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Boron triflouride etherate on alimina - a modified Lewis acid reagent.
Tetrahedron Letters,Vol.26,No.8,pp Printed in Great Britain
BORON TRIFLUORIDE
ETHERATE
ON ALIMINA
AN IMPROVED Seung-Hwa Hebrew
-
SYNTHESIS
Baek, Morris
University
1083-1086,1985
Srebnik
Pharmacy
A
0040-4039/85 $3.00 + .oo 01985 Pergamon Press Ltd.
MODIFIED LEWIS
ACID REAGENT.
OF CANNABIDIOL. and Raphael Mechoulam*
School,
Jerusalem
91120,Israel.
Boron trifluoride etherate on alumina catalyses the condensation of resAbstract: orcitimmonomethyl resorcinols with several monoterpenoid allylic alcohols: in contrast to parallel reactions with boron trifluoride etherate in solution the products obtained do not undergo further cyclisations. Cannabidiol
a major
(CBD,E),I
effects
in either animals
anxiety
and antidystonia
natural
cannabinoid
which does not cause psychotropic
or man, has recently been found to have antiepileptic, anti2 CBD and CBD-acid (which is easily decarboxyin man.
properties
lated to CBD) are present
in large amounts
in hashish
clinical
trials till now CBD from this natural
clinical
trials with CBD expanded
a practical
(up to ca 8%).
synthetic
Hence for most
As the scope of the
source was used.
route to this drug seemed desir-
able. The synthetic in mediocre erably
yields
and the unnatural
larger than those of CBD.
tion of (+)-e-mentha-diene-l-01 The "abn-CBD"
(2) obtained
a retro-Friedel-Crafts the reaction
lc,d,e
routes available
isolllrr("abn-CBD")
further
(2) with olivetol
followed
causing
of (3) with
(2
ations were observed CBD", L,
14% yield)
was separated crystalline
Numerous
on alumina
with this reagent
(2) and i&THc
is used as condensing
leads to CBD (2)
(k).3
reagent
as the major
pure oil or 41% yield as crystalline
On a 100 mm01 scale, the yields
6% yield)
the
product,
material.
in
No cyclis-
were much more polar (mainly
or much less polar (mainly compoundL,
reagents
"abn-
than CBD, the last
were 46% as an oil, and 37% as
on alumina,
or other active supports have been described and chemistry; 4a apparently BF3 on alumina and silica has in fuel and industrial chemistry. 4b Silica
fields of synthetic
been thus employed
mostly
A number of related in Table 1.
reactions
The general
follows:
BF3-etherate
aluminum
oxide (Woelm, grade
stirred
However
by
material.
used in various
sented
consid-
to CBD with BF3-etherate
of CBD to a'-THC
and as the rest of the products
with ease.
in amounts
so far is the condensaId (2) in the presence of weak acids.
may be converted
on a 0.8 mm01 scale,
55% yield as chromatographically
(2) is obtained
by recombination.
cyclisation
We report now that when BF3-etherate reaction
value as they lead to CBD
The best route to CBD described
in this reaction
reaction,
proceeds
are not of practical
with this reagent were performed.
procedure,
exemplified
(0.3 ml) was added under nitrogen
for the synthesis to a stirred
Ij (2 g) in dry dichloromethane
for I5 min at room temperature
(20 ml).
and then boiled for 1 min.
1083
The results are preof CBD, is as
suspension
of basic
The mixture
was
(+)-e-Mentha-2,8-dien-l-ol
1084
(4) (180 mg, 1.0 mmol)
(3) (122 mg, 0.8 mnol) and olivetol a;ded to the boiling
suspension
IO seconds with 10% aqueous additional organic
proportion
of the above sodium bicarbonate
by medium
elution
yields obtained to cyclization
pressure
delineated
Some of the reactions silica
Thus the reaction
in Table
solution
leading
However
which proceed
within
(50 ml) were added.
to dryness.
I were performed products
the reactions
All known reaction their physical
data
in disappointing
to cannabigerol
rather than on alumina,
The physical
was quenched
Ether (50 ml) and an The
The oil obtained
ether 2.5:97.5).
(Woelm silica gel "for partition
(29) in dry dichloromethane
29% yield.
to petroleum
low, or the desired
were either
(10 ml).
in the absence
of alumina
could not be isolated
the
at all, due
reactions.
by substituting
silica,
and the reaction
(5 ml) were
LC (230-400 mesh ASTM, silica gel 60 for column chromato-
with ethyl acetate
When the reactions
silica
by syringe
of sodium bicarbonate
layer was washed with brine, dried and evaporated
was separated graphy;
(40~41'C)
solution
in dichloromethane
products
yields
(E) when undertaken
produced described
to CBD or CBD methyl the desired
products
in the Table were
are indicated
(0.2 ml),
for 2 days leads to (8) in ether when undertaken
on
in rather low yields.
identified
(m.s., n.m.r. and i.r.) with those published
data of the new compounds
can be improved
for the alumina.
with BF3-etherate
(10 ml) at room temperature leading
on alumina
chromatography")
by comparison
or by direct
of
comparison.
in the Notes.
