fuem

markedly less' reactive towards electrophilic substitution than foran, pyrrole,
and thiophene. (The same effect was noted for the 1,3-azoles in Chapter 3.)
Nevertheless, electrophilic substitution is known in 1,2-azoles, occurring
principally at the C4 position. This selectivity is reminiscent of pyridine
chemistry where the position meta to the electronegative nitrogen atom is
the 'least deactivated' (see Chapter 5).
~
Br-Br
Br
Br
H~
,~nN
.tO)
In
(C;
~~N
~EB
~Br
Br
Y;N
Br
N:~~" Hi ;k
Nitration
,ulphonotion
unde, vigorou, condi:ori, are
also knoVin, as in the preparation of 4-nitro~~azole 4.31.
N02
t~
N
H
3.36
See the related preparation of

nitroimidazole 3.36.
nN__ ~N
O,
HN03
---.....
N
H
ES
... N'H
NO~' H~ ES
~~"-H
--
,~
I
'$
it
1]
Iil'
-H" ~No
Of1,20.:':
an:
_2HES
--
Ij
hI(~;N 4~1 1I
As we have seen with other electron-deficient heterocycles, the

introduction of an electrn-donating group promotes electrophilic
substitution, as in the facile bromination of aminoisothiazole 4.32.
~
'I"'~"
"
Br-Br
~rl
Ph
NH~S;t.T
Br
Br2
-~. . . .
Ph
f.:N
",HJ-(
H2
Br
_He
..
Ph
'j
"I(j
NH;<S~'N
4.32
4.4 Anion chemistry of isoxazoles, pyrazoles, and

isothiazoles
'
Isothiazoles and nitrogen-blocked pyrazoies can be deprotonated at the e5
position with a1kyl lithium reagents, and the resultant carbanions quenched
with a wide range of electrophiles, as in the preparation of 4.3~ and 4.34.,
I
~
;!l
0s .\.N
n-BuLi
---JI>~
Li
EB e
~n
EtO~S .... N
o
ee
n-BuLi.. Li EB
<!.._ ... N
0\s'"
N
Ph
..
MeI
4.33
P~
This useful methodology (complementary to the C4 ,selectivity of nonnal

electrophilic substitution) is not applicable to isoxazole chemistry because
the intennediate anions (such as 4.35) are rather unstable and decompose via
oxygen-nitrogen c1eavage.
0\
Ph
Ph
Ph
n-BuLi
Ph
LiEB C"efi'
(;N
!lO
o'"
4.35
lfowever, alkyl groups at the C5 position of isoxazoles can be deprotonated

and reacted with electrophi1es.
r1
~~;N
O
n-BuLi!lO
EB
Li
r1
e~_;N
Note the anafogy to the anions

derived from erotonate esters.
OR
Dimethyl isoxazole 4.14 can be selectively deprotonated at the C5 methyl

group, nearer the more electronegative oxygen atom. Although simple
deprotonation cannot afford an entry into C4 substitution in this system, it is
possible to generate a carbanion at the C4 position in a roundabout fashion.
Bromination of 4.14 affords the C4-functionalised isoxazole 4.36. Metalhalo gen exchange With n-butyIlithium at low temperature (-78C) generates
carbanion 4.37 which can be quenched with electrophiles to give isoxazoles
such as 4.38.
.
n-Bu~~~r
Br2
4.14
c;.1j ...\N
o
Li
n-BuLi
!lO
~'I
IN
\
4.36
t
J:)e
2.HCl
4.37
4.38
~e
~
N
4.5 Problems
Me
n-BuLi
1. What is the mechanism for the fonnation of isothiazolone 4.39?
eEB
N:::C-S
EtOH/H20
..
J.,
~
"
'):)-78
oC
~ \N
rf
(S . . N
NH
4.39
OR
Interestingly, 1, 3, 5-trimethyl
pyrazole is deprotonated on the
N-methyl group, faeilitating
reaetion with eleetrophiles at this
position.
.
EB
o'" .
eJ:S
o. efi
N'"
MeI/
;1
~
N
Et
I e
CHi

2. What general strategy might be employed to convert pyrazole to alcohol
4.40, a potent inhibitor of steroid biosynthesis.
steps
------~
HO
Ar
Ar::
~N ... N
Ar=
4.40
Vel
3. What is the product resulting from oxidation of 4.41?
HO'N~of
/
NaOCl ..
NaOH
'"
4.41
4. A synthesis of 2-cyanocyc1ohexanone 4.45 from cyclohexanone is shown

below. Fonnylation of cyclo/;Iexanone produces a mixture of keto/enol
tautomers 4.42 and 4.43, the equilibrium lying to the side of the enoI 4.42.
Treatment with hydroxylamine affords isoxazole 4.44, and base-inducd
fragmentation of the isoxazole rlng affords 4.45. Explain the regioselectivity
of the isoxazole formation, and the mechanism of the fragmentation process.
ex>
4.43
NHZOH..
~N
4.44
l.NaOMe
lO
CX~
4.45
4.6 References
Campbell, M.M. (1979). In H~terocyclic chemistry (ed. P.G. Sarnmes)
(Vol. 4 of Comprehensive organic chemistry. ed. D. Barton and W.D.
OIlis), p.993 (isoxazoles) and p.lO09 (isothiazoles) . .Pergamon Press,
Oxford.
Fleming, I. (1976). Frontier orbitals and organic chemical reactions,
p.77. Wiley, Chichester.
Fumiss, B.S., Hannaford, A.J., Smith, P.W.G., and TatcheIl, A.R.
(1989). In Vogel's textbook 01 practical organic chemistry (5th edn),
p.1149 (preparation of 3,5-dimethylpyrazole). Longman, Harlow.
Grimmett, M.R. (1979). In Heterocyclic chemistry (ed. P.G. Sammes)
Ollis), p.357 (pyrazoles). Pergamon Press, Oxford.
Kochetkov, N.K. and Sokolov, S.D. (1963). Adv. heterocyclic chem., 2,
365 (isoxazoles).
Kost, A.N. and Grandberg, I.I. (1966). Adv. heterocyclic chem., 6, 347
(pyrazoles).
SIack, R. and Wooldrige, K.R.H. (1965). Adv. hterocyclic chem., 4, 107 t
(isothiazoles).
"
Wakefield, B.J. and Wright, D.J. (1979). Adv. heterocyclic chem., 25, $,
147 (isoxazoles).
.~
5. Pyridines
5.1 Introduction
!:.
f
~
'1
;\
,1
,1
[
!
.l
pyridine 5.1 is a polar liquid (b.p. 115C) which is miscible with both
organic solvents and water. lt can formally be derived from benzene by
replacement of a eH group by a nitrogen atom. Pyridine is a highly aromatic
heterocyc1e, but the effect of the heteroatom makes its chemistry quite
distinct from that of benzene. The aromatic sextet of six 1t electrons is
complete without invoking participation of the lone pair on the nitro gen.
This is in ~irect contrast with the situation in pyrrole (Chapter 2) where the
aromatic sextet ineludes the lone pair on the nitrogen. Hence the lone pair of
pyridine is available for bonding without disturbing the aromaticity of the
ringo Pyridine is moderately basic (pKa=5.2) and can be quatemised with
alkylating agents to form pyridinium salts 5.2. Pyridine also forms
complexes with Lewis acids such as sulphur trioxide. This complex 5.3 is a
mild source of sulphur trioxide for sulphonation reactions (see Chapter 2).
o
EaN
I
Ea
O
N
~ S03
R-X
..
O
eN
x6
5.2
"
'!
so?
.(
Ea,
5.3
The effect of the heteroatom is to make the pyridine ring very unreactive
to normal electrophilic aromatic substitution. Conversely, pyridines are
susceptible to nuc1eophilic attack. These topics are discussed latero
;1
1
')
:1
,1
:!,
"
5.2 Synthesis of pyridines

Our retrosynthetic analysis of generalised pyridine 5.4 cornmences with an
adjustment of the oxidation level to produce dihydropyridine S.S. This
molecule can now be disconnected very readily. Cleavage of the carbonheteroatom bonds in the usual way leaves dienol 5.6 which ex~sts as diketone
5.7. The 1,5-dicarbonyl relationship can be derived from a Michael reaction
of ketone 5.8 and enone 5.9, which in tum can arise from condensation of
aldehyde 5.10 and ketone 5.11.
36 Pyridines
R3
R3
J6:~
I /.
Rl
:;>
'DR.
I
Rl
Rs
5.4
R\ O~H'~O
+
N
H
:;>
-NH3
Rs
5.5
rr.
Rl
OH OH Rs
R3
"'{'~
Rl
5.11
O
5.9
JI
R3
Rl
5.6
[R4
O
Rs
5.8
TI I
Rl.O
O R,
5.7
These processes are facilitated when RZ and R4 are e1ectron-withdrawing

groups such as esters. Furthermore, when ketones 5.11 and 5.8 are the same, ]
syn th'
ti
we have the basis for the classical Hantzsch pyridme
eSls'1
O
O
~
C02Et
~H: ~ EtO
t2
~3
)el
I I
N
OEt HN03
(-2H)
~ EtO
tr~
I ~
i
OEt
H
5.12
5.13
For instance, condensation of ethyl acetoacetate, formaldehyde, and

arnmonia gives dihydropyridine 5.12 which is readily oxidised with nitric acid
to give pyridine 5.13. Although the precise details of this multicomponent
condensation are not known, a reasonable pathway is shown below.
11
I
1-
!~
'I!
ffiO~O
I
~
Note that in this example R2 and

R4 are ethyl esters, so the
adjacent carbon is actually an
active methylene group. The
higher acidity and hence
nucleophilicity of these centres
facilitates the reaction sequence.
!I
t
.!i
i
o
EtO~OEt
~MJl.
N
H
5.12
II!
i
i'l

Sorne examples of dihydropyridines prepared in this way are shown below.
(The student is encouraged to work out the aIdehydes used in each s::ase.)
N~N
o H Ph o
EtoVfoEt
AMJl
OMe
MeO
N _.'
H
PrO
OPr
~
H
As well as being intennediates for the synthesis of pyridines, these . A consequence of the asymmetry
dihydropyridines are themselves an important cIass of heterocycles. For of 5.14 is that C4 is a stereogenic
centre. Hence the product is formed
instance, dihydropyridine 5.14 is a drug for lowering blood pressure. In the as a racemic mixture.
synthesis of 5.14 note that~arrying out the Hantzsch synthesis stepwise
allows for the preparation of anunsyinmetricaI dihydropyridine, having both
a methYfai:i.d an ethyl estero
-.
O
S? :?'oo
OMe
Heat
5.14
5.3 Electrophilic substitution of pyridines

Pyridine is virtualIy inert to aromatic electrophilic substitution. Consider
nitration of pyridine by nitric acid. First, as pyridine is a moderate base, it
will be almost completely protonated by the acid, making it much less
susceptible to electrophilic attack. Second, addition of the electrophile to the
small amount of unprotonated pyridine present in solution is not a facile
process.
Attack of the electrophile at the C2 or C4 position results in an
intennediate cation with partial positive charge on the electronegative
nitrogen atom. This is cIearly not energeticaIly favourable when compared to
C3 substitution, where no partaI positive charge resides on nitrogen. In faet
the produet of C3 substitution, nitropyridine 5.15, can be isolated from the
'el{.llustiveni~tion ofpyridine, but onlyin poor yeld.
11
il ,
38 Pyridines
Q N 02
N
a~
=-N
e~QN02
N H
ES
C2-attack
N02
C3-attack
mO~
N02
N02
OH
/-
N02
lJ
=--N
l.
d~
C4-attack
ES
C-alkylation of a stericallyhindered phenolate anion.
Pyridine can be activated to electrophilic substitution by conversion to

pyridine N -oxide 5.17. At frrst sight it is curious to consider oxidation (Le.
electron loss) as a means of activating a system to electrophilic substitution,
but 5.17 can act rather like a sterically-hindered phenolate anion towards
electrophiles, producing intermediate 5.18 which then loses a proton to
give substituted N-oxide 5.19. For this methodology to be useful it is of.
course necessary to remove the activating oxygen atom. Tbis can be done
with phosphorus trichloride, which becomes oxidised to phosphorus
oxychloride.
..
[O]
O
o'e
5.17
lO
e~
C1
~ ~5.18
_He
lO
6~
N
,et'"")
oe
PC13
Oe
6
r.,Na;
'fe
O-PC13
,
Na;
5.19
5.17
. Na;
E
-P0Cl3
lO
6
N
5.19
For instance, 4-nitropyridine 5.20 can be prepared from pyridine in three

steps by this methodology.
HO
AcOH
Jo
lIN03
H 2S04
Ne
oe
$.17
Jo
6,
PCl3
...
Ne
;
N
oe
5.20 .
Pyridine N-oxides can also be converted into synthetically useful 2chloropyridines 5.21 (see later).
R
0-6
Ne
e - , (;'
p/
1'\
Cl/
el
el ........",
Another approach to electrophilic substitution involves the chemistry of

