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Synthesis of quinoline and benzo[b]thiophene derivatives by ring annelation of pyridines and thiophenes
0040-4039/81/505097-04$02.00/O 01981 Pergamon Press Ltd.
Tetrahedron Letters,Vo1.22,No.50,pp 5097-5100,1981 Printed in Great Britain
OF QUINOLINE
SYNTHESIS
AND BENZO[b]THIOPHENE
BY RING ANNELATION
OF PYRIDINES
Albert M. van Leusen* Department
of Organic
Nijenborgh
Existing
methodology
sized quite recently
methods
for constructing
reverse
approach, Scheme
for annelating
Chemistry,
Groningen
pyridines Attempts
the thiophene
University,
The Netherlands
uLth Michael
to quinolines
ring to benzenes
of thiophenes,
to
scarce,
give
as was empha-
to reduce this gap prompt
situation
exists
are available
is hardly
accepxtohd
is extremely
of these authors
the same goal. A similar
to achieve
i.e. annelation
I
and Jan Willem Terpstra
16, 9747 AG Groningen,
by Ghera eX &.l
report our own efforts
AND THIOPHENES
pqhidinw and thiophenti treaot OJLbenzo[bl.tkiophenen, ht?bpetiv~q.
Selected ottho-tiubbtiuted &mt.ionaLized quinofine6
DERIVATIVES
us to
for benzothiophenes:
in variety
but again the
investigated.*
(Fkp-tolyd
0 II t-OMc
r
F!
OH
1
0
+ CH2-S-R (6)”
1
n.2
& “l,
The basis of our approach with pyridines
-or
as an electrophilic examples
s
XZH
+
X=H.72%
e
x-p-NO2
2
xzp-NO2
is the reaction
of conjugated
thiophenes - carrying
vicinal
To be synthetically
ably be chosen so that the three individual elimination) new method
take place concomitantly of ring annelation
are not easily obtained
in one operation.
allows substitution
5097
(Michael
for n.2
acceptor
a nucleophilic
type as well
I and II give characteristic and conditions addition,
We find this possible
patterns
otherwise.
X.H.59%
X=p-N02 n.2
that provide
substituents
steps
* 41
of the Michael
ring. Schemes
effective, reaction
for n-2
systems
substituents
center alpha to the heterocyclic
in some detail.
for n-1 20%
in quinolines
should prefer-
ring closure,
and
indeed. Also, the
and benzothiophenes
that
5098
Several
substituents
of methylpyridines,
are conceivable
to stabilize
or methylthiophenes,
required
group4 and by Hauser and Rhee5 on the synthesis sulfinyl
substituents
products
by base-induced
prepared
and investigated
carboxylate aldehyde
@),
(8).
Reaction
proceed
of the pyridine
for the Michael
of naphthalenes
useful for this purpose; 1,2-elimination
processes,
2-tosylmethylnicotinate sulfoxides
sulfoxide
Although
addition
acylation
-3a. An analogous
-lb with chalcone
addition.
Previous
has shown that sulfonyl they frequently
in our
and
lead to aromatized
respectively.6
(la), methyl
bases
work
We, thus, have
3-tosylmethylthiophene-2-
of the conjugate
gives 4, followed
mp 135-137.5'C, II
1R e
Scheme
(2a) and R-BuOK -
(2.5 equiv.)
were obtained,
the reaction
by a (thermal tin) elimination in the conversion
acid to
sulfoxide -5b to 6a
p-tolyl13
0
0
comparable
derivative
1
Tos
“Ia
0
to the reaction
-4a (59% yield,
ently the acidic OH in -4a prevents the expected
to
which by intra-
of p-toluenesulfenic
of the thiophene
72%
II).
+
gave the dihydro
@,
is postulated
base of -lb to 2a to give an enolate,
r
Under conditions
in 1,2-
in 6-benzoyl-5-hydroxy-7-phenylquinoline
no intermediates
series of steps is assumed
Scheme
despite
in the conjugate
lb and 5b, and 3-tosylmethylthiophene-2-carbox--
(DME) for 24 h at 20°C resulted
by Michael
(48% yield,
methyl
the corresponding
mp 134.5-135.5'C).
molecular
or thermal
charge
3,7
dimethoxyethane yield,
are especially
the negative
quinoline
creased
mp 170-172.5°C)8
a base-induced
gain in resonance
give the fully aromatized
of -lb, the pyridine
energy.'
of C(7)-H
in intermediate
A comparable
situation
exists
rather than the quinoline
elimination
of p-toluenesulfinic
mp 165-165.5'C),
-4b facilitates
in the thiophene
series.
presumably
the elimination
(2a) -
3a. Appar-
acid
On the other hand -la and 4-nitrochalcone
-3b (20% yield,
acidity
sulfone -la and chalcone
because
(TosH), (2b) the in-
of TosH.
