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Photoaddition of alcohols to methylthio-4-pyrimidinones
Tetrahedron
Letters
110. 11,
pp
PHOTOADDITION
951 - 954, 1977.
OF ALCOHOLS
Jean-Louis Institut
de Chimie (Received
Uracil’ efficiently
and 5-fluorouracil’
water
CNRS,
91190
Gif sur Yv ette,
1977; accepted for publication
2 February
derivatives
France
1977)
which react
a thiocarbonyl
chromophore
are completly
unreactive
photoaddition5.
leading
observation
on the irradiation
of 4-benzylthio-I-methylpyrimidinone 6 1-methylpyrimidinone suggested
to a 5, 6-dihydro-6-methoxy-
4-alkylthiopyrimidinone vestigate
Naturelles,
JOUIN
are the only known pyrimidinone
which possess
Our recent methanol
and Patrick
or methanol in the presence of light (photoaddition). In the case of 4 and thymine photohydrates have also been detected. In contrast, 4-thiouracil
and 2-thiouracil towards
in UK 24 January
TO METHYLTHIO-4-PYRIMIDINONES
FOURREY
Substances
in Great Britain.
with water
3
cytosine
des
Printed
Pergamon Press.
could undergo
the photochemistry
solvent
photoaddition.
of the 4-methylthiopyrimidinones
We were
in that a
thus prompted
1 and 2 in alcoholic
hv * R’OH I
k 1
R'
R=CH3 3a
CH,
3b
CH,CH3 Cl-1 (CH,),
35 % 30 % 33 %
c (eI-1,13
40 %
3c a -
951
Yield
t-t-i
to in-
solution,
952
No. 11
When irradiated7
in alcohol
methylthiopyrimidinone 2.
Compounds
3a-d
the corresponding 8,
9
. Similarly,
methoxy minor
pyrimidinone (route
2.
4 (oil)
by direct
treatment
pyrimidinone This
1
isopropanol,
must
with samples
with methyl
iodide
uridine
may arise
photoaddition
with CH2N2
from either
by direct
prepared
(Hilbert-
by reacting
Johnson
in methanol
unstable
1, 2- solvent
6 followed
reaction)
we obtained
with a substance 10 in methanol
the thermally
producing
1-methyl-4-
1 -methylpyrimidinones
comparison
2 was irradiated
derive
t-butanol)
to give the 4-alkyloxy-
which was found identical
of triacetyl
intermediate
step (route
nucleoside
(35 % yield)
A) or by 1, 4-solvent
elimination
rapidly
2,4-dialkyloxypyrimidines
after
The methoxy
r
identified
when the triacetyl
analogue
amount
1 disappeared were
ethanol,
(methanol,
isolated
Or>::H3
BrOCH,
3,4-dihydrophotoaddition
by a methanol
H3
i
7 CHPH
Zn(Hg)
1
/
Zn (Hg) SrCH3
*-------A I CH,
hu Route
B
c
\
x=s
!
)(‘CH3
Br
N’
b
i3J O
Y CH,
1.
s
I
hv
Route
A
on
addition-
1
04
in
B).
r
N/
its
*SH3
&H, -3a
x=0
I Zn @NO
No. 11
953
The fact that no deuterium irradiation
addition
and elimination
reactions
In order
of a) this result
to distinguish
state
between
pyrimidinone
reactions
example
is the substitution
recently
reported
In our effort we prepared mally
to test
compound
unstable
(X=S) which,
mediate
6,
Significantly,
nucleophile
recently
5 (X=0),
illustrated
Acknowledgements throughout
of cytosine
at C-4
is very
of
easy with
could readily
under-
B be available. A relevant 11 However, by hydroxylamine
pathway
(addition
be derived
: elimination
the above
at C-4)
rule
ground
at 0°C
from
state
to Dr J.
PO lonsky
product
.
yielded
a
labile
inter-
(via 5) of 3a -* of C-4
and C-6
photochemical
chemistry
neutral 15 C-6
2
the 3,6-dihydropyri-
efficiently solvent
results compete and,
more
centers forsuggest with general-
; this has been once again
of 4-benzylthio-l-methylpyrimidinone
: We are very grateful
14
the extremely
out direct
and could at least
at position
derivative
by zinc amalgam
electrophilicity
photochemistry
occurs
the 5-bromo
can be a precursor
we cannot
be considered
always
quantitatively
the relative
However,
in the case
this work.
to com-
of route
work up of the reaction
that the latter
in pyrimidinone
photoaddition
that pyrimidinone
agent in methanol
1 and _& which must
B must
reactions
exchange
could not be reduced
However,
of data concerning
route
at C-5
to synthetise derivative 4. For this purpose 13 BrOMe to 1 at -20°C. The former was ther-
and yielded
methylthio-4-pyrimidinones
that alternative
ly,
methanol
A).
exchange
B we attempted
thus demonstrating
of adduct 1 (route
A.
group
that the direct
with this reducing
of compounds
of the excited
route
suggest
-6 could not be obtained.