2-pyridone 5.22 and 4-pyridone 5.23. These are the tautomeric forms of 2and 4-hydroxypyridine respectively. They exist exc1usively in the pyridone
.fomi, the hydrogen atom being attached to the nitrogen atom, not the
oxygen. Their electronic structures are not adequately described by a single
valence representation, the lone pair from the nitrogen atom being delocalised
to a considerable extent onto the oxygen atom, as in mesomeric
representations 5.22a and 5.23a.
OH
I ..:
U
N
Clo
H
el
OH
N
H 5.22
uJ
,e
oe
H 5.22a
6
N
~
~
H 5.23
oe
[9
]
,
Ne
5.23a H
Both pyridones can react with electrophiles at positions ortho and para to
the activating oxygen atom. For instance, 4-pyridone reacts with
electrophiles at the C3 position (the mechanism can be formulated from
either mesomeric representation) to give intermediate 5.24. As with pyridine
N-oxides, reaction with phosphorus oxychIoride gives useful
chIoropyridines 5.25. We shall see the utJJity of 2- and 4-chIoropyridines in
the next section.
40 Pyridines
o
~JC!'
~1'Cl
o
E
5.24
N~
I
ED
Cl
.~
\-Cl
11
Cl
O-P,.... Cl
Cl~Cl
~
.;.o:
EaN~
5.25
5.4 Nucleophilic substitution of pyridines

Pyridine can be attacked by nucleophiles at the C2/C6 and C4 positions In a
manner analogous to the addition of nucleophiles to a carbonyl g'roup in a
1,20r 1,4 fashion. Attackat the C3/C5 positions is not favoured because the
negative charge on the intermediate cannot be delocalised onto the
electronegative nitrogen atom.
The actual mechanism is rather

complicated. Hydrogen gas is
evolved, but in reality free sodium
hydride is never generated. See
McGiII and Rappa (1988).
Under conditions of high temperatures the intermediate anion can rearomatise by 10ss of a hydride ion, even though it is a very poor leaving
group. This is illustrated by the Chichibabin reaction of pyridine and
sdamide to produce 2-aminopyridine 5.26. The immediate product of the
reaction is 5.27, the sodium salt of 5.26, as the eliminated hydride ion is
very basic. Protonation of this sodium salt during the aqueous workup then
regenerates 5.26. A simplistic rationale is shown below.
- NaH
N/.
5.26
NH2
Aq. workup
Qe
N
5.27
Ea
NH Na

These nucleophilic substitution reactions are much more facile when better
leaving groups (e.g. halide ions instead of hydride ions) are employed.
U
~J9
-ele
Do
'd:}x
(9
-ele
~-'
...
6:rt
x = NucIeophile
Nilcleophilic substitutions are widely used in pyridine chemistry. Sorne

examples are shown below.
~N~
el
~ NH3~~'
N
el
NH
2
HN(CH2eHeHV2
U
N
CI
~
N
N-NH2
H
6
6
SEt
me
Na SEt
..
el
~
N
NMe
H
el
~
N~
H 2NPh
OMe
6
N
l'
HNPh
HN~NH2
el
me
u N a 0M;
6
6
N
el
H2NMe ..
el
~H2NNH2 ..
Do
H2NNH2
Do
6
N
FinaIIy, before leaving this section, we shaIl consider the synthesis of

pyridotriazine 5.32, a potentiaI anti-fungaI drug. This synthesis ilIustrates
features of both electrophilic and nucleophilic pyridine chemistry.
Nitration of 4-pyridone 5.23 gives 5.28, and reaction with phosphorus
oxychloride affords chloropyridine 5.29. This pyridone-chloropyridine
conversion activates the system to nucleophilic attack by hydrazine, affording
5.30. The nitro group also facilitates nucleophilic attack by delocalisation of
negative charge in the intermediate.
.1
1'
42 Pyridines
5.29
N-AcyIation, reduction of nitro toamino, and condensation produce

dihydrotriazine 5.31. This system is readiIy dehydrogenated with manganese
dioxide to afford the fully aromatic heterocycle 5.32. Note how re1ativeIy
simple chemistry can be used to fonn a quite complex heterocycIe.
6 a a
o
N
H
5.28
N
H
5.23
e
HW NH2
el
N02
poel3
..
N02
H2NNH2 .~
__
~N02
N/.
tJ
N
5.29
5.30
(j'F
~
o
~F
H
HN ...
N~
&~02
I
/.
H!Pd/C
2
H
HN ... N
...
,.
~~2
Heat (-H20)
t.J
N
5.32
5.5 Anion chemistry of pyridines

We earlier drew a parallel between nucleophilic attack on the C2/C6 and C4
positions of pyridine and 1,2 and 1,4 addition of nucleophiles to a carbonyI
group. This analogy can be extended to deprotonation of aIkyl substituents at
the C2/C6 and C4 positions.
Cl~
N
e
(:l
e
o~e
R
~
o~
O O
~
)
eO
Just as a carbonyl group stabilises an adjacent negative charge as an

enoIate anion, so the anion derived from 2-methyl pyridine is stabilised by
delocalisation of the negative charge onto the eIectronegative nitrogen atom.
.1

A similar argument holds for 4-methyl pyridine. These stabilised anions can
then react with the usual range of e1ectrophiles.
Cl
NaNH2
..
Cl
Cl
lO
Cl
Me!
PhLi
lO
PhCH2Cl ..
N~
Li
Cl
Cl
_PhL_i_....
I N~
~
N
Na ffi
I /.
~
N
l.C02
..
2.HCl
Ov
I N'~~
Ll ffi
:f:l
.. I
N./.
l.H
'Coe
2
I ffi
n-BuLi
Ph
ffi
I
~~
..
OH
2.HCl
/.
Li
Na~ffi
e
Me!
-'
I ;;::.'
- - - - - ,..
./.
N
5.33
DialkyI pyridine 5.33 is selectively deprotonated at the C4 alkyl group,

illustrating the greater acidity of this position over the C3 position. With
regard to ring deprotonation, however, there are relatively few examples
knQwn for simple pyridines, in contrast to the extensive chernistry developed
for the five-membered ring heterocycles. This is because the resultant
organometallic species are good nucleophiles, and because pyridines are also
moderate electrophiles, polymerisation problems are ofien encountered. More
success has been achieved with substituted pyridines having an ortho
activating substituent (e.g. -CONHR, -NHCOR, -OMe,
-CH2NR2 etc). These substituents increase the rate of kinetic deprotonation
and stabilise the intermediate organolithium species by coordination.
For instance, 4-aminopyridine 5.34 can be converted to amide 5.35 which,
on treatment with two equivalents of butyI lithiurn, gives organornetallic
species 5.36. Formylation of the more reactive anion (the carbanion) then reprotonation of the arnide anion gives 5.37. Acidic hydrolysis rernoves the
activating group to release pyridine aldehyde 5.38.
The negative charge resulting

from deprotonation of Ihe ethyl
methylene group of 5.33 cannol
be delocalised onto the nitrogen
atom.
44 Pyridines
The metalation proceeds by initial
deprotonation of the amide
followed by ortho-directed
deprotonation at Ihe C3 position lo
produce the pseudo sixmembered ring organolithium
species 5.36.
j::~
HNi:
t-BuCOCI
!lo
6
N
5.34
----:-.....
n-BuLl
( 2 equivalents )
5.35
NH2
N
5.38
/,
Ea
Ll
5.36
;;!:~l X
C(H
6e"'~ie
I
HN
&H
.. HCI (conc.)
Heat
N
5.37
5.6 Problems
l. What is the rnechanisrn of this reaction?
~oo,m
NaOEt/EtOH
C02Et
Hint. Start by acetylatlng the
pyridine lo give a qualernary
cationic species. How can
deprolonation aftord a
nucleophilic enamine-like system?
2. The condensation of active rnethyI groups with aldehydes can be catalysed

with acetic anhydride as weIl as base. Suggest a possible rnechanism.
Ph
.N
PhCHO
A~O/AcOH
3. Rationalise the formation of Iactone 5.40 from pyridyl amide 5.39.

OMe
OMe
~M..
5.39
1. 2 eq. n-BuLl
2. p-MeOC6H 4CHO
..
O
5.40
4. Sorne pyridine N-oxides are not just synthetic intermediates, but are of
interest in their own right. For instance, pyridine N-oxide 5.41 is a new drug

i1
I
~
claimed to be useful for the treatment of senile dementia. What are the
mechanisms of the pyridone-forming step and the final displacement?
C1
~OE<
soa,.
~CN
5.7 References
Abramovitch, R.A. (1974). In Pyridine and its derivatives (The chemistry
01 heterocyclic compounds red. A. Weissburger and E.C. Taylor], Vol.
14, Supplement Parts 1 - 4). Wiley Interscience, New York.
Eisner, V. and Kuthum, J. (1972). Chem. rev., 72, 1 (dihydropyridines).
Fumiss, B.S., Hannaford, A.J., Smith, P.W.G., and Tatchell, A.R. (1989).
(preparation ofpyridine 5.13). Longman, Harlow.
K1insberg, E. (1974). In Pyridine and its derivatives (The chemistry 01
heterocyc/ic compounds red. A. Weissburger and E.C. Taylor], Vol. 14,
Parts 1-4). Wiley Interscience, New York.
McGill, C.K. and Rappa, A. (1988). Adv. heterocyc/ic chem., 44, 3.
Smith, D.M. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol.
40f Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis), p.3.
1'
i
1.
6. Quinolines and isoquinolines
6.1 Introduction
Quinoline and isoquinoline can
also be viewed as being formally
derived from naphthalene
Quinoline 6.1 and isoquinoline 6.2 are two isomeric heterocycIic systems,
which can be envisaged as being constructed from the fusion of a benzene
ring at the C2/C3 aild C3/C4 positions of pyridine respectively. They are
both ten 1t-electron aromatiq heterocycIes. Like pyridine, they are moderately
basic (pK a quinoline 4.9, pKa isoquinoline 5.1). Indeed quinoline is
sometimes used as a high boiling-point (237C) basic solvent.
6~3
7VN~2
8
NI
6.1
Note the numbering system for

isoquinoline
As with pyridine, the nitro gen atoms of quinoline and isoquinoline each
bear a lone pair of electrons not involved in aromatic bonding which can be
protonated, aIkylated, or complexed to Lewis acids. This chapter should be
read in conjunction with the chapter on pyridines as several points discussed
at length there are also relevant to the chemistry of quinoline ahd
isoquinoline.
6.2 Synthsis 01 quinolines and isoquinolines