7-Hydroxybenzo[blthiophene
derivatives
5099
TABLE.
Functionalized
Quinolines,
1, 5 or -8 using Substrates
Benzo[blthiophenes
and Dihydroderivatives
other than Chalcone
and 4-Nitrochalcone
(cd. Schemes
from I and II).
1
10s
1!
Synthesized
‘2
”
”
MP (OC)
From, and
46
114-116
s,
diMe maleate
a
-
14
114-116
la _'
diMe maleate
a
-
48
170-172
5,
diMe maleate
b
Me
40
165-166.5
la _'
Me crotonate
C
COOMe
Ph
30
182.5-184.5
&,
Me cinnamate
a
13a
COOMe
COOMe
OH
52
114-115.5
%,
diMe maleate
d
13a
COOMe
COOMe
OH
45
114-115.5
2,
diMe fumarate
C
-13b
Ph
COOMe
OH
43
148-149
z,
Me cinnamate
a
13c
COOH
COOH
H
68
240-260
(d) 8,
diMe maleate
e
13d
BZ
BZ
H
34
146-147
8,
titi-1,2-diBz-ethene
6
-13e
CH2-CH2-C(Me)2-C0
H
60
119-120
8,
6,6-diMe-2-cyclohexenone
9
14a
COOMe
COOMe
OH
30
152-154
5a _'
diMe fumarate
b
-14b
Ph
COOMe
OH
29
169-171
2,
Me cinnamate
a
-14c
Me
COOH
H
55
140-150
(d) 8,
Me crotonate
h
A
B
C
lla
COOMe
COOMe
-
lla
COOMe
COOMe
12a
COOMe
COOMe
-12b
COOMe
12c
Compd
Yield
(%)
Conditions
Conditions: a: 2.5 equiv. t-BuOK, DME, 20°C, 24-27 h; b: 2.5 equiv. NaOMe, DMSO, 20°C, 24-27 h; h; 6OoC, 2.5 4 equiv. h; c: t-BuOK, 4 equiv. ::BuOK, 4 equlv. DME, t-BuOK, 65OC, 2 DME, h; 6: 2OoC, 4 equiv. 24 h;Z-BuOK, d: 4 equiv. DME, NaOMe, 65OC, 2 DME, h and20°C, 20°C,24 40 h and DME, -2OoC,
C, 48 h. 1 h and 20°C, 3 h and 50°C, 20 min; h: 2 equiv. -t-BuOK, DME, 20 8:
6a and 6b (mp 180-182'C) -chalcone
were obtained
(2b) and the sulfone 2, -
from chalcone
respectively,
1 (X = H, n = 2, mp 176.5-177.5'C)I'
chalcone
(2a). In contrast -
elimination
4) elimination 184-184.5'C)
in 74% yield
in 55% yield].
spontaneously
-10.
and from 4-nitrodihydro
derivative
from -5a and -2a.
ring closure
oxygen to give intermediate
of TosH from -10 occurred
was isolated
of -' 5a
5b _'
the tosyl substituted
(8) - gave benzo[blthiophene
to the reaction
of the aldehyde
whereas
was formed
3-Tosylmethylthiophene-2-carboxaldehyde
(2a) and the sulfoxide -
_9 (mp 125-126'C)
to the aldehyde
with
group of -8 involves
In the absence of an acidic OH (as in
with t-BuOK
[with NaOMe compound -10 (mp
5 100
Further
results
of these reaction
principles
applied
to other Michael
acceptors
are collected
in the Table. The synthesis known chemistry.
of starting Methyl
materials3
1, -5 and 8 is outlined
2-methylpyridine-3-carboxylate
11
on bromination
(TosNa) gave -la (46% overall yield,
mp 106-107°C),
whereas
(NaI04) gave 2
mp 73-74.5'C).
