Synthesis of cannabinol by a modified Ullmann-ziegler cross-coupling

Article abstract of DOI:10.1055/s-0033-1338428

Cannabinol, a pharmaceutically interesting component of cannabis, was prepared by a modified Ullmann-Ziegler cross-coupling. Using easily obtainable starting materials, this convergent approach allows facile access to a variety of cannabinol derivatives. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338428

LETTER
▌1109
lSetyternthesis of Cannabinol by a Modified Ullmann–Ziegler Cross-Coupling
Synthesis of Cannabinol
Max P. Nüllen, Richard Göttlich*
Institut für Organische Chemie, Justus-Liebig-Universität Gießen, Heinrich-Buff-Ring 58, 35392 Gießen, Germany
Fax +49(641)9934349; E-mail: richard.goettlich@org.chemie.uni-giessen.de
Received: 14.12.2012; Accepted after revision: 28.03.2013
Synthetic routes towards cannabinol (CBN, 2) have been
of interest because it is not only a metabolite of THC12 and
therefore plays a significant role in forensic analytics,13,14
but has also shown potential for the development of anti-
biotic and antimycotic agents.15
Abstract: Cannabinol, a pharmaceutically interesting component
of cannabis, was prepared by a modified Ullmann–Ziegler cross-
coupling. Using easily obtainable starting materials, this convergent
approach allows facile access to a variety of cannabinol derivatives.
Key words: natural products, cross-coupling, palladium, copper,
cannabinoids
Being the oxidative degradation product of THC, one im-
portant route towards CBN derivatives is oxidative aro-
matization of tetrahydrocannabinols, which, in turn, can
be synthesized by condensation of 5-alkyl resorcinols
with substituted cyclohexanes.10,16 Although this strategy
allows a convergent synthesis, the CBN derivatives are
often obtained in poor yields.
Cannabis is one of the most ancient agricultural crops and
medicinal plants. There is evidence that as early as the
16th century BC, preparations of cannabis were used in
Egypt for treating a multitude of ailments. The chemical
analysis of its molecular constituents started in the 19th
century and by now more than 525 secondary metabolites
have been identified, of which the cannabinoids are the
most important group because they play a special role in
the biological activity of cannabis extracts. Although can-
nabis is best known for its recreational use as a psychotro-
pical drug, an effect that can be attributed to its constituent
Δ9-tetrahydrocannabinol (THC, 1; Figure 1), it possesses
a vast range of useful pharmaceutical properties. Among
the potential medical uses described so far are applica-
tions of cannabinoids as analgesics,1 anticonvulsants,
anti-inflammatories,2 and antibiotics.3 There is also evi-
dence of beneficial effects in the treatment of glaucoma,
epilepsy,4 Alzheimer’s disease,5 and many other disor-
ders.6 This biological activity is due to the interaction of
the cannabinoids with a system of two G-protein coupled
receptors (CB1 and CB2), the so-called endocannabinoid
system.7
Because cannabinol, as a dibenzo[b,d]pyran, contains an
aryl–aryl bond, a synthetic route including aromatic cross-
coupling as the key step followed by intramolecular for-
mation of the pyran moiety may be utilized to obtain CBN
derivatives (Scheme 1).14,17 This strategy allows cannabi-
nols to be synthesized in a convergent fashion starting
from easily obtainable or even commercially available
substrates, such as substituted benzoic acid derivatives (3)
and resorcinols (4).
OH
OR2
O
R1
R2O
O
C5H11
C5H11
2
O
R1
OR2
X
R2O
C5H11
OH
OH
H
4
3
H
O
O
C5H11
C5H11
Scheme 1 Retrosynthetic analysis of cannabinols
1
2
Based on our recent results with the Ullmann–Ziegler
cross-coupling of sterically hindered benzamides or resor-
cinols with aryl halides,18 we devised a synthesis that
allows facile access to many different CBN-derived com-
pounds.
Figure 1 Δ9-THC (1) and cannabinol (2)
Because CB1 and CB2 show differences in their function,8
there has been some effort towards finding selective li-
gands for each receptor.9,10 Many CB1 agonists show, for
example, strong psychotropic effects that prohibit various
applications in pharmacy.11
To verify the suitability of this method for the preparation
of cannabinol derivatives and to explore the scope of pos-
sible substrates, a variety of different 2-iodobenzamides
and resorcinol derivatives were employed to synthesize a
set of model compounds.
SYNLETT 2013, 24, 1109–1112
Advanced online publication: 29.04.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338428; Art ID: ST-2012-B1071-L
© Georg Thieme Verlag Stuttgart · New York