R=p-mentha1,8-dien-3-yl
OH C5"ll
C5"ll
. A M
(9)
(8)
1085
Table Condensations
of monoterpenes
. 0
with resorcinols
by catalysis
OH
OH
\/
(2.’
'!?ll
p H
(4)
with BF3 etherate
on aluminaa
Product(s)
Yield
CBD (la); m.p. and rotatEn identical to natural CBD
55% (as oil) 41% (tryst)
1
abn-CBD
(2)
14%
ld,e
(7) Q-.
-
ResorcinolC
Monoterpeneb
2,
I
6%
Id
51%
5
OH as above
(21
-Ref
C5Hll OCH3 OH as above
OH
(2)
70%
6
(2)
34%
7
35%
8
24%
9
18%
10
(l4_)
42%
11
dl - (2)
3.2%
lc
R=C(CH3)2C6H13
as above
as above;
R=CH3
as above
as above;
RN
OCli3 as above
0CH3 OH
HO
as above
as above;
R=C(CH3)2C6H13
CHO
as above
as above;
R=C5H11
as above;
R=C(CH3)2C6H13
dl - (E)
4670
cf fi for (-)-(lb)
as above;
R=C5H11
(8) +.A
13d
12
CH20H
a. For experimental Tilica. see text.
conditions
see text.
b 0.0 tunol. 5. 1.0 mol. _*
-d. For redcL ion on
1086
REFERENCES
1.
2.
CBD, Structure
a) R. Mechoulam
and Y. Shvo, Tetrahedron,
12, 2073 (1963);
b) R. Mechoulam
and Y. Gaoni, Tetrahedron
c) R. Mechoulam
and Y. Gaoni. J. An. Chem. SOc., 87, 3273 (1965); d) T. Petrzilka
W. Haefliger
and C. Sikemeier,
H.C. Dalzell
and G.R. Handrick, effects:
Antiepileptic R. Gagliardi,
J.M.
J. Am. Chem. SOC., 96, 5860 (1974).
Cunha,
E.L. Sanvito,
E.A. Carlini,
pharmacol.,
76, 245 (1982); antidystonia
A.W. Zuardi,
4394296
Angew.
Chem.,
effect:
21, 175 (1980);
and I.G. Karniol,
S.R. Snider and P. Consroe,
Psycho-
Neurology,
J. Am. Chem. SOC., 93, 217 (1971).
401 and 485 (1979); b) A.M. Madgavkar
3048693
A. McKillop
and D.W. Young,
and H.E. Swift, U.S. Patent
H. Hoenig and W. Horlitz,
(1982); Yu. I. Kozorezov,
37 (1973); K. Matsuura,
(MOSCOW)
Pharmacologia,
E. Finkelfarb
Int. Ed., 17, 487 (1978);
(1983); H.J. Mueller,
G.m.b.H.)
I. Shirakawa.
O.L. Ramos, C. Pimentel,
147 (1984).
Y. Gaoni and R. Mechoulam,
Synthesis,
A.E. Pereira,
N. Lander and R. Mechoulam,
effects:
4.a) G. Posner,
Lett. 1109 (1967); CBD. Synthesis:
Helv. Chim. Acta, 52, 1109 (1969); e) R.K. Razdan,
antianxiety
34, (suppl.) 3.
elucidation:
AND NOTES
Germ. Patent
(to Gulf Co)
(to Erdoelchemie
A.P. Rusakov and A.N. Kuleshova.
T. Watanabe,
Neftekhim.
A. Suzuki and M. Itoh, J. Catal.,
26, 127
(1972). 5.
T. Yamauchi,
Y. Shoyama,
6.
J.R. Leite,
E.A. Carlini,
Y. Matsuo
N. Lander and R. Mechoulam,
and I. Nishioka,
Chem. Pharm. Bull.,
7.
Physical
data of compound
(lo): an oil,[u]D-500(MeOH);
Pharmacology, n.m.r..
6 (CDC13)
1.78 (3H, s. CH3), 2.19 (3H. s. CH3), 3.80 (lH, br d. C-3H),4.56 (lH, br s, C-9H), 8.