Similarly,
yield)
(10% overall yield,
of methyl
3-methylthiophene-2-carboxylate
only briefly,
sulfenylation
essentially
(NBS) and sulfonylation (C7H7SNa)
bromination
l2 (bp 94-98'C/ll
involving
and oxidation
and sulfonylation
(60%
mm Hg, from 3-methylthiophene
.I
via 2-iodo derivative, " 129.5-131.5'C)
which
Grignard
derivative,
upon reduction
8 (34% overall yield,
mp 142-144'C).
and reaction with dimethyl
(LiEt3BH),
followed
by oxidation
Compound -5b (mp 93-96'C)
carbonate)
(pyridinium
was obtained
gave -5a (mp
dichromate)
analogously
to g
gave in
56% overall yield. To summarize,
we feel that our annelation
gated by Ghera eZ &,I
however,
ment for which we may benefit References
the synthesis
approach
to quinolines
is superior
of some of our starting
materials
3. 4. 5. 6.
7.
8. 1::
11.
:::
deserves
improve-
from Ghera's work.
and Notes
1. E. Ghera, Y.B. David and H. Rapoport, J. O&g. Chem., 46, 2059 (1981), 2.
to those investi-
and references cited therein. For syntheses of benzothiophenes from benzene derivatives, see: B. Iddon and R.M. Scrowston in Adv. -in He&hocy&c Chem., Vol. 11, A.R. Katritzky and A.J. Boulton (Eds.), Academic Press, New York, 1970, p. 206-236. For the alternative approach from thiophene derivatives, see: ibid, p. 236-238; C.G.M. Janssen, P.M. van Lier, P. Schipper, L.H.J.G. Simons and E.F. Godefroi, J. &Lg. Chem., 46, 3159 (1980); M.G. Reinecke and J.G. Newson, J. Am. Ckcm. Sot., 98, 3021 (1976), These and all-f rther new compounds gave satisfactory elemental microanalyses and consistent spectral data ( rH NMR, IR); yields have not been optimized in most cases. J. Wildeman, P.C. Borgen, H. Pluim, P.H.F.M. Rouwette and A.M. van Leusen, Te--ttakecLto~ L&., 1978, 2213. T;ljT;Hauser and R.P. Rhee, J. Ohg. Ckun., 43, 178 (1978), and 45, 3061 (1980). The use of cyanide as leaving group in quixne synthesis similar to refs. 4 and 5 has been reported meanwhile: G.A. Kraus and H. Sugimoto, T&&e&on L&., 1978, 2263; for otherwise Ckem. Comm., 1978, related naphthalene syntheses see: N.J.P. Broom and P.G. Sammes, J.cr 162; L. Contreras, C.E. Slemon and D.B. MacLean, T&&e&on Lett., 1978, 4237. Inaddition to esters and aldehydes other functional groups are usefns electrophilic centers, for example, cyanides as in 2-cyano-3-p-tolylsulfinylmethylthiophene (mp 89-92'C), the corresponding sulfone (mp 162-1640C) and its 3,4-isomer (mp 157-159oC), cd. ref. 4. Such reactions are under investigation now, as well as annelations of other heterocyclic nuclei. In 4a the substituents at C(7) and C(8) probably have the tiunn configuration, cd. note 10. Compare ref. 4. Methylation (CH2N2orMepSDq)of 7 (X = H, n = 2) gave both OMe derivatives (mp 174.3-176.3'C and mp 233.2-233.6oC). X-ray analysis of the latter compound (Me at the benzoyl oxygen), carried out by Mr. F. van Bolhuis of the Department of Chemical Physics of Groningen University, clearly demonstrates the &uti position of the substituents at C(4) and C(5), even though the 1H NMR coupling constant of C(4)-H, C(5)-H is only 1 Hz. Synthesized analogous to ethyl ester as described by: F. Bohlmann and D. Rahtz, Ckem. &?A., J. Hurst and Wibberley, J. Che.m. Sot., 1962, 119. 90, 2265 (1957); NBS-bromination: R.M. Scrowston and D.C. Shaw, J.C.S. P&Z&I I, 1976, 749. H. Suzuki, T. Iawo and T. Sugiyama, BuU. Ztit.-ClZm. Rti.., Kyoto Univ., Vol. 52, Nb. 3, 561 (1974).