The classical Skraup synthesis of quinolines is exemplified by the reaction of
aniline 6.3 with gIycerol 6.4 under acidic/oxidative conditions to produce
quinoline 6.1.
HO~OH
el
:::::...
6.3
OH
NH2
PhN02
H;rS4
Heat
6.4
JI>
O)
: : :. . I
N/.
6.1
At first sight this reaction appears to be another one of those ancient

heterocyclic syntheses that owe more to alcherny than to logic, but in fact
the processes involved are relatively straightforward.
Aromatc heterocyclic chemstry 47
H H
HO~OH
e
HO~OH
OH
6.4
H
0N-
-:820
6.5
(lf
~~~He
6.7
6.6
Protonation of glycerol 6.4 catalyses dehydration va secondary carbonium

ion 6.5 to give enol 6.6. Acid catalysed elimination of a second water
molecule affords acrolein 6.7. Thus glycerol acts essentially as a protected
fonu of acrolein, slowly releasing this unstable a,p-unsaturated aldehyde into
the reaction medium. Better yields are realised with this approach than if
acrolein itself is present from the start. The reaction proceeds with a Michael
addition of aniline 6.3 to acrolein, producing saturated aldehyde 6.8 which
cyclises va an aromatic substitution reaction to alcohol 6.9. Acid-catalysed
dehydration to 6.10 then oxidation yields quinoline 6.1. Nitrobenzene can be
used as a mild oxidant, as can iodine and femc salts..
Acrolein is a highly reactive olefin

Ihat is prone lo polymerlsation.
OH
, -. : . .
(O
~ ~
-2H
~H_
UN)
(()-...:::
~'.
N
6.10
6.1
6.9
Sorne examples of the Skraup synthesis are shown below.
HO~OH
OH
~
HO~OH
OH
,90-",:
~
aMe
OMe
The key intermediates in the synthesis of isoquinolines are Parylethylamines. Por instance, acylation of p-phenylethylamine 6.11 gives
amides oi general structures 6.12 which can be cyclised with phosphorus
oxychIoride to produce dihydroisoquinoline 6.13. Better yields are obtained
1:
48 Quinolines and isoquinolines

with e1ectron-donating groups on the aromatic ring facilitating this aromatic
substitution cyclisation.
OlNH
XitQ
I
6.14
This dehydrogenation is
the reverse of a normal
hydrogenation reaetion. The
dehydrogenation cap be earried
out under mUder eonditions when
a hydrogen aeeeptor (sueh as
eyelohexene) is present.
tu;NH
O=<
Base
6.11
x = Electton-donating
8ubstituent
X
RCOQ
POQ3
O?
..-:N
6.12
-2H
6.13
As in the Skraup quinoline synthesis, 10ss of two hydrogen atoms is

necessary to reach the fully aromatic system. However, this is usuaIly
accomplished in a separate step, utilising palladium cata1ysis to give
generalised isoquinoline 6.14. This is known as the Bisch1er-Napieralski
synthesis. The mechanism probably involves conversion of amide 6.12 to
protonated imidoyI chloride 6.15 followed by electrophilic aromatic
substitution to give 6.13. (For a similar activation of an amide to an
electrophilic species see the Vilsmeier reaction, Chapter 2.)
6.13
x = Electron-donarlng
The Pietet-Spengler synthesis is
usually used when the
tetrahydroisoquinoline oxidation
level is required.
Closely related to the Bischler-NapieraIski synthesis is the PictetSpengler synthesis, which utilises aldehydes rather than acylating species.
Condensation of J3-arylethylamines with aldehydes produces imines such as
6.16 which can be cyclised with acid to give tetrahydroisoquinoline 6.17. As
with the Bischler-Napieralski synthesis, electron-donating groups (typicalIy
methoxy groups) facilitate the cyclisation step. The Iower oxidation state of
6.17 as compared to 6.13 is a direct consequence of using a carbonylgroup at
the aldehyde rather than carboxylic acid oxidation leve!. Four hydrogen atoms
have to be removed from tetrahydroisoquinolines by oxidation to produce the
fully aromatic isoquinoline.
HCl
(YIfI
o~NH
6.17
substituent
<0=0)
~ I ?O
6.16
6.3 Electroph.ilic substitution of quinollne and

isoquinoline
Quinoline and isoquinoline undergo electrophilic substitution reactions more
easily than pyridine, though not surprisingly the incoming electrophile
attacks the benzenoid ringo As with pyridine, the nitro gen atoms of quinoline
and isoquinoline are protonated under the typically acidic conditions of
nitration or sulphonation, making the heterocyclic ring resistant to attack.
The CS and C8 positions are most susceptible to electrophilic attack.
(EED
oq .[\Sq-t;q]
H
6.18a H
6.18b H
Attack of an electrophile at CS of protonated quinoline gives cation

6.18a,b which is stabilised by resonance as shown without disturbing the
aromaticity of the adjacent pyridinium ringo However, attack of an
electrophile at C6 produces cation 6.19 which does not possess the same
resonance stabilisation of cation 6.18a,b. (The student should perform the
same exercise for the C7 and C8 positions and confirm that the same
arguments can be applied.)
~
oo~
.~
6.20
6.1
Por instance, nitration of quinoline gives an equaI mixture of regioisomers

6.20 and 6.21. However, nitration of isoquinoline is reasonably selective
(10:1) for the C5 position over the C8, affording mainly 6.22.
C()
6.2
6.4 Nucleophilic substitution of quinoline and

isoquinoline
Quinoline and isoquinoline undergo nucleophilic substitution reactions, like
pyridine.
'. 50 Quinolines and isoquinolines
CO
~
..-:
l.~/Heat
2. Aq. Workup
~
~
N"-:
~ NaOEt~
~
NH
el
N"-::
6.23
O)
~
..-:N
1. KNH2 / Heat
2. Aq. Workup
09
~ I
..-:N
6.24
~,
DEt
6.25
07
~
N"-:
NaOEt
..-:N
09
~ I
C1
NH2
6.26
..-::N
DEt
For instance, both quinoline and isoquinoline ~ndergo the Chichibabin

reaction (with fonnal hydride elimination, see Chapter 5) to gtve 2aminoquinoline 6.23 and l-aminoisoquinoline 6.24 respectively. Halogen
substituents ortho to the nitrogen atoms are easily displaced, as in the
preparations of 6.25 and 6.26.
~x~C1
x=NucleophiIe
(eX
~C1--.
~~
Note that nucleophilic displacement in isoquinolines occurs more easily at

the CI position than at the C3 ppsition (even though they are both ortho to
nitrogen) because displacement at C3 involves temporary disruption of the
benzenoid ringo
6.5 Anion chemistry of quinoline and isoquinoline

Alkyl groups at the C2 and C4 positions of quinoline can be deprotonated by
strong bases. This is because (as witb pyridine) the negative charge on the
resultant carbanions can be delocalised onto the electronegative nitrogen
atom, as in carbanion 6.27a,b.
~N'~
N
e
I----1~~
......
6.27a
6.27b
Such carbanions can be alkylated, acylated, or condensed with aldehydes:
~
~
/.
(IQ
~
..-::
l.KNHz
2.EtBr
...
LKNHz
2.PhCDzEt
11=
~
~
....::
I
.
~
~
N/.
Ph

AI
(JC) "'.
7
p-MoOC",,-
This type of chemistry is also observed with 1-methyI isoquinoline 6.28.

However 3-methyI isoquinoline is much Iess activated because delocalisation
of charge in 6.29a,b involves disruption of aromaticity of the benzenoid ringo
This phenomenon is closely related to the reluctance of 3-halo isoquinolines
to undergo nucleophilic substitution.
[~
9,7
1
"'-'::
~N
::::,.,.
ex;: 1
~
"'-'::
........ ,'"
6.29a
6.28
"- Ne
6.29b
As with pyridine, activated aIkyl groups can be condensed with aldehydes

under acidic as weIl as basic conditions, as in the preparation of 6.30 and
(i.31.
PhCHO
The reader is reterred to the

previous chapter (Problem 2) tor a
mechanlstic explanation ot such
condensations.
ZnCl2 /Heat
Ph
PhCHO
AeO/Heat
6.6 Problems
1. The synthesis of the important quinolone antibiotic 6.33 is shown. The
key stages are the Gould-Jacobson quinolone synthesis to give 6.32, and the
displacement reaction to afford 6.33. What are the mechanisms of these
reactions?
O
O
EtOJVl.OEt
lL __
F:(l.
Cl
NH2
OEt
Heat
Do
~ I
C::::,.,.
6.32
N
H
NH
o
F~C02Hl.HN~
rN M,)JN
HClRN ~
6.33
Et
C0 Et
F;o:)' 2
2.HCl
~~r-----
FroC02Et
1. NaH ..
r'
2. EtI
Cl. ::::,.,.
N
Et
1. NaOH! 2. HCl
FW
O
Cl::::""
N
Et
C02H
52 Quinolines and isoquinolines

2. A synthesis of the naturaIly-occurring isoquinoline alkaloid 6.34 is shown
below. What reagents might be used to accomplish each transformation?
o
R0:(f'H
RO:::-"
Step 1
RO~~
N0
ROJ
I
---.~
I
2
RO
:::-..
Step 2
RO
. R 0 :IQ j
____
NH2 Step3 RO
~ o~NH
Step 4
HO
'?'
I
OMe
. Step 5
Step 6
HO
OH
OMe
OMe
6.7 References
Adams, R. and Sloan, A.W. (1941). Organic syntheses, Coll. Vol. 1,478
(a real blood-and-thunder preparation of quinoline).
CIaret, P.A. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol. 4
of Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis) ,
p.155 (quinolines) and p.205 (isoquinolines). Pergamon Press, Oxford.
Furniss, B.S., Hannaford, A.J., Smith, P.W.G., and Tatchell, A.R. (1989).
Vogel 's textbook oi practical organic chemistry (5th edn), p.1l85 (a
rather more safety-conscious preparation of quinoline). Longman, Harlow.
Grethe, G. (ed.) (1981). In lsoquinolines (The chemistry oi heterocyclic
compounds red. A. Weissburger and E.C. Taylor], Vol. 3, Part 1). Wiley
Interscience, New York. .
Jones, G. (1977, 1990). In Quinolines (The chemistry oi heterocyclic
compounds red. A. Weissburger and E.C. Taylor], Vol. 32, Parts 1, 2,
and 3). Wiley Interscience, New..York.
Kathawala, G.F., Coppola, G.M., and Schuster, H.F. (ed.) (1989). In
Isoquinolines (The chemistry oi heterocyclic compounds red. A.
Weissburger and E.C. Taylor], Vol. 3, Part 2). Wiley Interscience, New
York.
Manske, R.H.F. anrl Kalka, M. (1953). Organic reactions, 7, 59 (Skraup
synthesis).
.
WQa1ey, W.M. and Govindachari, T.R. (1951). Organic reactions, 6, p.151
<:Pictet-Spengler synthesis).
:1
."!':.'
'7. Indoles
7.1 Introduction
Fusion o' a ben;zene ring onto the C2/C3 positions of pyrrole formally
produces the correspondng benzopyrrole 7.1 known as ndole. An analogous
theoretical transformation can be envisaged to form benzofuran 7.2 and
benzothiophene 7.3. This chapter will concentrate exclusively on ndole, by
far the most important member of this series.
4
500
6~
N
H 1
7.3
7.2
7.1
~
~s)J
~
~o)J
1 2
Indole is a ten-1t electron aromatic system. As with pyrrole, delocalisation

of the lone pair of electrons from the nitro gen atom is necessary for
aromaticity. The single overall 'electronic structure of indole is not
completely described by structure 7.1, because this implies localisation of the
lone pair on the ntrogen atom. Mesomeric representation 7.1a makes a
contribution to the electronic structure of ndole, as to a les ser extent do
mesomeric representations where the negative charge occurs on the benzenoid
ringo
[ (Q
I
7.1
7.1a
A consequence of this delocalisation is that the lone pair is not available

for protonation under moderately acidic conditions so, like pyrrole, ndole is
another weakly basic heterocycIe. Another similarity to pyrrole is that being
an 'electron-rich' heterocycle indole easily undergoes aromatic electrophilic
substitution, and is also rather unstable to oxidative (electron-Ioss)
conditions. However, an important difference emerges here, in that whereas
pyrrole preferentially reacts with electrophiles at the C2/C5 positions, indole
substitutes selectively at the C3 position. The reasons for this will be
discussed latero
, 54 Indoles
Neurotransmitters are naturallyoeeurring substanees whieh eHeet

ehemieal eommunieation between
nerve cells by binding at specifie
sites on the cell surtace called
receptors.
HistoricaIly, interest in indo les arose with the isolation and

characterisation of members of the enonnous family of ndole alkaloids, such
as lysergic acid 7.4. Many ndole alkaloids possess nteresting and sometimes
usefuI biological activities. Although natural product chemistry is still an
active area of primarily academic research, considerably more effort is
expended nowadays n the preparation of ndole derivatives as potential
drug candidates. Following on from the observations that certain indole
aIkaloids or their semi-synthetic derivatives (e.g. lysergic acid diethylamide,
LSD 7.5) have potent central nervous system activity, it was established that
the simple indole S-hydroxytryptamine 7.6 s a major neurotransmitter.
Many ndole derivatives which mimic or block the binding of tbis
neurotransmitter to ts 'receptors have been synthesised and are beginning
to find use in the treatment of various psychological disorders.
o
z
HO~.
NH
I I
~
7.4 X=OH
7.5 X=NEtz
7.6
7.2 Synthesis of indofes

As might be expected for a large branch of heterocyclic chemistry, many
syntheses of ndoles have been developed. We shall restrct our di,scussion to
two, commencing wth the widely-used Fischer synthesis.
The Fischer synthesis is the condensation of an aryl h)'drazine with a
ketone followed by cyclisation of the resultant hydrazone under acidic
conditions to give the correspondng indole, as illustrated by the prepatation
of2-phenyl indole 7.9.
Ph~
Ph -N-NH2
H
7.7
Ph-N-N=< AcOH or~

H
Ph ZnQ2
7.8
~
~N)l.,Ph
7.9
The actual cyclisation stage is not as imponderable as it appears. The first

step is the acid~catalysed equilibration between hydrazone 7.8 and ene
hydrazine 7.10. The next step, which is irreversible, is a concerted
electrocyclic reaction, forrning a strong carbon-<:arbon bond, and breaking a
weak nitrogen-nitrogen bond. The resulting imine 7.11 immediately rearomatises by tautomerisation to aniline 7.12. Finally, acid-catalysed
elimination of arnmonia fonns indole 7.9, reminiscent of the last step of the
Knorr pyrrole synthesis (Ch~pter 2).
iC! _
e,
- _i?

H
,,(l..H
Ph-N-N~ 'H
H EIlI
Ph
7.10
~.NH2
~
~N.J.l..ph
7.9
..
~N)(Ph
H
The electrocyclic reaction is very similar to the Claisen rearrangement of