1110
M. P. Nüllen, R. Göttlich
LETTER
To prepare the organocopper precursor necessary for the
Ullmann–Ziegler coupling, a substituted resorcinol meth-
yl ether (5) was treated with n-butyllithium in the pres-
ence of TMEDA to effect ortho-lithiation and
subsequently transmetallated with CuBr·SMe2 (Scheme
2). To effect the coupling, a solution of a 2-iodobenz-
amide (6) in NMP and [Pd(PPh3)4] was added and the re-
action mixture was heated to 60 °C for 12 hours to give
the unsymmetrical biaryl 7. Use of one equivalent of
CuBr·SMe2 led to unsatisfactory results, with monoaryl-
copper(I) species 8 being generated as intermediate (Ta-
ble 1, entry 1). Very good yields were obtained by
employing 0.5 equivalents CuBr·SMe2 and with Gilman
cuprate (9) as coupling precursor (Table 1, entry 2).19
Table 1 Substrate Scope of the Approach
Entry Ar2CuLi
Ar–I
Product Yield
(%)
O
O
O
O
Ni-Pr2
Cu
1
7a
31
I
O
8
6a
6a
6a
O
Ni-Pr2
CuLi
I
2
7a
7b
97
86
2
O
O
O
O
1. n-BuLi, TMEDA
2. CuBr⋅SMe2
9a
R
R
Cu or R
Cu
DME, 0 °C, 2 h
O
O
Ni-Pr2
2
O
O
O
9
5
8
O
CuLi
I
3
2
3. Pd(PPh3)4, 6
DME–NMP (1:1)
60 °C, 12 h
9b
O
R
O
Ni-Pr2
O
Ni-Pr2
O
NR2
O
2
i-Bu
CuLi
4
I
7c
73
84
2
O
O
R1
9c
6a
6
7
O
Ni-Pr2
O
Scheme 2 Ullmann–Ziegler cross-coupling
I
CuLi
5
7d
2
Using this protocol, several model compounds resembling
the substitution pattern of cannabinol and bearing alkyl-
as well as methoxy substituents were prepared, varying
the resorcinol and the 2-iodobenzamide component. All
examples were obtained in good to excellent yields in the
range 67–97%.
O
O
9a
6b
tallic reagent in the presence of a copper catalyst, best re-
sults were obtained when stoichiometric amounts of a
copper salt were used to prepare the Gilman cuprate prior
to adding the benzyl bromide. Whereas the catalytic reac-
tion using n-BuMgBr and 10 mol% Li2CuCl4 (Kochi’s
catalyst) yielded an inseparable 79:21 mixture of substitu-
tion product 12 and the dehalogenated by-product 13, the
reaction with pre-formed n-Bu2CuLi gave exclusively the
desired product. With this ortho-lithiation precursor in
hand, we turned our attention to the Ullmann–Ziegler
coupling.
These encouraging results indicate that the modified Ull-
mann–Ziegler coupling may be very useful as the key step
in the preparation of CBN-type cannabinoids. Especially
compound 7c, with its isobutyl substituent, which was ob-
tained in 73% (Table 1, entry 4), is of particular interest;
due to its high structural resemblance to the precursor nec-
essary for the synthesis of the natural product cannabinol
(pentyl substituent instead of isobutyl), this is a very
promising result with regard to a potential synthesis of
cannabinol.
Using the protocol described above, two equivalents of
resorcinol ether 12 were converted into the corresponding
Gilman cuprate and subsequently coupled with 2-iodo-
benzamide 6a to give biphenyl 14 in 75% yield (Scheme
4). Although only one equivalent of 12 ends up in the cou-
pling product, this is only a minor drawback because the
second equivalent can be easily recovered during workup.
With this in mind, we tackled the synthesis of the natural
product cannabinol. Starting from 3,5-dihydroxybenzoic
acid (10), benzyl bromide 11 was prepared in very good
yields. In a subsequent step, the halide was subjected to a
cuprate-driven substitution to yield the 5-alkyl resorcinol
ether 12 (Scheme 3). Although there are procedures in
which this transformation is effected with an organome-
Synlett 2013, 24, 1109–1112
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Cannabinol
1111
O
OH
O
O
In conclusion, it was demonstrated that a modified Ull-
mann–Ziegler coupling is a very useful key step in the
synthesis of dibenzo[b,d]pyran natural products in general
and CBN-type cannabinoids in particular. To show this,