(Received
in
UK 30 September
1981)
Tetrahedron Letters,Vo1.22,No.50,pp 5097-5100,1981 Printed in Great Britain
OF QUINOLINE
SYNTHESIS
AND BENZO[b]THIOPHENE
BY RING ANNELATION
OF PYRIDINES
Albert M. van Leusen* Department
of Organic
Nijenborgh
Existing
methodology
sized quite recently
methods
for constructing
reverse
approach, Scheme
for annelating
Chemistry,
Groningen
pyridines Attempts
the thiophene
University,
The Netherlands
uLth Michael
to quinolines
ring to benzenes
of thiophenes,
to
scarce,
give
as was empha-
to reduce this gap prompt
situation
exists
are available
is hardly
accepxtohd
is extremely
of these authors
the same goal. A similar
to achieve
i.e. annelation
I
and Jan Willem Terpstra
16, 9747 AG Groningen,
by Ghera eX &.l
report our own efforts
AND THIOPHENES
pqhidinw and thiophenti treaot OJLbenzo[bl.tkiophenen, ht?bpetiv~q.
Selected ottho-tiubbtiuted &mt.ionaLized quinofine6
DERIVATIVES
us to
for benzothiophenes:
in variety
but again the
investigated.*
(Fkp-tolyd
0 II t-OMc
r
F!
OH
1
0
+ CH2-S-R (6)”
1
n.2
& “l,
The basis of our approach with pyridines
-or
as an electrophilic examples
s
XZH
+
X=H.72%
e
x-p-NO2
2
xzp-NO2
is the reaction
of conjugated
thiophenes - carrying
vicinal
To be synthetically
ably be chosen so that the three individual elimination) new method
take place concomitantly of ring annelation
are not easily obtained
in one operation.
allows substitution
5097
(Michael
for n.2
acceptor
a nucleophilic
type as well
I and II give characteristic and conditions addition,
We find this possible
patterns
otherwise.
X.H.59%
X=p-N02 n.2
that provide
substituents
steps
* 41
of the Michael
ring. Schemes
effective, reaction
for n-2
systems
substituents
center alpha to the heterocyclic
in some detail.
for n-1 20%
in quinolines
should prefer-
ring closure,
and
indeed. Also, the
and benzothiophenes
that
5098
Several
substituents
of methylpyridines,
are conceivable
to stabilize
or methylthiophenes,
required
group4 and by Hauser and Rhee5 on the synthesis sulfinyl
substituents
products
by base-induced
prepared
and investigated
carboxylate aldehyde
@),
(8).
Reaction
proceed
of the pyridine
for the Michael
of naphthalenes
useful for this purpose; 1,2-elimination
processes,
2-tosylmethylnicotinate sulfoxides
sulfoxide
Although
addition
acylation
-3a. An analogous
-lb with chalcone
addition.
Previous
has shown that sulfonyl they frequently
in our
and
lead to aromatized
respectively.6
(la), methyl
bases
work
We, thus, have
3-tosylmethylthiophene-2-
of the conjugate
gives 4, followed
mp 135-137.5'C, II
1R e
Scheme
(2a) and R-BuOK -
(2.5 equiv.)
were obtained,
the reaction
by a (thermal tin) elimination in the conversion
acid to
sulfoxide -5b to 6a
p-tolyl13
0
0
comparable
derivative
1
Tos
“Ia
0
to the reaction
-4a (59% yield,
ently the acidic OH in -4a prevents the expected
to
which by intra-
of p-toluenesulfenic
of the thiophene
72%
II).
+
gave the dihydro
@,
is postulated
base of -lb to 2a to give an enolate,
r
Under conditions
in 1,2-
in 6-benzoyl-5-hydroxy-7-phenylquinoline
no intermediates
series of steps is assumed
Scheme
despite
in the conjugate
lb and 5b, and 3-tosylmethylthiophene-2-carbox--
(DME) for 24 h at 20°C resulted
by Michael
(48% yield,
methyl
the corresponding
mp 134.5-135.5'C).
molecular
or thermal
charge
3,7
dimethoxyethane yield,
are especially
the negative
quinoline
creased
mp 170-172.5°C)8
a base-induced
gain in resonance
give the fully aromatized
of -lb, the pyridine
energy.'
of C(7)-H
in intermediate
A comparable
situation
exists
rather than the quinoline
elimination
of p-toluenesulfinic
mp 165-165.5'C),
-4b facilitates
in the thiophene
series.
presumably
the elimination
(2a) -
3a. Appar-
acid
On the other hand -la and 4-nitrochalcone
-3b (20% yield,
acidity
sulfone -la and chalcone
because
(TosH), (2b) the in-
of TosH.
