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Aromatic Heterocyclic Chemistry
Aromatic Heterocyclic Chemistry
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
20
28
5
6
7
8
9
Pyridines
35
46
Indoles
53
61
67
10
Pyrimidines
73
II
Answers to problems
78
Index
87
1. Introduction
el
N~N
H I~ 11 H
EtN ~ N /'--- NEt
1.1
1.3
[ s>-=<s ]
1.5
1.6
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
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
eO~eO~Oel
eN
H
eN
H
eN
H
Ii
1
I
f~
r
j
'1
I
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
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 symbol
denotes a
dlsconnection. an analytical
process in which a structure is
transformed into a suitable
precursor
1,.
I
I
.....
OEt
~C02Et
O
1.18
~C02Et
NH
1.19 ,
..
r<?
~N, ... H
H
1.20
r
1
1
f
,i
1.22
1.23
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
-rr,
1.26
!Be
e-e,
e!B
'l-ze)
NH
OH
NH3
~--nrO O
1.26
6 Introduction
[O]
R)lNJl. R
-2H
Do
I /.
N
1.1.7
1.28
1
i
H H
NH3
1.1.9
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
.'
((1
NH2
(see benzimido.zole syntMsis, Chapter 1)
NH
2
Vl
NH2
Electrophilic fragmenfs
No. oC ring atolOS
O
RAX
~~R
Rl~R2
R~R
O~
"k"
O
rt
NH2
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
Br':
I
~
OH
+
EtO
"Jl-OEt
~~
- H20
-EtOH
Br'(JC(
~ I -..;::
C0 2Et
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.
i
f
.)
r1
1
1;
!
'J
2.1 Introduction
<1
The numbering of heterocycles 11
generally starts at the heteroatom
aH
Ne H
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
~ ~
X
El)
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
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
"
R3
~Rl~R4'
O O
+ RNH2,H2S,H20
2.13
-~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
1
j
HS--..
S
2J8
O O
Ph-O-O O
1
f
PhD-O O
I
1
2.16
H2S
1I
1
1
ft
I
!
.1
Ph~
/-Ph
\.
}>2SS
- - - . Ph~
O O
H2S
tT-Ph
S S
Ph
--fJS
Ph
2.19
(i
2.22
R2
R3
W"
R-1!...N)-.. R4
H
2.13
~C02Et
2.25
~
~
AcOH
~C02Et
-.
o
.. N,
..
- CsHuOH
<><C02Et
O
El)
HUNH
~C02Et
~CsHll
N .... OH
2.26
~C02Et
..
AcOH
Zn
NH2
2.27
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
O~,Hll
c0.2Et
C02Et
~j
,lo
0y
~ ~
N
COlEt H
Ph
Ph
Ph
___t_
b(
N
H
Ph
Ph
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
1
1
I
~
I!
r
~
ji
g
~
li
~
:;
.~
,
~~
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
Oyo
H
Relativo Rato
s
O
1.2 x lOZ
NH
5.6x 108
Cl
H~NM~
ele
2.30
El)
..
-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
:::::::::
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
o
o
N
H
CH1O/HNEt1
AcOH
..
CH1O/HNM~
..
HCl
--O
CH1O/HNMez
AcOH
~NEtl
N
H
~NMel
S
. ~NM~
O
AcOH
~NM~
X
PhCOCIAlCl3
..
~O
f?y0
Ph
O
EtBr
ES
CH;:=. NMel
..
~
s
1,
---fJS
CHzO
COZMe
HCI
"
AcONOz
NO z
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
.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
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
Me
Me
n-BuLi
..
Li lB
CIP(O)(O:t)2
2.2
2.37
~ ,,0
S
~""OEt
2.38
OEt
I
I
I
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
QyO
H
2.44
~OH
N
H
2.4S
I
I
![JO
N0
2.33
2.2
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).
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):
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
~1
!
