Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Chemistry
David T. Davies
S
-"
-"eN
S
-'"
-",eN
S
-'"
-",eN
OXFORD
VNIVERSITY PRBSS
Contents
Introduction 1
2 Pyrroles, thiophenes, and furans 10
3 Oxazoles, imidazoles, and thiazoles 20
4 Isoxazoles, pyrazoles, and isothiazoles 28
5 Pyridines 35
6 Quinolines and isoquinolines 46
7 Indoles 53
8 Five-membered ring heterocyc1es with three or foUr heteroatoms 61
9 Six-membered ring heterocycles containing one oxygen atom 67
10 Pyrimidines 73
II Answers to problems 78
Index 87
1 1. Introduction
?
el
N~N
H I~ 11 H
EtN ~ N /'--- NEt
1.1 1.3
s s
[ s>-=<s ]
1.5 1.6
o N
5.1
o H
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.
I
2 Introduction
H H H
[ )~XH
H ~ H
. lOo H*H 1 H*H
H .4 H H H
H
H
I
H H H
1.Sa l.8b 1.9 1
The earbon atoms in benzene are sp2 hybridised, and the hydrogen atoms
J
1
are in the same plane as the earbon atoms. The remaining six p orbital s are at Ii
~ghLanglest()the plane of the rin.g and c~oniai~~~1X1telecftollf. Benzene
fulfils the HckeIcrltena for aromatidtyasapplieirtocyclic poI yenes 1
I
containing 4n + 2 electrons (where n=l in this case) in filled p orbital s ~
eapable of overlap.
I
Although two mesomeric representations 1.8a,b can be drawn for benzene, 1
this does not imply two rapidly-interconverting forros. Rather, the six 1t
f~
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'
oN
.0 N
H
5.1 :U
eO~eO~Oel
eN eN eN
H H H
r
j
'1
Thus, delocalisation of the nitrogen lone pair completes the sextet of
electrons required for aromaticity. These two examples illustrate the point
Aromatic heterocyclic chemistry 3
o es
N
5.1 10.1
N
6.1
o N
H
2.1
(~
N
H
3.2
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.
oN
H
1[)
s o
o
2.1 2.2 2.3
In fact the thorny problem as'to how aromatic is a particular heterocyc1e or For a review on the concept of
series of heterocycles has been a preoccupation of physical organic chemists heterocyclic aromaticity see
Katritzky et al (1991).
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.
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. f
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
'F 0 + H2N-R2
cataIytic He
.. Rl
=N-R2 1.12
,!
I
-H2O
1.10 Rl 1.11 Rl 1
~+He -H
~-H20 ,i
1,
H,e H
RIX~
R1,O-H _He R O-H e
Rl Cf/H +H
~e ><~~H ~ l(N,H ~ N ... H
I
~
Rl Rl I 'H Rl I Rl I
Rz , R2 Rz
H 2N-R2 I
1.13 1.14 1.15
precursor
O
~
~C02Et
NH
.. r<?
~N, ... H
1.18 1.19 , H 1.20
r 1 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
Aromatic heterocyclic chemistry 5
1
f 1.23. Note that in the hydrolytic disconnection step the carbon becomes
,i 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
RO 1.24
. >
RO 1.25
>
R'o-SH
Let us see how this disconnection approach can rationalize the synthesis of
pyrrole 2.16.
~
N -0r- OH NH2
-0r- ~--nr-
H O OH O O
2.16 + NH3 1.26
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, I
!Be
e-e,
e!B
1.26 O O 'l-ze)
NH
j
6 Introduction
R)lNJl. R
H
[O]
-2H
Do
R
I /.
N R
!
1.1.7 1.28
~NH2' __R_)l
__a~
~NH2
..
I
1.30 '1
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
1
06
[ I
O
R1'NAR ~ .. Rl....N
EB R
1
, 2 , 2
H t.33a H 1.33b
r
EEB
Ojo o-E
Rl....NJt: R
,'-' 2
.. RIEB
'NI R2
H H
r
1
1
1
Nucleopbilic fragments
No. oC ring atolOS
1 NH3 , HzO ,HzS (see Chapters 2 and 5)
Aromatic heterocyclic chemistry 7
!
.'
NH2
4 ((1
~ NH
2
(see benzimido.zole syntMsis, Chapter 1)
"k" O
O
R
(see Chapter 1 and coumarin synthesis. Chapter 9)
3
U
rt
NH2
R
(see oxazole synthesis, Chapter 3. and Knorr pyrrole
synthesis, Chapter 2)
8lntroduction
The reaction of an acylating species Amides can eyc1ize in this manner as, for example, in the aeylation of amino
with a nucleophile is shown below. acids 1.34 to afford oxazolidinones 1.35.
o (o O O
O
excess A Rl)f~AR2 R100
R2 Cl
N~
~ ~
R100H H ....~yO
NH2 1.34 R2 1.35
R2 i
Aeylating speeies are thus ineluded in both electrophilic and f
nuc1eophilie/electrophilic eategories in Table 1.1. For a related example see
the synthesis of oxazoles in Chapter 3.
I
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 f
the preparation of coumarin 9.16. I
For the.slke of simplicity in this fext O
H
the two-stage process is abbreviated
Br': Br'(JC(
I
Ihus: "Jl-OEt C0 2Et
I ~ O
+ ~~ ~~ I -..;::
~ OH EtO O - H20 ~ O O
-EtOH
9.16
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.
r1 Aromatic heterocyclic chemistry 9
1 The first two (Acheson and Paquette) are still very good texts even today. Of
1; 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
'J
1
i
a
leve!. See Gilchrist for discussion of the nuc1eophilic/electrophilic
fragment approach to heterocyclic synthesis.
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
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
<1 heteroatom. Consequently the lone pair is not available for protonation and
hence these heterocycles are not basic.
The numbering of heterocycles 11
generally starts at the heteroatom 4-~,?
S~ __ )
aH
I 2
NI
H
Ne H 2.1
I Th~ basis and extent of their aromaticity is discussed 'in Chapter 1. In
H
Under extreme conditions of summary, the capacity for the lone pair on a particular heteroatom to be
acidity pyrrole is protonated, but deloc3.1.ised is inversely related_t() the. electronegativity of the heteroatom. For,
at the C2 position. 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.
2.4d
y]
Me
pyrrole nitrogen would lead to a
X=NH,S,O
non-aromatic cation.
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
Aromatic heterocyclic chemistry 11
2.9
2.10
In contrast to the pyrrole and thiophene series, the furan nucleus occurs in Terpenes are plant-derived
natural products constructed of
many plant-derived terpenes such as 2.11. The most important furan-
multiples of the five-carbon
containing drug is 2.12, which reduces gastric acid secretion and is important hydrocarbon isoprene.
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.
12 Pyrroles, thiophenes, andfurans
R;z R3
~Rl~R4'
O O
2.13 + RNH2,H2S,H20 1I
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-
-~O . . -(}O I
consecutive condensations. H
1
1l
1)- ~H ......_ _
H H
1
f
I
2.16
P2SS H2S
1
... ~ Ph~C02Me i
Ph-i)-Ph
O O
Ph S Ph HCl
JO----
Ph S C02Me
i
O O
2.19 2.20
When hydrogen sulphide' is the heteroatom source the mechanism is 1
1
similar to the pyrrole case. 1
HS--..
