Regiospecifically deuterated (-)-Δ9-tetrahydrocannabivarins

Article abstract of DOI:10.1039/b205459k

Deuterated (-)-Δ⁹-tetrahydrocannabivarins (Δ⁹-THCVs) can be used as markers for confirming the illicit use of marijuana. Here, we first describe an efficient synthesis of side chain deuterated Δ⁹-THCVs from the respective 5-propylresorcinols specifically deuterated at the side chain. Our approach involved the development of optimal, high yield methods for the introduction of deuterium at the C-3′ and C-2′ position of the side chain.

Full text of DOI:10.1039/b205459k

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Regiospecifically deuterated (؊)-ꢀ9-tetrahydrocannabivarins
Spyros P. Nikas, Ganesh A. Thakur and Alexandros Makriyannis*
Center for Drug Discovery, Departments of Pharmaceutical Sciences and of Molecular and
Cell Biology and Institute of Materials Science, University of Connecticut, Storrs,
Connecticut 06269, USA. E-mail: makriyan@uconnvm.uconn.edu; Fax: (ϩ1) 860 486 3089
1
Received (in Cambridge, UK) 6th June 2002, Accepted 24th September 2002
First published as an Advance Article on the web 24th October 2002
Deuterated (Ϫ)-∆9-tetrahydrocannabivarins† (∆9-THCVs) can be used as markers for confirming the illicit use of
marijuana. Here, we first describe an efficient synthesis of side chain deuterated ∆9-THCVs from the respective
5-propylresorcinols specifically deuterated at the side chain. Our approach involved the development of optimal,
high yield methods for the introduction of deuterium at the C-3Ј and C-2Ј position of the side chain.
Introduction
Cannabis (marijuana), obtained from Cannabis Sativa contains
a mixture of natural cannabinoids and is one of the most com-
monly used drugs among recreational substance abusers. (Ϫ)-
∆9-Tetrahydrocannabinol (∆9-THC), the major ingredient and
most active constituent of marijuana, is quickly metabolized
principally to 11-hydroxy-∆9-THC, 9-carboxy-11-nor-∆9-THC,
and 8β, 11-dihydroxy-∆9-THC and their glucuronide con-
jugates. Deuteration and tritiation of these cannabinoids either
at the alkyl side chain1–3 or at the tricyclic ring4 allows them
to be used as mass spectral internal standards1–4 and also as
probes for studying the cannabinergic system.
Marinol, the trade name for synthetic (Ϫ)-∆9-THC, is a
recommended drug for the treatment of refractory nausea and
vomiting associated with cancer chemotherapy5 and for ano-
rexia6 associated with weight loss in patients with AIDS. The
assays for ∆9-THCs presently available do not allow the dif-
ferentiation between Marinol and marijuana users. Recently,7
studies involving incubation of ∆9-THCV with human hepato-
cytes, demonstrated that the presence of ∆9-THCV metabolites
Scheme 1
could be related to the use or ingestion of cannabis-related
product(s). However, the development of proper assays using
∆9-THCV, as a marker for cannabis use and abuse, requires
specifically deuterated cannabivarins in high isotopic purity.
This goal is the subject of this publication.
dimethoxybenzaldehyde 1 and undeuterated ethylmagnesium
bromide to obtain the corresponding alcohol 2c (Scheme 1).
This could, in turn, be deoxygenated to 3c following an earlier
approach8,9 we developed for the preparation of specifically
deuterated 5-pentylresorcinols. This methodology was based on
mesylate formation followed by triethylborohydride reduction.
However, mesylation or tosylation of 2c led to multiple by-
products, probably due to the instability of the respective
benzylic mesylates10 or tosylates. Alternatively, direct benzylic
deoxygenation of alcohol 2c under catalytic hydrogenation
conditions11 gave 3c in 77% yield.
Generally, ∆9-THC analogs can be synthesized by the con-
densation of a chiral monoterpene with an appropriately sub-
stituted resorcinol. However, the synthesis of regiospecifically
side chain deuterated 5-propylresorcinols without significant
deuterium loss or scrambling represents a special challenge. The
present work describes the methodologies we have developed
for the preparative scale synthesis of specifically side chain
deuterated 5-propylresorcinols and the corresponding (Ϫ)-∆9-
tetrahydrocannabivarins in high deuterium purity. Synthesis of
such deuterated compounds had not been reported previously
and suitable procedures were required for their synthesis.