4;
!
t
'1
N
H
3.5
l.,':,
X=O,NH,S
'1! 2
'~f2
4J
1:
1,'
3.6
1
r
,t
I
I
I
j
He
(~
-.
N
H
3.7a
3.Th
fr~
N
H
3.8
3.9
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
Base
3.10
3.13
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
l.NaOH
2.Hel
yNy R3~
-"... O
p~NH2.Ha
~Pb lE:::~.)
el
Ph)[N
.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.
I
i.
t
f
I
I
f
r
tl
.~
dicarbo~yl
~~
'
MeO
I~
H~
e e
"
MeO
NH4 0Ac
MeO
.'jit'
:
;1
1i
y
f,
, )[~
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
(~
S
3.31
.~.
, H
yO H
"7:\
o~ N~H
Q '
HO~N
::)~,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"
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
1
f
I,
j
i
1
\
Heat
(~
X
l/N
~_;>8
n-BuU
Ea
l/N
~ _~
LiEa
X 3.37
3.38
E
. [[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
Ph
1
-;
- HBr
3.41
(o
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
3.33
Ph
Ph~
Br
Heat
1[,
O
3.44
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).
'iffW
ffF. --
w"'nm:wm-gm
775 G7
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
3~NHl
~'N)
2
4.6
lI
1.
1
.~I
I: R):;)
d:
4.1 Synthesis
~
;;
"fj
tone
:~10. ~
Rz
Rl
R3
l:!:N
OH
~
~
Rl
O N,XH
Rl
X=O,NH,S
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
~
O
4.14
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.
o
~
MeO
MeO
4.15
HO,
O
N
~C02Et
4.17
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
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
J-l
N:)\'NH
4.30
2
il
1
'J
l
]
.J
~N'H
w" '-...A
C;
-HCl
f,
r'},
1'/ / '
/'
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
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
~
'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
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~
0\
Ph
Ph
Ph
n-BuLi
Ph
LiEB C"efi'
(;N
!lO
o'"
4.35
r1
~~;N
O
n-BuLi!lO
EB
Li
r1
e~_;N
OR
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
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
------~
HO
Ar
Ar::
~N ... N
Ar=
4.40
Vel
HO'N~of
/
NaOCl ..
NaOH
'"
4.41
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)
(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).
.~
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
:!,
"
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
O
~
C02Et
~H: ~ EtO
t2
~3
)el
I I
N
OEt HN03
(-2H)
~ EtO
tr~
I ~
i
OEt
H
5.12
5.13
11
I
1-
!~
'I!
ffiO~O
I
~
!I
t
.!i
i
o
EtO~OEt
~MJl.
N
H
5.12
II!
i
i'l
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
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
..
[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
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 ........",
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
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
U
~J9
-ele
Do
'd:}x
(9
-ele
~-'
...
6:rt
x = NucIeophile
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
.1
1'
42 Pyridines
5.29
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
Cl~
N
e
(:l
e
o~e
R
~
o~
O O
~
)
eO
.1
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
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?
.N
PhCHO
A~O/AcOH
~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
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).
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.
6.1 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
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
:::::...
6.3
OH
NH2
PhN02
H;rS4
Heat
6.4
JI>
O)
: : :. . I
N/.
6.1
H H
HO~OH
e
HO~OH
OH
6.4
H
0N-
-:820
6.5
(lf
~~~He
6.7
6.6
OH
, -. : . .
(O
~ ~
-2H
~H_
UN)
(()-...:::
~'.
N
6.10
6.1
6.9
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:
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
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
oq .[\Sq-t;q]
H
6.18a H
6.18b H
oo~
.~
6.20
6.1
C()
6.2
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
~x~C1
x=NucleophiIe
(eX
~C1--.
~~
~N'~
N
e
I----1~~
......
6.27a
6.27b
~
~
/.
(IQ
~
..-::
l.KNHz
2.EtBr
...
LKNHz
2.PhCDzEt
11=
~
~
....::
I
.
~
~
N/.
Ph
(JC) "'.
