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Synthesis and nucleophilic substitutions of 3-alkyl-5-chloroisoxazoles
Tetrahedron Printed in
Letters,Vol.25,No.4l,Pp Great Britain
0040-4039/84 $3.00 + .oo 01984 Perqamon Press Ltd.
4587-4590,1984
SYNTUCSIS AND IWCLFDPEILIC SUBSTI’IUTIONS OF 3-ALKYL-5-CRLOROISOXAZOLES 1* t and K.F. Albizati R.V. Stevens Department of Chemistry and Biochemistry University of California at Los Angeles Los Angeles, CA 90024
Summarv. nitrile chloride
A 3-alkyl-5-chloroisoxazole synthesis to 1 ,l-dichloroethylene, an oxides in these adducts by various nucleophiles
In connection cycloaddi of
with
methods
protocols
were
of
A direct
for a route
both
and not
%hen various
in
isoxax 01 ine isolated
observcd
tDeceased
synthesis
of
syathesizing (1)
to
synthesize
thienamycin
(3)
cycloaddition Substitution of
y&
(2)
which
would
of
(1).
be more efficient
isoxazoles
(1)
in
A number
than
which
of the
nitrone-olef
3-alkyl-J-alkoxy-isoxaxoles
a family
oxides
allowing to allow
were
1,3-dipolar
have
access wide
are
presumed (5)
detected.
formed The
cycloaddition
described
availability to
to in
would
existing
allow
relatively variation.
two-step
alkynyl rare
’
arise
by
be isolated compounds tended
easy
products.
blarch 9, 1984
4587
of
ability
to
Unf or-
compounds
we avoided in
as colorless
with of
These
the oils
and hydroxamoyl
process.
regioisomeric
to
this
are
direct
6
(4)
to be higher
the
oxides
ethers.
class
Thus,
sequence.
dehydrochlorination
cycloaddition
al ternative
nitrile
Rowever,
of
in l,l-dichloroethylene could
the
of
approach.4
a variety
this
structural
generated
this
of
and econaaical
the 5-chloroisoxazoles7
interme¿iate
as reaction
on the
the
showu in Table 1. Coth nitro 8 precursors, although the yields
(6)
nor
reports
depends
enough
is
a more versatile
nitrile
oxide
chloroisoxazoles
ther
flexible
the yields
nitrile
to
problem
me thods
triethylamine
solids
converting
isolated
(1)
and developed
excess
this
A few
synthetic
ayproach
as
to
isoxazole
tunately,
the for
the
P? and F2.
solution
P2 of
on
a method
sought
alkoxyacetylenes.
scarce
studies
envisioned
Y/e
.3
variation
vary
our
tion, 2 we raquired
is described based on inexpensive dipolarophile. is also described.
presente or
halides
crystalline could
the latter. a
serve The 5-
5,5-dichlor~A~-
isoxaxolines
4-chloroisoxazoles
of
were were
neinever
4589
the mixture purif
ied
strates,
was f iltered
8 solution
2.5
solution
of
to
mixture
was partitioned
\Vhen the the were
chloride not
a
or
of
added’
crystallization
and the filtrate
crystallixation
by
or
equivalents
gel
between
silica
gel
ether
products
investigated,
Table
The
m. Using
halide
and water
in
treated were
obtain
3-5
produced
halides
a crude
product
which
were as
was
at 25’C.
equivalents
of
sub-
slowly
The reaction
was purified
in good yield
Substitution
(Table
II) .ll and
of S-Chloroisoxazoles
Nucleophile~ Conditions
Product
a 6 Yidld
0
TJ
55
fa
NKICH,
70
6h/SS'C
NaOCH, 18 h/65"C
99
-%H,
NaOCH,@
II
5 h/SD'C
0SLi
II
10 h/60 %
7
:O
12
OJO
-9
48
0
LI
II
2h/25'E
' Al1 i~~xaroles were fully characterized spectroscopically; b Yields represent chrcmatographically pure products; ' The vere
generated
and piperidine
from were
the alcohol deprotonated
and
sodium
with
metal,
n-S-i
in
a nucleophile
2-lithio-1,3-dithiane
NmcH,O 2h/6O'C
alkoxides
isoxazoles
1 ,l-dichloroethylene
in l,l-dichloroethylene to
with
although
Nucleophilic
II.