Synthesis of the trideuterated compounds 2a and 3a was
1
achieved following the same reaction sequence. The H-NMR
spectrum of 3a showed no deuterium loss at the C-3Ј position
and no scrambling at the C-2Ј and C-3Ј positions. Additionally,
the percentage of deuterium incorporation was determined by
mass spectrometry using a field ionization technique and was
found to be identical to that of the deuterated reagent ethyl
bromide. Deprotection of dimethyl ether groups with BBr3 at
Ϫ78 ЊC gave 4a in 96% yield.
Results and discussion
Our initial approach to the synthesis of deuterated propyl-
resorcinols involved a model Grignard reaction between 3,5-
Our efforts to synthesize the corresponding pentadeuterated
compound 3b by following the same sequence were less
successful. Catalytic hydrogenolysis of compound 2b gave
the resorcinol dimethyl ether 3b with approximately 20–24%
deuterium loss and/or scrambling between the C-1Ј and C-2Ј
positions as observed by 1H-NMR (Fig. 1, a). Furthermore, the
† (Ϫ)-∆9-Tetrahydrocannabivarin is
a common name used for
(6aR,10aR)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-propyl-6H-di-
benzo[b,d]pyran-1-ol. This name was first proposed by Frans
W. H. M. Merkus (Nature, 1971, 232, 579) to describe a (Ϫ)-∆9-tetra-
hydrocannabinol homologue, in which the side chain is C3H7 instead
of C5H11.
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J. Chem. Soc., Perkin Trans. 1, 2002, 2544–2548
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b205459k

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Chart 1
isolated in only 50–64% yields. Literature reports17,18 of a
modified version of this type of coupling reaction outlined
the use of the tosyl functionality as a better leaving group.
However, if the reaction is carried out using copper() iodide as
a catalyst, a substantial amount of homocoupled by-product is
still formed.18
We overcame these difficulties by employing a cross-coupling
approach between 3,5-dimethoxybenzyl toluene-p-sulfonate 6
and C2H3C2H2MgBr in the presence of Li2CuCl4 which led to
the desired product 3b in 81% yield (Scheme 2).
Fig. 1 Expansion of 1H-NMR (500 MHz) spectra of 3b obtained
from a. catalytic hydrogenolysis, b. hydrogenolysis using TMSCl–NaI,
c. copper()-catalyzed Grignard cross-coupling. The arrows indicate
signals due to the deuterium loss and or scrambling at the C-1Ј position
(δ ∼2.5) and at the C-2Ј position (δ ∼1.6).
isotope ratio analysis on the molecular ion cluster showed
21% deuterium loss (sum of ions containing 2H4 and 2H3).
These results suggests deuterium loss occurs in this reaction
that can be accounted for by an earlier reported mechanism11a
for the catalytic hydrogenolysis of benzylic alcohols. Addition-
ally, the percentage of loss was found to be dependent on
the reaction time and scale. A subsequent attempt using
TMSCl–NaI based deoxygenation12 of 2b led to products
exhibiting 9–10% deuterium loss based on 1H-NMR (Fig. 1, b)
and isotopic ratio analysis (10% from the sum of ions con-
taining 2H4 and 2H3). The reaction leading to the desired
product 3b is believed to involve formation of a benzylic
iodide13,14 (Chart 1), followed by reductive dehalogenation
using in situ generated TMSH.12b The observed deuterium loss
may be explained by invoking DI elimination of the benzylic
iodide to the intermediate alkene,15 which readily undergoes
HI addition followed by TMSH reductive dehalogenation
(Chart 1).
Scheme 2
The reaction was clean, high yielding with only small
amounts of by-products (7–10%) and was scaled up to 30.0 g.
The H-NMR spectrum of the resulting O,O-dimethylpropyl-
resorcinol (Fig. 1, c) showed no deuterium loss or isotopic
scrambling. Also, isotope ratio analysis of the molecular ion
cluster showed that the percentage of deuterium incorporation
was identical to that of the reagent. Subsequently, deprotection
of the methoxy groups to provide 4b (96% yield) was achieved
using BBr3 at Ϫ78 ЊC.