7
p-MoOC",,-
[~
9,7
1
"'-'::
~N
::::,.,.
ex;: 1
~
"'-'::
........ ,'"
6.29a
6.28
"- Ne
6.29b
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
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
[ (Q
I
7.1
7.1a
, 54 Indoles
o
z
HO~.
NH
I I
~
7.4 X=OH
7.5 X=NEtz
7.6
Ph~
Ph -N-NH2
H
7.7
~
~N)l.,Ph
7.9
iC! _
e,
- _i?
,,(l..H
Ph-N-N~ 'H
H EIlI
Ph
7.10
~.NH2
~
~N.J.l..ph
7.9
..
~N)(Ph
H
~j-CQ --
~
~'OH
7.12
Cope rearrangement
Claisen rearrangement
7.13
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
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
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
~
~
NO
Pd/C
Jo
~o
~MUz
7.24
7.20
Pjrp
~N)J
Jo
NH
7.1 H
Meo'((
I
----..
?'
N0
N
H
COzEt
0=0:
<
'
Me0'(tJ
I I
OJ
----..
N02
W)--J>-Jo ~H
~J
~MJ
(f)N
I
O:~H
iJ:'(
E
7.25
~
~N~E
I
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
~N;J
~OAC
~N;J
NMez
H
7.27
)=NMez
CI
00
7.1
1. POCl3 I HCONMez
'
~H
UNj/
7.28
~
~ I
:::-..
.N
H
7.30'
N02
..
~H'
UN~
7.28
Pyridine
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
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
~
~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
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
~
~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).
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
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
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
1.("N 2
5 I
triazoles
N"
H
8.8
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
Ph
Ph
~-(
_N_aO_Et--.....
~o'
lfA
EtO __
ES e~O'
Na
N-(
Ph
-O'
8.14
~'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.
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
()
R2 -
C:N-H
~(9
H 2N-OH
rSf'OMe
EtOH, heat
N
8.21
60>
N
8.22
.![~
8.8
N'
: !)~
10
e eN
111
;NfB
8.8
?"--r N"'J
~
..
Et02C-C= C-C02Et
Heat
8.23
af N2'
No eN
~$
'-Vf"'J
111
C'1
Rl
----1.....
Heat
Rl
.,Jf..N-N\N\
8.24' .
N'
~
R2
8.27
1/
\\
~ ,N
N
H
)loH
N-N
/!-.'N
N'
)loe
pKa
= 5.63
pKa
= 4.76
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
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~
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
~-(
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.
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
\
[ (]
[ (]
N
H
5.23a
5.23
9.3a
9.3
PhVPh
9.10
-Hp
ti
I
BF3 Do
Ph
Ph~Ph
9.11
9.13
po
Ph
HCl04
Ph
Ph
9.12
ClO~
:-'0EB
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
n
H
I I
Ph
9.13
n
r
HCl04
Do:-...
Ph
Ph
9.11
0Ell
9.12
Ph
ClO e
4
~
Ph
9.17
9.18
-EtOH
Ph
9.16
Ph
~~
~3>
UO.Jl.
VOHO~Ph ~ VOHo~Ph
Ph
9.20
9.19
3>
~
U
9.23
OH
9.21
9.22
= Leaving group
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
9.1
5.1
0$
(\0
9.2
Cl
N
9,3
H 5.22
N
H
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
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
m
O
y.~~/
9.29
yoANH
9.32
99"
~
N
H
9.30
HO
7f
W
,
H2N
9.31
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
~.JC)
I ~;N
~O}
9.6
9.33
~
yo}
OMe
~NM~
yo}
9.34
OMe
9.35
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
f:e:J
N
10.4
10.5
H
10,6
10.7
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.
R,JCl
;>
R4
10.11
10.15
10.16
~o
Ha
EIOH
Heat
H OEt
..
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
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
IN~O
eN
FIN03
N0
Heat
'L
eNE
N~O
10.20
10.21
N02'(NH
FIN03
..