Substrete
thiophenol
crude
hydroxamoyl
by
chrcrsatography. were
displacement
Jo
chrcmatography.
triethylamine
of
the hydroxamoyl
5-chloroisoxazoles
extensively
concentrated
sil ica
at 0-C.
b
Carbon the
dry
‘IUF,
nucleophiles
sodium
salt
of
4590
Nu-/ THF 25-66°C
'N" 6
L
w
dimethyl
malonste
failed
by ether
extraction
with
products
of
elimination
i soxaz 01 e mechanism
to ptovide final
cleavage
althongh
any products
purification were
of
displacement.
by crystallixation The products
observed.
free-radical
substitution
The isoxazoles or
y&
silica
gel
presumably an SRNl
arise
prooess
were
isolated
chromatography. y&
is
No
an addition-
an
intriguing
possibility. Acknowledaaments. KFA wishes
to
This
thank
and Professor
work was supported
the Upjohn
D. John Faulkner
by a grant
frcm
the National
Company and the University for
advice
concerning
of
Institutes
California
for
of
graduate
Health.
fellowships
the eanuscript.
Notes 1.
Current
address.
2.
Stevens.
R.V.;
3.
Much of the work in this area Heterocvm, 1982, u, 463.
4.
a)
&g.
Grunanger, Linoei.,
the Scripps Albisati,
K.F.
Institution
of
J_. Chem Soc., has been
Oceanography. Chem -+
compiled
in
P.; Langella, D.R. Gazz -. * 1959, ti, 1958, 24, 163; c) Kozikowski, A.P.;
La Jolla,
Commun _., a
recent
1784; b) Goldstein,
1139.
California.
1982.
104.
review.
See
Kametani,
Grunanger, P. u. S. J_. Otp. Chem -*
A-b.
* 1983 , 41.
5.
Most methods for preparing this class of compounds utilize strongly basic reagents. Butledge, T.F. “Acetylenic Compounds”; Reinhold Dooks, New York, 1968, pp. 35-44. Tetrahedron Lett 1978, 3103 see Tanaka, K.; Shirashi. S.; Nakai, T.; Ishikawa, N. --** reasonably general solution to this problem.
6.
A brief study by Micetich has demonstrated that the ni11 undergo cycloaddition with l,l-dichloroethylene. Intl 1970, &, 225 and Micetich, R.G.; Chin, C.G. -SI
1.
Partial NUR data for í-chloroisoxazoles: NkiR (CDC13) -6 165 (isoxazole C-3),
‘8 -S
100
T.
Sea Also for 8
relatively stable arylnitrile oxides See Ricetich, R.G. 02. Ptep. Pz. Can. J. -* Chem 1970, 43. 1371. l
NIiR (CDCl ) -6 6.5-6 .O (isoxazole (isoxazole S-4) I -6 155 (isoxasole
C-4 ll); C-5).
Oxides”:
1971.
13C
8.
Grunanger.
9.
For the additions, approximately l-5 hour.
10.
N-chlorosuccinimide a) These intermediates were produced fras the oximes by treatment with Tetrahedron, 1976, 32. 1599 and Liu, K.-C.; Shelton, B.R.; Uowe, in DRF; see Stevens, R.V. R.K. J. -g. Chem 8 1980. 42, 3916; b) procedure f ras A.A. Bagedorn, private communication; -* Dissertation of K. Albisati, the syntheris of this substance is described in the Ph.D. C) University of California at Los Angeles, 1983.
ll.
substrates bearing Similar displacements of 5-chloroisoxasoles has been accomplished with See Postovskii. a t C-4 and on 3-pheny 1-5-chloroi soxax 01 e . electron-withdrawing group GAti. Obshchei Khim, 1959, 22. 3446; Speroni, G.; Giachetti, E. iny.; Sokolw. S.V. w. Ita1 3 1953, &z, 192 and ref. 6. -*
P.;
Grundmann,
C.
“‘Ihe
a constant-addition mm01 of nitrile
(Received ín USA 11 June
1984)
Nitrile
funnel was oxide precursor
Springer-Verlag, utilized. in 5-25
Berlin,
lhe addition rates ml. of l.l-dichloroethylene
were per
.
