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Reaction of N-(4-pyridylmethyl)-amide N-oxides with acetic anhydride
Tetrahedron Letters Vol. 21, pp 3921 - 3924 @Pergmon Press Ltd. 1980, Printed in Great Britain
REACTION
OF N-(4-PYRIDYLMETHYL)-AMIDE Miguel
Departamento
F. Braha*
de Quimica
Universidad Summary:
dimerization
the pyridine
N-OXIDES
and Maria
Complutense.
acetic
prompted
us to study
anhydride
new type of dimer When $ was
not previously treated
This
(s, 12H, 4CH3),
2H, 2H para-phenyl), 280-2°C
under
aceticanhydride
at the atom attached
(DMF-water)
atoms
of g with
to
this
neuroleptic
for new derivatives
of heteroaromatic
reviewed
reagent,
N-oxi-
by Oae and 0gino3
which
resulted
in a
reported. anhydride
acetic
compound
was
under
reflux
recrystallized
to its spectroscopic
6.80
(s, 2H, 2CH),
8.60
(d,
for 1.5 hours
from DMF, m.p.
data.
which
showed
suggested
awhite
336-8°C
absorption
place.
8.90
liquors
bands
The
to
: 478 (M+), 240
'H-NMR
(F3C-COOH
suggested
(s,
spectrum
a solid
(22%), m.p.
3200 and 1650 cm-' showed
to 2 in which
signals
90MHz):
7.35
(d, 4H, 4H a-pyridine). produced
in IR near
mass
similar
The fact that
in the NMR spectrum
MS
(s, 4H, 4H ortho-phenyl),
of the mother
a structure
ture of the 2 and E isomers
7.20
4H, 4H B-pyridine),
pressure
has taken
had disappeared
of the reaction
has been excellently
NH and CO respectively.
peak at 476 which
J, is a powerful The search
: 3300 and 1630 (NH and CO amide);
reduced
due to the amide hydrogen
with
as N,N' -di-(3,5-dimethylbenzoyl)-1,2-di-(4-pyridyl)-
$, according
+ 1); IR (KBr)
Removal,
with
identified
ethylenediamine 2.30
Spain.
occurs
metabolite.
interest
which
the reaction
(42%) appeared.
give a compund (Mt)/2
the main
as the theoretical
des with
solid
Quimicas.
ring.
its N-oxide * $ being
of & as well
ANHYDRIDE
Rodriguez
N-oxides
N-(4-pyridylmethyl)-3,5_dimethylbenzamide' agent,
ACETIC
de Ciencias
Madrid-3.
This dimerization
compounds.
WITH
L. LBpez
Facultad
Orgbnica.
of N-(4-pyridylmethyl)-benzamide
Reaction
yielded
0040-4039/80/1001-j92jsO2.00/0
a molecular
the loss of two
due to the methine
that the compound
could
protons
be a mix-
of N,N'-di-(3,5-dimethylbenzoyl)-l,2-di-(4-pyridyl)-
vinylenediamine and 7.45
4. IH-NMR spectrum (CDC13 90 MHz) : 2.39 (s, 12H, 4CH3), 7.18 % (two doublets corresponding to the 4 hydrogen atoms of the s position
of the pyridine
ring
2H, 2H ortho-phenyl), corresponding
in the Z/E mixture), 7.63
7.28
(s, ZH, 2H para-phenyl),
(s, 2H, 2H ortho-phenyl),
to the 4 hydrogen
atoms
8.46 and 8.59
of the a position
7.55
of the pyridine
ring
the Z/E mixture). Catalytic relationship
hydrogenation
between
of $, yielded
the compounds.
2 which
confirmed
(s,
(two doublets
the structural
in
3924
a)i R-CONH--HP
-
OAc R-CONS-
R;H-$tj
~
-;GJNHCO-R
=
F-NHCO-R
+ R-CONH-f R= 3,5-(
CH3)2-C6H3-
The fact that takes
place
rization
of which
similar
explains
2 or $ suggesting
In order
to comfirm
same conditions with
to give R alkyl
that
process follows
of this dimeriration treated
the corresponding
reac-
to &. The
the yield
cage"mechanism
N-oxides.
the extension
with
rise
to modify
N-oxides
were
give
a "radical
for other
2, dime-
in a transfer
would
does not seem
the reaction
the reaction
rise to radicals
of 2. The latter,
or inhibitors
that
to suggest
giving
by Oae and Traynelis4
N-(4-pyridylmethyl)-amide diamines
seems
process
disproportionation
precusors
to that observed
isolated
cleavage
the formation
by a radical
of radical
of either
2 and ,4 were
via a homolytic
tion followed presence
I
acetic
reaction
other
anhydride
under
the
N,N'- diacyl-1,2-di-(4-pyridyl)-ethylen
or aryl groups.
References. 1. M.F. BraRa, J.M. Castellano and F.P. Rabaddn, Arch. de Farmacol. Y Toxicol., IV, 237 (1978). 2. P.D.G. Jal6n, E. Gonzrilez, A. Idoipe, 1704 (1979).
M.R.M. LarraRaga and M. F. Brafia,Arzneim-Forsch,29_,
3. S. Oae and K. Ogino, Heterocycles,5, 583 (1977). 4. a) S. Oae, T. Kiato and Y. Kitaoka,
., j34_, 3359 (1962).
b) S. Oae, Y. Kitaoka and T. Kitao, Tetrahedron, 2D_,2685 (1964). c) V.J. Traynelis and A.I.
Gallagher, J. Am. Chem. Sot., 87, 5710 (1965).