NAo
I ~
N
10.22
10.23
~Ne
~N,",]
_ye
~N
N)X
~N
~
x = NucIeophile
Y = Leaving group
~NJl.NPh
H
~N
Na
ee
OMe
~Jl.CI
..
~N
~NJl.OMe
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
~Ph0
~~NO
H
10.25
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
MoN~ +
~o
H
2.46
2.47
2.43
2.48
[ 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
'
r
f
--.~~
Ac08
ON0
(.:OE!) H
l_'
,
H f i N 02
lO
AcO""",,
3.33
NHz
r \_
Ph
H~
I/~
NaOH
lO
PhCOCl
l.S0C12
lO
2.MezNH
~+N
l.."""-)l --+-
..
-"'0 P\-N
~_ ').....
H
H
...
~ _')
Br
--jIoo
Ph~
NHz
--jIoo
3.44
Ph~
.-.Jt
r
H~
(J-
_2......
31-:--:--...::..:.;...:.:.:....:.:..::.-.::.:!--=.:=----_2_.3_2_ _ _ _ _ _ _ _
Direct los8 01 HE!)
_
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.
MeO'N~O
MeI
3.45
ES
H
"""
e
o~l
>=C=<.~
srfN
NH2
I
CN
NH2
rt
S"NNH
-CN
('br't.J
4.39
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
HO'N~O/
/
'"
4.41
NaOCl
[31
~O~
[3+2] ..
NaOH
4.46
4.47
~N
ClH
4.43
4.45
O~C02Et
COzEt
Ph
6
N
82 Answers to problems
OMe
lrr-~
5.39
n-BuLi
(2eq. )
Do
O
OMe
H
~
I
Ar
5.40
(O
f}f
ro~~{ ~ HuH
) N{
o
~OEt
C0 Et
CN
CN
- ~ )l~CN
2
H~\
/.EtOH
JXCN. JXCN
H
~-: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
~)
o,
Et
NH
Et
HC!.
HN~
HN~
OH
Art H
(OH
Ar~NOZ----Ar~NOZ -OH~~NOz
H H
~eOH
'-l..:HzNOz
_ _ _4_........
or Hz/P~
~N02
Ar
~NHz
Ar
~ 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
Ph-N-NH,
H
oD. ~
~N~
H
NdJ.
~N~
Cl~NM~
NM~
7.38
,......
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
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
11
CH3 -S(CH3h
Ea
NaH
11
Do-
(-H2)
eCH2-S(CH3) 2
Ea
Corey'syld
8.36
:)
:{
,',1,
'.
l
OC .0-....
Co --
8.21
OMe
e O,
EtO-H ~
-NH-2--'~
~-(
R NH2
O~....J;r-O-N
l~
O~
8.22
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
w~
aMe
9.35
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
86 Answers to problems
"
[ (CJ2
(N
~Jl.oe
..
...
'G~ ~
10.20
10.20a
,Ph0NH
~N~O
H
]>'
.
0
~~~OEt
O
Ph0x
,Ph
NH
~x +
10.25
H2N
10.27
~2O
OEt
10~16
10.28
-+
OEt
H+
OEt
10.26
eN
CN
........... HfD -EtOH J :
r OEt....
H~
'o
O
10.29
~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
_~------~._~-...._
_ ..... __ ._ .. _o, .,
_
............. _ - ..... , . . . . . ..
"
_.,\-.___
..
_._..
..
__ ...-..-......,_~
'"
_'......
. _. __. ,._--__.._.
...
-..
_.-.
-_.
.
__
.
.
----_......
.... _-- ....._. - ..........
...'"
....
..-.......... _.....
..
=. ---_............. _'
0 .. _ . . . ji
- . ... _
l. - , . _ , '
'a .
.a
"'_110 _ _ _ _ _ ... _ _
_
..__
~.
,'" '7
aa __ _
--~
_, _
_0-0 , _
.'
--~ &
...
..... "