Physical
1.66 (3H, s. CH3),
(lH, br s. C-9H). 4.65
5.54 (IH, br s, C-2H), 6.21 (2H, s, arom H).; m/e 258 (M+, strong).
data of compound
(g):
an oil,
[aJ ,,
-87'(MeOH);
(2x3H. s. CH3), 3.87 (lH, br, C-3H), 4.50 and 4.60 6.31, 6.45,
16, 1164 (1968).
24, 141 (1982).
(2H, s, arom H), 7.20
(lH,t,arom
n.m.r.,
6 (CDC13)
(ZxlH, br s, C-9H),
1.68 and 1.81
5.47 (lo, br s, C-211).
H); m/e 244 (M+); i.r., V, 3395,
1615, 1585,
B80cm'I. 9.
Physical
data of compound
1.25 (6H,S,CH3), m/e 398(M+); 10.
Physical
11.
Physical
3.72 (6H,s,CH3),
4.39
(2H,s,C-9H),
n.m.r.,
5.17 (lH,br s,C-2H),
data of compound
(32); an oil, racemic;
2.46 (ZH,t,benzylic),
n.m.r..
6.45 (2H,s,arom
6 (CDC13) 0.89 (3H,t,CH3),
H),
3.67 (lH,br C-2H), 4.70 (2H S,
1.70
C-9H). 5.82 (lH,br
6.18 (2H.br s arom H); m/e 314 (M+); i.r. u 3420, 1630, 1580, 885cm-I. data
for
cowound
(2):
an oil, racemic,
n.m.r.,
6 (CDC13) 0.84 (3H,t,CH3),
(6Hs br s,CH3) 3.74 (1H. br C-2H). 4.71 (2H, br s.C-9H)._;.87 12.
6 (CDC13) 0.90 (3H,t.CH3),
i.r., u 1575, 880cm-I,
1.72 (6H,2s,CH3), C-6H).
(E-L?):an oil, [a] D-103'(MeOH);
5, at-am H); m/e 370 (M+); i.r. v 3430,
1629, 1580, 885cm
R. Mechoulam
Lett.,
and 8. Yagen,
Acknowledgement: Neurological
(Received
Financial
Tetrahedron
support
and Communicative
in UK 2 January
1985)
.
5349 (1964).
of this research
Diseases
and Stroke
1.20
(lH,br d. c-6tl), 6.31 (2~. br
by the US National is gratefully
Institute
acknowledged.
of
BORON TRIFLUORIDE
ETHERATE
ON ALIMINA
AN IMPROVED Seung-Hwa Hebrew
-
SYNTHESIS
Baek, Morris
University
1083-1086,1985
Srebnik
Pharmacy
A
0040-4039/85 $3.00 + .oo 01985 Pergamon Press Ltd.
MODIFIED LEWIS
ACID REAGENT.
OF CANNABIDIOL. and Raphael Mechoulam*
School,
Jerusalem
91120,Israel.
Boron trifluoride etherate on alumina catalyses the condensation of resAbstract: orcitimmonomethyl resorcinols with several monoterpenoid allylic alcohols: in contrast to parallel reactions with boron trifluoride etherate in solution the products obtained do not undergo further cyclisations. Cannabidiol
a major
(CBD,E),I
effects
in either animals
anxiety
and antidystonia
natural
cannabinoid
which does not cause psychotropic
or man, has recently been found to have antiepileptic, anti2 CBD and CBD-acid (which is easily decarboxyin man.
properties
lated to CBD) are present
in large amounts
in hashish
clinical
trials till now CBD from this natural
clinical
trials with CBD expanded
a practical
(up to ca 8%).
synthetic
Hence for most
As the scope of the
source was used.
route to this drug seemed desir-
able. The synthetic in mediocre erably
yields
and the unnatural
larger than those of CBD.
tion of (+)-e-mentha-diene-l-01 The "abn-CBD"
(2) obtained
a retro-Friedel-Crafts the reaction
lc,d,e
routes available
isolllrr("abn-CBD")
further
(2) with olivetol
followed
causing
of (3) with
(2
ations were observed CBD", L,
14% yield)
was separated crystalline
Numerous
on alumina
with this reagent
(2) and i&THc
is used as condensing
leads to CBD (2)
(k).3
reagent
as the major
pure oil or 41% yield as crystalline
On a 100 mm01 scale, the yields
6% yield)
the
product,
material.
in
No cyclis-
were much more polar (mainly
or much less polar (mainly compoundL,
reagents
"abn-
than CBD, the last
were 46% as an oil, and 37% as
on alumina,
or other active supports have been described and chemistry; 4a apparently BF3 on alumina and silica has in fuel and industrial chemistry. 4b Silica
fields of synthetic
been thus employed
mostly
A number of related in Table 1.