phenyI allyI ether 7.12 to give phenoI 7.13.
H
~j-CQ --
~
~'OH
7.12
Cope rearrangement
Claisen rearrangement
7.13
Sorne examples of the Fischer indole synthesis are shown below.

OMe
OMe
Ph -N-NH2
H
J')y--+ Q
O
OMe
OMe
Ph -N-NH2
H
Ph -N-NH2
H
CV)
oD
O~SPh
~SPh
VN~
::::".
p*
+ oaNM~
::::".
ft-NH2
::::".
Me0V::=CrNM~
---+~
N-NH2
H
7.15
7.14
Meo'Q
Aza-Cope rearrangement
_-.~ F~
+
oD
F~~.JV
F
H
An interesting regioselectivity question arises with the use of

unsymmetrical ketone 7.14 to prepare indole 7.15. Two ene hydrazines 7.16
R
Diaza-Cope rearrangement
56 Indo/es
and 7.17 can fonn, which would give rise to indoles 7.15 and 7.18
respectively.
SPh
Q):~I
7.7
YSPh
N"
H
NH
-----
SPh
7.16 (major )
Ph -N-NH2
(c(
N
?'
~
7.15
~
SPh'
~N~
H
7.17 (minor )
7.18
In such cases the most thennodynamically stable ene hydrazine, Le. the one
with the more highly substituted double bond, fonns preferentially. In this
particular example there is also extra stabilisation derived from conjugation
of the lone pairs of electrons on the sulphur atom with the double bond. This
regioselectivity in ene hydrazine fonnation is then reflected in the
regioselectivity of indole fonnation.
The more recent Leimgruber synthesis is illustrated by the
aminomethylenation of nitrotoluene 7.19 to give 7.20, followed by
hydrogenation to produce ndole 7.1.
lO
7.19
W
7.1 H
7.20
The combination of fonnyl pyrrolidine acetal 7.21 and nitrotoluene 7.19

produces electrophilic cation 7.22 and nuc1eophilic carbanion 7.23a,b which
react together affording enamine 7.20.
cr:
7.19
?'
~N~oe
1'"
~
7.233
X
--HeNO
N~
"
~OMe
'eOMe~
H:
~~
~N02
7.23~
('9Me
AEDo
-eN
7.21
.. ~I/(JED
-e--I.....
-OMe
7.22
UMn '-:N02
-H

Hydrogenation of enamine 7.20 reduces the nitro group giving aniline
7.24, then elimination of pyrrolidine produces indole 7.1. Note the similarity
of this ring closure step to the last step of the Fischer synthesis. In both
cases the ev.entual C2 carbon atom is forrnaIIy at the carbonyl oxidation
level, even though it occurs as either an imine (Fischer synthesis) or an
enamine (Leimgruber synthesis). Elimination of arnrnonia or pyrrolidine
respectively is analogous to a condensation process involving elimination of
water (as in the Knorr pyrrole synthesis).
~
~
NO
Pd/C
Jo
~o
~MUz
7.24
7.20
Pjrp
~N)J
Jo
NH
7.1 H
Sorne examples of the Leimgruber synthesis are shown below.
Meo'((
I
----..
?'
N0
N
H
COzEt
0=0:
<
'
Me0'(tJ
I I
OJ
----..
N02
7.3 Electrophilic substitution of indoles

As an electron-rich heterocycle, indole easily undergoes electrophilic
substitution. However whereas pyrrole reacts preferentialIy at the C2/C5
positions (see Chapter 2), ~dole reacts preferentially at the C3 position.
E(f)
W)--J>-Jo ~H
~J
~MJ
(f)N
I
O:~H
iJ:'(
E
7.25
~
~N~E
I
One explanation. is that attack at C2 results in disruption of the aromaticity

of the benzenoid ring, as in intermediate 7.25. This is therefore a high-energy
intermediate, and this reaction pathway is slower because the rust step is ratedeterrnining. AIso the C3 selectivity is in accord with the electrophile
attacking the site of highest electron density on the ringo In essence,indole
tends to react like an enamine towards electrophiles, with substitution
58 Indo/es
occurring at the C3 position, iuthough substitutfon occurs at the e2 position
when the C3 position is blocked.
'
Indole itseIf is unstable to the mineral acid conditions for nitration. The
nitration of substituted indoles is quite complex and the outcome is dependent
on the precise reaction conditions.
Like pyrrole, indole readily undergoes the Mannich reaction affording' the
aminomethyl derivative 7.26. A variety of nuc1eophiles can displace 'the
amine va an elimination foIlowed by a 1,4-addition reaction, as in the
preparation of acetate 7.27.
Pjr--p
~NMez
~N).I
HNMez
AcOH
H
7.26
7.1
This is the reactive electrophilic

species of the Mannich reaction.
CH2 =
~N;J
~OAC
~N;J
NMez
H
7.27
This is the reactive electrophilic

specles of the Vilsmeier reaction.
The Vilsmeier reaction proceeds extremely weIl with indoles giving

aldehydes such as 7.28.
)=NMez
CI
00
7.1
1. POCl3 I HCONMez
'
~H
UNj/
7.28
Aldehyde 7.28 is another useful synthetic intermediate, readily undergoing

condensation reactions with active methylene compounds such as malonic
acid and nitromethane to produce 7.29 and 7.J0.
~
~ I
:::-..
.N
H
7.30'
N02
..
~H'
UN~
7.28
Pyridine
Acylation of the C3 p9sition can also be iJccomplished w~th acid ch1orides,

as illustrated in the synthesis of indole 7'.34, a drug for the treatment of
deptession. Reaction of indole 7.31 with oxalyl chloride affords C3substitutyd product 7.32 even though the benzene ring is very electron-rich.
Converson to amide 7.33 is foIlowed by reduction with lithium aluminium
hydride which remove's both carbonyl groups, affording the target indole
7.34.

O
Cl~C1
Meo~
7
I I
~
MeO
N
H
7.31
----~~
MeO~C1
~
MeO
7.32
C~)
Ph
rNPh
MC0:JCrN~
:
MeO
N
H
7.33
7.34
7.4 Anion chemistry 01 indole
Treatment of indole (pKa 17) with strong bases such as butyI lithium,
Grignard reagents, or metal hydrides produces the corresponding indolyI
anion, which reacts with electrophiles either on nitrogen or at the C3
position. With lithium, sodium, or potassium as counterion the indolyl
anion tends to react on nitrogen, as in the preparation of 7.35. However, with
magnesium as the counterion the intermediate has an essentially covalent
rather than ionic structure, and reaction tends to occur at the C3 position, as
inthe preparation of7.36.
~.
~N)l
7.1
NaH
MeI
..
..
7.35 Me
EtMgBr!
~~
O:J) :r
,J
~
~N)J
-MgBr2
7.36
MgBr
When the nitrogen is blocked, deprotonation can occur at the C2 position,

adjacent to the electronegative heteroatom. This offers a means of introducing
electrophiles at this position, complementing the C3 selectivity shown by
classical electrophilic substitution. For instance, alcohol 7.37 can be prepared
in this way using ethylene oxide as the electrophile.
~
~N)J
7.35
Me
n -BuLi
OJe
Me
.. r0P
~N~OH
Ea 1. ~
Li
2.HC1/H20
7.37
Me
60 Indo/es
7.5 Problems
1. Devise a synthesis of the antidepressant drug 7.38.
7.38
~
~N~
~NMez
2. The synthesis of amino ester 7.41 is shown below. What is the

mechanism of the conversion of 7.39 to 7.40.
COzEt
RO
~NM~
~N)J
(RO~C02Et
~
?" I
I
N02
Heat
::-..
7.39 H
C~Et
MIz
RO
Raney nickel ~ ~
N02
~N)J
Hz
7.40
7.41
R == PhCH2
3. It was ntended to prepare imine 7.43 from ndole 7.42. by deprotonation

at the C2positon then quenching with benzontrile followed by an aqueous
workup. However, the isolated products were ketone 7.44 and sulphonamide
7.45. Account for this observaton.
7.42
~
~N)J
I
0=5=0
I
Ph
l.n-BuLi
)(:2. Ph-C::N
3. HCl H 20
7'''~Ph
H
~Ph
I
0=5=0
7.43
NH
Ph
NH
, 2
0=5::0
I
7.45
Ph
7.6 References
Brown, R.T. and Joule, J.A. (1979). In Heterocyclic' chemistry (ed. P.O.
Sammes) (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and
W.D. Ollis), p.411 (indoles and related systems). Pergamon Press,
Oxford.
.
Furniss, B.S., Hannaford, A.J., Smith, P.W.O., and Tatchell, A.R. (1989).
(preparaton of ndole 7.9). Longman, Harlow.
Houlihan, W.J. (ed.) (1972). Indo/es (The chemistry 01 heterocyclic
compounds red. A. Wessburger and E.C.Taylor], Vol. 25, Parts 1 - 3).
Wiley Interscience, New York.
Leimgruber, W. (1985). Organic syntheses, 63, 214 (ndole synthess).
Robinson, B. (1969). Chem. rev., 69, 227 (Fischer indole synthess).
Saxton, J.E. (ed.) (1979). Indo/es (The chemistry 01 heterocyclic
compounds
red. A. Wessburger and E.C. Taylor], Vol. 25, Part 4). Wiley Interscence,
New York.
Sundberg, R.J. (1970). The chemistry 01 indo/es. Academic Press,
New York.
8. Five-membered ring
heterocycles with three or tour
heteroatoms
8.1 Introduction
The broad category of five-membered ring heterocycles containing three or
four heteroatoms encompasses many heterocyclic systems. Obviously there
is considerable variation in the physical and chemical properties of such a
large group of heterocycles. For instance, with regard to aromaticity,
oxadiazole 8.3 is considered to be less aromatic than triazole 8.8 or tetrazole
Note the parallel with furan belng

less aromatic than pyrrole,
Chapter 2 ..
8.9.
N-N
4(N 3
~
"N 2
0 1
8.1
4
5
~"
f( ')
\\
... N
O
8.3
O
8.2
N 3
![s,.N\ 2
f( S ~
~~
S"
8.5
8.6
N-N
I
8.4
4 N-N 3
5
1.( ,.'N 2
NI
H
8.9
tetrazole
tN-N\\
O
"N
8.10
.oxadiazoles
.
.
oxatnazole
!C,,'N
2
NI
H
8.7
thiadiazoles
N-N
t 'N
S"
N 3
thiatriazole
8.11
Nevertheless, this collection of heterocycles does share certain characteristics.

The trend we have seen of decreasing tendency towards electrophilic
substitution on going from furan, pyrrole, and thiophene to the azoles is
continued into these series. The presence of additional'pyridine-like' nitrogen
atoms renders these systems particularly 'electron-deficient', and electrophilic
substitution is of little importance.
Conversely, nucleophilic substitution (which we have se en in earlier
chapters on 1,3-azoles and pyridines) does occur in these systems, especially
when the carbon atom concemed is between two heteroatoms, as in the
displacement reactions of oxadiazole 8.12 and tetrazole 8.13.
1.("N 2
5 I
triazoles
N"
H
8.8
62 Five-membered rings with three or tour heteroatoms

Once again note the analogy with
standard carbonyl chemistry.
2-(
)0"
o)
~R
HO
ae
HOAR
~~-(
(N-N
NaOPh
)IZ'N
el
N'
PhOe)H
~~-N
_a e
)Z ,N
"
PhO
8.13
HO
N-{
AN
HO
o'
_ele
,N
8.tl
HO
-ele
NaOH
N
H
N-N
PhO
A"
N,N
H
Another similarity with azoles is that there are examples of deprotonation

of alkyi substituents between two heteroatoms followed by quenching the
resultant carbanions with electrophiles, as in the preparation of oxadiazole
8.14.
Ph
Ph
~-(
_N_aO_Et--.....
~o'
lfA
EtO __
ES e~O'
Na
N-(
Ph
-O'
8.14
Ring deprotonation is also known with certain members of these series.

Carbanion 8.15 is stable at low temperature (-70C) and can be trapped with
electrophiles, but on wanning to roomtemperature it decomposes with rlng
fragmentation and extrusion of nitrogen. This fragmentation process is
reminiscent of the base-catalysed cleavage of isoxazoles (Chapter 4).
N-N
H
~'N
N"
n-BuU
...
N-N
UES e
Ph
ES
Li
("'N-~
e
I!..N""N
Ph~
N-N
Br2
I!.. "N
"
"
BrJ!.. N,N
N
Ph
8.15
-N2
Ph
PhNe:N
UES
8.15
For simplicity we shall now consider the synthesis of just three I1lembers
of these series, 1,2,4-oxadiazole 8.3, 1,2,3-triazole 8.7, and tetrazole 8.9.
8.2 Synthesis of 1,2,4-oxadiazoles

Disconnection of the C5-oxygen bond in 8.1'6 leads to iminoalcohol 8.17
which occurs as amide 8.18. Cleavage of the amide linkage leads to an
activated carboxylic acid 8.20 plus the heteroatom-containing amidoxime
8.19.
l~
R2
R2
N-{
;:>
R,J{ N'OH
OH
8.16
N'OH
R2
H 2N-{
N ....
OH
8.18
8.19
HN-{
~
~
R~
8.17
R2
;:>
+ R(.Jl. X
8.20
. X = Leaving group
Amidoximes can be prepared by acid-cataIysed additon ofhydroxylamine to

nitriles.
()
R2 -
C:N-H
~(9
H 2N-OH
An example of this approach to oxadiazoles is shown by the conversion of

ester 8.21 to oxadiazole 8.22, prepared as a potentiaI candidate for the
treatment of senile dementia. Simple esters are metabolically unstable in man
because of the high activity of esterases. These enzymes catalyse the
.hydrolysis of esters to carbaxy~ic acids. A cornmon tactic in drug research
when confronted with ~e problem of metabolic instability of a biologically
active ester is to replace the ester group with a small heterocycle (often
oxadiazole), to try to produce a biologically-active molecule with improved
metabolic stability. This concept o replacing fragments of a molecule by
groups with broadly similar physicochemical parameters in a systematic
manner is known as bioisosteric replacement. In this instance oxadiazole
8.22 can mimic both the physical and biological properties of 8.21, but it is
obviously not a substrate for esterases.
rSf'OMe
EtOH, heat
N
8.21
60>
N
8.22
8.3 Synthesis of 1,2,3-triazoles

These are best prepared by a 1,3-dipolar cycloaddition of an azide and an
acetylene.
H-C:C-H
.![~
8.8
N'
For instance, triazole 8.8 itself has been prepared by cycloaddition of

hydrazoic acid to acetylene.
: !)~
64 Five-membered rings with three or Jour heteroatoms

H
10
e eN
111
;NfB
8.8
?"--r N"'J
~
A1though a simple mechanisrn can bedrawn for this transfonnation, it is

only useful as a 'book-keeping exercise' to ensure that the correct structure is
drawn for the producto In reality the reaction is a concerted process and the
usual considerations of nucleophilic and electrophilic attack do not apply.
Excellent yields are achieved in these cycloadditions when electronwithdrawing groups are present on the acetylene, as in the preparation o
trizole 8.23.
..
Et02C-C= C-C02Et
Heat
8.23
8.4 Synthesis of tetrazoles

Tetrazale jtseft explades an
heating with 1055 aftwa malecules
af N2'
Tetraioles of general structure 8.24 can be prepared in a very simifar manner

to triazoles, except that ni triles are used rather than acetylenes. Once again
the reaction with azides is a concerted cycloaddition process.
No eN
~$
'-Vf"'J
111
C'1
Rl
----1.....
Heat
Rl
.,Jf..N-N\N\
8.24' .
N'
~
R2
Let us now consider the synthesis of tetrazole 8.27, an inhibitor of the

enzyrne ornithine decarboxylase, which catalyses the conversion of ornithine
8.25 to diamine 8.26.
8.27
The tetrazole moiety is an exceIlent bioisosteric replacement for a

