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A novel method for the isoprenylation of β-dicarbonyl compounds
Tetrahedron Letters,Vol.26,No.51,pp Printed in Great Britain
6337-6340,198s
A NOVEL METHOD FOR THE ISOPRENYLATION
*a G.
a) b)
Centre
de Recherches
Centre
de Saint-Fons
BP 62 Recherches
de
b MOREL
MIGNANI, D.
COMPOUNDS
OF R-DICARBONYL
Y.
COLLEUIL~E
(Carrikres)
- 69192 - SAINT-FONS de Vitry-sur-Seine -
BP 14 - 94400
ABSTRACT
and
0040-4039/85 $3.00 + .OO 01985 Perqanon Press Ltd.
- RHONE-POULENC CEDEX - FRANCE RHONE-POULENC SANTE
RECHERCHES
- VITRY-SUR-SEINE CEDEX - FRANCE
:
The water-soluble composition rhodium/tris (sodium 3-sulfophenyl) phosphine (TPPTS) selectively catalyses the condensation of isoprene with active methylene compounds. An efficient synthesis of isofeprazone is described.
Many biologically active substances are “mere-terpenoids “, i.e. contain in for instance, on the ring of a phloroglucinol their structure an isoprenyl group (I), sub-structure, or on the central atom of a B-dicarbonyl substrate. Synthesis of these structures is usually carried out by isoprenylation with the formallf,)(-dimethylallyl cation (2). However different problems arise :
-
A mixture
- Double
of
bond
the
monosubstituted
isomerization
: terminal
- Lack of reqioselectivity at Cl or C4.
because
We found
comprised
of
3-sulfophenyl)
(I
that the use of a water-soluble phosphine phosphine
regiospecificity
equivalent
(TPPTS)
bond
-1
isoprene developed rhodium-I,
and
of
compounds
is
obtained.
allvlic
cation
and internal. the
reactivitv
of
the
as the alkylating agent and a catalyst in our laboratories (3), tris (sodium gave the required selectivity and
efficiently. Isoprene 1, in
(1 equivalent)
a H2OiCH30H Compounds 2 and 2 were isolated 2 and 1 show numerous tautomeric
double
and disubstituted
isomerization
reacts
at room temperature
with
barbituric
(75/25) mixture catalyzed by Rhl/TPPTS/Na2C03. in 50 % overall yield and a -2/3 molar ratio forms in solution (4). Under our conditions,
was observed
(5).
2 6337
acid of
35/65.
partial
6338
tituted
Meldrum’s acid 2 reacts under derivative 5 with no isomerization 0
similarly of the
mild double
conditions to give bond (60%isolated
the monosubsyield) (6).
‘S-P
a new and efficient synthesis of Taking advantage of this reaction, isofeprazone 6 was developed, starting from isoprene and readily available I,2 -diphenyl 3,5-dioxopyrazolidine (7). Isofeprazone 6 and especially its isomer feprazone I are potent anti-inflammatory substances with weak ulcerogenic properties (8).
-6 type
7
Isomerization catalysts (5).
substitution
of 4 to z
is
easily
Under more vigorous conditions occured , giving a mixture of
carried
(lOO°C, isomers!,
out
with
Pd/C,
PdC12(PhCN)2
16 h, H 0/C2H50H) double _fJ in quantitative 2 and 21
yield
(9).
The addition of activated methylene compoundsto disymnetric dienes such as isoprene is generally poorly regioselective (10). However, the use of a RhI/ TPPTS system permits this reaction to be very selective with exclusive attack on the monosubstituted double bond. Since the catalytic system is water soluble, it is easily separated from the organic layer and recycled without any loss of activity.
Preparation
of
isofeprazone
6
: (11).
In a 500 ml round bottomed flask, was placed 55.5 g (220 mMo1) 1,2-diphenyl 3,5-dioxopyrazolidine, 0.41 g (Rh Cl COD)2, 6.02 g tris (sodium 3-sulfophenyl) phosphine and 1.5 g of Na CO . Air was replaced by argon and then 200 ml water, 50 ml methanol and medium was magnetically stirred 48 H 22 ml (220 mMolf izoprene were added. The reaction and washed with water. 61.7 g at 25’C. A white precipitate formed, which was filtered of -6 was obtained (87 % yield). m.p.
128 - 130°C
Acknowledgment
(lit.
(8)
125-126°C).
: We are grateful
for
the
technical
assistance
of
F. GRASS.
6339
(I)
3.W.
Cornforth,
Chem.
(2)
V.K.
Ahluwalia,
K.K.