reactions
The general
follows:
BF3-etherate
aluminum
oxide (Woelm, grade
stirred
However
by
material.
used in various
sented
consid-
to CBD with BF3-etherate
of CBD to a'-THC
and as the rest of the products
with ease.
in amounts
so far is the condensaId (2) in the presence of weak acids.
may be converted
on a 0.8 mm01 scale,
55% yield as chromatographically
(2) is obtained
by recombination.
cyclisation
We report now that when BF3-etherate reaction
value as they lead to CBD
The best route to CBD described
in this reaction
reaction,
proceeds
are not of practical
with this reagent were performed.
procedure,
exemplified
(0.3 ml) was added under nitrogen
for the synthesis to a stirred
Ij (2 g) in dry dichloromethane
for I5 min at room temperature
(20 ml).
and then boiled for 1 min.
1083
The results are preof CBD, is as
suspension
of basic
The mixture
was
(+)-e-Mentha-2,8-dien-l-ol
1084
(4) (180 mg, 1.0 mmol)
(3) (122 mg, 0.8 mnol) and olivetol a;ded to the boiling
suspension
IO seconds with 10% aqueous additional organic
proportion
of the above sodium bicarbonate
by medium
elution
yields obtained to cyclization
pressure
delineated
Some of the reactions silica
Thus the reaction
in Table
solution
leading
However
which proceed
within
(50 ml) were added.
to dryness.
I were performed products
the reactions
All known reaction their physical
data
in disappointing
to cannabigerol
rather than on alumina,
The physical
was quenched
Ether (50 ml) and an The
The oil obtained
ether 2.5:97.5).
(Woelm silica gel "for partition
(29) in dry dichloromethane
29% yield.
to petroleum
low, or the desired
were either
(10 ml).
in the absence
of alumina
could not be isolated
the
at all, due
reactions.
by substituting
silica,
and the reaction
(5 ml) were
LC (230-400 mesh ASTM, silica gel 60 for column chromato-
with ethyl acetate
When the reactions
silica
by syringe
of sodium bicarbonate
layer was washed with brine, dried and evaporated
was separated graphy;
(40~41'C)
solution
in dichloromethane
products
yields
(E) when undertaken
produced described
to CBD or CBD methyl the desired
products
in the Table were
are indicated
(0.2 ml),
for 2 days leads to (8) in ether when undertaken
on
in rather low yields.
identified
(m.s., n.m.r. and i.r.) with those published
data of the new compounds
can be improved
for the alumina.
with BF3-etherate
(10 ml) at room temperature leading
on alumina
chromatography")
by comparison
or by direct
of
comparison.
in the Notes.
R=p-mentha1,8-dien-3-yl
OH C5"ll
C5"ll
. A M
(9)
(8)
1085
Table Condensations
of monoterpenes
. 0
with resorcinols
by catalysis
OH
OH
\/
(2.’
'!?ll
p H
(4)
with BF3 etherate
on aluminaa
Product(s)
Yield
CBD (la); m.p. and rotatEn identical to natural CBD
55% (as oil) 41% (tryst)
1
abn-CBD
(2)
14%
ld,e
(7) Q-.
-
ResorcinolC
Monoterpeneb
2,
I
6%
Id
51%
5
OH as above
(21
-Ref
C5Hll OCH3 OH as above
OH
(2)
70%
6
(2)
34%
7
35%
8
24%
9
18%
10
(l4_)
42%
11
dl - (2)
3.2%
lc
R=C(CH3)2C6H13
as above
as above;
R=CH3
as above
as above;
RN
OCli3 as above
0CH3 OH
HO
as above
as above;
R=C(CH3)2C6H13
CHO
as above
as above;
R=C5H11
as above;
R=C(CH3)2C6H13
dl - (E)
4670
cf fi for (-)-(lb)
as above;
R=C5H11
(8) +.A
13d
12
CH20H
a. For experimental Tilica. see text.
conditions
see text.
b 0.0 tunol. 5. 1.0 mol. _*
-d. For redcL ion on
1086
REFERENCES
1.
2.
CBD, Structure
a) R. Mechoulam
and Y. Shvo, Tetrahedron,
12, 2073 (1963);
b) R. Mechoulam
and Y. Gaoni, Tetrahedron
c) R. Mechoulam
and Y. Gaoni. J. An. Chem. SOc., 87, 3273 (1965); d) T. Petrzilka
W. Haefliger
and C. Sikemeier,
H.C. Dalzell
and G.R. Handrick, effects:
Antiepileptic R. Gagliardi,
J.M.
