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Action of phenyl isocyanide dichloride on cyclic tertiary amines a new and convenient dealkylation reaction
No. 43, pp 3765 - 3768, 1974.
Tetrrhedron Letterr
ACTION TERTIARY
OF
PHENYL
AMINES
G.
LECLERC*
"Institut
ISOCYANIDE
A NEW
de
AND
de
E.R.A.
DICHLORIDE
ON
C.N.R.S.
Chimie
Organique,
393
C.N.R.S.
du
C.G.
Facultg
142 du
During
1
phenyl
presence cycle,
of the
studies
isocyanide
related
triethylamine phenylurea
to
the
dichloride as
acid
derivative
STRASBOURG
FacultL
de
Pharmacie
STRASBOURG
publication
synthesis was
acceptor. J was
REACTION
de MBdecine
67083
(PID)
CYCLIC
WERMUTH**
67000
(Reoeived in UK 9 September 1974; accepted for
dine
Printed in Great Iritain.
DEALKYLATION
and
Pharmacologic,
**Laboratoire
Preaa.
CONVENIENT
, B. ROUOT*
E.R.A.
Per-n
of
derivatives
+
of
cloni-
with
thiourea
in the
the
expected
hetero-
of
obtained.
--c
/NH\
C6H5-N=C
C6H5-N=C
1974)
18 September
treated
Instead
CEDEX
\NH
/c=s
NEb3
H2N-CS-NH2
H20
CSH5-NH
The amines The
has
recent
leading
to
formation
of hygroscopic
salts
by
the
-CO-NEk2
action
of
been
observed previously apparently without further 3 disclosure of the action of PID on N-unsubstituted carbodiimides
A-N=C
NH
in accordance
-
with
k
/N
R-N=C
the
equation
1 =
PID
on
tertiary
investigation aziridines
:
Rl
R2
X
A
-R--N=C=N
'X
RlgR2
prompted cyclic
us
to publish
tertiary
our
own
=
H,or
work,
alkyl
related
amines.
3765
to
the
action
of
PID
with
2
.
3766
No. 43
Thus to
give 4.6
3H),
(m,
formamidine and
PID
reacted
a hygroscopic
urea
4H)
salt
which
(s,
after
(s,
(NMR
: (CDC13)
4H).
By
cd=
3.62
3.15
reacted the
4H),
d =
(s,
:
N2)
(CDC13)
C)
3H),
to
with d=
3.58
N-methyl
2.4
give
(m,
the
(m,
at
2H),
instantaneously
chlorourea
as did
2.08
irradiation (s,
C, under 4
(24 - 26"
: d =
(NMR
hydrolysis,
3.69
3H),
(NMR
pyrrolidine 4.0
4H),
ring-opened
4H),
1.82
(s,
chloro-
(q.
4H),
hydrolysis.
N-methylaziridine give,
- 75'
(n=4)
decomposed
,B (n = 4) ,4 after
(AcOEt. A
azetidine
(quintuplet, the
3.72
2H)
to
give
.J = 5.5
quintuplet
(s,
(Et20,-
derivative
the
the
Hz.
frequency
showing
2
chlorourea
2H), the
75"
3.01
of
PID
d = 3.09
derivative
(8,
quartet
presence
C) with
: (CDC13)
(NMR
3H),
gave
2
3.60
(q,
2 singlets
3 linear
methylene
groups.
Cl
R-NDH,)”2
C6 H 5 -N=C
+
-
C
c;>@H2)"
H -N=C< '
pH2)n-Cl
5
I
J
C6H5-N=C
i
I
A
c
B
NH-CO-N-(CH2);;-Cl
C6H5_
I
‘NnCH2)n LJ
I
‘gH5n =5
yield= (R=Et
n=6
NH -CO-N
321”
73 % mp=
171’C
yield=58
yield=
76%
When they and
gave
after
characterized
obtained
by
the
5-
n= 2
yield=87
%
mp=105’C
2
n=3
yield=75
%
mp=
85’C
3
n=4
yield=73
%
mp=
79’C
4
-N=C=O
C6H5
)
B
mp=130°C
N-methylpiperidine hydrolysis by
of
IR and
addition
N-methylazepine
of
or the
NMR)
N-ethylpiperidine
iminochlorocompound exclusively
phenylisocyanate
behaved
similarly,
the to
urea
was E
reacted
(n = 5)
derivative
with
PID,
(isolated 2,
also
piperidine.