1
The only previously reported19 synthesis of unlabelled ∆9-
THCV had been carried out by a three step sequence involving
first coupling of 5-propylresorcinol with (Ϫ)-cis-verbenol to
give the thermodynamically more stable ∆8-THCV isomer,
which was further transformed to the ∆9-isomer by HCl
addition–elimination reactions20 in a 21% overall yield. We
obtained significantly improved results through a single step
procedure used earlier21 for the synthesis of (Ϫ)-∆9-THC.
Thus, condensation of resorcinols 4a and 4b with (ϩ)-trans-
p-mentha-2,8-dien-1-ol in the presence of BF3ؒEt2O and
anhydrous magnesium sulfate afforded 5a and 5b in 28 and 29%
isolated yield respectively (Scheme 3).
We also explored the ionic hydrogenation of 2b using triethyl-
1
silane.16 This reaction was promising as both H-NMR and
isotopic ratio analysis indicated the absence of deuterium
scrambling or loss. However, the poor yields (19–21%) of this
reaction prompted us to search for alternative options.
We thus turned to an approach involving C–C bond for-
mation through a Li2CuCl4 based Grignard cross-coupling.17
A survey of the literature led to two references1,3 related to
the coupling between 3,5-dimethoxybenzyl bromide with
either but-3-enylmagnesium bromide or n-butylmagnesium
bromide under Li2CuCl4 catalyzed conditions. The draw-
back of these approaches was the formation of substantial
amounts (28–42%) of homocoupled and reduction by-
products, whereas the desired cross-coupled product was
The 1H-NMR spectrum of specifically labeled (Ϫ)-∆9-
THCVs showed no deuterium loss or isotopic scrambling.
These results clearly indicate that the BBr3 mediated demethyl-
ation followed by BF3ؒEt2O induced terpenylation is not
associated with any carbon–deuterium bond cleavage in these
molecules.
J. Chem. Soc., Perkin Trans. 1, 2002, 2544–2548
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1,3-Dimethoxy-5-(1Ј-hydroxy[2Ј,2Ј,3Ј,3Ј,3Ј-2H5]propyl)benzene
2b
The synthesis was carried out as for 2a starting from 3,5-
dimethoxybenzaldehyde 1 (3.5 g, 21.1 mmol) and C2H3C2H2Br
(4.1 g, 35.9 mmol), Mg (0.87 g, 35.8 mmol) in anhydrous Et2O
(36 mL) and anhydrous THF (70 mL) to yield 97% (5.9 g)
2b as a viscous oil; δH (CDCl3) 1.86 (1H, br s, OH), 3.78 (6H,
s, OMe), 4.51 (1H, s, 1Ј-H), 6.36 (1H, t, J 2.1, 2-H), 6.50 (2H,
d, J 2.1, 4-H, 6-H); δC 9.3 (septet, J 19.1, C-3Ј), 30.9 (qt, J 19.1,
C-2Ј), 55.5 (OMe), 76.1 (C-1Ј), 99.5 (C-2), 104.0 (C-4, C-6),
147.5 (C-5), 161.0 (C-1, C-3), 147.5 (C-5); m/z (EI) 201.1418
(Mϩ, C11H11D5O3 requires 201.1413, 44%), 184 (2), 167 (68),
139 (100), 124 (20), 77 (9).
Scheme 3
Conclusions
In summary, the first synthesis of side chain specifically deuter-
ated (Ϫ)-∆9-tetrahydrocannabivarins has been achieved in high
isotopic purity without any deuterium scrambling or loss. An
approach based on the catalytic hydrogenolysis of a benzylic
alcohol was satisfactory only for the synthesis of (Ϫ)-∆9-THCV
deuterated at the terminal methyl group of the side chain. How-
ever, Li2CuCl4 catalyzed Grignard cross-coupling was found to
be the most suitable route for the synthesis of both side chain
tri- and penta-deuterated (Ϫ)-∆9-THCVs.