Letters,Vol.25,No.4l,Pp Great Britain
0040-4039/84 $3.00 + .oo 01984 Perqamon Press Ltd.
4587-4590,1984
SYNTUCSIS AND IWCLFDPEILIC SUBSTI’IUTIONS OF 3-ALKYL-5-CRLOROISOXAZOLES 1* t and K.F. Albizati R.V. Stevens Department of Chemistry and Biochemistry University of California at Los Angeles Los Angeles, CA 90024
Summarv. nitrile chloride
A 3-alkyl-5-chloroisoxazole synthesis to 1 ,l-dichloroethylene, an oxides in these adducts by various nucleophiles
In connection cycloaddi of
with
methods
protocols
were
of
A direct
for a route
both
and not
%hen various
in
isoxax 01 ine isolated
observcd
tDeceased
synthesis
of
syathesizing (1)
to
synthesize
thienamycin
(3)
cycloaddition Substitution of
y&
(2)
which
would
of
(1).
be more efficient
isoxazoles
(1)
in
A number
than
which
of the
nitrone-olef
3-alkyl-J-alkoxy-isoxaxoles
a family
oxides
allowing to allow
were
1,3-dipolar
have
access wide
are
presumed (5)
detected.
formed The
cycloaddition
described
availability to
to in
would
existing
allow
relatively variation.
two-step
alkynyl rare
’
arise
by
be isolated compounds tended
easy
products.
blarch 9, 1984
4587
of
ability
to
Unf or-
compounds
we avoided in
as colorless
with of
These
the oils
and hydroxamoyl
process.
regioisomeric
to
this
are
direct
6
(4)
to be higher
the
oxides
ethers.
class
Thus,
sequence.
dehydrochlorination
cycloaddition
al ternative
nitrile
Rowever,
of
in l,l-dichloroethylene could
the
of
approach.4
a variety
this
structural
generated
this
of
and econaaical
the 5-chloroisoxazoles7
interme¿iate
as reaction
on the
the
showu in Table 1. Coth nitro 8 precursors, although the yields
(6)
nor
reports
depends
enough
is
a more versatile
nitrile
oxide
chloroisoxazoles
ther
flexible
the yields
nitrile
to
problem
me thods
triethylamine
solids
converting
isolated
(1)
and developed
excess
this
A few
synthetic
ayproach
as
to
isoxazole
tunately,
the for
the
P? and F2.
solution
P2 of
on
a method
sought
alkoxyacetylenes.
scarce
studies
envisioned
Y/e
.3
variation
vary
our
tion, 2 we raquired
is described based on inexpensive dipolarophile. is also described.
presente or
halides
crystalline could
the latter. a
serve The 5-
5,5-dichlor~A~-
isoxaxolines
4-chloroisoxazoles
of
were were
neinever
4589
the mixture purif
ied
strates,
was f iltered
8 solution
2.5
solution
of
to
mixture
was partitioned
\Vhen the the were
chloride not
a
or
of
added’
crystallization
and the filtrate
crystallixation
by
or
equivalents
gel
between
silica
gel
ether
products
investigated,
Table
The
m. Using
halide
and water
in
treated were
obtain
3-5
produced
halides
a crude
product
which
were as
was
at 25’C.
equivalents
of
sub-
slowly
The reaction
was purified
in good yield
Substitution
(Table
II) .ll and
of S-Chloroisoxazoles
Nucleophile~ Conditions
Product
a 6 Yidld
0
TJ
55
fa
NKICH,
70
6h/SS'C
NaOCH, 18 h/65"C
99
-%H,
NaOCH,@
II
5 h/SD'C
0SLi
II
10 h/60 %
7
:O
12
OJO
-9
48
0
LI
II
2h/25'E
' Al1 i~~xaroles were fully characterized spectroscopically; b Yields represent chrcmatographically pure products; ' The vere
generated
and piperidine
from were
the alcohol deprotonated
and
sodium
with
metal,
n-S-i
in
a nucleophile
2-lithio-1,3-dithiane
NmcH,O 2h/6O'C
alkoxides
isoxazoles
1 ,l-dichloroethylene
in l,l-dichloroethylene to
with
although
Nucleophilic
II.