leading
by
a clean
reaction
to
to
No. 43
the
3767
demethylated It
kylation TLC).
derivative
is noteworthy
without
any
It clearly
give
ring-opened
(n 3
5) to
of
the
to
steric
hindrance reacted
2.82
112' (6,
to
the
using
4.1
(m,
lH),
4.6
small
proceeds compounds
cyclic
it reacts
hindered
amines
with
amine,
in a decrease
the =
of ring-opened with
of
failed
approach
d
reaction
by
deal-
(NMR
and
(n < 4)
larger
to
ones
2.
by
give
: (CDC13)
C, NMR
3H),
type
result
excluding readily
the
,B, whereas
type
that
would
reacts
1,2,6_trimethylpiperidine
lidine (mp =
of
expected
groups
PID
of
cases
formation
that
compounds
PID,
in these
significant
compounds
give
methyl
that
appears
It was
mitted
,6.
of
(m,
(d,J
IH)
PID.
However
5, M+
of
the
Thus,
probably
bulk
when
due
sub-
to
1,2.5-trimethylpyrro-
ring-opened
- 5 Hz,
: MS
reactivity.
to react,
corresponding
1.15
increase
3H),
compound
1.5
= 268,
2
(d, J - 5 Hz,
f =
177 4
3H),
fragmen-
tation).
+
2’
C6H5-N=C
-
-
I
C6 H6-NH-CO-N
/’
‘Cl I
To get was g
mixed
with
(mp = 94"
a further
an
C)
insight
unsymmetrical
being
the
eg
mechanism
of
this
reaction
1,2_dimethylpyrrolidine,
PID
compound
obtained.
Cl
+
into
amine
-
C6H5-N=C\/
-C 6
H
5
I
-NH-CO-N
,”
C! 6 =
The spectrum 4.5
2H).
compared
structure
(CDC13)
d
(m,
and
IH)
with
that
It would philic
attack
rather
than
the
action
had
shown
by an
of the
SN
=
1.13
assigned
(d,
after
J - 5 Hz,
especially
by
its
3H), MS
careful 2.8
examination
(s, 3H),
(M+ - 254,
m e
3.54
of
its
NMR
(t, J = 5 Hz.
177, @( fragmentation)
of z. seem
the
cyanogen
that
chlorine
, type
same
i was
the
mechanism
ion
on
of reaction. bromide
direction
the
of less
Elderfield
on unsymmetrical of
opening.
the
cleavage
hindered and
side
Hageman
pyrrolidines
involves of 6
the
nucleomolecule,
in a study
and
asiridines
of
3766
No. 43
The method, mild
not
action
of
previously
conditions,
degradation
in very
of
tertiary
utilizing
a non-toxic
isolation
of
the
synthesis
of
the Work
PID
continues
on
tertiary
reported, good
for
yields.
amines. reagent
on
(without
and
REFERENCES
1)
B. Rouot,
2) Von
E.
G. Leclerc
K;hle,
internat. 3) D.A.
4) NMR
032
were
All
new
MS.
14722
on
and
H.A.
gave
it presents of
and
an attractive
ring-opening
is akin
yield)
to
the
and
which
asymmetric
under Von
Braun
advantages
of
of allowing
can
be
cyclic
extension
the
precursors
urea of
the for
derivatives.
this
reaction.
FOOTNOTES
Wermuth,
Klauke,
and a, on
internal
out
compounds and
as
AND
for
H.
Chim.
Ther.,
Tarnow
and
5, G.
545
(1973)
Zumach,
Angew.
Chem.
(1969)
recorded
TMS
carried
Elderfield
the
so,
were
with
20
C.G. E.
Giacobbe
T.J.
6) R.C.
absorption
S,
(C.A.,
spectra
solution 5) MS
Edit.,
Tomalia,
3 754
and
B. Anders,
of
presents
or
reaction
loss
application ’ *
utility,
thus
intermediates
tetrazolyl
the
This
Nevertheless
chloroformamidine amino
amines
dealkylation
a LKB
J. Midland,
a Perkin
Elmer
reference.
Chemical,
U.S.
Pat.
R
12 A or R
Chemical
Shifts
12 B in CDC13 in
d
9000
Hageman,
proper
Dow
1974)
J.