7-Hydroxybenzo[blthiophene
derivatives
5099
TABLE.
Functionalized
Quinolines,
1, 5 or -8 using Substrates
Benzo[blthiophenes
and Dihydroderivatives
other than Chalcone
and 4-Nitrochalcone
(cd. Schemes
from I and II).
1
10s
1!
Synthesized
‘2
”
”
MP (OC)
From, and
46
114-116
s,
diMe maleate
a
-
14
114-116
la _'
diMe maleate
a
-
48
170-172
5,
diMe maleate
b
Me
40
165-166.5
la _'
Me crotonate
C
COOMe
Ph
30
182.5-184.5
&,
Me cinnamate
a
13a
COOMe
COOMe
OH
52
114-115.5
%,
diMe maleate
d
13a
COOMe
COOMe
OH
45
114-115.5
2,
diMe fumarate
C
-13b
Ph
COOMe
OH
43
148-149
z,
Me cinnamate
a
13c
COOH
COOH
H
68
240-260
(d) 8,
diMe maleate
e
13d
BZ
BZ
H
34
146-147
8,
titi-1,2-diBz-ethene
6
-13e
CH2-CH2-C(Me)2-C0
H
60
119-120
8,
6,6-diMe-2-cyclohexenone
9
14a
COOMe
COOMe
OH
30
152-154
5a _'
diMe fumarate
b
-14b
Ph
COOMe
OH
29
169-171
2,
Me cinnamate
a
-14c
Me
COOH
H
55
140-150
(d) 8,
Me crotonate
h
A
B
C
lla
COOMe
COOMe
-
lla
COOMe
COOMe
12a
COOMe
COOMe
-12b
COOMe
12c
Compd
Yield
(%)
Conditions
Conditions: a: 2.5 equiv. t-BuOK, DME, 20°C, 24-27 h; b: 2.5 equiv. NaOMe, DMSO, 20°C, 24-27 h; h; 6OoC, 2.5 4 equiv. h; c: t-BuOK, 4 equiv. ::BuOK, 4 equlv. DME, t-BuOK, 65OC, 2 DME, h; 6: 2OoC, 4 equiv. 24 h;Z-BuOK, d: 4 equiv. DME, NaOMe, 65OC, 2 DME, h and20°C, 20°C,24 40 h and DME, -2OoC,
C, 48 h. 1 h and 20°C, 3 h and 50°C, 20 min; h: 2 equiv. -t-BuOK, DME, 20 8:
6a and 6b (mp 180-182'C) -chalcone
were obtained
(2b) and the sulfone 2, -
from chalcone
respectively,
1 (X = H, n = 2, mp 176.5-177.5'C)I'
chalcone
(2a). In contrast -
elimination
4) elimination 184-184.5'C)
in 74% yield
in 55% yield].
spontaneously
-10.
and from 4-nitrodihydro
derivative
from -5a and -2a.
ring closure
oxygen to give intermediate
of TosH from -10 occurred
was isolated
of -' 5a
5b _'
the tosyl substituted
(8) - gave benzo[blthiophene
to the reaction
of the aldehyde
whereas
was formed
3-Tosylmethylthiophene-2-carboxaldehyde
(2a) and the sulfoxide -
_9 (mp 125-126'C)
to the aldehyde
with
group of -8 involves
In the absence of an acidic OH (as in
with t-BuOK
[with NaOMe compound -10 (mp
5 100
Further
results
of these reaction
principles
applied
to other Michael
acceptors
are collected
in the Table. The synthesis known chemistry.
of starting Methyl
materials3
1, -5 and 8 is outlined
2-methylpyridine-3-carboxylate
11
on bromination
(TosNa) gave -la (46% overall yield,
mp 106-107°C),
whereas
(NaI04) gave 2
mp 73-74.5'C).