(3)
a)
E.Kuntz
b)
RHONE-POULENC
(4) Z
z and 3 CH3
:
Arora,
MHZ,
1.47;
(di 2.45
1~1
(IOO),
(5)
BASF.
German
(6)
a)
2
2
128
a)
69
Chem.
Sot.
2,314,910
Perkin
I, 335
(1982).
(20.6.75).
(11.5.81).
HMDS)
I,56
-
2
(s)
:
;
(t)
/
IR (KBr,
MS
:
m/z
95
(21),
82
(21),
39
(33),
27
(69).
Mitsui
(%)
4.82
;
H.Ruhkopf, M.
Ber.
CH2
;
2.20 =O 154
(15b10.68).
G.Pala,
S. Casadio,
A. Mantegani 183,
(b)
E. Cereda,
(c)
Istituto
and
191
-
- CH2
-1
F-g
41
(7),
;
221
(16),
196
(78)y
(46).
(27),
68
137
(loo),
HMDS)
=CH
:
- CH<(m)
(m)
1800-1750
:
(24),
3.48
1_
2.20c;t
><,i(
;
s) 1.69 et
; VC
= C
: 1650.
(33),
136
(35),
109
55
(80),
43
67
(55)~
(s) 4.73
hc'=
CH2
(23),
: 890.
108
(22)~
(75)~
Industries,Ltd.
820
129,347
177,
;
(30.10.78)
(1940)
- Czechoslovak
Hruby
(86),
&.68
8,059,181
7J,
42
CDC13, mm,
(25),
Patent
:m/z(%j:264
MHz,
155
Petrochemical
et 4.55
(KBr, ,-I)
3200.~~
(360
v C
81
(s) 4.61
(22-9-67).
cm-')
:
. IR
CH2 RK /
;
56 (32),
CH
1.72
1.57
3750-
(47),
H NMR
- CH I CH
1.75
:
1,267,682
9o"c,
m.P.
:
3apanese
(8)
44,771
(s)
(s)
(64),
Patent
-CH2-
b)
3.
Patent
d6, PPm,
;3 :A -
et4.67;
a)
Jolly,
Patent
DMSO
A/ CH2\ (m) 1.90 et CH2' v c=o-: 1770-1700; vNH(OH)
(7)
(1968).
^s
- CH&'
b)
102
- French
- European
(360
(s)
4,
and R.S.
(RHONE-POULENC)
H NMR
:n&H3
in Britain
Patents129,345
E. Marazzi
C.
Bianchi,
- Uberti,
(15*10*68),
B. Lumachi,
Arzneim.
- Forsch.
Donetti,
Tetrahedron
129,346
(15*10*68),
E. Crescenzi,
A.Donetti,
(Drug
Res.)
22,
11,
4977
171,
174,
(1972).
E. Bellora de ANGEL1
and
A.
S.P.A.
French
Patent
2,515,646
Lett
(29.10.82).
(1980).
6340
(9)
g,!J
and 10
:
HNMR (360 MHz, CCC13,ppm
, HMDS) : - CH1 (s), 1.49, 1.52, 1.62; -CH2 - CH2(m) 1.98;
- CH2 - CH2 (m) 1.98 ; _
>
4.62 ;
>
c = CH - CH2 (t) 4.99 internal=1,6.
'
;c=c,
C = CH - CH - (d Z ; PHENYL
IR(KBr,
cm-')
) 2.56 ;>C
= CH (s), 4.61 2
7.11 to 7.25. ratio >
: 900 ; v Ar : 1600 and 1500 ;
C = C
: 1755 and 1720;
VC =o
mono substitution
et
VC
= C
: 1650;
: 700 and 760.
v
C = CH2
MS
: m/z (%) 388 (45), 320 (24), 265 (IOO), 264 (71), 212 (7), 211 (12)~ 195 (6),
183 (221, 77 (901, 69 (311, 41 (51).
(IO) R. Baker, Chem. rev. 73, 487 (1973). (11)
5
. HNMR (360 MHz, CDC13,PPm, 1
-CH
2
-CH
(m) 7.09. Phenyl
21
-C-
H (m) 2.23 - 2.17
IR (KBr, cm-')
vc=o:
: 1595 - 1490/700_750.
252 (181, 184
(Received
HMDS)
( 19),
MS
:
;
- CH3 (511.67
-f-
y (t)
1750 - 1720 ; VC
3.36
/!