Org.
analysis
Chem.,
and
14,
appropriate
105
(1949)
IR,
UV
and
NMR
Tetrrhedron Letterr
ACTION TERTIARY
OF
PHENYL
AMINES
G.
LECLERC*
"Institut
ISOCYANIDE
A NEW
de
AND
de
E.R.A.
DICHLORIDE
ON
C.N.R.S.
Chimie
Organique,
393
C.N.R.S.
du
C.G.
Facultg
142 du
During
1
phenyl
presence cycle,
of the
studies
isocyanide
related
triethylamine phenylurea
to
the
dichloride as
acid
derivative
STRASBOURG
FacultL
de
Pharmacie
STRASBOURG
publication
synthesis was
acceptor. J was
REACTION
de MBdecine
67083
(PID)
CYCLIC
WERMUTH**
67000
(Reoeived in UK 9 September 1974; accepted for
dine
Printed in Great Iritain.
DEALKYLATION
and
Pharmacologic,
**Laboratoire
Preaa.
CONVENIENT
, B. ROUOT*
E.R.A.
Per-n
of
derivatives
+
of
cloni-
with
thiourea
in the
the
expected
hetero-
of
obtained.
--c
/NH\
C6H5-N=C
C6H5-N=C
1974)
18 September
treated
Instead
CEDEX
\NH
/c=s
NEb3
H2N-CS-NH2
H20
CSH5-NH
The amines The
has
recent
leading
to
formation
of hygroscopic
salts
by
the
-CO-NEk2
action
of
been
observed previously apparently without further 3 disclosure of the action of PID on N-unsubstituted carbodiimides
A-N=C
NH
in accordance
-
with
k
/N
R-N=C
the
equation
1 =
PID
on
tertiary
investigation aziridines
:
Rl
R2
X
A
-R--N=C=N
'X
RlgR2
prompted cyclic
us
to publish
tertiary
our
own
=
H,or
work,
alkyl
related
amines.
3765
to
the
action
of
PID
with
2
.
3766
No. 43
Thus to
give 4.6
3H),
(m,
formamidine and
PID
reacted
a hygroscopic
urea
4H)
salt
which
(s,
after
(s,
(NMR
: (CDC13)
4H).
By
cd=
3.62
3.15
reacted the
4H),
d =
(s,
:
N2)
(CDC13)
C)
3H),
to
with d=
3.58
N-methyl
2.4
give
(m,
the
(m,
at
2H),
instantaneously
chlorourea
as did
2.08
irradiation (s,
C, under 4
(24 - 26"
: d =
(NMR
hydrolysis,
3.69
3H),
(NMR
pyrrolidine 4.0
4H),
ring-opened
4H),
1.82
(s,
chloro-
(q.
4H),
hydrolysis.
N-methylaziridine give,
- 75'
(n=4)
decomposed
,B (n = 4) ,4 after
(AcOEt. A
azetidine
(quintuplet, the
3.72
2H)
to
give
.J = 5.5
quintuplet
(s,
(Et20,-
derivative
the
the
Hz.
frequency
showing
2
chlorourea
2H), the
75"
3.01
of
PID
d = 3.09
derivative
(8,
quartet
presence
C) with
: (CDC13)
(NMR
3H),
gave
2
3.60
(q,
2 singlets
3 linear
methylene
groups.
Cl
R-NDH,)”2
C6 H 5 -N=C
+
-
C
c;>@H2)"
H -N=C< '
pH2)n-Cl
5
I
J
C6H5-N=C
i
I
A
c
B
NH-CO-N-(CH2);;-Cl
C6H5_
I
‘NnCH2)n LJ
I
‘gH5n =5
yield= (R=Et
n=6
NH -CO-N
321”
73 % mp=
171’C
yield=58
yield=
76%
When they and
gave
after
characterized
obtained
by
the
5-
n= 2
yield=87
%
mp=105’C
2
n=3
yield=75
%
mp=
85’C
3
n=4
yield=73
%
mp=
79’C
4
-N=C=O
C6H5
)
B
mp=130°C
N-methylpiperidine hydrolysis by
of
IR and
addition
N-methylazepine
of
or the
NMR)
N-ethylpiperidine
iminochlorocompound exclusively
phenylisocyanate
behaved
similarly,
the to
urea
was E
reacted
(n = 5)
derivative
with
PID,
(isolated 2,
also
piperidine.