2 . ~ ft
Ph-O-- ~ Ph~ ~ H O ( ) - 1
O O If9 EB,.o~o H -cJ O
n
J!..J>- -H20 ! / \ / H
.....- ~_/<, -+- Ph
-01=Q \.. /\
Y'f'" ....-Ph4-_ 1(-
HEB
1
Ph S
2.17
Ph S OH SH SO
I
However, the situation is slight1y difierent when phosphorus (V) t
sulphide is used. This reagent converts ketones to thioketones, by exchange
I
of a phosphorus-sulphur double bond with a carbon-oxygen double bond.
+
!
1
.1
I
Aromatic heterocyclic chemistry 13
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).
O H~o O O
~ O
~C02Et ~C02Et ~C02Et ~C02Et
2.25
~
~
AcOH
o
-... N,
- CsHuOH
~CsHll
.. <><C02Et
HUNH
El)
~
~
N .... OH
Zn
AcOH
..
NH2
2.27
2.26
,lo
0y ~
C",..l'
~NX:O ~
E ~ ~
i
H2N C02Et H
Et
2
- N C02Et
1
0
--E
H '
The Knorr pyrrole synthesis CO.)Et J
consists of a ketone and amine
condensing to give an enamine, ,lo ~j ~ C1- :( N N
followed by intramolecular H H
cyclisation of this enamine onto
the remaining ketone.
c0.2Et
)0
O~,Hll
HlN
~
CO Et
~
I 0J:C,Hl1
N
~
K- N
COlEt C,Hl1
~ ~
COlEt COlEt H COlEt H
Ph Ph
lL X
Ph
Ph:t
X ~
Ph
Ph
___t_
b(
H HlN' Ph N
H
Ph N
H
Ph
Note that pyrrole reacts with AH three heterocycles undergo aromatic substitution reactions, though their
electrophiles on carbon, lika an
enamine. reactivities vary considerably. Let us consider a generalised mechanism and
how the stability of the two possible intermediates affects the position of f
4
substitution. l
COj:'[OE~
t}
eO~ rrfLE
e
XH
e 2.28a
XH
2.28b
XH
2.28c
Ji: O-E X
f
E E
1
0-.
U
)' [
5 ~
H E
~
e
-H
-. X
1
X=NH,S,O 2.298 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
I
~
e2 position over the e3 position. The 'actual isomer ratio depends on the 1
heterocycle, the electrophile, and the precise conditions,aUhoughin many I!
cases such reactions are virtuaHy regiospecific, and only the e2 substitution
I
i
r
~
. Aromalle hel",ocyelie eheml.<try 15
products are isolated. Very reactive electrophiles (such as the nitronium ion
ji N02+) exhibt low~r selectivity because they tend to be less discriminating
g , as to where they attack the heteroaromatic nucleus.
~ Thi': ease of electrophilic substitution is pyrrole > furan > thiophene >
li benzene. ,
~ pyrrole is extremely reactive towards electrophiles wmle thiophene, the T.o give a quantitative feel for
these oifferences in reactivity,
:; most aromatlc of the trio, is much less reactive. At a very rough
data for the bromination of three
.~ approximation, the reactivity of thiophene is of the order of a heteroatom- representative derivatives are
, substituted benzene derivative such as phenol. Despite large differences in shown below.
~~
. 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 ,N-
dimethyIformamide, followed by a hydrolytic workup.
o X
X=NH,S,O
Oyo
H
The reaction proceeds by formation of the electrophilic Vilsmeier complex X Relativo Rato
2.30, followed by electrophilic substitution of the heterocycle. The formyl
group is generated in the hydrolytic workup. Pyrrole, thiophene, and furan all s
undergo this formylation which is highly selective for the e2 position. O 1.2 x lOZ
NH 5.6x 108
Cl
-HNM~
.. QyO
H
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 :::::::::
important theoretical point:
furans Whilst!he meohanism shown above applies to pyrrole and !hiophene,!he
2.3
( ' ~ ES H
Aod'
Ac~ O H
2.31 232 Ca
Thiophene, alkyI-substituted furans, and especially pyrrole, undergo
O
233
N0
2
1
Mannich reactions. ~
oN
H
CH1O/HNEt1
AcOH
.. ~NEtl
N
H
o S
CH1O/HNM~
HCl
.. ~NMel
S
--OO
CH1O/HNMez
AcOH
. ~NM~ O
This involves condensation of the heterocycle, formaldehyde, and an amine
I f
(usually a secondary amine) to give an aminomethyl derivative.
1
Me1NH+CHzO
AcOH ES
CH;:=. NMel
I
f
.. ~NM~ ~
X
---fJ-
S COZMe
CHzO
HCI
" O
AcONOz
~
NO z
1
o
~
H
o N
H
NaNH2
po Oe
N
Na$
MeI
po
O
N
Me
2.34
2.1
r:- J?~
O~
O
O ~H~ Qyo
OEt
po Do
N
H Cr: MgBr
N H
H H
2.1 2.35 2.36
J
18 Pyrroles, thiophenes, and furans .j
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 i
furan and alkylation produces 2.39. A second deprotonation.at the e5 J
position and alkylation gives bromide 2.40. Displacement of -fue bromide t
affords nitrile 2.41, and acidic hydrolysis yields the target furan 2 . 4 2 . i
o N
n-BuLi
.. I
I
Me Me Me
2.37
The precise nature of the carbon-
lithium bond is beyond the scope
of this book. Organolithium
intermediates are here
represented as carbanion and o S
n-BuLi
.. o
S
e Li lB CIP(O)(O:t)2 ~ ,,0
S ~""OEt I
catlon to emphasise differences in
OEt
properties and reactivities as 2.2 2.38
compared with tull covalent bonds.
.,
2.42. 2.41
2.5 Problems
1.
M~cOs
ii H
2.43
QyO ~OH
N
!
H H
I
H
2.44 2.4S
I
Aromatic heterocyclic chemistry 19
o O
![J-
O N0 2
2.2 2.33
o S
PhCOCI
Phyf)
O
2.2
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).
Pergamon Press, Oxford.
Meth-Cohn, O. (1979). In Heterocyclic chemistry (ed. P.G. Sammes)
(Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D.
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):
3. Oxazoles, imidazoles, and
1
thiazoles
3.1 Introduction
i g;
Oxazole 3.1, imidazole 3.2, and thiazole 3.3 are the parent structures of a 1:
1
They are isomeric with the 1,2-azoles isoxazole, pyrazole, and isothiazole l.,':,
(see Chapter 4). Their aromaticity derives from delocaliSation of a lone pair
from the second heteroatom, 3.4a-e.
(vXJ
....-... (~
x
EIl
Ne
~
e
()
x
N
EIl
~ e(~
x
EB
~
'
C)e
X
EB
I
i
I
3.4a
X=O,NH,S
3.4b 3.4c 3.4d . 3.4e
j
~
The biosynthesis of histamine
involves decarboxylation of the
The imidazole ring occurs naturalIy in histamine 3.5, an important !
4;
~1
NH2
!
'1
N
H
3.5 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
1
r
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.
,t
I
I
j
I
Aromatic heterocyclic chemistry 21
Imidazole (pK a=7.0) is more basic than oxazole (pKa=O.8) or thiazole The statement lhat oxazole has a
(pKa=2.5). This increased basicity arises from the greater electron-releasing pK a of 0.8 means that the
protonated form of oxazole is a
capacity of two nitrogen atoms relative to a combination of nitrogen and a
very strong acid.
heteroatom of higher electronegativity. AIso note that a symmetrical Therefore oxazole (as the free
resonance-stabilised cation 3.7a,b is formed. base) is a very weak base indeed.
r He
(~
N
-.