carboxylic acid, being a small, polar, acidic hetercycIe.
N-N
1/
\\
~ ,N
N
H
)loH
N-N
/!-.'N
N'
)loe
pKa
= 5.63
pKa
= 4.76

Tetrazole 8.27 is sufficiently similar to ornithine 8.25 in its physical
properties to bind to the active site of the enzyme. However, as it obviously
cannot undergo the decarboxylation process, it acts as an inhibitor of the
enzyme.
The sy'nthesis commences. with alkylation of t}1e stabilised carbanion
derived from cyanoester 8.29 with iodide 8.28 to give adduct 8.30
H
HN
o<
~ I
8.28
8.29/
N~I ----~'"
NaH
.........
HN
CN
-<-C02Et
N-N
N
conc. HCl
N'
......1 - - - - . H
NH 2
.2HO
\\
8.27
Cycloaddition with sodium azide followed by acidification during aqueous

workup affords tetrazole 8.31.
R-C::N
HCl
N-N
// N
R~N'
H
8.31
Note that the first-formed product from the cycloaddition is actually the
sodium tetrazolate salt 8.32. Protonation affords the neutral tetrazole 8.31.
Prolonged acidic hydrolysis accomplishes several transformations: hydrolytic
removal of both the phthalimide and acetyl nitro gen protecting groups, and
hydrolysis/decarboxylation of the ester. The net result is to produce the target
tetrazole 8.27 as its dihydrochloride salt. This tetrazole-assisted
decarboxylation is mechanistical1y very similar to the decarboxylation of
malonyl half-esters 8.33.
G H,?)
RIO~O
8.33
RIO~
66 Five-membered rings with three or four heteroatoms
8.5 Problems
1. TrilzoIes and tetrazoles can be alkylated on nitrogen under basic
conditions, as in the s~thesis of the clinically-used antifungaI drug 8.35 in
which ~,2,4-triazole is alkylated by a chloromethyI ketone and an epoxide,
both go.bd alkylating agents. What is the mechanism of formation of epoxide
8.34? Of compounds 8.34 and 8.35, which is achiraI and which is racemic?
'(!l.I
0Y'el
el
bo
F::;--
Cl
~ I
Alel3
~?
~N'N~
H..
F::;--
'=N
~ I
Et3N
191F
(CH3h::O
NaH
fN'N~OH N,N~
Nd
'=N
~I
8.35
:;
o
N,N~
'=N
~I
.'
8.34
2. What is the mechanism of formation of oxadiazole 8.22?
~-(
l~)
rSf'OMe
N
8.21
EtOH .heat
O~
8.22
8.6 References
Butler, R.N. (1977). Adv. heterocyclic chem.,21, 323 (tetrazoles).
Clapp, L.B. (1976). Adv. heterocyclic chem, 20, 65, (1,2,4-oxadiazoles) .
Gilchrist, T.L. (1985). Heterocyclic chemistry, p.8t (l,3-dipolar
cycloadditions in heterocyclic synthesis). Longman, Harlow.
Gilchrist, T.L. and Gymer, G.E. (1974). Adv. heterocyclic chem., 16, 33
(1 ,2,3-triazoles).
.
Grimmett, M.R. (1979). In Heterocyclic chemistry (ed. P.G. Sammes)
(Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and
yv.D. OIlis), p.357 (triazoles and tetrazoles). Pergamon Press, Oxford.
9. Six-membered ring
heterocycles containing one
oxygen atom
9.1 Introduction
The pyrilium cation 9.1, 2-pyrone 9.2, 4-pyrone 9.3, and their benzo-fused
analogues the benzopyrilium cation 9.4, coumarin 9.5, chromone 9.6, are the
parent structures of a series of six-membered ring heterocycles containing one
oxygen atom. The impetus for research in tbis area comes from the enormous
number of plant-derived natural products based on the benzopyrilium,
coumarin, and .chromone structures.
50I
5
10
El:)
2
9.1
60)3
7::::""
0'-' 2
8
El:) 1
9.4
(]
O 9.2
9.5
ro
O
ClCt
::::....
8
10 9.3
: I
8
0 1
9.6
The red,violet, and blue pigments of flower petals are called anthocyanins,
and are glycosides of various benzopyrilium cations. Delphinidin chloride
9.7, for example, is a blue pigment. KheIlin 9.8 is a natural product which
has found clinical application in the treatment of bronchial asthma and has
been the starting point for the design of many totalIy synthetic chromones
with improved biological properties.
OH
OMe O
HO
~
"o-VO~
OMe
OH
9.8
Coumarln 9.5 is itself a natural product which occurs in lavender oil and has
been found in over sixty species of plants.
In natural product chemstry, the

acetal formed between an aliphatic
or aromatic alcohol and a sugar is
termed a glycoside.
68 Six-membered ring heterocycles containing one oxygen atom
The pyrylium cation 9.1 is the oxygen analogue of pyridie and is a sbr
1t-electron aromatic system. Nevertheless, being a cation it is reactive
towards nuc1eophiles and is readily hydrolysed to give dialdehyde 9.9. These
reactions are reversible, a fact which has been used in a synthesis of 9.1 from
9.9. At low pH (high acidity) the equilibrium lies to the si~e o the pyrylium
species 9.1 but if the medium is basified then hydrolysis of 9.1 occurs to
give 9.9. This is because one mole ofhydroxide is consumed on going from
pyrylium cation 9.1 to neutral aldehyde 9.9. Increasing the hydroxide
concentration therefore forces the equilibrium from left to right.
~O
OH
H
9.1
The carbonyl groups of 4-pyrone
and 4-pyridone absorb at
approximately 1650 cm- 1 and
1550 cm- 1 respectively. The
lower energy of the pyridone
absorption reflects greater single
bond character, and hende
greater delocalisation.
9.9
\
In contrast, 2- and 4-pyrones are considered to have relatively Httle

aromatic character. Whereas in an analogous nitrogen series 4-pyridone 5.23
has significant aromatic character (mesomeric representation 5.23a making a
considerable contribution to the overall electronic distribution), aromatic
mesomeric representation 9.3a makes less of a contribution to the overalI
electronic structure of 4-pyrone. As with furan, the higher electronegativity
of oxygen leads to heterocyc1es of lttle aromaticity in cases where
.delocalisation of electron density from the heteroatom is a prerequisite for
that aromaticity.
O
[ (]
[ (]
N
H
5.23a
5.23
9.3a
9.3
Let us now consider the synthesis of a pyrylium salt, a coumarin, and a

chromone.
9.2 Synthesis 01 a pyrylium salt

A typical pyrilium salt synthesis is illustrated by the preparation of salt
9.12. The precursor to 9.12 is pyran 9.11, available by dehydration of 1,5diketone 9.10. Note the si:milarity of this sequence to the Hantzch pyridine
synthesis, Chapter 5. Also, the dehydrative cyclisation of a diketone to.
oxygen heterocycle 9.11 is reminiscent of furan syntbesis, Chapter 2.
O
PhVPh
9.10
-Hp
ti
I
BF3 Do
Ph
Ph~Ph
9.11
9.13
po
Ph
HCl04
Ph
Ph
9.12
ClO~
:-'0EB

One hydrogen atom has to be removed from the C4 posltion ofpyran 9.11
to produce the pyrylium cation, but it is important to reallse that the
hydrogen atom is lost not as a proton but as a negatively-charged hydride
ion. The process is therefore ap oxidation of pyran 9.11.
EIl
J.
H
Ph~P~
1
Ph~Ph~Ph~Ph --"Ph~Ph
e,
OH
9.13
H"
9.14a
OH
9.14b
Ph
Ph
9.15
A suitable oxidant is cation 9.14a,b, derived from a,~-unsaturated ketone

9.13 by protonation under strongly acidic conditions in the abence of water.
Quenching of this cation with a hydride ion (from the C4 position of 9.11)
produces thesaturated ketone 9.15. The balanced equation is shown below.
n
H
I I
Ph
9.13
n
r
HCl04
Do:-...
Ph
Ph
9.11
0Ell
9.12
9.3 Synthesis of coumarins
Ph
ClO e
4
~
Ph
9.17
9.18
In practise a Knoevenagel condensation i"eaction yields coumarin 9.16

directly, without isolation of diester 9.17. The mechanism is shown below .
-EtOH
Ph
Mos! pyrylium sal!s have electronPh donating aromatic substiluents al

the C2, C4, or ca positions which
9.15
serve to stablise the positive charge
by resonance.
Let us consider the synthesis of bromocoumarin 9.16, a compound which

exhibits biolo"gical activity against parasitic trematodes that cause
schistosomiasis, a very cOmn:1on disease in the tropics. Retrosynthetic
c1eavage oflactone 9.16 gives diester 9.17, which in principIe can be derived
from condensation of ortho-hydroxybenzaldehyde 9.18 and diethyl malonate.
9.16
Ph
70 Six-membered ring heterocycles containing one oxygen atom
9.4 Synthesis of chromones

Let us consider the synthesis of flavone 9.19, which is the parent of a large
series of natural products. Disconnection of the carbon-oxygen bond in the
usual way results in enol 9.20 which exists as 1,3-diketone 9.21. This 1,3dicarbonyl relationship can be exploited in the classical rnanner yielding
ortho-hydroxyacetophenone 9.22. The synthetic problem centres on
rnethodology for the C-~enzoylation of the enolate derived frorn9.22 with
sorne activated benzoic acid derivative 9.23.
~~
~3>
UO.Jl.
VOHO~Ph ~ VOHo~Ph
Ph
9.20
9.19
3>
~
U
9.23
OH
9.21
9.22
= Leaving group
In practice, the Konstanecki-Robinson synthesis of chrornones

commences with O-benzoylation not C-benzoylation, to afford ester 9.24.
Base-catalysed rearrangernent produces the required 1,3-diketone 9.21, via
intramolecular benzoylation of the intermediate enolate. Acid-catalysed
dehydration then affords flavone 9.19.
oc
o
OH
9.22
O
PhCl
Pyridine
..
oC
~
9.24
l.KOH
0-1<.,0
..
2. AcOH
Ph
~ACOH/H2S04
I
...
~
OH
Ph
~ Ph
UO.Jl.
9.19
9.21
9.5 Reactions with nucleophiles

Although sorne examples of eIectrophilic substitution are known, the
chemistry of these series is dominated by nucleophilic ring-opening
reactions, sornetimes followed by ring-closure to give new heterocycles. Por
instance, arninolysis of 9.1,9.2, and 9.3 leads to pyridine 5.1 and pyridones
5.22 and 5.23.
9.1
5.1
0$
(\0
9.2
Cl
N
9,3
H 5.22
N
H
5.23
Aromatic heterocyclic chemstry 71

The mechanism of the conversion of 4-pyrone to 4-pyridone involves an
initial Michael reaction followed by ring-opening. Tautomerisation of enol
9.25 to aldehyde 9.26, followed by cyclisation, affords 4-pyridone 5.23.
(o
0.)
. ~H
o ~NH3
9.3
-H2O
4
N
H
~
~
NH2
JI
H01)
9.25
NH2
5.23
H~~
fo'~
~
~
9.26
H NH2
The reaction of pyrilium salts with nucleophiles may involve electrocyclic

ring-opening of the intermediate dienes, as in the formation of ketone 9.27.
PhLi..
)L~keph
C'0') e~ectrocy~lic.. .J
Ao.R
~())l
~
0e
nngopenmg
Ph
C104e
Ph
9.27
A similar susceptibility to nucleophilic attack is observed in the benzofused series. Coumarin 9.5 is hydrolysed by hydroxide. to carboxylate salt
9.28. This process is reversible, and acidification regenerates the lactone.
~oAo
NaOH
..
. ~
v--.
Hel
9.5
9.28
Ao
ES
Na
An important difference between the monocyclic and benzo-fused series is

that reactions with amines do not lead to the corresponding heterocycles in
the benzo-fused series. For instance, aminolysis of chromone 9.29 affords
phenol 9.30. Benzopyridone 9.32 is not produced. The facile tautomerisation
between 9.25 and 9.26 would analogously give ketone 9.31 in this series.
This high-energy intermediate is not aromatic, and the reaction stops at
phenoI9.30.
.
m
O
y.~~/
9.29
yoANH
9.32
99"
~
N
H
9.30
HO
7f
W
,
H2N
9.31
Phenols do no! exis! or reac! in

their tau!omeric keto forms.
72 Six-membered ring heterocycles containing one o:x:ygen atom
9.6 Problems
1. What is the mechanism of the conversion of pyrone 9.2 to pyridone 5.22
by aminolysis?
u
o
llN'-;~O
9.2
5.22
2. Explain the formation of pyrazole 9.33.
~.JC)
I ~;N
~O}
9.6
9.33
3. Howcan chromone 9.34 be converted to 9.35?

o
o
~
yo}
OMe
~NM~
yo}
9.34
OMe
9.35
4. What is the mechanism of this cyclisation?
AcOH
VOHO~Ph -H-2-S0-4~"
9.21
~
UO~Ph
9.19
9.7 References
Horing, E.C. et al. (19,55). Organic synthesis, Coll. Vol. IIr, 165
(experimental details of a Knoevenagel condensation to give a coumarin
ester).
Livingstone, R. (1977). In Rodd's Chemistry of carbon compounds, Vol.
IV, p.2 (pyrilium salts; 2- and 4-pyrones); p.69 (benzopyrilium salts); p.96
(coumarins); p.138 (chromones). EIsevier, Amsterdam.
Staunton, J. (1979). In Heterocyclic chemistry (ed. P.O. Sammes) (Vol. 4
of Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis), p.607
(pyrilium sa1ts); p~629 (2-pyrones and coumarins); p.659 (4-pyrones
and chromones). Pergamon Press, Oxford.
Wheeler, T.S. (1963). Organic synthesis, CoIl. Vol. IV, 479 (experimental
details for the preparation of flavone).
10. Pyrimidines
10.1 Introduction
Fonnal replacement of a eH unit in pyridine 5.1 by a nitrogen atom leads to
the series of three possible diazines, pyridazine 10.1, pyrimidine 10.2, and
pyrazine 10.3. Like pyridine they are fully aromatic heterocyc1es. The effect
of an additional nitro gen atom as compared to pyridine accentuates the
essential features of pyridine chemistry. Electrophilic substitution is difficult
in simple unactivated diazines because of both extensive protonation under
strongly acidic conditions and the inherent lack of reactivity of the free base.
Nuc1eophilic displacements are comparatively easier.
O,
4
5
6
~ ~N
N1
10.1
4
3
2
5 ~N 3
6 ~JI 2
N 1
10.2
r:-
N4
6~)l
1
10.3
3
2
5~3
6
~__ jJ
NI
5.1
Interestingly, the second electronegative heteroatom reduces the capacity of

the diazines to tolerate the positive charge resulting from protonation.
Pyridazine 10.1 (pKa== 2.24), pyrimidine 10.2 (pKa == 1.23), and pyrazine
10.3 (pKa == 0.51) are al! far less basic than pyridine (pKa == 5.23).
The most important of the diazines is pyrimidine 10.2. Pyrimidine
derivatives uracil10.4, thymidine 10.5, and cytosine 10.6 are the monocyc1ic
'bases' of nuc1eic acids. The bicyclic bases are the purines adenine 10.7 and
guanine 10.8. The purine ring is essentially a fusion of the pyrimidine and
imidazole rings.
NH2
f:e:J
N
10.4
10.5
H
10,6
10.7
The actual biosynthesis of purines (illustrated below in abbreviated form

for the nucIeotide adenosine monophosphate AMP 10.9) involves
construction of a pyrimidine ring onto a pre-fonned imidazole.
10.8
Nucleotides are the monomeric
building blocks 01
deoxyribonucleic acid (DNA) in