(s) 4.70
;
; Phenyl (m) 7.23 and
= C : 1650
; vc =CH2:890;
: m/z (%) : 320 (29) , 265 (321, 264 ('loo),
183 (50), 105 (13), 77 (86).
in France
Giy
28 February
1985)
6337-6340,198s
A NOVEL METHOD FOR THE ISOPRENYLATION
*a G.
a) b)
Centre
de Recherches
Centre
de Saint-Fons
BP 62 Recherches
de
b MOREL
MIGNANI, D.
COMPOUNDS
OF R-DICARBONYL
Y.
COLLEUIL~E
(Carrikres)
- 69192 - SAINT-FONS de Vitry-sur-Seine -
BP 14 - 94400
ABSTRACT
and
0040-4039/85 $3.00 + .OO 01985 Perqanon Press Ltd.
- RHONE-POULENC CEDEX - FRANCE RHONE-POULENC SANTE
RECHERCHES
- VITRY-SUR-SEINE CEDEX - FRANCE
:
The water-soluble composition rhodium/tris (sodium 3-sulfophenyl) phosphine (TPPTS) selectively catalyses the condensation of isoprene with active methylene compounds. An efficient synthesis of isofeprazone is described.
Many biologically active substances are “mere-terpenoids “, i.e. contain in for instance, on the ring of a phloroglucinol their structure an isoprenyl group (I), sub-structure, or on the central atom of a B-dicarbonyl substrate. Synthesis of these structures is usually carried out by isoprenylation with the formallf,)(-dimethylallyl cation (2). However different problems arise :
-
A mixture
- Double
of
bond
the
monosubstituted
isomerization
: terminal
- Lack of reqioselectivity at Cl or C4.
because
We found
comprised
of
3-sulfophenyl)
(I
that the use of a water-soluble phosphine phosphine
regiospecificity
equivalent
(TPPTS)
bond
-1
isoprene developed rhodium-I,
and
of
compounds
is
obtained.
allvlic
cation
and internal. the
reactivitv
of
the
as the alkylating agent and a catalyst in our laboratories (3), tris (sodium gave the required selectivity and
efficiently. Isoprene 1, in
(1 equivalent)
a H2OiCH30H Compounds 2 and 2 were isolated 2 and 1 show numerous tautomeric
double
and disubstituted
isomerization
reacts
at room temperature
with
barbituric
(75/25) mixture catalyzed by Rhl/TPPTS/Na2C03. in 50 % overall yield and a -2/3 molar ratio forms in solution (4). Under our conditions,
was observed
(5).
2 6337
acid of
35/65.
partial
6338
tituted
Meldrum’s acid 2 reacts under derivative 5 with no isomerization 0
similarly of the
mild double
conditions to give bond (60%isolated
the monosubsyield) (6).
‘S-P
a new and efficient synthesis of Taking advantage of this reaction, isofeprazone 6 was developed, starting from isoprene and readily available I,2 -diphenyl 3,5-dioxopyrazolidine (7). Isofeprazone 6 and especially its isomer feprazone I are potent anti-inflammatory substances with weak ulcerogenic properties (8).
-6 type
7
Isomerization catalysts (5).
substitution
of 4 to z
is
easily
Under more vigorous conditions occured , giving a mixture of
carried
(lOO°C, isomers!,
out
with
Pd/C,
PdC12(PhCN)2
16 h, H 0/C2H50H) double _fJ in quantitative 2 and 21
yield
(9).
The addition of activated methylene compoundsto disymnetric dienes such as isoprene is generally poorly regioselective (10). However, the use of a RhI/ TPPTS system permits this reaction to be very selective with exclusive attack on the monosubstituted double bond. Since the catalytic system is water soluble, it is easily separated from the organic layer and recycled without any loss of activity.
Preparation
of
isofeprazone
6
: (11).
In a 500 ml round bottomed flask, was placed 55.5 g (220 mMo1) 1,2-diphenyl 3,5-dioxopyrazolidine, 0.41 g (Rh Cl COD)2, 6.02 g tris (sodium 3-sulfophenyl) phosphine and 1.5 g of Na CO . Air was replaced by argon and then 200 ml water, 50 ml methanol and medium was magnetically stirred 48 H 22 ml (220 mMolf izoprene were added. The reaction and washed with water. 61.7 g at 25’C. A white precipitate formed, which was filtered of -6 was obtained (87 % yield). m.p.
128 - 130°C
Acknowledgment
(lit.
(8)
125-126°C).
: We are grateful
for
the
technical
assistance
of
F. GRASS.
6339
(I)
3.W.
Cornforth,
Chem.
(2)
V.K.
Ahluwalia,
K.K.