H
[ H
r
]
3.7a 3.Th
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.
~
.{-N R3 3
}[N ::>- Rl / ~ Rl-<- N'(R
Rl O"-R3 OH OH ~
OH O 3.12
3.10 3.11
R2 NHl O 1~
R
2Ji
Rl
X O R3 Ax ~
R1-t .1r- R3
O O
3.15 3.14
3.13
Base
3.13 3.10
R~~R3
;I~ea
R
yNy R3~
R
O ('S"O
~2 R
)::.0 el ~
e0 3.16
f
Ph)[N
~ ~
0~C02;
.
l.NaOH
Ph
r N
Ph.J!....O~~Et
1
Ph
3.23
2.Hel
3.22 3.21 I
Drugs which reduce inflammation
are often used to treat the
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
i.
symptoms of arthritis.
aminoketone hydrochloride salt 3.20. Such aminoketones are oiten isolated as t
the corresponding salts because. the free aminoketones are prone to
dimerisation, having both nucleophilic and electrophilic centres. (For a f
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 . I
hydrolysis then affords the biologicalIy-active carboxylic acid 3.23.
~~
' MeO
o
!
H~
"
I~
F
e e
NH4 0Ac MeO
MeO
f, ~
, )[~ ~
R)(OH
1; ~
~
R
2X
Rl
O
S;RJ
::>
RXO NH2
R S R3 R S RJ Rl X SAR3
3.26 3.27 3.28 9 3.30
X=CI,Br,I
-HCl
Heat
(~ S
Thiocarbonyl compounds are
much more nucleophilic than '
3.31 carbonyl compounds,because
The mechanism fOf the fonnation of thiazole 3.31 involves initia! of the lower electronegativity
of sulphur as comparad to
nucleophilic attack by sulphur followed by a cyc1ocondensation.
oxygen.
. .~.
240xazbles, imidazoles, and thiazoles
ffJ
"7:\ Q '
o~ N~H HO~N
, H
I
fcr:
yO H
::)~,r ~ ~~
S~ S
H
--- H~~~ ~_~ I
H S
HO \;-N
S;I
3.31 J
The thioamides themselves are convenientIy prepared from the corresponding '~
ainides by treatment with phosphorus (V) sulphide (see the Paal-Knort I
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 t
and not a carbon substituent. For instance, thiourea itself is used in the ,~
preparatin of 2-aminothiazoles such as 3.32.
:rO
a Heat
!i
3.32
J"
f
3.5 Electrophilic substitution reactions of oxazoles, 1:
imidazoles, and thiazoles ~
As with pyridine, not only does
the electronegative nitrogen atom
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
I
i
wlthdraw electro n density from
the ring, but under the acidic
groups can facilitate electrophilic attack, as in the preparation of oxazoles I
conditions of many electrophilic 3.34 and 3.35. Dimethylamino oxazole 3.33 is essentially functioning like 'i
reactions the azole nitrogen is
protonated. The azolium callon is
relatively inert tq further attack by
a positively charged electrophile.
an enamine in this reaction.
't
1
~
f
!
- H
ffJ
~
N
) [ \\
1
f
~
NOz S /"'--.OMe i
Heat
I
~
Aromatic heterocyclic chemistry 25
l/N l/N
(~
Ea
n-BuU
~_;>8 LiEa ~ _~ 3.38
X X 3.37 X E
Sirnilarly, aIkyl groups at the C2 positions (but not the C4 or e5 positions) There is a useful analogy
can be deprotonated giving carbanions 3.39a,b which can also be quenched between resonance-stabilised
anion 3.39a,b and an ester
with electrophiles to afford 1,3-azoles 3.40. enolate anion. Note that in both
cases the negative charge can be
delocalised onto a heteroatom.
I/N8 . Ea] Ea
[~ ~-BuLlp ~ ~Ll ~ ~_\..U ~ [~N~E
N . [[N.Ea
O
x 8 X~
RO~8
X X
X=O,NR,S 3.39a 3.39b 3.40
Sorne examples of both the aboye types of reactivity are given below t08
[~ RO~
~~O
1. n-BuLi
~
N 2M"lNCHO
CPh3
Ph
(~
S
1. n-BuLi
2.CH3CHO
3.HO/H2O
~
r.~
Ph
OH
;rN OH
Ph
;rN
O~
1. n-BuU
~ ~ ~Ph
2.P~CO Ph O Ph
3.HO/H2O
[~
N
Me
1. n-BuLi
2.PhCHO ~
3.HO/H2O
f.V
. l:'f
Me
Ph
(~
S
1. n-BuLi
2.MeI
\lO
't.~
260xazoles, imidazoles, and thiazoles
t
1
-;
- HBr ~
3.41
It
The nitro group plays a key role as an electron-acceptor in this reaction, t
Once again this reactivity parallels which a1so illustrates the fact that imidazole is a good nucleophile. However, f
r
certain features of carbonyl
no activation is necessary with 2-halo-l,3-azoles, which can react with
I
chemistry. Compare the reaclion of
aniline with chloroformates, below. nucleophiles, as shown by the preparations of 3.42 and 3.43.
(o Ph Ph e) Ph
H2NPh
o NHPh o NHPh 3.42 '1
~
f
[~ ~ (~~ L t
O
RO~NPh
s~Br
eOMe
S OMe
~
<
H 3.8 Problems
1. Suggest a synthesis of oxazole 3.33.
1
~
1
l
3.33
1
2. A less general synthesis of oxazoles is the condensation of bromoketones t
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, N-
formylation, and cyclocondensation?
o Ph
Ph~
Br Heat
1[, O
3.44
Aromatic heterocyclic chemistry 27
COzEt
MeO'N~O
3A5
3.9 References
Campbell, M.M. (1979). In Heterocyclic chemistry (ed. p.a. Sammes)
(Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D.
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).
ffF. -- 'iffW w"'nm:wm-gm 775 G7
!
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 f
"',
4 3 4 3 J
5eN 2o
I
5C:('l2
NI
H
1
I
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 electron- f
withdrawing effeet of the adjaeent heteroatom. Isoxazole and isothiazole are. i
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).
e e
ICN
x~
~ ICJ
x
~ eN
x
~ 4~Je
x
~ eeN
x~
ES ES ES ES
4.4a 4.4b 4.4c 4.4d 4.4e
".
X=O,NH,S
~'N)
4
3~NHl
4.6
2
5
lI
Although there are a few examples of naturally-oceurring 1,2-azoles, many
totally synthetie derivatives have found pharmaeeutieal application.
1.
1
I
1
1
.~I 4.1 Synthesis f isoxazoles and pyrazoles
Aromatic heterocyclic chemistry 29
I: R):;)
;;
"fj
d:
which wold exist as ketone 4.9. This in turn is clearly derived from 1,3-
tone
:~10. ~ Rz
l:!:N
R3
~
~
b R3
~ r; R
4.11
4.12
H2NOH
HzNNHz
Rl OH k Rl O N,XH Rl O
4.13 HzNSH
4.8 4.9 4.10
4.7
X=O,NH,S In practice hydr'xylamine and
hydrazine are very reactive
nucleophiles, far more so than
might be expected from
conslderation of simple physical
This ana1ysis suggests that condensation of 4.10 with hydroxylamine 4.11, parameters. The inceased
hydrazine 4.12, or thiohydroxylamine 4.13 should give tbe corresponding nucleophilicity of a heteroalom
when bonded to a second
1,2-azole. This approacl represents an important route to isoxazoles and
hereoatom is ~no"Vn as the a
pyrazoles, but thiohydroxylamine 4.13, although known, is far too unstable
effect. For a theoretical
for synthetic purposes. The synthesis of isotbiazoles will be mentioned latero rationalislion of the a effeet in
The mechanism of the forward process is illustrated by the preparation of terms of frontier obitals see
isoxazole 4.14 and is simply two consecutive condensations. Fleming, 1976.