which is stored the genetic
inlormation of the cell.
74 Pyrimidines
NH2
steps
NH2
f:CJ
N
I
10.9
N~N
~NJl..NJ1
~N-rNH2
NJl_.~O
I
N,
H
The enzymes that manipulate nucleotides, nucleic acids, etc. are the points
of therapeutic intervention for a number of diseases involving celI replication
disorders such as cancers and viral infections. For instance, AZT 10.10, an
inhibitor of the enzyme reverse transcriptase, is an anti-viral drug currently
used in the treatment of AIDS.'
We shaIl now go on to consider the synthesis and chemistry of the
pyrimidine ring system.
10.2 Synthesis of pyrimidines

Disconnection of the N1-C6 bond in generalised pyrimidine 10.11 in the
usual way produces enol 10.12, which exists as ketone 10.13. Similarly,
disconnection of the carbon-nitrogen double bond in 10.13 yields a
dicarbonyI compound 10.14 and an amidine 10.15. This retrosynthetic
analysis, suggesting the combination of bis-electrophilic and bis-nucleophilic
components, is the basis of a very general pyrimidine synthesis.
R3
R,JCl
;>
R4
10.11
10.15
10.16
Where R4 is a hydrogen or carbon atom, 10.15 is simply an amidine.

However, urea 10.16, thiourea 10.17, or guanidine 10.18 and their derivatives
may be used. These nucleophiles may be condensed with ester and nitrile
functionalities as weIl as with aldehydes and ketones. Such condensations to
afford pyridimidine derivatives are usually faciIitated by acid or base cata1ysis,
although certain combinations of reactive electrophilic and nucleophilic
cornpounds require no cataIyst at al!. Sorne examples are shown beIow.
Ph
~o
Ha
EIOH
Heat
H OEt
* Prepared by in situ hydrolysis of

Ha
..
rk
OEt
H~OEt
OEt
llNAs
H
O
NaOEt
EtOH
o
.)lOEt
NaOEt
EtO.,l.O
~tr
EtOH
Ha
EtOH
Me
10.19
NaOH
".tN
- -... .JtN
Ph
Note that several of these examples produce pyrimidones, analogous to the

pyridones previously encountered in Chapter 5. A representative mechanism
is shown for the preparation of 2-pyrimidone 10.19, and is simply two
consecutive condensations.
fo~e
oi(~
..
~H
yO
NHMe
HN~O
'NAo
Me
10.19
fNrO
NHMe
Hel
Me
~N
-H,O ~
41
-H2O
H~'"
H
HEIl
"N
~N
~ro
N~O..-- H~~
EIl
NHMe
Me
.,
,J
76 Pyrimidines
10.3 Electrophilic substitution of pyrimidones

As mentioned earlier, electrophilic substitution on unactivated pyrimidihes is
of Httle importance, But, as with pyridine, the pyrimidine nucIeus can be
activated towards electrophilic attack by employing N-oxides or pyrimidones,
for the same reasons as were discussed in Chapter 5.
For instance, nitration of 2-pyrimidone 10.20 affords nitropyrimidone
10.21. With doubly-actiyated systems such as 10.22, nitration to give 10.23
can occur without heating.
IN~O
eN
FIN03
N0
Heat
'L
eNE
N~O
10.20
10.21
N02'(NH
FIN03
..
NAo
I ~
N
10.22
10.23
10.4 Nucleophilic substitution of pyrimidines

Leaving groups at the C2, C4, and C6 positions of pyrimidines can be.
displaced by nucleophiles, with the negatiye charge of the intermediate
delocalised oyer both nitro gen atoms.
~Ne
~N,",]
_ye
~N
~--kY ~ ~--KY- ~ ~__ Jl.

N
N)X
~N
~
x = NucIeophile
Y = Leaving group
~NJl.NPh
H
~N
Na
ee
OMe
~Jl.CI
..
~N
~NJl.OMe
Chlorinated pyrimidines themselves are often accessible from the

corresponding pyrimidones by reaction witb phosphorus oxychloride.
(Again, see Chapter 5 for an explanation of this sort of reaction.) For
instance, aminopyrlmidine 10.24 can be synthesised by the cIassicaI sequence
depicted below..
o
/OEt
O
.
)(NH POCl3
Cl
~N
NH2
NH3
~N
~nOHN~
NH ---+-~M~ ----.. ~~T~ ---+- ~M~
N
N
N
2
10.24
l'
10.5 Problems
1. Write a mechanism for this nitration, but starting from an' alternative
mesomeric representation of 10.20 that helps to explain the increased
susceptibility of such pyrimidones to electrophilic attack.
Heat
2. Barbiturates (pyrimidine triones such as 10.25) used to be widely used as

sedatives, but have now largely been superseded by drugs with fewer sideeffects. Suggest a synthesis of 10.25.
~Ph0
~~NO
H
10.25
3. There are severa! preparations of cytosine 10.6 available, one of which is

the condensation of nitrile 10.26 with urea 10.16. Propose a mechanism for
this reaction.
NH2
CN
H+O
OEt
Et
10.26
NH2
HCl
N o
H20 I EtOH
H2
10.16
Jo
eN
I NAo
H
10.6
10.6 References
Brown, D.l. (1962). In The pyrimidines (The chemistry 01 heterocyclic
compounds [ed. A. Weissburger and E.C. Taylor], Vol. 16). Wiley
Intersciene, New York.
Brown, D.J. (1970). In The pyrimidines (The chemistry 01 heterocyclic
compounds (ed. A. Weissburger and E.e. Taylor], Vol. 16, Supplements 1
and 2). Wiley Interscience. New York.
Fumiss, B.S., Hannaford, A.J., Smith, P.W.G., and Tatchell, A.R. (1989).
Vogel's textbook 01 practical organic chemistry (5th edn), p.l177
(preparation of barbiturate 10.25). Longman, Harlow. ,
Hurst, D.T. (1980). An introduction to the t;:henistry and biochemistry 01
pyrimidines, purines, and pteridines. Wiley, New York.
11 . Answers to problems
11.1 Answers to problems in Chapter 2

Note that the reaction proceeds
with attack of the ami no group on
the least hindered ketone.
1. Reaction of diketone 2.46 with aminoketone 2.47 produces enamine 2.48

which is not isoIated, but cyclises directly to give pyrrole 2.43.
MoN~ +
~o
H
2.46
2.47
2.43
2.48
2. The Ione pair of eIectrons of 2.44 is delocalised on to the carbonyl group

as shown, increasing the eIectron density at the aldehydic carbon atom. This
renders it les s reactive to nucleophilic attack.
[ Qyo
H
2.44
Under acidic conditions alcohol 2.45 readily gives cation 2.49a,b which is
stabilised by a similar delocalisation of the nitrogen Ione pairo
2.45
~l
2.49a
2.49b
This highly electrophilic species then reacts with alcohol 2.45 to give dimer
2.50. Repetition of this process Ieads to polymeric material.
~r~OH-+
~OH-+
polymcr
E9
N
N
N
.
N
H
H
2.45
H
2.50
3. As discussed in Chapter 2, interception of cation 2.31 with a nuc1eophilic

counterion such as acetate produces the 2,5-addition product 2.32.
Tetrafluoroborate is a non-nucleophilic counterion and hence the only
pathway availabIe to 2.31 is los s of a pro ton to give nitrofuran 2.33 directly.
'
r
f
--.~~
Ac08
ON0
(.:OE!) H
l_'
,
H f i N 02
lO
AcO""",,
1. Application of our generalised oxazole retrosynthesis Ieads to a simple

glycine derivative.
.
3.33
The forward synthesis is shown below:
NHz
r \_
Ph
H~
I/~
NaOH
lO
PhCOCl
l.S0C12
lO
2.MezNH
2. The mechanism of this oxazole formation is identical to that of the

Hantzch thiazole synthesis. However, because of the reduced nucleophilicity
of a carbonyl group as compared to a thiocarbonyI (due to the higher
electronegativity of oxygen), this synthesis only proceeds under vigorous
conditions (high temperatures, arnide component as solvent, etc).
H~N,H
p)1.. ~H. Hm~PhN'H

-(
;-Br
~+N
l.."""-)l --+-
..
-"'0 P\-N
~_ ').....
H
H
...
~ _')
Br
--jIoo
Ph~
NHz
--jIoo
3.44
The alternative sequencewould give a positional isomer of oxazole 3.44.
Ph~
.-.Jt
r
H~
(J-
_2......
31-:--:--...::..:.;...:.:.:....:.:..::.-.::.:!--=.:=----_2_.3_2_ _ _ _ _ _ _ _
Direct los8 01 HE!)
_
4. The mechanism is a straightforward Friedel-Crafts acylation.
Pyridine..
- AcOH
N02
2.33
80 Answers to problems
3. Bromination of 3.45 gives a bromoketone which is condensed with
thiourea to give aminothiazole ester 3.47. This is then hydrolysed to acid
3.46.
Ketone 3.45 itse1f is readily prepared by nitrosation of ethyl acetoacetate

followed by O-methylation.
C02Et
MeO'N~O
MeI
3.45

1. The reaction is a Michael addition followed by elimination of cyanide ion.
ES
H
"""
e
o~l
>=C=<.~
srfN
NH2
I
CN
NH2
rt
S"NNH
-CN
('br't.J
4.39
2. The overall strategy is to protect the nitrogen of pyrazole (as an acetal),

deprotonate, introduce the side chain as an electrophile, then deprotect.
HC(OMe)3
N)N
n-BuLi
N)N
..
Ll'ES
N)N
H,C,-OMe
OMe
OH
~N,..N
4.40
Ar
HCl/HP
Ar H
HC,-OMe
/
OMe
0W
\
N"N
/'1.Ar2 CO
2.NH4 Cl / HzO
ArAr I
H,C,-OMe
OMe
3. Oxidation of oxime 4.41 produces nitrile oxide 4.46 which cyclises to

isoxazole 4.47.
'ES
HO'N~O/
/
'"
4.41
NaOCl
[31
~O~
[3+2] ..
NaOH
4.46
4.47
4. Reaction with hydroxylamine occurs on the aldehyde group of the more

reactive minor tautomer 4.43 affording isoxazole 4.44. Methoxide-induced
fragmentation as shown gives enolate 4.48 which is quenched by a proton in
the workup to afford 2-cyanocyc1ohexanone 4.45.
Aromatic heterocyclic chemistry. 81
~N
ClH
4.43
4.45

1. The process is essentially artalogous to a Michael reaction.
O~C02Et
COzEt
2. A reasonable mechanism is:-
Ph
6
N
3. Pyridyl amide 5.39 is easliy metallated at the C3 position. Quenching

with the aldehyde, and cyclisation of the resulting alcohol 5.42 onfo the
amide group, produces lactone 5.40.
OMe
lrr-~
5.39
n-BuLi
(2eq. )
Do
O
OMe
H
~
I
Ar
5.40
4. The reaction probably proceeds via enaminoester formation then

cyclisation.
(O
f}f
ro~~{ ~ HuH
) N{
o
~OEt
C0 Et
CN
CN
- ~ )l~CN
2
H~\
/.EtOH
JXCN. JXCN
H
In fact nucleophilic substitution of pyridine N-oxides occurs more easiIy

than on simple pyridines, as the nitrogen atom is positively charged.

1. The quinolone synthesis involves an addition-elimination reaction
folIowed by an intramolecular aromatic acylation.
O
~-:J
EtO~OEt
E~~O)
F~ r~iEt -EtOH~F~:..J I
Cl~NHz""""
Heat
Cl~N
H
\'f~'''
~ ~
r o O COzEt
OEt -.:.
Cl
I
N
r o O COzEt
---.:.
Cl
I
N
H 6.32
'
"*1"
'e'~1

The displacement reaction occurs by initial nuc1eophilic attack on the
benzenoid ring (with the negative charge being delocalised onto the oxygen
atom as shown) then elimination of chIoride ion. The presence of the fluorlne
substituent is essential for this displacement, activating the ring towards
nuc1eophi1ic attack by its electron-withdrawing inductive effect.
~)
o,
F~CO_Z_ _..~ ~~CO~C1/H20~ F~~H

C~NjJ
r~jJ
rN~NjJ
HN~
Et
NH
Et
HC!.
HN~
HN~
2: Step 1. Condensation of the aldehyde with nitro methane under basic

conditions produces the cx,~-unsaturated nitro compound.
OH
Art H
(OH
Ar~NOZ----Ar~NOZ -OH~~NOz
H H
~eOH
'-l..:HzNOz
Step 2. Lithium aluminium hydride was used, although hydrogenation can

also effect this type of reduction.
LiA1H
_ _ _4_........
or Hz/P~
~N02
Ar
~NHz
Ar
Step 3. Acylation of the amine with an acid chloride in the presence of an

appropriate base gave the amide.
.
RCHzCOCI
~ Ar~N~R
11
NEt3
Step 4. This isoquinoline fonnation is of course an example of the BischlerNapieralski synthesis, although phosphorus trichIoride was actually used in
this example, not phosphorus oxychloride.
Step 5. Sodium borohydride was used to reduce the imine to the amine.
H
RIXNR3
..
Step 6. The catecholic and phenolic ethers were removed by treatment with
hydrobromic acid. Benzyl ethers are frequently removed by reduction (e.g.
hydrogenation) but reduction, of course, would not remove the methyl ether.
The mechanism of the deprotection is shown below.
R~
~0_CH3
EB
H
R~
fl -CH3Br,..
~0_CH3
EB,
~r
R~
OH
Et
84 Answers fo problems

1. Indole 7.38 was prepared by a Fischer ndole synthesis followed by Na1kylation as shown.
Ph-N-NH,
H
oD. ~
~N~
H
NdJ.
~N~
Cl~NM~
NM~
7.38
2. The nitroacetate (pKa = 6.79) protonates the tertiary amine funtionality

of indole 7.39, facilitating the elimination of methylamine to give cation
7.46. Conjugate addition ofthe nitroacetate anion then produces 7.40.
,......
Ro~r.Ea
IJ
fMez - HNMez
H
N. ~
:::--
RO~
7
Do
IV
N~ '1
Eal~
e(
"..;
C02Et
RO~C02Et
N02
Do:::--
7.46
7.40
N
H
N02
R = PhCH2
3. As intended, C2 carbanion 7.47 attacked the nitrile giving 7.48, which

unexpectedly attacked the adjacent sulphonyl group giving ndolyl anion
7.49. During the acidic aqueous workup this anion is quenched and the
reactive N-sulphonyI imine functionality is readily hydrolysed affording
ketone 7.44 and sulphonamide 7.45.
7.47
O:J
:::--
N
I
0=5=0
I
Ph
e~1
C
(111N
OpyPh -- ("n-I1
~~~
(1
o=s=o e
U~h~
Ph
Ea
Li
7.48
. Ea
L1
Ph
Ha.,
H20
Gn
~~~
Ph
7.44
o=s=o
I
7.49
Ph
I
7.45
Ph

1. Sulphur ylid 8.36 s the key intermediate in the formaton of epoxide
8.34. Epoxide 8.34 s racemic but alcohol 8.35 is achiral.
O
O
1
11
CH3 -S(CH3h
Ea
NaH
11
Do-
(-H2)
eCH2-S(CH3) 2
Ea
Corey'syld
8.36
:)
:{
,',1,

2. This oxadiazole formation involves O-acylation of the amidoxime
followed by a condensation.
'.
l
OC .0-....
Co --
8.21
OMe
e O,
EtO-H ~
-NH-2--'~
~-(
R NH2
O~....J;r-O-N
l~
O~
8.22
11.8 Answers to Problems in Chapter 9

1. The mechanism is similar to the 4-pyrone example.
tLcl~--.
0
~
o 4 -o
~OH~O
9.2
'--.
NH2
NH3
'a'
~n
HO
N
O
4'~~0
H
2. The first stage is the same as the preparation of 9.30, then cyclisation
affords the pyrazole.
oc9
''\N
,
?'
9.33
::::...
OH
3. This is a Mannich reaction (see Chapter 2) and is an unusual example of

an electrophilic substitution on a chromone.
w~
aMe
9.35
4. The reaction is a straightforward acid-catalysed condensation, passing

through carbonium ion 9.36a,b.
oa'""t
aHph
ro
o
9.19
d
Ph
a
E9
ruQHe
Ph
-Hza
[~H
::::...
a E9 Ph""---'
9.36a
d.fH 1
~
a/.
9.36b E9
Ph
eL'
N
5.22

1. The overall electronic distribution of 2-pyrimidone has a considerable
"
contribution from mesomer 10.20a.
[ (CJ2
(N
~Jl.oe
..
...
'G~ ~
10.20
10.20a
The mechanism of nitration is shown below.
2. Disconnection of barbiturate 10.25 produces bis-electrophile 10.27 and

urea. In practice malonate ester 10.28 (X =OEt) is used.
,Ph0NH
~N~O
H
]>'
.
0
~~~OEt
O
Ph0x
,Ph
NH
~x +
10.25
H2N
10.27
~2O
OEt
10~16
10.28
3. Hydrolysis of acetal10.26 Ieads to reactive aldehyde 10.29 in situ.