1,3-Dimethoxy-5-[3Ј,3Ј,3Ј-2H3]propylbenzene 3a
To a solution of alcohol 2a (8.8 g, 44.2 mmol) in glacial acetic
acid (147 mL) was added 10% Pd/C (613 mg) and the resulting
suspension was stirred vigorously under a hydrogen atmosphere
for 13 h at rt. Upon completion the reaction mixture was
diluted with Et2O, brine and water and the catalyst removed
by filtration through Celite. The organic phase was separated,
diluted with water and neutralized by portionwise addition
of solid NaHCO3. The organic layer was separated and the
aqueous phase was extracted with Et2O. The combined organic
layer was washed with brine, dried over MgSO4 and the
solvent evaporated under reduced pressure. Purification by flash
column chromatography (Et2O–petroleum ether; 6 : 94) on
silica gel afforded 3a as a colorless liquid in 77% yield (6.2 g);
δH (CDCl3) 1.61 (2H, t, J 7.5, 2Ј-H), 2.53 (2H, t, J 7.6, 1Ј-H),
3.78 (6H, s, OMe), 6.30 (1H, t, J 2.1, 2-H), 6.35 (2H, d, J 2.1,
4-H, 6-H); δC 13.2 (septet, J 19.1, C-3Ј), 24.3 (C-2Ј), 38.5 (C-1Ј),
55.4 (OMe), 97.8 (C-2), 106.7 (C-4, C-6), 145.4 (C-5), 160.9
(C-1, C-3); m/z (EI) 183.1336 (Mϩ, C11H13D3O2 requires
183.1339, 60%), 165 (15), 153 (100), 138 (8), 122 (10), 91 (20),
Experimental
All reagents and solvents were purchased from Aldrich
Chemical Company unless specified otherwise and used with-
out further purification. C2H3CH2Br and C2H3C2H2Br were
obtained in 99% isotopic purity from Aldrich. Melting points
were determined on a micro-melting point apparatus and are
uncorrected. NMR spectra were recorded in CDCl3, unless
otherwise stated, on a Bruker DMX-500 instrument (1H
at 500.13 MHz, 13C at 125.77 MHz). Chemical shifts are in
δ (ppm) relative to internal TMS and J values are given in Hz.
Low,high-resolution mass spectra and isotopic ratio analysis
were performed on a Micromass 70-VSE instrument at the
School of Chemical Sciences, University of Illinois at Urbana-
Champaign. Flash column chromatography employed silica gel
60 (230–400 mesh).
2
77 (26); m/z (FI) 183 (Mϩ, 98.7% incorporation of H3), 182
(1.1% 2H2), 181 (0.1% 2H1) and 180 (0.1% 2H0).
1,3-Dihydroxy-5-[3Ј,3Ј,3Ј-2H3]propylbenzene 4a
To a solution of 3a (6.0 g, 32.8 mmol) in anhydrous CH2Cl2
(328 mL) at Ϫ78 ЊC under an argon atmosphere was added
BBr3 (82 mL, 1.0 M solution in CH2Cl2) over a period of 15
min. Following the addition the reaction temperature was
gradually raised (35 min) to rt and stirring was continued for
4 h. The reaction was quenched by the addition of MeOH
and crushed ice at 0 ЊC, the resulting mixture was warmed to rt,
stirred for 40 min and the volatiles removed under reduced
pressure. The residual oil was diluted with AcOEt and the solu-
tion was washed with sat. NaHCO3, water and brine. The
organic layer was dried over MgSO4, filtered and concentrated
under reduced pressure. Purification by flash column chroma-
tography on silica gel using Et2O–petroleum ether (50 : 50)
as eluent afforded 4a (4.9 g) in 97% yield as a white solid;
mp 85–86 ЊC; δH (CDCl3) 1.59 (2H, t, J 7.5, 2Ј-H), 2.47 (2H, t,
J 7.6, 1Ј-H), 4.72 (2H, br s, OH), 6.17 (1H, t, J 2.1, 2-H), 6.24
(2H, d, J 2.1, 4-H, 6-H); δC (CDCl3 ϩ DMSO-d6) 13.0 (septet,
J 19.0, C-3Ј), 24.0 (C-2Ј), 37.9 (C-1Ј), 100.4 (C-2), 107.3 (C-4,
C-6), 145.2 (C-5), 157.7 (C-1, C-3); m/z (EI) 155.1032 (Mϩ,
C9H9D3O2 requires 155.1026, 75%), 137 (25), 125 (100), 77 (10),
69 (21).
