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Europium catalyzed intramolecular oxazole Diels-Alder reactions for the synthesis of benzopyrano[4,3-b]pyridines and benzo[h]-1,6-naphthyridines
Tetrahedron Letters,Vol.30,No.l8,pp Printed in Great Britain
0040-4039/89 $3.00 Pergamon Press plc
2355-2358,1989
+ .OO
EUROPIUM CATALYZED INTRAMOLECULAR SYNTHESIS
OXAZOLE DIELS-ALDER
REACTIONS FOR THE
OF BENZOPYRANO[4,3-bJPYRIDINES
AND
BENZO[hJ-1,6_NAPHTHYRIDINES
Jeremy I. Levin American Cyanamid Company Medical Research Division, Lederle Laboratories Pearl River, New York
10965
ABSTRACT: Intramolecular oxazole-olefin Diels-Alder reactions proceed, europium(fodh to provide substituted SH-Ill-benzopyranoI4,3-blpyridines yields.
Inthepast several years, 5-oxo-5H-[l]-benzopyrano[4,3-blpyridine pharmacologically
interesting compounds.1,2,3
inotropic, anti-allergic,
activity.
\--/
\-N
chromones.1,2 cycloaddition
derivatives
1 have attracted attention as
These tricyclic annelated pyridines have been reported to possess
analgesic and anti-inflammatory
usually been accomplished
in the presence of the Lewis acid and benzoIh]-1,6 naphthyridines in moderate
The synthesis of these novel heterocycles
has
-
through the condensation of enamines or malonic acid derivatives with substituted
More recently, Taylor has shown that these ring systems can be constructed via intramobzcular reactions of suitably substituted
It was our intention to investigate
tria2ines.l
the applicability
of intramolecular
the synthesis of this ring system and the related nitrogen-containing
oxazole-olefin
compounds
compounds of general structure 1 and 2 is shown below:
aX=OH & X=NH*
2355
Diels-Alder
2. The retro-synthetic
methodology analysis
for
for
2356
Cycloaddition
reactions
of oxazoles
are well precedented, having first been described by Kondrat’eva in 1957.5 Since
that preliminary account, this reaction has been used on numerous occasions for the synthesis of pyridines both natural and unnatural in origin.6
Several examp 1e s o f intramolecular
oxazole Diels-Alder reactions have also been published,6,7
including one example utilizing a substituted Z-phenyl oxazole as the Diels-Alder substrate.8
This is particularly
noteworthy since 2-phenyl oxazoles are extremely unreactive heterodienes due to steric and electronic effects. The synthesis of 2-co-hydroxyphenyl)oxazole, o-iodophenol
5 was accomplished using a convergent four-step sequence.
was first acetylated with acetic anhydride/pyridine.
catalyzed coupling with 2-tri-n-butyltin
This aryl iodide then underwent
oxazole, followed by hydrolysis of the acetate to provide phenol 3 in 75%
overall yield.g Subsequent acylation of 3 was best achieved by deprotonating by addition of the appropriate
Thus,
palladium
acid chloride.
Analogously,
the phenol with sodium hydride followed
alkylation of the sodium phenoxide with the appropriate
allylic bromide provided the aryl ethers z and fi in good yield. This variety of olefinic side chains was chosen to investigate the electronic requirements
of the dienophile in the intramolecular
2 R = COCH = CHC02Et (89%) § R=COCH=CHCH3 (86%) Z R = CH2CH = CHCH3 (49%) 8 R = CH2CH = CHCO$t+ (76%)
1) NaWTHF 9-
2) RCOCI or RX
The requisite intermediates
for the construction of benzonaphthyridine
alkylation of the known 2-(o-aminophenyl)oxazole,10 /-\
4-
11
( i-Pr)zNEl
1) NaH 2) Br ~~&+I,
CHCb
Oxazole-olefin
derivatives 2 were prepared by acylation or
as shown below.
RCOCI
9 1p IL
cycloadditions.