Acknowledgements:This work was supported by the grants given to one of the authors (M.L.L.R.) from‘LaboratoryMade S.A. of Madrid and the Ministry of Education and Science of Spain, which is gratefully acknowledged. (Received in UK 2 July 1980)
REACTION
OF N-(4-PYRIDYLMETHYL)-AMIDE Miguel
Departamento
F. Braha*
de Quimica
Universidad Summary:
dimerization
the pyridine
N-OXIDES
and Maria
Complutense.
acetic
prompted
us to study
anhydride
new type of dimer When $ was
not previously treated
This
(s, 12H, 4CH3),
2H, 2H para-phenyl), 280-2°C
under
aceticanhydride
at the atom attached
(DMF-water)
atoms
of g with
to
this
neuroleptic
for new derivatives
of heteroaromatic
reviewed
reagent,
N-oxi-
by Oae and 0gino3
which
resulted
in a
reported. anhydride
acetic
compound
was
under
reflux
recrystallized
to its spectroscopic
6.80
(s, 2H, 2CH),
8.60
(d,
for 1.5 hours
from DMF, m.p.
data.
which
showed
suggested
awhite
336-8°C
absorption
place.
8.90
liquors
bands
The
to
: 478 (M+), 240
'H-NMR
(F3C-COOH
suggested
(s,
spectrum
a solid
(22%), m.p.
3200 and 1650 cm-' showed
to 2 in which
signals
90MHz):
7.35
(d, 4H, 4H a-pyridine). produced
in IR near
mass
similar
The fact that
in the NMR spectrum
MS
(s, 4H, 4H ortho-phenyl),
of the mother
a structure
ture of the 2 and E isomers
7.20
4H, 4H B-pyridine),
pressure
has taken
had disappeared
of the reaction
has been excellently
NH and CO respectively.
peak at 476 which
J, is a powerful The search
: 3300 and 1630 (NH and CO amide);
reduced
due to the amide hydrogen
with
as N,N' -di-(3,5-dimethylbenzoyl)-1,2-di-(4-pyridyl)-
$, according
+ 1); IR (KBr)
Removal,
with
identified
ethylenediamine 2.30
Spain.
occurs
metabolite.
interest
which
the reaction
(42%) appeared.
give a compund (Mt)/2
the main
as the theoretical
des with
solid
Quimicas.
ring.
its N-oxide * $ being
of & as well
ANHYDRIDE
Rodriguez
N-oxides
N-(4-pyridylmethyl)-3,5_dimethylbenzamide' agent,
ACETIC
de Ciencias
Madrid-3.
This dimerization
compounds.
WITH
L. LBpez
Facultad
Orgbnica.
of N-(4-pyridylmethyl)-benzamide
Reaction
yielded
0040-4039/80/1001-j92jsO2.00/0
a molecular
the loss of two
due to the methine
that the compound
could
protons
be a mix-
of N,N'-di-(3,5-dimethylbenzoyl)-l,2-di-(4-pyridyl)-
vinylenediamine and 7.45
4. IH-NMR spectrum (CDC13 90 MHz) : 2.39 (s, 12H, 4CH3), 7.18 % (two doublets corresponding to the 4 hydrogen atoms of the s position
of the pyridine
ring
2H, 2H ortho-phenyl), corresponding
in the Z/E mixture), 7.63
7.28
(s, ZH, 2H para-phenyl),
(s, 2H, 2H ortho-phenyl),
to the 4 hydrogen
atoms
8.46 and 8.59
of the a position
7.55
of the pyridine
ring
the Z/E mixture). Catalytic relationship
hydrogenation
between
of $, yielded
the compounds.
2 which
confirmed
(s,
(two doublets
the structural
in
3924
a)i R-CONH--HP
-
OAc R-CONS-
R;H-$tj
~
-;GJNHCO-R
=
F-NHCO-R
+ R-CONH-f R= 3,5-(
CH3)2-C6H3-
The fact that takes
place
rization
of which
similar
explains
2 or $ suggesting
In order
to comfirm
same conditions with
to give R alkyl
that
process follows
of this dimeriration treated
the corresponding
reac-
to &. The
the yield
cage"mechanism
N-oxides.
the extension
with
rise
to modify
N-oxides
were
give
a "radical
for other
2, dime-
in a transfer
would
does not seem
the reaction
the reaction
rise to radicals
of 2. The latter,
or inhibitors
that
to suggest
giving
by Oae and Traynelis4
N-(4-pyridylmethyl)-amide diamines
seems
process
disproportionation
precusors
to that observed
isolated
cleavage
the formation
by a radical
of radical
of either
2 and ,4 were
via a homolytic
tion followed presence
I
acetic
reaction
other
anhydride
under
the
N,N'- diacyl-1,2-di-(4-pyridyl)-ethylen
or aryl groups.
References. 1. M.F. BraRa, J.M. Castellano and F.P. Rabaddn, Arch. de Farmacol. Y Toxicol., IV, 237 (1978). 2. P.D.G. Jal6n, E. Gonzrilez, A. Idoipe, 1704 (1979).
M.R.M. LarraRaga and M. F. Brafia,Arzneim-Forsch,29_,
3. S. Oae and K. Ogino, Heterocycles,5, 583 (1977). 4. a) S. Oae, T. Kiato and Y. Kitaoka,
., j34_, 3359 (1962).
b) S. Oae, Y. Kitaoka and T. Kitao, Tetrahedron, 2D_,2685 (1964). c) V.J. Traynelis and A.I.
Gallagher, J. Am. Chem. Sot., 87, 5710 (1965).
Acknowledgements:This work was supported by the grants given to one of the authors (M.L.L.R.) from‘LaboratoryMade S.A. of Madrid and the Ministry of Education and Science of Spain, which is gratefully acknowledged. (Received in UK 2 July 1980)