He
O O) O GH
~r-( ~
~--.~ HzN-OH H OH
~~r-.
O
\
O
4.14
H
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 O
Jl~Jl'R HzNOH
~
R 3 +
Rz The general reactions of H2NOH
and H2NNHR with unsymmetrical
diketones are shown here.
+
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 electron-
witbdrawing 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.
30 Isoxazoles, pyrazoles, and isothiazoles
o o
~
MeO
MeO
4.15
O o
~
HO,
O N
~C02Et
4.17
4.19 \1\
~W) - + )J
I 4.18 Rl O
Rl'-- eO
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:
4.18
(-2H)
Aromatic heterocyclic chemistry 31
n
Br
"O~NH-t-Bu
. H2N-t-Bu n
Br
~'o~
~
Br
n
N'O~Br,
OH O OH
4.28 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.
J-l
N:)\'NH 4.30
2
il
1
!
~N'H
'J
l
n
N
r
S
-HCl
~
]
.J w" '-...A C;
~
L
32 Isoxazoles, pyrazoles, and isothiazoles
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
I'$
Br Br
(C;
O
Iil'
Y;N N:~~" Hi ;k -H" ~No
Nitration an:
,ulphonotion Of1,20.:':
unde, vigorou, condi:ori, are
also knoVin, as in the preparation of 4-nitro~~azole 4.31.
Ij
hI(~;N 4~1 1I
N02
I
~
;!l
Aromatic heterocyclic chemistry 33
0s .\.N n-BuLi
---JI>~ Li
EB e 0\s'" N
~n
EtO~S .... N 4.33
o
<!.._ ... N
N
Ph
n-BuLi.. Li EB ee P~
N
MeI
..
o
0\
Ph Ph Ph Ph
n-BuLi LiEB C"efi'
N !lO (;N
o'" ~
4.35
lfowever, alkyl groups at the C5 position of isoxazoles can be deprotonated
and reacted with electrophi1es.
~~;N
O
r1 n-BuLi!lO
Li
EB r1
e~_;N
Note the anafogy to the anions
derived from erotonate esters.
0
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
eJ:S
o. efi N
~'I
N-methyl group, faeilitating
~
Br2 c;.1j ...\N n-BuLi
!lO IN
\ reaetion with eleetrophiles at this
position. .
o o'" . 2.HCl
~
4.14 4.36 4.37 4.38
N
4.5 Problems Me
n-BuLi '):)-78
oC
1. What is the mechanism for the fonnation of isothiazolone 4.39?
~ \N
eEB o N'"
N:::C-S
EtOH/H20
K
.. rf
(S . . NNH
MeI/
;1
I e
CHi
4.39
~ N
Et
J.,
~
"
34 Isoxazoles, pyrazoles, and isothiazoles
steps
------~
HO n
~N ... N 4.40 Ar= Vel
Ar Ar::
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.
o
ex>
4.43
NHZOH.. ~N
4.44 o
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)
(Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D.
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). I
.~
4
5. Pyridines
5.1 Introduction
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
!:.
f
ringo Pyridine is moderately basic (pKa=5.2) and can be quatemised with
,1
oEaN
H
I
. H
Ea
O N
R-X
.. OeN
I
x6
5.2
[
1 ~ S03 R
"
!
.l
'!
I
OEa, 5.3
I so?
.(
! 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
rr.
R3 R3
J6:~
I /. :;>
'DR. I I :;>
Rl N Rs Rl N Rs -NH3
Rl OH OH Rs
H 5.6
5.4 5.5
R\ O~H'~O R3 JI
I
TI I
R3
Rl
+
O
~ "'{'~
Rl O
[R4
O Rs Rl.O O R,
5.11 5.9 5.8 5.7
~
O C02Et ~H: ~ EtO
t2
)el
I I
N
OEt HN03
(-2H)
~ EtO tr~
I ~ i
N
OEt
11
~3 H I
~
5.12
For instance, condensation of ethyl acetoacetate, formaldehyde, and
5.13
I
arnmonia gives dihydropyridine 5.12 which is readily oxidised with nitric acid
to give pyridine 5.13. Although the precise details of this multicomponent 1-
condensation are not known, a reasonable pathway is shown below. I
!~
O 'I!
;
ffiO~O I
Note that in this example R2 and ~
R4 are ethyl esters, so the
adjacent carbon is actually an !I
active methylene group. The
higher acidity and hence
nucleophilicity of these centres
t
.!i
N~N
I
o H Ph o
EtoVfoEt MeO OMe
AMJl N _.'
H
~
I
N
O O
~
PrO OPr
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 Heat
5.14
OMe
il ,
38 Pyridines
Q N 02
e
N H
~
e~QN02
N H
~
l.
a
=--N
e
N02
H
N02
C2-attack
.
a~ ~
d~ ~ OH C3-attack
=--
N
e ES /-
N N
H N02 H
mO~
N02
lJ N
~
O
N
ES
~
N
C4-attack
C-alkylation of a sterically-
hindered phenolate anion.
e
o N
[O]
.. O
. Na;
o'e
5.17
E E
~ H E
5.17
~
e~
lO
C1
~ ~5.18
_He
lO
,
Na;
5.19
E
G E
Oe
E
5.19 6~ N 6
r.,Na;
-P0Cl3
lO
6
N
,et'"")
oe 'fe
PC13 O-PC13
Aromatic heterocyclic chemistry 39
oN
HO
AcOH
Jo
O Ne
I
lIN03
H 2S04
Jo
6,
Ne
PCl3
... ;N
$.17 oe oe 5.20 .
0--
6
Ne
e - , (;'
p/
Cl/ 1'\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 2-
and 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
U
I ..:
N OH
~
~ el N
H 5.22
6N
~
~ N
H 5.23
oe
[ Clo
H
~
uJ
,e
. N oe
H 5.22a
[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!'
o ~1'Cl
Cl
E
5.24
I
N~
I
.~
I
e
H \-Cl
O
11
ED Cl
e O-P,.... Cl
Cl~Cl
E ~
I .;.o:
N EaN~
I
5.25 H
The actual mechanism is rather Under conditions of high temperatures the intermediate anion can re-
complicated. Hydrogen gas is aromatise by 10ss of a hydride ion, even though it is a very poor leaving
evolved, but in reality free sodium
hydride is never generated. See
group. This is illustrated by the Chichibabin reaction of pyridine and
McGiII and Rappa (1988). 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/.
NH2
Aq. workup Qe
N
Ea
NH Na
5.26 5.27
Aromatic heterocyclic chemistry 41
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
~ N X
'd:}x x
(9 -ele
...
6:rt
~-' x = NucIeophile
~ NH3~~'
N el N NH
2
6
N
HN(CH2eHeHV2
Do
N
I
el SEt
~H2NNH2 ..