CN
-+
OEt
H+
OEt
10.26
eN
CN
........... HfD -EtOH J :
r OEt....
H~
'o
O
10.29
Condensation of aldehyde 10.29 with urea followed by cyclisation onto the

nitrile produces cytosine 10.6. Observe how cyclisation onto a nitrile affords
the amino functionality directly, as compared with the three step sequence
used in the synthesis of 10.24 where an ester is used in the cyclisation step.
~N
~N
CN
NHz
H2N~O
HJ: O
10.29
NH z
C-lo
H
10.6
-H20
e"
..
lo;
=--N
e"
NHz
,.4.
~
~
2
NH
H'"r
~/H
NH
eNE
N~O
.iN~O
~NEB
e'"
...
H
)[~2
N
H
Index
a.-effect 29
acetyl nitrate 15
acid chlorides 6
a.-aminoketone 13
arnmonia 5
AMP, biosynthesisof 74
anion chemistry of
furan 17
imidazole 25
indole 59
isoquinoline 50
isothiazole 32
isoxazole 32
pyrazole 32
pyridine 42
pyrrole 17
quinoline 50
tbiazole 25
anthocyanins 67
aryl hydrazines 54
.i,2 azoles 28
1,3 azoles 20
AZT 74
barbiturates 77
benzene 2
benzopyrilium cation 67
bioisosteric replacement 63
Bischler-Napieralski synthesis
(isoquioline) 48
Chichibabin reaction 40
chIorophyll 11
chromone 67
Claison rearrangement 55
condensation 3
Cope rearrangement 55
coumarin 67
cytosme 73
delocalisation 3
delphinidin chloriqe 67
dihydropyridines 37
disconnection 4
DNA 73
drugs for the treatment of
AIDS 74
asthma 31
bacterial infection 27
depression 60
fungal infection 41, 66
infiammation 22
schizophrenia 18
senile dementia 45,63
sleep disorders 77
trematode infection 69
ulcers 1,11
electrophilic substitution of
furan 14
imidazole 24
mdole 57
isoquinoline 49
isotbiazole 32
isoxazole 32
oxazole 24
pyrazole 32
pyridine 37
pyridine N-oxide 38
pyridones 39
pyrimidones 76
pyrrole 14
quinoline 49
tbiazole 24
thiophene 14
Fischer synthesis (mdole) 54
fiayone 70
furan 10
Gould-Jacobson synthesis
(quinolone) 51
Hantzsch pyridine synthesis 36
Hantzsch thiazole synthesis 23
heteroaromaticity 1
histamine 20
hydrazine 29
hydrogen suIphide 12
hydroxyIamine 29
5-hydroxytryptamine 54
imidaiole 20
imidoyl halide 22
indole 53
isoquinoline 46
isotbiazole 28
isoxazole 28
Khellin 67
Knorr synthesis (pyrrole) 14
Konstanecki-Robinson synthesis
(chromone) 70
Leimgruber synthesis (indole) 56
lysergic acid 54
Mannich reaction 16, 58
neurotransmitters 54
nitriIe oxides 30
nucleic acids 73
nucleophilic substitution of
imidazoIes 26
isoquinolines 49
oxazles 26
pyrldines 40
pyrimidines 76
quinolines 49
thiazoles 26
ornithine 64
ortho-activating substituents 43
oxadiazoIes 61
oxazoles 20
oxazolidmones 8
Paal-Knorr synthesis (pyrroIe,
tbiophene, furan) 12
phosphorus oxychloride 15,47
phosphorus sulphide 12
Pictet-Spengler synthesis
(isoqumoline) 48
pyrazole 28
purlne 73
pyridine 35
pyridme N-oxide 38
pyridine sulphur trioxide complex 15,
35
pyridones 39
pyridontriazine 41
pyrylium c.ation 67
pyrimidines 73
pyrones 67
pyrroIe 10
Quinoline 46
resonance 2
retrosyn thesis 4
Robinson-GabrieI synthesis
(oxaZole) 21
Skraup synthesis (quinoline) 46
synthesis of
chromones 70
coumarins 69
furans 11
heterocycles, principies of 3-8
-imidazoIes 22 indoles 54
isoquinolines 46
isothiazoles 29
oxadiazoles 62
oxazoles 21
pyrazoles 29
pyridines 35
pyrylium salt 68
pyrimidines 74
pyrroles 11
qumolines 46
tetrazoles 64
88 Index
thiazoles 23
thiophenes 11
triazoles 63
tetrazoles 61
thiamin 20
thiazoles 20
thiopherie 10
thymidine 73
. triazole 61
uracil 73
Vilsmeierformylation 15,58
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Aromatic Heterocyclic Chemistry