several model key intermediates with a substitution pat-
tern resembling cannabinol were prepared. The com-
pounds were obtained in good to excellent yields starting
form easily accessible starting materials. A variety of
groups may be introduced to the resorcinol moiety, for ex-
ample, by cuprate-mediated benzylic substitution or by
subjecting a substituted benzaldehyde to a combination of
the Wittig olefination and a hydrogenation step. The other
part of the molecule may be derived from a wide range of
commercially available benzoic acids.
Me2SO4, K2CO3
acetone, 60 °C, 4.5 h
87%
HO
OH
O
O
10
NaBH4, MeOH
THF, 70 °C, 2.5 h
93%
OH
Br
PBr3, CH2Cl2, r.t., 2 h
93%
O
O
O
O
11
As a further proof of principle, the procedure was extend-
ed to a synthesis of cannabinol, which was synthesized in
a total yield of 15% over nine steps (longest linear se-
quence of reactions, starting from 3,5-dihydroxybenzoic
acid).
n-Bu2CuLi, THF
–20 °C, 1.5 h
61%
C5H11
References and Notes
O
O
O
O
(1) Martin, B. R.; Lichtman, A. H. Neurobiology of Disease
1998, 5, 447.
12
13
(2) Pertwee, R. G. Euphytica 2004, 140, 73.
Scheme 3 Synthesis of 1,3-dimethoxy-5-pentyl benzene 12
(3) Mechoulam, R. Br. J. Pharmacol. 2005, 146, 913.
(4) Marsicano, G.; Goodenough, S.; Monory, K.; Hermann, H.;
Eder, M.; Cannich, A.; Azad, S. C.; Cascio, M. G.;
Gutiérrez, S. O.; van der Stelt, M.; López-Rodriguez, M. L.;
Casanova, E.; Schütz, G.; Zieglgänsberger, W.; Di Marzo,
V.; Behl, C.; Lutz, B. Science 2003, 302, 84.
O
Ni-Pr2
C5H11
1) BBr3, CH2Cl2
O
OH
–78 °C to 40 °C, 12 h
(5) Eubanks, L. M.; Rogers, C. J.; Beuscher, A. E. IV.; Koob, G.
F.; Olson, A. J.; Dickerson, T. J.; Janda, K. D. Mol.
Pharmacol. 2006, 3, 773.
2) AcOH–toluene (1:1)
110 °C, 5 h
O
O
O
C5H11
51% over 2 steps
15
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14
MeLi, THF
–78 °C to r.t., 1 h
OH
TFA, CH2Cl2
r.t., 10 min
OH
85%
O
C5H11
HO
HO
C5H11
2
16
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Scheme 4 Conversion of biphenyl 14 into CBN
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In the next step, biaryl 14 was treated with BBr3 to cleave
the methyl ether protecting groups. After hydrolysis with
methanol and aqueous workup, the crude product was
subjected to acidic cyclization to give lactone 15 in 51%
yield over two steps. The cannabinol synthesis was com-
pleted by introducing the geminal methyl groups through
the addition of two equivalents of methyllithium to give
tertiary benzylic alcohol 16, which was cyclized by treat-
ment with trifluoroacetic acid to yield cannabinol (2) in
85% over two steps (Scheme 4).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1109–1112

1112
M. P. Nüllen, R. Göttlich
LETTER
(18) Nüllen, M. P.; Göttlich, R. Synthesis 2011, 1249.
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(19) Typical Procedure: The resorcinol derivate (2 equiv) and
anhydrous TMEDA (2 equiv) were dissolved in anhydrous
1,2-dimethoxyethane (DME) and cooled to 0 °C before
adding n-butyllithium (2.5 M in hexanes, 2.2 equiv) by using
a syringe. The mixture was stirred for 1.5 h then CuBr·SMe2
(1 equiv) was added and stirring was continued for 30 min.
[Pd(PPh3)4] (7.5 mol%), aryl iodide (1 equiv) and anhydrous
NMP were added and the reaction mixture was heated for 12
h in a sealed Schlenk tube. The reaction was quenched by the
addition of saturated aqueous NH4Cl solution, followed by
extraction of the aqueous layer with MTBE (3×). The
combined organic layers were washed with concentrated
aqueous NH3 solution and brine, before being dried with
MgSO4. After removal of the solvents, the desired biphenyl
compound was isolated by flash chromatography.
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Synlett 2013, 24, 1109–1112
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