N CI ~
N N-NH2
H
6 N
me
Na SEt
.. 6N
:
l'
el HNPh
U N
H2NMe ..
el ~
N NMe
6 N
H 2NPh
~
6N
H
el HN~NH2
6
me
u N a 0M;
N el
~
N~ OMe N
H2NNH2
Do
6N
)
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.
e (j'F H ~F
6 a a
o o el HW NH2 ~ HN ... N~
I I
N02
poel3 I
N02
H2NNH2 .~
__
~N02 o &~02
N N
..
N/.
tJ
N
~ I
N
/.
H H
5.29 5.30
5.23 5.28
H!Pd/C
2
F
H I .
HN ... N ,.
...
Heat (-H20) ~~2
t.J N
5.32
Cl~
N e
(:l
e
O O
N
~
N
e
o~e
R
~
e
R
o~ 5
~ )
eO
A similar argument holds for 4-methyl pyridine. These stabilised anions can
then react with the usual range of e1ectrophiles.
Cl .. Cl ~
NaNH2 Me!
lO
N N e N
Na ffi
ClN
PhLi
lO Cl
N~ e
PhCH2Cl ..
~
I /.
N Ph
ffi
Li
ClN
_PhL_i_.... Cl
I N~ e
l.C02
2.HCl
..
Ov
I N'~~ 'Coe
2
Ll ffi I ffi
M n-BuLi
:f:l
.. I
N./. e
l.H
~
~~
I
o
2.HCl
..
/.
H
OH
~
Li N
Na~ffi
e
The negative charge resulting
from deprotonation of Ihe ethyl
I ;;::.' - - - - - ,..
-' ./.
Me!
~
methylene group of 5.33 cannol
be delocalised onto the nitrogen
N atom.
5.33
j::~
deprotonation of the amide
followed by ortho-directed
deprotonation at Ihe C3 position lo HNi:
6 6e"'~ie
produce the pseudo six-
Ea
membered ring organolithium t-BuCOCI Ll
species 5.36.
!lo
----:-.....
n-BuLl
( 2 equivalents )
I /,
N N 5.36
5.34 5.35
NH2 O
;;!:~l X HN O
C(H
N
5.38
.. HCI (conc.)
Heat &H
N
5.37
5.6 Problems
l. What is the rnechanisrn of this reaction?
NaOEt/EtOH ~oo,m
C02Et
Hint. Start by acetylatlng the 2. The condensation of active rnethyI groups with aldehydes can be catalysed
pyridine lo give a qualernary
with acetic anhydride as weIl as base. Suggest a possible rnechanism.
cationic species. How can
deprolonation aftord a Ph
nucleophilic enamine-like system?
(
.N
PhCHO
A~O/AcOH O N
OMe
OMe
~M..
1. 2 eq. n-BuLl
2. p-MeOC6H 4CHO
..
O
5.39 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
Aromatic heterocyclic chemistry 45
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?
~
o C1
. H
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).
Vogel's textbook 01 practical organic chemistry (5th edn), p.1168
(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.
Pergamon Press, Oxford.
1'
i
1.
.
6. Quinolines and isoquinolines
6.1 Introduction
Quinoline 6.1 and isoquinoline 6.2 are two isomeric heterocycIic systems,
Quinoline and isoquinoline can which can be envisaged as being constructed from the fusion of a benzene
also be viewed as being formally
derived from naphthalene
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.
5 4
6~3
7VN~2
8 NI
Note the numbering system for 6.1
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.
HO~OH
el O)
OH 6.4
H H
HO~OH HO~OH
e
I
OH
6.4
6.5
H
-:820
0N- ~
H
~~~He
(lf
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 Acrolein is a highly reactive olefin
the reaction medium. Better yields are realised with this approach than if Ihat is prone lo polymerlsation.
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..
OH
, -. : . .
(O -2H (()-...::: ~H_
~ ~ N ~'.
N UN)
6.1 6.10 H 6.9 H
HO~OH
OH
~
aMe
HO~OH
OH
~
,90-",:
~
N
~
1:
OMe
OlNH 6.11
2
RCOQ
Base tu;NH
O=< 6.12
x = Electton-donating POQ3 R
8ubstituent
XitQ
~
I ~
..-:N -2H
O?
6.14 R 6.13 R
This dehydrogenation is As in the Skraup quinoline synthesis, 10ss of two hydrogen atoms is
the reverse of a normal necessary to reach the fully aromatic system. However, this is usuaIly
hydrogenation reaetion. The
dehydrogenation cap be earried
accomplished in a separate step, utilising palladium cata1ysis to give
out under mUder eonditions when generalised isoquinoline 6.14. This is known as the Bisch1er-Napieralski
a hydrogen aeeeptor (sueh as synthesis. The mechanism probably involves conversion of amide 6.12 to
eyelohexene) is present. 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.)
R
6.13
x = Electron-donarlng substituent
The Pietet-Spengler synthesis is Closely related to the Bischler-NapieraIski synthesis is the Pictet-
usually used when the Spengler synthesis, which utilises aldehydes rather than acylating species.
tetrahydroisoquinoline oxidation
level is required.
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
<0=0)
O
~ I ?- N
6.16
(YIfI
o~NH
6.17
Aromatic heterocyclic chemistry 49
oq .[\Sq-t;q]
H 6.18a H 6.18b H
oo~
~
.~
I N
+
6.1 6.20
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
CO ~ ~ NaOEt~
~
l.~/Heat f
~,
~
..-: 2. Aq. Workup ~
~
N
N"-: NH
2 ~ N"-:: el ~ N"-: DEt
6.23 6.25
O)
07 09 09
1. KNH2 / Heat NaOEt
~ ..-:N 2. Aq. Workup
~
~ ..-:N ~ I ..-:N
~
~ I ..-::N
~-
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
~ I----1~~
......
~N'~
N e
6.27a 6.27b e
Such carbanions can be alkylated, acylated, or condensed with aldehydes:
~
~
l.KNHz
~ /. 2.EtBr
... ~ ....::
N N
(IQ ~
LKNHz I .
11=
~ ..-::
2.PhCDzEt ~ N/. Ph
N
Aromatic heterocyclic chemistry 51
AI
(JC) "'.
7 e p-MoOC",,-
9,7
::::,.,.
1 "'-'::
~N
[~
~ "'-'::
e ex;: 1
~
........ ,'"
~
"- Ne
6.28 6.29a 6.29b
PhCHO
ZnCl2 /Heat The reader is reterred to the
previous chapter (Problem 2) tor a
mechanlstic explanation ot such
condensations.
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 O O
F:(l.
Cl
= I
NH2
lL __
OEt
Heat
Do
C0 Et
F;o:)' 2
~ I
C::::,.,. N
I 1. NaH ..
2. EtI
FroC02Et
r'
Cl. ::::,.,.
I
N
I
6.32 H Et
1. NaOH! 2. HCl
r
o
FW
NH O
F~C02Hl.HN~ C02H
HClRN ~
rN M,)JN 6.33 Et
2.HCl
~~r----- Cl::::""
I
N
Et
I
52 Quinolines and isoquinolines
o
R0:(f'H
I ~
RO~~
I
N0 ROJ
---.~ I
2
____
. R 0 :IQ j
Step 4 I '?' I
+ ~ OMe
HO
Step 6
. Step 5
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.
500
6~
1
N
1 2
3
~
~o)J
~
~s)J
7 H 1
7.2 7.3
7.1
, ,
[ (Q I
H
7.1 7.1a
HO~.
I I
NH
z
~ N
7.4 X=OH H
7.5 X=NEtz
7.6
iC! _ e, - _i?