NHR R = COCH=CHCQEt (85%) R=COCH=CHCH3 (87%) R = CCCF3 (89%)
substrate 5 was chosen for our first cycloaddition attempt.
degassect odichlorobenzene
Thus, the oxazole-olefin
was dissolved in
(0.03M solution) and then refluxed for 16 h. Unfortunately, no reaction was observed and
starting material was recovered unchanged.
However, upon addition of 7 mole % of europiumffod)3
I=-/ Eu(fod)3 o-DCB
jJ_ X = 0 (46%) 5 x=0 $f X=NH
14 X = NH (75%)
to the reaction, the
2358
7)
a) Turchi, I. J.; Cullen, T. G. Heterocvcles a
2463 (19841.
b) Shimada, S.; Tojo, T. Chem. Pharm. Bull. &
4247 (19831.
cl Levin, J. I.; Weinreb, S. M. J. Am. Chem. Sot. m 8) 9)
1397 (1983).
Levin, J. I.; Weinreb, S. M. J. Ore. Chem. & 4325 (1984). a) Bailey, T. R. Tetrahedron
Lett. Z
4407 (19861.
b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, I’. Svnthesis 693 (1987). 10) Cass, W. E. J. Ore. Chem. &&,785 (1942). 11) a) Naito, T.; Yoshikawa, T.; Ishlkawa, F.; Isoda, S.; Omura, Y.; Takamura, I. Chem. Pharm. Bull l3_ 869 (19651, b) Yoshikawa, T.; Ishikawa, F.; Omura, Y.; Naito, T. Chem. Pharm. Bull. n
873 (19651.
12) All compounds exhibited satisfactory IR, MS, *H NMR, 13C NMR and elemental analyses. 13) The increased reactivity of 8 is presumably due to both increased mobility of the olefin-containing (relative to 5) and electron donation to the oxazole from the aromatic oxygen substituent.
This electron donation is
moderated by an a-carbonyl group in each of the other oxazole-olefin substrates. 14) Padyukova, N. S.; Florent’ev, V. L. Khim. Geterotsikl. (Received
in
USA
17
February
1989)
Soedin. (Enal. Transl.15
side chain
555 (1973).
0040-4039/89 $3.00 Pergamon Press plc
2355-2358,1989
+ .OO
EUROPIUM CATALYZED INTRAMOLECULAR SYNTHESIS
OXAZOLE DIELS-ALDER
REACTIONS FOR THE
OF BENZOPYRANO[4,3-bJPYRIDINES
AND
BENZO[hJ-1,6_NAPHTHYRIDINES
Jeremy I. Levin American Cyanamid Company Medical Research Division, Lederle Laboratories Pearl River, New York
10965
ABSTRACT: Intramolecular oxazole-olefin Diels-Alder reactions proceed, europium(fodh to provide substituted SH-Ill-benzopyranoI4,3-blpyridines yields.
Inthepast several years, 5-oxo-5H-[l]-benzopyrano[4,3-blpyridine pharmacologically
interesting compounds.1,2,3
inotropic, anti-allergic,
activity.
\--/
\-N
chromones.1,2 cycloaddition
derivatives
1 have attracted attention as
These tricyclic annelated pyridines have been reported to possess
analgesic and anti-inflammatory
usually been accomplished
in the presence of the Lewis acid and benzoIh]-1,6 naphthyridines in moderate
The synthesis of these novel heterocycles
has
-
through the condensation of enamines or malonic acid derivatives with substituted
More recently, Taylor has shown that these ring systems can be constructed via intramobzcular reactions of suitably substituted
It was our intention to investigate
tria2ines.l
the applicability
of intramolecular
the synthesis of this ring system and the related nitrogen-containing
oxazole-olefin
compounds
compounds of general structure 1 and 2 is shown below:
aX=OH & X=NH*
2355
Diels-Alder
2. The retro-synthetic
methodology analysis
for
for
2356
Cycloaddition
reactions
of oxazoles
are well precedented, having first been described by Kondrat’eva in 1957.5 Since
that preliminary account, this reaction has been used on numerous occasions for the synthesis of pyridines both natural and unnatural in origin.6
Several examp 1e s o f intramolecular
oxazole Diels-Alder reactions have also been published,6,7
including one example utilizing a substituted Z-phenyl oxazole as the Diels-Alder substrate.8
This is particularly
noteworthy since 2-phenyl oxazoles are extremely unreactive heterodienes due to steric and electronic effects. The synthesis of 2-co-hydroxyphenyl)oxazole, o-iodophenol
5 was accomplished using a convergent four-step sequence.