Substrete
thiophenol
crude
hydroxamoyl
by
chrcrsatography. were
displacement
Jo
chrcmatography.
triethylamine
of
the hydroxamoyl
5-chloroisoxazoles
extensively
concentrated
sil ica
at 0-C.
b
Carbon the
dry
‘IUF,
nucleophiles
sodium
salt
of
4590
Nu-/ THF 25-66°C
'N" 6
L
w
dimethyl
malonste
failed
by ether
extraction
with
products
of
elimination
i soxaz 01 e mechanism
to ptovide final
cleavage
althongh
any products
purification were
of
displacement.
by crystallixation The products
observed.
free-radical
substitution
The isoxazoles or
y&
silica
gel
presumably an SRNl
arise
prooess
were
isolated
chromatography. y&
is
No
an addition-
an
intriguing
possibility. Acknowledaaments. KFA wishes
to
This
thank
and Professor
work was supported
the Upjohn
D. John Faulkner
by a grant
frcm
the National
Company and the University for
advice
concerning
of
Institutes
California
for
of
graduate
Health.
fellowships
the eanuscript.
Notes 1.
Current
address.
2.
Stevens.
R.V.;
3.
Much of the work in this area Heterocvm, 1982, u, 463.
4.
a)
&g.
Grunanger, Linoei.,
the Scripps Albisati,
K.F.
Institution
of
J_. Chem Soc., has been
Oceanography. Chem -+
compiled
in
P.; Langella, D.R. Gazz -. * 1959, ti, 1958, 24, 163; c) Kozikowski, A.P.;
La Jolla,
Commun _., a
recent
1784; b) Goldstein,
1139.
California.
1982.
104.
review.
See
Kametani,
Grunanger, P. u. S. J_. Otp. Chem -*
A-b.
* 1983 , 41.
5.
Most methods for preparing this class of compounds utilize strongly basic reagents. Butledge, T.F. “Acetylenic Compounds”; Reinhold Dooks, New York, 1968, pp. 35-44. Tetrahedron Lett 1978, 3103 see Tanaka, K.; Shirashi. S.; Nakai, T.; Ishikawa, N. --** reasonably general solution to this problem.
6.
A brief study by Micetich has demonstrated that the ni11 undergo cycloaddition with l,l-dichloroethylene. Intl 1970, &, 225 and Micetich, R.G.; Chin, C.G. -SI
1.
Partial NUR data for í-chloroisoxazoles: NkiR (CDC13) -6 165 (isoxazole C-3),
‘8 -S
100
T.
Sea Also for 8
relatively stable arylnitrile oxides See Ricetich, R.G. 02. Ptep. Pz. Can. J. -* Chem 1970, 43. 1371. l
NIiR (CDCl ) -6 6.5-6 .O (isoxazole (isoxazole S-4) I -6 155 (isoxasole
C-4 ll); C-5).
Oxides”:
1971.
13C
8.
Grunanger.
9.
For the additions, approximately l-5 hour.
10.
N-chlorosuccinimide a) These intermediates were produced fras the oximes by treatment with Tetrahedron, 1976, 32. 1599 and Liu, K.-C.; Shelton, B.R.; Uowe, in DRF; see Stevens, R.V. R.K. J. -g. Chem 8 1980. 42, 3916; b) procedure f ras A.A. Bagedorn, private communication; -* Dissertation of K. Albisati, the syntheris of this substance is described in the Ph.D. C) University of California at Los Angeles, 1983.
ll.
substrates bearing Similar displacements of 5-chloroisoxasoles has been accomplished with See Postovskii. a t C-4 and on 3-pheny 1-5-chloroi soxax 01 e . electron-withdrawing group GAti. Obshchei Khim, 1959, 22. 3446; Speroni, G.; Giachetti, E. iny.; Sokolw. S.V. w. Ita1 3 1953, &z, 192 and ref. 6. -*
P.;
Grundmann,
C.
“‘Ihe
a constant-addition mm01 of nitrile
(Received ín USA 11 June
1984)
Nitrile
funnel was oxide precursor
Springer-Verlag, utilized. in 5-25
Berlin,
lhe addition rates ml. of l.l-dichloroethylene
were per
.