Aromatic heterocyclic chemistry 55
H
,,(l..H
Ph-N-N~ 'H
H EIlI Ph
H
7.10
~ ~.NH2 ..
~N.J.l..ph ~N)(Ph
7.9 H H
The electrocyclic reaction is very similar to the Claisen rearrangement of Cope rearrangement
phenyI allyI ether 7.12 to give phenoI 7.13.
H
~j-CQ -- ~
~'OH Claisen rearrangement
7.12 7.13
Ph -N-NH2
H + O
J')y--+ Q
R
OMe OMe Diaza-Cope rearrangement
Ph -N-NH2
H + oD
CV)
H
O~SPh ~SPh
Ph -N-NH2
H + VN~ 7.15
7.14 H
Meo'Q
r l + oaNM~ ---+~
Me0V::=CrNM~
I I
::::". N-NH2 ::::". N
p*
H H
F F
r l + _-.~ F~
F~~.JV
. ::::".
F ft-NH2 oD
F F H
and 7.17 can fonn, which would give rise to indoles 7.15 and 7.18
respectively.
SPh
SPh
Ph -N-NH2
H ~I
~
7.7
Q ~ I
YSPh
N"
H
NH -----
7.17 (minor )
~N~
SPh'
H
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.
7.19 7.20
lO
W 7.1 H
!
7.19 ?' I H
" N~
~
[ ~
~N~oe
7.233 o
1'"
\
~~
~N02
7.23~
e
y H
('9Me
AEDo
-eN
7.22
-e--I.....
-OMe
.. ~I/(JED
H
UMn '-:-
H
N02 -H
e
Aromatic heterocyclic chemistry 57
. O ~o
~
~ H
I z Jo Pjrp
~ NO
z
Pd/C ~MUz Jo ~N)J
7.24 NH
7.20 7.1 H
Sorne examples of the Leimgruber synthesis are shown below.
Meo'((
I ?' ----..
Me0'(tJ
I I~
~ N0 ' N
2
H
COzEt
0=0:
< ~
I
N02
----..
OJ H
O:~H
iJ:'( E
~
~N~E
I
7.25 H H
Pjr--p ~NMez
~N).I HNMez ~N;J
H AcOH H
This is the reactive electrophilic 7.1 7.26
species of the Mannich reaction.
e
CH2 = NMez ~OAC
~N;J
H
7.27
o
~H'
~
N02
~ I
:::-..
.N
I .. UN~ Pyridine
H 7.30' 7.28 H
Cl~C1 o
Meo~
I I
O
MeO~C1
7
----~~ ~ I I
MeO ~ N MeO N O 7.32
H
C~)
7.31
l B
Ph
O rNPh
MC0:JCrN~
: I I
MeO N O
H
7.34 7.33
~. ..
W
MeI
NaH ..
~N)l
7.1 H 7.35 Me
EtMgBr!
~~
O:J) :r
,J
MgBr
-MgBr2
~
~N)J
7.36 H
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 (RO~C02Et
~
RO
Raney nickel ~ ~
C~Et
~NM~ N02 ?" I I
~N)J Heat ::-.. N N02 Hz ~N)J MIz
7.39 H H 7.40 H 7.41
R == PhCH2
7'''~Ph NH
, 2
0=5::0
I
7.45
H O 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).
Vogel's textbook 01 practical organic chemistry (5th edn), p.1161
(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
N-N
~"
4(N 3
~
5 "N 2
\\
f( ') ... N .oxadiazoles
4 N 3 4 3
0 1 O O N
8.1 8.2 8.3 5 !C,,'N
NI
2 1.("N 2
5 I
N"
4 N 3 H H
![s,.N\ 2 ~~
N-N
5 f( S ~ S"
thiadiazoles 8.7 triazoles 8.8
I
8.4 8.5 8.6
4 N-N 3 N-N
5 1.( ,.'N 2 tN-N\\ . t 'N
"N . S"
NI tetrazole O oxatnazole thiatriazole
H
8.9 8.10 8.11
o) 2-( NaOH
~
~~-(
,N
_ele
~
N-{
AN
~R
)0"
ae 8.tl HO HO o'
HO
HO -ele (N-N NaOPh ~~-N _a e
. N-N
el
)IZ'N
N'
~
PhO
)Z ,N
N
" PhO A"
N,N
PhOe)H 8.13 H H
HOAR
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.
i
Ph Ph Ph
~ _N_aO_Et--..... ~-( O N-(
~o'
Na
ES e~O'
EtO __
lfA ~
~
-O'
N
8.14
ES
("'N-~ -N2 e
Li e I!..N""N ~
PhNe:N
Ph~ 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.
R2 R2 R2 R2
O
HN-{
l~
~ ;:>
;:> N-{ H 2N-{
+ R(.Jl. X
R~
~ N ....
R O R,J{ N'OH N'OH OH
OH O
8.18 8.19 8.20
8.16 8.17
. X = Leaving group
rSf'OMe
N
8.21
O
EtOH, heat
60>
N
8.22
: !)~
64 Five-membered rings with three or Jour heteroatoms
H
10
e eN
111 ;NfB 8.8
?"--r N"'J
H ~ H
Et02C-C= C-C02Et
Heat
..
8.23
~
Rl 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 N-N
1/ \\ $
~ ,N
N
/!-.'N
N' + H pKa = 5.63
H e
)loH
)loe +
$
H pKa = 4.76
Aromatic heterocyclic chemistry 65
o<
O O
8.29/
~ I
.........
N~I ----~'"
NaH
O
8.28
N-N
~
\\
N conc. HCl
HN N' ......1 - - - - -
2
. H
NH 2 .2HO
8.27
HCl N-N
R-C::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,?) o
RIO~O RIO~
8.33
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?
F '(!l.I 0Y'el
el bo
~
F::;-- Cl
~?
H..
~N'N~
F::;-- '=N
Y Alel3 ~ I Et3N ~ I
F F
(CH3h::O 191F
NaH
fN'N~OH N,N~
Nd F
8.35
.
7
~I
F
.'
'=N
F
:;
o
7
~I
F
N,N~
'=N
8.34
2. What is the mechanism of formation of oxadiazole 8.22?
o
~-(
rSf'OMe
l~) O~
N EtOH .heat N
8.21 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.
O
4 4
50I
6 ~
3
2
U (]
10
El:)
9.1 0 O 9.2 10 9.3
1
5 5
ro
O
4 4
60)3
7::::""
8
0'-' 2
El:) 1
9.4
ClCt
::::....
8
9.5
O
1
O
: I
8 0 1
I
In natural product chemstry, the
9.6 acetal formed between an aliphatic
or aromatic alcohol and a sugar is
The red,violet, and blue pigments of flower petals are called anthocyanins, termed a glycoside.
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.
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 9.9
\
The carbonyl groups of 4-pyrone In contrast, 2- and 4-pyrones are considered to have relatively Httle
and 4-pyridone absorb at aromatic character. Whereas in an analogous nitrogen series 4-pyridone 5.23
approximately 1650 cm- 1 and has significant aromatic character (mesomeric representation 5.23a making a
1550 cm- 1 respectively. The considerable contribution to the overall electronic distribution), aromatic
lower energy of the pyridone mesomeric representation 9.3a makes less of a contribution to the overalI
absorption reflects greater single
bond character, and hende
electronic structure of 4-pyrone. As with furan, the higher electronegativity
greater delocalisation. 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 O
[ (] O [ (] N
H
Ph n :-'0EB Ph
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
Ph~P~
o J. H [ 1 OH
Ph~Ph~Ph~Ph --"Ph~Ph
e,
H" OH O
Ph Ph
n
H H
9.13
Ph
I I
9.11
O Ph
HCl04
Ph
n
Do:-...
r I
0Ell Ph
ClO e
+ Ph
~
O
Ph Ph
Mos! pyrylium sal!s have electron-
Ph donating aromatic substiluents al
the C2, C4, or ca positions which
9.12 4 9.15 serve to stablise the positive charge
by resonance.