J. Am. Chem. SOC., 96, 5860 (1974).
Cunha,
E.L. Sanvito,
E.A. Carlini,
pharmacol.,
76, 245 (1982); antidystonia
A.W. Zuardi,
4394296
Angew.
Chem.,
effect:
21, 175 (1980);
and I.G. Karniol,
S.R. Snider and P. Consroe,
Psycho-
Neurology,
J. Am. Chem. SOC., 93, 217 (1971).
401 and 485 (1979); b) A.M. Madgavkar
3048693
A. McKillop
and D.W. Young,
and H.E. Swift, U.S. Patent
H. Hoenig and W. Horlitz,
(1982); Yu. I. Kozorezov,
37 (1973); K. Matsuura,
(MOSCOW)
Pharmacologia,
E. Finkelfarb
Int. Ed., 17, 487 (1978);
(1983); H.J. Mueller,
G.m.b.H.)
I. Shirakawa.
O.L. Ramos, C. Pimentel,
147 (1984).
Y. Gaoni and R. Mechoulam,
Synthesis,
A.E. Pereira,
N. Lander and R. Mechoulam,
effects:
4.a) G. Posner,
Lett. 1109 (1967); CBD. Synthesis:
Helv. Chim. Acta, 52, 1109 (1969); e) R.K. Razdan,
antianxiety
34, (suppl.) 3.
elucidation:
AND NOTES
Germ. Patent
(to Gulf Co)
(to Erdoelchemie
A.P. Rusakov and A.N. Kuleshova.
T. Watanabe,
Neftekhim.
A. Suzuki and M. Itoh, J. Catal.,
26, 127
(1972). 5.
T. Yamauchi,
Y. Shoyama,
6.
J.R. Leite,
E.A. Carlini,
Y. Matsuo
N. Lander and R. Mechoulam,
and I. Nishioka,
Chem. Pharm. Bull.,
7.
Physical
data of compound
(lo): an oil,[u]D-500(MeOH);
Pharmacology, n.m.r..
6 (CDC13)
1.78 (3H, s. CH3), 2.19 (3H. s. CH3), 3.80 (lH, br d. C-3H),4.56 (lH, br s, C-9H), 8.
Physical
1.66 (3H, s. CH3),
(lH, br s. C-9H). 4.65
5.54 (IH, br s, C-2H), 6.21 (2H, s, arom H).; m/e 258 (M+, strong).
data of compound
(g):
an oil,
[aJ ,,
-87'(MeOH);
(2x3H. s. CH3), 3.87 (lH, br, C-3H), 4.50 and 4.60 6.31, 6.45,
16, 1164 (1968).
24, 141 (1982).
(2H, s, arom H), 7.20
(lH,t,arom
n.m.r.,
6 (CDC13)
(ZxlH, br s, C-9H),
1.68 and 1.81
5.47 (lo, br s, C-211).
H); m/e 244 (M+); i.r., V, 3395,
1615, 1585,
B80cm'I. 9.
Physical
data of compound
1.25 (6H,S,CH3), m/e 398(M+); 10.
Physical
11.
Physical
3.72 (6H,s,CH3),
4.39
(2H,s,C-9H),
n.m.r.,
5.17 (lH,br s,C-2H),
data of compound
(32); an oil, racemic;
2.46 (ZH,t,benzylic),
n.m.r..
6.45 (2H,s,arom
6 (CDC13) 0.89 (3H,t,CH3),
H),
3.67 (lH,br C-2H), 4.70 (2H S,
1.70
C-9H). 5.82 (lH,br
6.18 (2H.br s arom H); m/e 314 (M+); i.r. u 3420, 1630, 1580, 885cm-I. data
for
cowound
(2):
an oil, racemic,
n.m.r.,
6 (CDC13) 0.84 (3H,t,CH3),
(6Hs br s,CH3) 3.74 (1H. br C-2H). 4.71 (2H, br s.C-9H)._;.87 12.
6 (CDC13) 0.90 (3H,t.CH3),
i.r., u 1575, 880cm-I,
1.72 (6H,2s,CH3), C-6H).
(E-L?):an oil, [a] D-103'(MeOH);
5, at-am H); m/e 370 (M+); i.r. v 3430,
1629, 1580, 885cm
R. Mechoulam
Lett.,
and 8. Yagen,
Acknowledgement: Neurological
(Received
Financial
Tetrahedron
support
and Communicative
in UK 2 January
1985)
.
5349 (1964).
of this research
Diseases
and Stroke
1.20
(lH,br d. c-6tl), 6.31 (2~. br
by the US National is gratefully
Institute
acknowledged.
of