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Aromatic Heterocyclic Chemistry

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Aromatic Heterocyclic

Oxazoles, imidazoles, and thiazoles

Isoxazoles, pyrazoles, and isothiazoles

Quinolines and isoquinolines

Five-membered ring heterocyc1es with three or foUr heteroatoms

Six-membered ring heterocycles containing one oxygen atom

1.1 Heterocyclic chemistry

1.2 Aromaticity and heteroaromaticity

Aromatic heterocyc1es are described as being heteroaromatic, and we shall

The compound numbering system

A difficulty arises with five-membered heterocycles such as pyrrole, which

Aromatic heterocyclic chemistry 3

In fact the thorny problem as'to how aromatic is a particular heterocyc1e or

1.3 Synthesis of heterocycles

For a review on the concept of

The disconnection approach to synthesis essentiaHy involves working

Now consider condensation of ammonia with ketoester 1.18. The isolated

Aromatic heterocyclic chemistry 5

In a retrosynthetic sense, formal hydrolysis of the carbon-nitrogen bond of

Unlike our initial imine disconnection which is restricted to nitro gen

Retrosynthetic analysis suggests a double condensation between diketone

Returning to the synthesis of pyrrole 2.16, dl.ketone 1.26 can be regarded as a

In this particular instance the correct oxidation level autornatically results

Examples of this cyclisation-oxidation strategy include the synthesis of

Aromatic heterocyclic chemistry 7

(see Chapters 2 and 5)

H2N- NH2 ,H2N- OH

(see pyrazole and isoxazole syntMsis, Chapter4)

(see thiazole syntMsi~, Chapter 3, and pyrimidine syntMsis, Chapter 10)

(see isoqulnoline syntMsis, Chapter 6)

(X = leaving group. ego CI- see benziml%ole syntMsis. Chapter 1

and isoquinoline syntMsis. Chapter 6)

(see thiazole syntMsis, Chapter 3)

(~ (see quinoline syntMsis, Chapter 6)

"--.R. R2 = alkyl or O-a/kyl

(see pyrrole. thiopMne. andfuran syntheses. Chapter 2)

Nucleophilic LElectrophilic fragments

(see Chapter 1 and oxazole synthesis. Chapter 3)

(see Chapter 1 and coumarin synthesis. Chapter 9)

(see oxazole synthesis, Chapter 3. and Knorr pyrrole

Aeylating speeies are thus

These eoncepts of retrosynthesis and heterocycle construction will help put

Aromatic heterocyclic chemistry 9

Warren, S. (1978). Designing organic syntheses, p.l50-172. Wiley,

2. Pyrroles, thiophenes, and,

Under extreme conditions of

Th~ basis and extent of their aromaticity is discussed 'in Chapter 1. In

Note that protonation of the

Aromatic heterocyclic chemistry 11

Acetylenic thiophene 2.9, found in sorne species of higher plnts, is one

Chlorophyll-a Is a plant pigment

2.2. Synthesis of pyrroles, thiophenes, and furans

Terpenes are plant-derived

12 Pyrroles, thiophenes, andfurans

The forward process is known as the Paal-Knorr synthesis. Tbis is a ver':!

However, the situation is slight1y difierent when phosphorus (V)

When hydrogen sulphide' is the heteroatom source the mechanism is

The Paal-Knorr synthesis can similarly be applied to thiophenes, e.g.

Aromatic heterocyclic chemistry 13

The mechanism 01 the cyclisation

Our retrosynthetic ana1ysis of the Paa1-Knorr.synthesis leads to a prob1em

Returning again to pyrr01es, probably the most widely-used method for

The a.-aminoketones are often prepared by nitrosation of an active

As a.-aminoketones are prone to se1f-condensation (see page 22 for a