9.3 Synthesis of coumarins
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.
-EtOH
70 Six-membered ring heterocycles containing one oxygen atom
~3>
UO.Jl. VOHO~Ph ~ VOHo~Ph
~ ~~ 3> ~
U + 9.23
Ph OH
9.19 9.20 9.21 9.22 x = 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.
O O
oc
o O O
~ OH
PhCl
Pyridine
.. oC
~
I
0-1<.,0
l.KOH
2. AcOH
..
~ACOH/H2S04
~
I ...
OH Ph
~ Ph
UO.Jl.
O
9.22 9.24 Ph 9.21 9.19
o 0$
9.1
o N
5.1
(\0
9.2
Cl N
H 5.22
O
O O
O
9,3
6 N
H 5.23
Aromatic heterocyclic chemstry 71
9.3
O O
JI O
6 H01) ~
fo'~
-H2O
4 ~ 9.26
5.23
N H NH2
H H
The reaction of pyrilium salts with nucleophiles may involve electrocyclic
ring-opening of the intermediate dienes, as in the formation of ketone 9.27.
~ C'0') e~ectrocy~lic.. .J
)L~keph
0e
PhLi..
Ao.R
~ Ph
~())l
nngopenmg
O Ph
C104e 9.27
~ .
NaOH
.. . ~
~oAo Hel v--. O
H
Ao
O
e ES
9.5 9.28 Na
m m
O O O
y.~~/
9.29
yoANH 2
9.30
O HO
7f
9.32
99" ~ N
H W~ O
H2N
,
9.31
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 9.2
o o
o
llN'-;~O
H 5.22
~
yo}
? ~NM~
yo}
OMe 9.34 OMe 9.35
o o
~
VOHO~Ph -H-2-S0-4~"
AcOH
~
UO~Ph
9.21 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.
5
6
O,
4
~ ~N
3
2
5 ~N 3
6 ~JI 2
4
5
6~)l
r:-
N4
p 3
2
5~3
6
4
~__ jJ 2
N1 N 1 1 NI
10.1 10.2 10.3 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
H
N N
H H
10.4 10.5 10,6 10.7 10.8
NH2 steps
I
R
NH2 o o
. N~N ~N-rNH2
f:CJ
N N
~NJl..NJ1 NJl_.~O
I N,
I
R 10.9
R H R H 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.
R,JCl
R N R4
;>
10.11 10.15
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
10.16
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
~
Aromatic heterocyclic chemistry 75
H OEt
H
O
~tr
NaOEt
~
EtOH
o
.)lOEt NaOEt
~
EtO.,l.O + EtOH
Ha ~
EtOH
Me
10.19
NaOH ".tN
- -... .JtN
Ph
oi(~ .. O
fo~e
~H
yO
-H,O ~
o
fNrO NHMe
HN~O NHMe
Me
Hel
~N 'NAo
41
-H2O
H~'"
H
~
"N
o O
IN~O
eN
FIN03
~
N0 'L
2
I N eNE FIN03 N02'(NH
.. I ~
Heat
N~O NAo N o
H H H H
10.20 10.21 10.22 10.23
~N Y = Leaving group
~NJl.NPh
~
~N
~Jl.CI
Na
ee
OMe
.. ~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 O Cl NH2
N
10.24
Aromatic heterocyclic chemistry 77
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
~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
Et
NH2 HCl
Jo eN
I NAo
H+O
OEt H2N o H20 I EtOH
H
10.26 10.16 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
MoN~ +
~o
H
2.46 2.47 2.48 2.43
[ Qyo H
2.44
H
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 2.49a
~l
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
I
Aromatic heterocyclic chemistry 79
--.~~ ON0
2
lO H f i N 02 Pyridine.. (J-
Ac08 (.:OE!) H AcO""",, H - AcOH N02
l_'
,
_2......
3.33
H~
r
~ NHz NaOH ~
H~
r \_ Ph
l.S0C12
PhCOCl
lO
I/- 2.MezNH
lO
H~N,H
Ph~
Ph~ --jIoo --jIoo
Br NHz
80 Answers to problems
C02Et
MeI
MeO'N~O
3.45
[
o
o~l
H """
>=C=<.~
srfN ~ rt
s
I
CN
NH2
1 ('br't.J
NH2 -CN S"NNH
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.
n
N)N
HC(OMe)3
~
n
N)N
n-BuLi
..
Ll'ES e n
N)N
H I I
H,C,-OMe HC,-OMe
OMe / OMe
4.40
OH
Ar
n
~N,..N
Ar H
HCl/HP
0W
ArAr I
U
I
\
N"N
/'1.Ar2 CO
2.NH4 Cl / HzO
H,C,-OMe
OMe
3. Oxidation of oxime 4.41 produces nitrile oxide 4.46 which cyclises to
isoxazole 4.47.
'ES [31
HO'N~O/ NaOCl ~ ~O~ [3+2] ..
/ '" NaOH
~N
U O
ClH
4.43
4.45
O~C02Et
COzEt
Ph
6 N
OMe
lrr-~
n-BuLi
Do
(2eq. )
5.39 O
OMe
~
H Ar
I ~
O
N
O
5.40
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.
O ~-:J \'f~'''
EtO~OEt E~~O)
F~ r~iEt -EtOH~F~:..J I ~ ~ ~
O r o O COzEt r o O COzEt
OEt -.:. I ---.:. I I
Cl~NHz"""" Heat Cl~N Cl ~ N Cl ~ N '
H H 6.32
"*1"
'e'~1
Aromatic heterocyclic chemistry 83
~) e o, e o
F~CO_Z_ _..~ ~~CO~C1/H20~ F~~H
C~NjJ r~jJ rN~NjJ
r NH Et HN~ Et HC!. HN~ Et
HN~
2: Step 1. Condensation of the aldehyde with nitro methane under basic
conditions produces the cx,~-unsaturated nitro compound.
o OH (OH e
Art H - Ar~NOZ----Ar~NOZ -OH~~NOz
~ H H H
'-l..:HzNOz ~eOH
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~ ~ R~ R~
EB
H fl -CH3Br,..
~0_CH3 ~0_CH3 ~
EB, OH
H ~r
84 Answers fo problems
Ph-N-NH,
H
oD. ~ ~N~
H Cl~NM~
NdJ. ~
~N~
~
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.
,...... 0 C02Et
Ro~r.Ea RO~ e( RO~C02Et
I IJ fMez - HNMez 7 I "..; N02 7 I I
:::-- N. ~ H Do ~ N~ '1 Do:::-- N N02
IV Eal~ H
H H 7.46 7.40 R = PhCH2
7.47 O:J
:::--
I
N
I
e~1
C
Ph
OpyPh -- ("n-I1
~~~
Ph
Ha.,
Gn
~~~
Ph
0=5=0
I (111N (1 N Ea . Ea N H20 7.44 o
I
o=s=o e Li L1 I
Ph U~h~ o=s=o
I
7.48 7.49 Ph
I
7.45 Ph
1
:)
:{
,',1,
Aromatic heterocyclic chemistry 85
'. Co -- ~
EtO-H ~ ~-(
OC .0-....
