Tetrahedron Letters,Vol.26,No.8,pp 1083-1086,1985 0040-4039/85 $3.00 + .

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Printed in Great Britain 01985 Pergamon Press Ltd.

BORON TRIFLUORIDE ETHERATE ON ALIMINA - A LEWIS

MODIFIED ACID REAGENT.
AN IMPROVED SYNTHESIS OF CANNABIDIOL.

Seung-Hwa Baek, Morris Srebnik and Raphael Mechoulam*

Hebrew University Pharmacy School, Jerusalem 91120,Israel.

Abstract: Boron trifluoride etherate on alumina catalyses the condensation of res-

orcitimmonomethyl resorcinols with several monoterpenoid allylic alcohols: in con-
trast to parallel reactions with boron trifluoride etherate in solution the products
obtained do not undergo further cyclisations.

Cannabidiol (CBD,E),I a major natural cannabinoid which does not cause psychotropic

effects in either animals or man, has recently been found to have antiepileptic, anti-
2
anxiety and antidystonia properties in man. CBD and CBD-acid (which is easily decarboxy-
lated to CBD) are present in large amounts in hashish (up to ca 8%). Hence for most
clinical trials till now CBD from this natural source was used. As the scope of the

clinical trials with CBD expanded a practical synthetic route to this drug seemed desir-

able.
lc,d,e
The synthetic routes available are not of practical value as they lead to CBD
in mediocre yields and the unnatural isolllrr("abn-CBD") (2) is obtained in amounts consid-
erably larger than those of CBD. The best route to CBD described so far is the condensa-
Id
tion of (+)-e-mentha-diene-l-01 (2) with olivetol (2) in the presence of weak acids.
The "abn-CBD" (2) obtained in this reaction may be converted to CBD with BF3-etherate by
a retro-Friedel-Crafts reaction, followed by recombination. However with this reagent
the reaction proceeds further causing cyclisation of CBD to a'-THC (2) and i&THc (k).3

We report now that when BF3-etherate on alumina is used as condensing reagent the
reaction of (3) with (2 on a 0.8 mm01 scale, leads to CBD (2) as the major product, in
55% yield as chromatographically pure oil or 41% yield as crystalline material. No cyclis-
ations were observed and as the rest of the products were much more polar (mainly "abn-
CBD", L, 14% yield) or much less polar (mainly compoundL, 6% yield) than CBD, the last
was separated with ease. On a 100 mm01 scale, the yields were 46% as an oil, and 37% as
crystalline material.

Numerous reagents on alumina, or other active supports have been described and
Silica

used in various fields of synthetic chemistry; 4a apparently BF3 on alumina and silica has
been thus employed mostly in fuel and industrial chemistry. 4b

A number of related reactions with this reagent were performed. The results are pre-
sented in Table 1. The general procedure, exemplified for the synthesis of CBD, is as
follows: BF3-etherate (0.3 ml) was added under nitrogen to a stirred suspension of basic
aluminum oxide (Woelm, grade Ij (2 g) in dry dichloromethane (20 ml). The mixture was
stirred for I5 min at room temperature and then boiled for 1 min. (+)-e-Mentha-2,8-dien-l-ol

1083
 1084

(3) (122 mg, 0.8 mnol) and olivetol (4) (180 mg, 1.0 mmol) in dichloromethane (5 ml) were
a;ded to the boiling suspension (40~41'C) by syringe and the reaction was quenched within
IO seconds with 10% aqueous solution of sodium bicarbonate (10 ml). Ether (50 ml) and an
additional proportion of the above sodium bicarbonate solution (50 ml) were added. The

organic layer was washed with brine, dried and evaporated to dryness. The oil obtained

was separated by medium pressure LC (230-400 mesh ASTM, silica gel 60 for column chromato-
graphy; elution with ethyl acetate to petroleum ether 2.5:97.5).

When the reactions delineated in Table I were performed in the absence of alumina the
yields obtained were either low, or the desired products could not be isolated at all, due

to cyclization reactions.

Some of the reactions which proceed in disappointing yields on alumina can be improved
by substituting silica (Woelm silica gel "for partition chromatography") for the alumina.

Thus the reaction leading to cannabigerol (E) when undertaken with BF3-etherate (0.2 ml),
silica (29) in dry dichloromethane (10 ml) at room temperature for 2 days leads to (8) in
29% yield. However the reactions leading to CBD or CBD methyl ether when undertaken on
silica, rather than on alumina, produced the desired products in rather low yields.

All known reaction products described in the Table were identified by comparison of

their physical data (m.s., n.m.r. and i.r.) with those published or by direct comparison.

The physical data of the new compounds are indicated in the Notes.

R=p-mentha-
1,8-dien-3-yl

OH

C5"ll

C5"ll
.
(8)
A
M

(9)
 1085

Table I
Condensations of monoterpenes with resorcinols by catalysis with BF3 etherate on aluminaa

.
Monoterpeneb

OH
ResorcinolC

OH
Product(s)

CBD (la); m.p. and

rotatEn identical
Yield

55% (as oil)

41% (tryst)
-Ref

0
2, (2.’
\/
p H (4)
'!?ll
to natural CBD
abn-CBD

(7)
Q-.
(2)

-
14%
6%
ld,e
Id

OH
as above (21 51% 5
C5Hll

OCH3
OH
as above
(2) 70% 6

OH R=C(CH3)2C6H13

as above as above; R=CH3 (2) 34% 7

as above as above; RN 35% 8

OCli3
as above
24% 9

0CH3
HO OH

18% 10

as above as above; R=C(CH3)2C6H13 (l4_) 42% 11

CHO
as above; R=C5H11
dl - (2) 3.2% lc

as above as above; R=C(CH3)2C6H13 dl - (E) cf fi

4670
for (-)-(lb)

CH20H
as above; R=C5H11 (8) 13d 12
+.A

a. For experimental conditions see text. b 0.0 tunol. 5. 1.0 mol.