Similarly,
yield)
(10% overall yield,
of methyl
3-methylthiophene-2-carboxylate
only briefly,
sulfenylation
essentially
(NBS) and sulfonylation (C7H7SNa)
bromination
l2 (bp 94-98'C/ll
involving
and oxidation
and sulfonylation
(60%
mm Hg, from 3-methylthiophene
.I
via 2-iodo derivative, " 129.5-131.5'C)
which
Grignard
derivative,
upon reduction
8 (34% overall yield,
mp 142-144'C).
and reaction with dimethyl
(LiEt3BH),
followed
by oxidation
Compound -5b (mp 93-96'C)
carbonate)
(pyridinium
was obtained
gave -5a (mp
dichromate)
analogously
to g
gave in
56% overall yield. To summarize,
we feel that our annelation
gated by Ghera eZ &,I
however,
ment for which we may benefit References
the synthesis
approach
to quinolines
is superior
of some of our starting
materials
3. 4. 5. 6.
7.
8. 1::
11.
:::
deserves
improve-
from Ghera's work.
and Notes
1. E. Ghera, Y.B. David and H. Rapoport, J. O&g. Chem., 46, 2059 (1981), 2.
to those investi-
and references cited therein. For syntheses of benzothiophenes from benzene derivatives, see: B. Iddon and R.M. Scrowston in Adv. -in He&hocy&c Chem., Vol. 11, A.R. Katritzky and A.J. Boulton (Eds.), Academic Press, New York, 1970, p. 206-236. For the alternative approach from thiophene derivatives, see: ibid, p. 236-238; C.G.M. Janssen, P.M. van Lier, P. Schipper, L.H.J.G. Simons and E.F. Godefroi, J. &Lg. Chem., 46, 3159 (1980); M.G. Reinecke and J.G. Newson, J. Am. Ckcm. Sot., 98, 3021 (1976), These and all-f rther new compounds gave satisfactory elemental microanalyses and consistent spectral data ( rH NMR, IR); yields have not been optimized in most cases. J. Wildeman, P.C. Borgen, H. Pluim, P.H.F.M. Rouwette and A.M. van Leusen, Te--ttakecLto~ L&., 1978, 2213. T;ljT;Hauser and R.P. Rhee, J. Ohg. Ckun., 43, 178 (1978), and 45, 3061 (1980). The use of cyanide as leaving group in quixne synthesis similar to refs. 4 and 5 has been reported meanwhile: G.A. Kraus and H. Sugimoto, T&&e&on L&., 1978, 2263; for otherwise Ckem. Comm., 1978, related naphthalene syntheses see: N.J.P. Broom and P.G. Sammes, J.cr 162; L. Contreras, C.E. Slemon and D.B. MacLean, T&&e&on Lett., 1978, 4237. Inaddition to esters and aldehydes other functional groups are usefns electrophilic centers, for example, cyanides as in 2-cyano-3-p-tolylsulfinylmethylthiophene (mp 89-92'C), the corresponding sulfone (mp 162-1640C) and its 3,4-isomer (mp 157-159oC), cd. ref. 4. Such reactions are under investigation now, as well as annelations of other heterocyclic nuclei. In 4a the substituents at C(7) and C(8) probably have the tiunn configuration, cd. note 10. Compare ref. 4. Methylation (CH2N2orMepSDq)of 7 (X = H, n = 2) gave both OMe derivatives (mp 174.3-176.3'C and mp 233.2-233.6oC). X-ray analysis of the latter compound (Me at the benzoyl oxygen), carried out by Mr. F. van Bolhuis of the Department of Chemical Physics of Groningen University, clearly demonstrates the &uti position of the substituents at C(4) and C(5), even though the 1H NMR coupling constant of C(4)-H, C(5)-H is only 1 Hz. Synthesized analogous to ethyl ester as described by: F. Bohlmann and D. Rahtz, Ckem. &?A., J. Hurst and Wibberley, J. Che.m. Sot., 1962, 119. 90, 2265 (1957); NBS-bromination: R.M. Scrowston and D.C. Shaw, J.C.S. P&Z&I I, 1976, 749. H. Suzuki, T. Iawo and T. Sugiyama, BuU. Ztit.-ClZm. Rti.., Kyoto Univ., Vol. 52, Nb. 3, 561 (1974).
(Received
in
UK 30 September
1981)