In the absence
mation
of the amino
2 by adding neutral
in neutral
that
be inadvertent
substitution
such nucleophilic
reminiscent
like its analogue
1:2 mixture
Since
a mechanism
route
When 1 was treated midinone
with nucleophilic
admitted
evidences 1.2 satisfactory .
is the most
reaction
it was currently
provided
the
B assuming
than deuterium
it would
the two mechanisms,
chemistry.
5,6-dihydropyrimidinones
are faster
of route
is not unexpected.
this new photosubstitution
go these
in 1 and -3a by repeating
with route A ; in the case
(tautomerization
ground
was detected
is in agreement
the methanol
pare
incorporation
in CH30D
6, 16
.
for encouragement
and support
954
No.
11
REFERENCES
I.
- J.G.
Burr,
references
S.Y.
Nature,
Wang,
-.M.
Shetlar, Fikus,
H.A. 1, 3
4
- G.J.
5
- E.
6
- J.L.
R.
Deboer,
M. 9
-3
and E.
and H.E.
Prystas
Kanaoka, and P.
(filter
Shugar,
Gabriel,
Photochem.Photobiol.,
W.
Tautz
and R.
4,
Duschinsky,
521 (1965). Biochemistry,
and F.
and D.S.
12-
P.M.
Schalke
13-
R.Duschinsky,
P.D.
Caesar,
15-
W.
Hauswirth,
219 (1966).
Biophvs.Acta, 18,
22,
213,
253 (1970).
23 (1973).
799 (1974).
Letters,
3201
(1976).
in alcohol
Chem.Soc.,
Czech.
under nitrogen
in good yield
N-CH3
with a Hanau
and J. J.
Fox,
Ors.Svnth.,
4,
36.
H6
1035 (1966). is treated
A.
Med.
1922(1968). 391 (1976).
Nussbaum,
Chem.,
: 7.40).
848 (1971).
Chem.Comm.,
Tautz, J.
: 5.76,
J.Chem.Soc.,
J.C.S.,
W.
31,
if 2,4-di-t-butoxy-pyrimidine
H5
J.Org.Chem.,
Hall,
2001 (1930).
carbonate.
: 3.44,
Hewlins,
2,
Chem.Comm.,
of potassium
Gabriel,
B.S.
J. Am.
Coll.
Fuchs,
and C.D.
14-
Bull.,
Tetrahedron
Johnson,
: 1.63.
Br0wnandM.J.E.
Burchenal
Biochim.
of r (or 2) is irradiated
Sorm,
ll-D.M.
J.H.
Johns,
m,
Photochem.Photobiol.,
can be obtained
T.
Naturforsch,
Chem.Pharm.
in the presence
Wong
and H.E.
Jouin,
and T. B.
a
Boehinger,
cut off X< 280 nm).
: 6 ppm C-CH3
J.L.
T.
Johns,
M solution
Hilbert
with ICH3
lo-
24, 315 (1976).
and D.
Gordon,
Klinghoffer
Fourrey
- Compound
(3d
Photobiol.,
M.P.
Sato and Y.
- G. E.
Photochem.
Wierzchowski
0.
TQ 150 lamp 8
cited therein. 690 (1961).
Kleber
Fisher
10
193 (1968)
(1964).
Fahr,
- A 2.5
h.
190,
K.L.
Lozeron,
1844
- E. G.
7
Photochem.,
and general
M.D. 2
Advances
la
M.
Hoffer,
E.
Grundberg,
47 (1967).
695 (1963).
Hahn and S.Y.
Wang,
Biochem.Biophvs.Res.Comm.,
43
1614
(1972). W.A.
Summers,
C.
Enwall,
J.G.
Burr
and R. L.
Letsinger.
Photochem.
295 (1973). 16 - We are most
thankful
to M.G.
Henry
for his skillful
technical
assistance.