_* -d. For redcL ion on
Tilica. see text.
 1086

REFERENCES AND NOTES

1. CBD, Structure elucidation: a) R. Mechoulam and Y. Shvo, Tetrahedron, 12, 2073 (1963);
b) R. Mechoulam and Y. Gaoni, Tetrahedron Lett. 1109 (1967); CBD. Synthesis:

c) R. Mechoulam and Y. Gaoni. J. An. Chem. SOc., 87, 3273 (1965); d) T. Petrzilka
W. Haefliger and C. Sikemeier, Helv. Chim. Acta, 52, 1109 (1969); e) R.K. Razdan,
H.C. Dalzell and G.R. Handrick, J. Am. Chem. SOC., 96, 5860 (1974).

2. Antiepileptic effects: J.M. Cunha, E.A. Carlini, A.E. Pereira, O.L. Ramos, C. Pimentel,
R. Gagliardi, E.L. Sanvito, N. Lander and R. Mechoulam, Pharmacologia, 21, 175 (1980);
antianxiety effects: A.W. Zuardi, I. Shirakawa. E. Finkelfarb and I.G. Karniol, Psycho-

pharmacol., 76, 245 (1982); antidystonia effect: S.R. Snider and P. Consroe, Neurology,

34, (suppl.) 147 (1984).

3. Y. Gaoni and R. Mechoulam, J. Am. Chem. SOC., 93, 217 (1971).
4.a) G. Posner, Angew. Chem., Int. Ed., 17, 487 (1978); A. McKillop and D.W. Young,
Synthesis, 401 and 485 (1979); b) A.M. Madgavkar and H.E. Swift, U.S. Patent (to Gulf Co)
4394296 (1983); H.J. Mueller, H. Hoenig and W. Horlitz, Germ. Patent (to Erdoelchemie
G.m.b.H.) 3048693 (1982); Yu. I. Kozorezov, A.P. Rusakov and A.N. Kuleshova. Neftekhim.
(MOSCOW) 37 (1973); K. Matsuura, T. Watanabe, A. Suzuki and M. Itoh, J. Catal., 26, 127
(1972).
5. T. Yamauchi, Y. Shoyama, Y. Matsuo and I. Nishioka, Chem. Pharm. Bull., 16, 1164 (1968).

6. J.R. Leite, E.A. Carlini, N. Lander and R. Mechoulam, Pharmacology, 24, 141 (1982).
7. Physical data of compound (lo): an oil,[u]D-500(MeOH); n.m.r.. 6 (CDC13) 1.66 (3H, s. CH3),
1.78 (3H, s. CH3), 2.19 (3H. s. CH3), 3.80 (lH, br d. C-3H),4.56 (lH, br s. C-9H). 4.65
(lH, br s, C-9H), 5.54 (IH, br s, C-2H), 6.21 (2H, s, arom H).; m/e 258 (M+, strong).

8. Physical data of compound (g): an oil, [aJ ,, -87'(MeOH); n.m.r., 6 (CDC13) 1.68 and 1.81

(2x3H. s. CH3), 3.87 (lH, br, C-3H), 4.50 and 4.60 (ZxlH, br s, C-9H), 5.47 (lo, br s, C-211).

6.31, 6.45, (2H, s, arom H), 7.20 (lH,t,arom H); m/e 244 (M+); i.r., V, 3395, 1615, 1585,
B80cm'I.
9. Physical data of compound (E-L?):an oil, [a] D-103'(MeOH); n.m.r., 6 (CDC13) 0.90 (3H,t.CH3),
1.25 (6H,S,CH3), 3.72 (6H,s,CH3), 4.39 (2H,s,C-9H), 5.17 (lH,br s,C-2H), 6.45 (2H,s,arom H),
m/e 398(M+); i.r., u 1575, 880cm-I,
10. Physical data of compound (32); an oil, racemic; n.m.r.. 6 (CDC13) 0.89 (3H,t,CH3), 1.70
1.72 (6H,2s,CH3), 2.46 (ZH,t,benzylic), 3.67 (lH,br C-2H), 4.70 (2H S, C-9H). 5.82 (lH,br
C-6H). 6.18 (2H.br s arom H); m/e 314 (M+); i.r. u 3420, 1630, 1580, 885cm-I.
11. Physical data for cowound (2): an oil, racemic, n.m.r., 6 (CDC13) 0.84 (3H,t,CH3), 1.20
(6Hs br s,CH3) 3.74 (1H. br C-2H). 4.71 (2H, br s.C-9H)._;.87 (lH,br d. c-6tl), 6.31 (2~. br
5, at-am H); m/e 370 (M+); i.r. v 3430, 1629, 1580, 885cm .
12. R. Mechoulam and 8. Yagen, Tetrahedron Lett., 5349 (1964).

Acknowledgement: Financial support of this research by the US National Institute of

Neurological and Communicative Diseases and Stroke is gratefully acknowledged.

(Received in UK 2 January 1985)