leading
by
a clean
reaction
to
to
No. 43
the
3767
demethylated It
kylation TLC).
derivative
is noteworthy
without
any
It clearly
give
ring-opened
(n 3
5) to
of
the
to
steric
hindrance reacted
2.82
112' (6,
to
the
using
4.1
(m,
lH),
4.6
small
proceeds compounds
cyclic
it reacts
hindered
amines
with
amine,
in a decrease
the =
of ring-opened with
of
failed
approach
d
reaction
by
deal-
(NMR
and
(n < 4)
larger
to
ones
2.
by
give
: (CDC13)
C, NMR
3H),
type
result
excluding readily
the
,B, whereas
type
that
would
reacts
1,2,6_trimethylpiperidine
lidine (mp =
of
expected
groups
PID
of
cases
formation
that
compounds
PID,
in these
significant
compounds
give
methyl
that
appears
It was
mitted
,6.
of
(m,
(d,J
IH)
PID.
However
5, M+
of
the
Thus,
probably
bulk
when
due
sub-
to
1,2.5-trimethylpyrro-
ring-opened
- 5 Hz,
: MS
reactivity.
to react,
corresponding
1.15
increase
3H),
compound
1.5
= 268,
2
(d, J - 5 Hz,
f =
177 4
3H),
fragmen-
tation).
+
2’
C6H5-N=C
-
-
I
C6 H6-NH-CO-N
/’
‘Cl I
To get was g
mixed
with
(mp = 94"
a further
an
C)
insight
unsymmetrical
being
the
eg
mechanism
of
this
reaction
1,2_dimethylpyrrolidine,
PID
compound
obtained.
Cl
+
into
amine
-
C6H5-N=C\/
-C 6
H
5
I
-NH-CO-N
,”
C! 6 =
The spectrum 4.5
2H).
compared
structure
(CDC13)
d
(m,
and
IH)
with
that
It would philic
attack
rather
than
the
action
had
shown
by an
of the
SN
=
1.13
assigned
(d,
after
J - 5 Hz,
especially
by
its
3H), MS
careful 2.8
examination
(s, 3H),
(M+ - 254,
m e
3.54
of
its
NMR
(t, J = 5 Hz.
177, @( fragmentation)
of z. seem
the
cyanogen
that
chlorine
, type
same
i was
the
mechanism
ion
on
of reaction. bromide
direction
the
of less
Elderfield
on unsymmetrical of
opening.
the
cleavage
hindered and
side
Hageman
pyrrolidines
involves of 6
the
nucleomolecule,
in a study
and
asiridines
of
3766
No. 43
The method, mild
not
action
of
previously
conditions,
degradation
in very
of
tertiary
utilizing
a non-toxic
isolation
of
the
synthesis
of
the Work
PID
continues
on
tertiary
reported, good
for
yields.
amines. reagent
on
(without
and
REFERENCES
1)
B. Rouot,
2) Von
E.
G. Leclerc
K;hle,
internat. 3) D.A.
4) NMR
032
were
All
new
MS.
14722
on
and
H.A.
gave
it presents of
and
an attractive
ring-opening
is akin
yield)
to
the
and
which
asymmetric
under Von
Braun
advantages
of
of allowing
can
be
cyclic
extension
the
precursors
urea of
the for
derivatives.
this
reaction.
FOOTNOTES
Wermuth,
Klauke,
and a, on
internal
out
compounds and
as
AND
for
H.
Chim.
Ther.,
Tarnow
and
5, G.
545
(1973)
Zumach,
Angew.
Chem.
(1969)
recorded
TMS
carried
Elderfield
the
so,
were
with
20
C.G. E.
Giacobbe
T.J.
6) R.C.
absorption
S,
(C.A.,
spectra
solution 5) MS
Edit.,
Tomalia,
3 754
and
B. Anders,
of
presents
or
reaction
loss
application ’ *
utility,
thus
intermediates
tetrazolyl
the
This
Nevertheless
chloroformamidine amino
amines
dealkylation
a LKB
J. Midland,
a Perkin
Elmer
reference.
Chemical,
U.S.
Pat.
R
12 A or R
Chemical
Shifts
12 B in CDC13 in
d
9000
Hageman,
proper
Dow
1974)
J.
Org.
analysis
Chem.,
and
14,
appropriate
105
(1949)
IR,
UV
and
NMR