was first acetylated with acetic anhydride/pyridine.
catalyzed coupling with 2-tri-n-butyltin
This aryl iodide then underwent
oxazole, followed by hydrolysis of the acetate to provide phenol 3 in 75%
overall yield.g Subsequent acylation of 3 was best achieved by deprotonating by addition of the appropriate
Thus,
palladium
acid chloride.
Analogously,
the phenol with sodium hydride followed
alkylation of the sodium phenoxide with the appropriate
allylic bromide provided the aryl ethers z and fi in good yield. This variety of olefinic side chains was chosen to investigate the electronic requirements
of the dienophile in the intramolecular
2 R = COCH = CHC02Et (89%) § R=COCH=CHCH3 (86%) Z R = CH2CH = CHCH3 (49%) 8 R = CH2CH = CHCO$t+ (76%)
1) NaWTHF 9-
2) RCOCI or RX
The requisite intermediates
for the construction of benzonaphthyridine
alkylation of the known 2-(o-aminophenyl)oxazole,10 /-\
4-
11
( i-Pr)zNEl
1) NaH 2) Br ~~&+I,
CHCb
Oxazole-olefin
derivatives 2 were prepared by acylation or
as shown below.
RCOCI
9 1p IL
cycloadditions.
NHR R = COCH=CHCQEt (85%) R=COCH=CHCH3 (87%) R = CCCF3 (89%)
substrate 5 was chosen for our first cycloaddition attempt.
degassect odichlorobenzene
Thus, the oxazole-olefin
was dissolved in
(0.03M solution) and then refluxed for 16 h. Unfortunately, no reaction was observed and
starting material was recovered unchanged.
However, upon addition of 7 mole % of europiumffod)3
I=-/ Eu(fod)3 o-DCB
jJ_ X = 0 (46%) 5 x=0 $f X=NH
14 X = NH (75%)
to the reaction, the
2358
7)
a) Turchi, I. J.; Cullen, T. G. Heterocvcles a
2463 (19841.
b) Shimada, S.; Tojo, T. Chem. Pharm. Bull. &
4247 (19831.
cl Levin, J. I.; Weinreb, S. M. J. Am. Chem. Sot. m 8) 9)
1397 (1983).
Levin, J. I.; Weinreb, S. M. J. Ore. Chem. & 4325 (1984). a) Bailey, T. R. Tetrahedron
Lett. Z
4407 (19861.
b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, I’. Svnthesis 693 (1987). 10) Cass, W. E. J. Ore. Chem. &&,785 (1942). 11) a) Naito, T.; Yoshikawa, T.; Ishlkawa, F.; Isoda, S.; Omura, Y.; Takamura, I. Chem. Pharm. Bull l3_ 869 (19651, b) Yoshikawa, T.; Ishikawa, F.; Omura, Y.; Naito, T. Chem. Pharm. Bull. n
873 (19651.
12) All compounds exhibited satisfactory IR, MS, *H NMR, 13C NMR and elemental analyses. 13) The increased reactivity of 8 is presumably due to both increased mobility of the olefin-containing (relative to 5) and electron donation to the oxazole from the aromatic oxygen substituent.
This electron donation is
moderated by an a-carbonyl group in each of the other oxazole-olefin substrates. 14) Padyukova, N. S.; Florent’ev, V. L. Khim. Geterotsikl. (Received
in
USA
17
February
1989)
Soedin. (Enal. Transl.15
side chain
555 (1973).