Photobiol.
,E
Letters
110. 11,
pp
PHOTOADDITION
951 - 954, 1977.
OF ALCOHOLS
Jean-Louis Institut
de Chimie (Received
Uracil’ efficiently
and 5-fluorouracil’
water
CNRS,
91190
Gif sur Yv ette,
1977; accepted for publication
2 February
derivatives
France
1977)
which react
a thiocarbonyl
chromophore
are completly
unreactive
photoaddition5.
leading
observation
on the irradiation
of 4-benzylthio-I-methylpyrimidinone 6 1-methylpyrimidinone suggested
to a 5, 6-dihydro-6-methoxy-
4-alkylthiopyrimidinone vestigate
Naturelles,
JOUIN
are the only known pyrimidinone
which possess
Our recent methanol
and Patrick
or methanol in the presence of light (photoaddition). In the case of 4 and thymine photohydrates have also been detected. In contrast, 4-thiouracil
and 2-thiouracil towards
in UK 24 January
TO METHYLTHIO-4-PYRIMIDINONES
FOURREY
Substances
in Great Britain.
with water
3
cytosine
des
Printed
Pergamon Press.
could undergo
the photochemistry
solvent
photoaddition.
of the 4-methylthiopyrimidinones
We were
in that a
thus prompted
1 and 2 in alcoholic
hv * R’OH I
k 1
R'
R=CH3 3a
CH,
3b
CH,CH3 Cl-1 (CH,),
35 % 30 % 33 %
c (eI-1,13
40 %
3c a -
951
Yield
t-t-i
to in-
solution,
952
No. 11
When irradiated7
in alcohol
methylthiopyrimidinone 2.
Compounds
3a-d
the corresponding 8,
9
. Similarly,
methoxy minor
pyrimidinone (route
2.
4 (oil)
by direct
treatment
pyrimidinone This
1
isopropanol,
must
with samples
with methyl
iodide
uridine
may arise
photoaddition
with CH2N2
from either
by direct
prepared
(Hilbert-
by reacting
Johnson
in methanol
unstable
1, 2- solvent
6 followed
reaction)
we obtained
with a substance 10 in methanol
the thermally
producing
1-methyl-4-
1 -methylpyrimidinones
comparison
2 was irradiated
derive
t-butanol)
to give the 4-alkyloxy-
which was found identical
of triacetyl
intermediate
step (route
nucleoside
(35 % yield)
A) or by 1, 4-solvent
elimination
rapidly
2,4-dialkyloxypyrimidines
after
The methoxy
r
identified
when the triacetyl
analogue
amount
1 disappeared were
ethanol,
(methanol,
isolated
Or>::H3
BrOCH,
3,4-dihydrophotoaddition
by a methanol
H3
i
7 CHPH
Zn(Hg)
1
/
Zn (Hg) SrCH3
*-------A I CH,
hu Route
B
c
\
x=s
!
)(‘CH3
Br
N’
b
i3J O
Y CH,
1.
s
I
hv
Route
A
on
addition-
1
04
in
B).
r
N/
its
*SH3
&H, -3a
x=0
I Zn @NO
No. 11
953
The fact that no deuterium irradiation
addition
and elimination
reactions
In order
of a) this result
to distinguish
state
between
pyrimidinone
reactions
example
is the substitution
recently
reported
In our effort we prepared mally
to test
compound
unstable
(X=S) which,
mediate
6,
Significantly,
nucleophile
recently
5 (X=0),
illustrated
Acknowledgements throughout
of cytosine
at C-4
is very
of
easy with
could readily
under-
B be available. A relevant 11 However, by hydroxylamine
pathway
(addition
be derived
: elimination
the above
at C-4)
rule
ground
at 0°C
from
state
to Dr J.
PO lonsky
product
.
yielded
a
labile
inter-
(via 5) of 3a -* of C-4
and C-6
photochemical
chemistry
neutral 15 C-6
2
the 3,6-dihydropyri-
efficiently solvent
results compete and,
more
centers forsuggest with general-
; this has been once again
of 4-benzylthio-l-methylpyrimidinone
: We are very grateful
14
the extremely
out direct
and could at least
at position
derivative
by zinc amalgam
electrophilicity
photochemistry
occurs
the 5-bromo
can be a precursor
we cannot
be considered
always
quantitatively
the relative
However,
in the case
this work.
to com-
of route
work up of the reaction
that the latter
in pyrimidinone
photoaddition
that pyrimidinone
agent in methanol
1 and _& which must
B must
reactions
exchange
could not be reduced
However,
of data concerning
route
at C-5
to synthetise derivative 4. For this purpose 13 BrOMe to 1 at -20°C. The former was ther-
and yielded
methylthio-4-pyrimidinones
that alternative
ly,
methanol
A).
exchange
B we attempted
thus demonstrating
of adduct 1 (route
A.
group
that the direct
with this reducing
of compounds
of the excited
route
suggest
-6 could not be obtained.