R NH2
8.21 l OMe
e O,
-NH-2--'~ O~....J;r--
O-N
l~ O~
N N 8.22
N
11.8 Answers to Problems in Chapter 9
1. The mechanism is similar to the 4-pyrone example.
tLcl~--.
o 4 -o
0
~OH~O
~ 'a' 0
4'~~0 ~n
~HO N O
eL' N o
'--. NH2 H 2
H H
9.2 NH3
2. The first stage is the same as the preparation of 9.30, then cyclisation 5.22
affords the pyrazole.
oc9
''\N
,
?' N
9.33 ::::... I H
OH
3. This is a Mannich reaction (see Chapter 2) and is an unusual example of
an electrophilic substitution on a chromone.
a
w~
aMe 9.35
oa'""t
a a
H ruQHe
aHph a a Ph
E9
-Hza
ro
~
o
a
9.19
d
Ph
[~H ::::... a E9 Ph""---'
9.36a
d.fH 1
~ a/.
9.36b E9
Ph
86 Answers to problems
(N
[ (CJ2'G~ ~
H
... .. ~Jl.oeI
H J
10.20 10.20a
The mechanism of nitration is shown below.
,Ph0NH Ph0x NH
,Ph
0 . O
~~~OEt
]>'
~N~O
H
~x + H2N
~2O O OEt
10.25 10.27 10~16 10.28
CN eN CN
~
........... HfD -EtOH J :
OEt -+ H~ r OEt- ....
H+
OEt
'o H
H O
10.29
10.26
H2N~O
-H20
..
H
~
=--N
e"
,.4. NHz
o
~
~
H
.iN~O NH
2
10.29
NH z NH
H'"r ~/H
~NEB
C-lo eNE
N~O
...
H
e'"
)[~2
N
H
O
H H
10.6
Index
a.-effect 29 electrophilic substitution of oxazles 26
acetyl nitrate 15 furan 14 pyrldines 40
acid chlorides 6 imidazole 24 pyrimidines 76
a.-aminoketone 13 mdole 57 quinolines 49
arnmonia 5 isoquinoline 49 thiazoles 26
AMP, biosynthesisof 74 isotbiazole 32
anion chemistry of isoxazole 32 ornithine 64
furan 17 oxazole 24 ortho-activating substituents 43
imidazole 25 pyrazole 32 oxadiazoIes 61
indole 59 pyridine 37 oxazoles 20
isoquinoline 50 pyridine N-oxide 38 oxazolidmones 8
isothiazole 32 pyridones 39
isoxazole 32 pyrimidones 76 Paal-Knorr synthesis (pyrroIe,
pyrazole 32 pyrrole 14 tbiophene, furan) 12
pyridine 42 quinoline 49 phosphorus oxychloride 15,47
pyrrole 17 tbiazole 24 phosphorus sulphide 12
quinoline 50 thiophene 14 Pictet-Spengler synthesis
tbiazole 25 (isoqumoline) 48
anthocyanins 67 Fischer synthesis (mdole) 54 pyrazole 28
aryl hydrazines 54 fiayone 70 purlne 73
.i,2 azoles 28 furan 10 pyridine 35
1,3 azoles 20 pyridme N-oxide 38
AZT 74 Gould-Jacobson synthesis pyridine sulphur trioxide complex 15,
(quinolone) 51 35
barbiturates 77 pyridones 39
benzene 2 Hantzsch pyridine synthesis 36 pyridontriazine 41
benzopyrilium cation 67 Hantzsch thiazole synthesis 23 pyrylium c.ation 67
bioisosteric replacement 63 heteroaromaticity 1 pyrimidines 73
Bischler-Napieralski synthesis histamine 20 pyrones 67
(isoquioline) 48 hydrazine 29 pyrroIe 10
hydrogen suIphide 12
Chichibabin reaction 40 hydroxyIamine 29 Quinoline 46
chIorophyll 11 5-hydroxytryptamine 54
chromone 67 resonance 2
Claison rearrangement 55 imidaiole 20 retrosyn thesis 4
condensation 3 imidoyl halide 22 Robinson-GabrieI synthesis
Cope rearrangement 55 indole 53 (oxaZole) 21
coumarin 67 isoquinoline 46
cytosme 73 isotbiazole 28 Skraup synthesis (quinoline) 46
isoxazole 28 synthesis of
delocalisation 3 chromones 70
delphinidin chloriqe 67 Khellin 67 coumarins 69
dihydropyridines 37 Knorr synthesis (pyrrole) 14 furans 11
disconnection 4 Konstanecki-Robinson synthesis heterocycles, principies of 3-8
DNA 73 (chromone) 70 -imidazoIes 22 -
drugs for the treatment of indoles 54
AIDS 74 Leimgruber synthesis (indole) 56 isoquinolines 46
asthma 31 lysergic acid 54 isothiazoles 29
bacterial infection 27 oxadiazoles 62
depression 60 Mannich reaction 16, 58 oxazoles 21
fungal infection 41, 66 pyrazoles 29
infiammation 22 neurotransmitters 54 pyridines 35
schizophrenia 18 nitriIe oxides 30 pyrylium salt 68
senile dementia 45,63 nucleic acids 73 pyrimidines 74
sleep disorders 77 nucleophilic substitution of pyrroles 11
trematode infection 69 imidazoIes 26 qumolines 46
ulcers 1,11 isoquinolines 49 tetrazoles 64
88 Index
'"
_.
_.,-~--
, __ '\-'--."
..__ .. _............. _- ..
......-~-
......
= ,_. _ _ . -.... _ -
,-
..-
.,
"_-'''_ "
__
::'.-
...,.._. __...-..--_. . . -
__
:'::':':'::":':"~":.:.:.:":::.:'
_TIo_~.
....._
_._., .2 .....
_--- ;. d , _. . _
"
_ ,_ _ c:-. ' , ._
, _ _,_
_ _ c-_
.. .. - . __ . - ........
,
... -
o 2
-
...._
_.,\-.___
_
....
_._-
_~------~._~--
_ ..... __ ._ .. _o, .,
__ ...-..-......,-
.. " ..
_~
_- ..
............. _ - ..... , . . . . . ..
..-.......... _..... ..
'" =. ---_...........-
. _. __. ,._---
'......
.. _'
'a .
- . ... _
__.._.
0 .. _ . . . ji
"'_110 _ _ _ _ _ ... _ _
.a
l. - , . _ , '
_
-_.
..__
_......
--~ ....-..
__ .
~.
._.-.
,'" '7
-----
aa __ _
.'
_, _ _0-0 , _ _
&
...-
...
'"
..... "
-
_
"'0__---_. __
" ..... _ ... ,.._ ... _
........ .... -.......
._~--
. . . . _0, .,
'"
_.
_.,-~--
, __ '\-'--."
..__ .. _............. _- ..
......-~-
......
= ,_. _ _ . -.... _ -
,-
..-
.,
"_-'''_ "
__
::'.-
...,.._. __...-..--_. . . -
__
:'::':':'::":':"~":.:.:.:":::.:'
_TIo_~.
....._
_._., .2 .....
_--- ;. d , _. . _
"
_ ,_ _ c:-. ' , ._
, _ _,_
_ _ c-_
.. .. - . __ . - ........
,
... -
o 2