(3)
a)
E.Kuntz
b)
RHONE-POULENC
(4) Z
z and 3 CH3
:
Arora,
MHZ,
1.47;
(di 2.45
1~1
(IOO),
(5)
BASF.
German
(6)
a)
2
2
128
a)
69
Chem.
Sot.
2,314,910
Perkin
I, 335
(1982).
(20.6.75).
(11.5.81).
HMDS)
I,56
-
2
(s)
:
;
(t)
/
IR (KBr,
MS
:
m/z
95
(21),
82
(21),
39
(33),
27
(69).
Mitsui
(%)
4.82
;
H.Ruhkopf, M.
Ber.
CH2
;
2.20 =O 154
(15b10.68).
G.Pala,
S. Casadio,
A. Mantegani 183,
(b)
E. Cereda,
(c)
Istituto
and
191
-
- CH2
-1
F-g
41
(7),
;
221
(16),
196
(78)y
(46).
(27),
68
137
(loo),
HMDS)
=CH
:
- CH<(m)
(m)
1800-1750
:
(24),
3.48
1_
2.20c;t
><,i(
;
s) 1.69 et
; VC
= C
: 1650.
(33),
136
(35),
109
55
(80),
43
67
(55)~
(s) 4.73
hc'=
CH2
(23),
: 890.
108
(22)~
(75)~
Industries,Ltd.
820
129,347
177,
;
(30.10.78)
(1940)
- Czechoslovak
Hruby
(86),
&.68
8,059,181
7J,
42
CDC13, mm,
(25),
Patent
:m/z(%j:264
MHz,
155
Petrochemical
et 4.55
(KBr, ,-I)
3200.~~
(360
v C
81
(s) 4.61
(22-9-67).
cm-')
:
. IR
CH2 RK /
;
56 (32),
CH
1.72
1.57
3750-
(47),
H NMR
- CH I CH
1.75
:
1,267,682
9o"c,
m.P.
:
3apanese
(8)
44,771
(s)
(s)
(64),
Patent
-CH2-
b)
3.
Patent
d6, PPm,
;3 :A -
et4.67;
a)
Jolly,
Patent
DMSO
A/ CH2\ (m) 1.90 et CH2' v c=o-: 1770-1700; vNH(OH)
(7)
(1968).
^s
- CH&'
b)
102
- French
- European
(360
(s)
4,
and R.S.
(RHONE-POULENC)
H NMR
:n&H3
in Britain
Patents129,345
E. Marazzi
C.
Bianchi,
- Uberti,
(15*10*68),
B. Lumachi,
Arzneim.
- Forsch.
Donetti,
Tetrahedron
129,346
(15*10*68),
E. Crescenzi,
A.Donetti,
(Drug
Res.)
22,
11,
4977
171,
174,
(1972).
E. Bellora de ANGEL1
and
A.
S.P.A.
French
Patent
2,515,646
Lett
(29.10.82).
(1980).
6340
(9)
g,!J
and 10
:
HNMR (360 MHz, CCC13,ppm
, HMDS) : - CH1 (s), 1.49, 1.52, 1.62; -CH2 - CH2(m) 1.98;
- CH2 - CH2 (m) 1.98 ; _
>
4.62 ;
>
c = CH - CH2 (t) 4.99 internal=1,6.
'
;c=c,
C = CH - CH - (d Z ; PHENYL
IR(KBr,
cm-')
) 2.56 ;>C
= CH (s), 4.61 2
7.11 to 7.25. ratio >
: 900 ; v Ar : 1600 and 1500 ;
C = C
: 1755 and 1720;
VC =o
mono substitution
et
VC
= C
: 1650;
: 700 and 760.
v
C = CH2
MS
: m/z (%) 388 (45), 320 (24), 265 (IOO), 264 (71), 212 (7), 211 (12)~ 195 (6),
183 (221, 77 (901, 69 (311, 41 (51).
(IO) R. Baker, Chem. rev. 73, 487 (1973). (11)
5
. HNMR (360 MHz, CDC13,PPm, 1
-CH
2
-CH
(m) 7.09. Phenyl
21
-C-
H (m) 2.23 - 2.17
IR (KBr, cm-')
vc=o:
: 1595 - 1490/700_750.
252 (181, 184
(Received
HMDS)
( 19),
MS
:
;
- CH3 (511.67
-f-
y (t)
1750 - 1720 ; VC
3.36
/!
(s) 4.70
;
; Phenyl (m) 7.23 and
= C : 1650
; vc =CH2:890;
: m/z (%) : 320 (29) , 265 (321, 264 ('loo),
183 (50), 105 (13), 77 (86).
in France
Giy
28 February
1985)