In the absence
mation
of the amino
2 by adding neutral
in neutral
that
be inadvertent
substitution
such nucleophilic
reminiscent
like its analogue
1:2 mixture
Since
a mechanism
route
When 1 was treated midinone
with nucleophilic
admitted
evidences 1.2 satisfactory .
is the most
reaction
it was currently
provided
the
B assuming
than deuterium
it would
the two mechanisms,
chemistry.
5,6-dihydropyrimidinones
are faster
of route
is not unexpected.
this new photosubstitution
go these
in 1 and -3a by repeating
with route A ; in the case
(tautomerization
ground
was detected
is in agreement
the methanol
pare
incorporation
in CH30D
6, 16
.
for encouragement
and support
954
No.
11
REFERENCES
I.
- J.G.
Burr,
references
S.Y.
Nature,
Wang,
-.M.
Shetlar, Fikus,
H.A. 1, 3
4
- G.J.
5
- E.
6
- J.L.
R.
Deboer,
M. 9
-3
and E.
and H.E.
Prystas
Kanaoka, and P.
(filter
Shugar,
Gabriel,
Photochem.Photobiol.,
W.
Tautz
and R.
4,
Duschinsky,
521 (1965). Biochemistry,
and F.
and D.S.
12-
P.M.
Schalke
13-
R.Duschinsky,
P.D.
Caesar,
15-
W.
Hauswirth,
219 (1966).
Biophvs.Acta, 18,
22,
213,
253 (1970).
23 (1973).
799 (1974).
Letters,
3201
(1976).
in alcohol
Chem.Soc.,
Czech.
under nitrogen
in good yield
N-CH3
with a Hanau
and J. J.
Fox,
Ors.Svnth.,
4,
36.
H6
1035 (1966). is treated
A.
Med.
1922(1968). 391 (1976).
Nussbaum,
Chem.,
: 7.40).
848 (1971).
Chem.Comm.,
Tautz, J.
: 5.76,
J.Chem.Soc.,
J.C.S.,
W.
31,
if 2,4-di-t-butoxy-pyrimidine
H5
J.Org.Chem.,
Hall,
2001 (1930).
carbonate.
: 3.44,
Hewlins,
2,
Chem.Comm.,
of potassium
Gabriel,
B.S.
J. Am.
Coll.
Fuchs,
and C.D.
14-
Bull.,
Tetrahedron
Johnson,
: 1.63.
Br0wnandM.J.E.
Burchenal
Biochim.
of r (or 2) is irradiated
Sorm,
ll-D.M.
J.H.
Johns,
m,
Photochem.Photobiol.,
can be obtained
T.
Naturforsch,
Chem.Pharm.
in the presence
Wong
and H.E.
Jouin,
and T. B.
a
Boehinger,
cut off X< 280 nm).
: 6 ppm C-CH3
J.L.
T.
Johns,
M solution
Hilbert
with ICH3
lo-
24, 315 (1976).
and D.
Gordon,
Klinghoffer
Fourrey
- Compound
(3d
Photobiol.,
M.P.
Sato and Y.
- G. E.
Photochem.
Wierzchowski
0.
TQ 150 lamp 8
cited therein. 690 (1961).
Kleber
Fisher
10
193 (1968)
(1964).
Fahr,
- A 2.5
h.
190,
K.L.
Lozeron,
1844
- E. G.
7
Photochem.,
and general
M.D. 2
Advances
la
M.
Hoffer,
E.
Grundberg,
47 (1967).
695 (1963).
Hahn and S.Y.
Wang,
Biochem.Biophvs.Res.Comm.,
43
1614
(1972). W.A.
Summers,
C.
Enwall,
J.G.
Burr
and R. L.
Letsinger.
Photochem.
295 (1973). 16 - We are most
thankful
to M.G.
Henry
for his skillful
technical
assistance.
Photobiol.
,E