1,3-Dimethoxy-5-(1Ј-hydroxy[3Ј,3Ј,3Ј-2H3]propyl)benzene 2a
[2,2,2-2H3]Ethylmagnesium bromide. To a stirred mixture of
magnesium turnings (3.31 g, 136.16 mmol) and anhydrous Et2O
(14 mL), under an argon atmosphere was added a solution of
C2H3CH2Br (15.25 g, 136.16 mmol) in anhydrous Et2O (122
mL) over a period of 1 h. Subsequently the reaction mixture
was refluxed for an additional 10 min and then cooled to 0 ЊC.
Reaction of 3,5-dimethoxybenzaldehyde with organomagne-
sium reagent. To a stirred solution of aldehyde 1 (13.3 g,
80.1 mmol) in anhydrous THF (267 mL) at Ϫ78 ЊC, under an
argon atmosphere was added the above Grignard reagent over a
period of 30 min. The reaction temperature was then gradually
raised (30 min) to rt and stirring continued for 1 h. The reaction
was quenched by dropwise addition of sat. aqueous NH4Cl, the
crude suspension was diluted with AcOEt and brine, and stirred
vigorously. The organic layer was separated and the aqueous
phase extracted with AcOEt. The combined organic layer was
washed with brine, dried (MgSO4) and solvent evaporated
under reduced pressure. The residue obtained was purified by
flash column chromatography on silica gel (AcOEt–petroleum
ether; 30 : 70) afforded 15.6 g of 2a (98% yield) as a viscous oil;
δH (CDCl3) 1.70 (1H, dd, J 13.6 and J 5.9, 2Ј-H), 1.77 (1H, dd,
J 13.6 and J 7.1, 2Ј-H), 1.94 (1H, br s, OH), 3.79 (6H, s, OMe),
4.51 (1H, t, J 6.5, 1Ј-H), 6.36 (1H, t, J 2.1, 2-H), 6.50 (2H, d,
J 2.1, 4-H, 6-H); δC 9.5 (septet, J 18.7, C-3Ј), 31.7 (C-2Ј), 55.5
(OMe), 76.2 (C-1Ј), 99.5 (C-2), 104.0 (C-4, C-6), 147.5 (C-5),
161.0 (C-1, C-3); m/z (EI) 199.1281 (Mϩ, C11H13D3O3 requires
199.1288, 43%), 182 (2), 167 (69), 139 (100), 124 (19), 77 (9).
3,5-Dimethoxybenzyl alcohol 5
To a solution of 1 (34.5 g, 207.8 mmol) in methanol (1.38 L) at
Ϫ10 ЊC was added sodium borohydride (15.8 g, 416 mmol)
gradually over a period of 30 min. The reaction was stirred
for 1 h and then quenched by the addition of sat. aqueous
NH4Cl, the volatiles were removed in vacuo and the residue
was extracted with AcOEt. The organic layer was washed
with brine, dried over MgSO4 and the solvent removed under
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J. Chem. Soc., Perkin Trans. 1, 2002, 2544–2548

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reduced pressure. The product was purified through a short
column of silica gel (AcOEt–petroleum ether; 30 : 70) to give
the title compound as a white solid in 95% yield (33.1 g);
mp 47–49 ЊC (lit.,18 mp 48 ЊC).
6α-Me), 1.44–1.38 (4H, m, 7-H, 6β-Me, especially 1.40, s, 6β-
Me), 1.56 (2H, t, J 7.6, 2Ј-H), 1.72–1.66 (4H, m, 6a-H, 11-H,
especially 1.68, br s, 11-H), 1.95–1.89 (1H, m, 7-H), 2.17–2.15
(2H, m, 8-H), 2.41 (2H, td, J 7.6 and J 2.7, 1Ј-H), 3.19 (1H,
br d, J 11.0, 10a-H), 4.79 (1H, s, OH), 6.14 (1H, d, J 1.4, 2-H),
6.26 (1H, d, J 1.4, 4-H), 6.30 (1H, m, 10-H); m/z (EI) 289.2116
(Mϩ, C19H23D3O2 requires 289.2121, 88%), 274 (100), 246 (55),
206 (92), 168 (19), 115 (11), 91 (10), 77 (14); m/z (FI) 289 (Mϩ,
3,5-Dimethoxybenzyl toluene-p-sulfonate 6
The title compound was prepared according to the reported
procedure18 using alcohol 5 (31.7 g, 188.7 mmol), CH3Li
(203 mL, 1.4 M solution in Et2O) and toluene-p-sulfonyl
chloride (34.2 g, 227.2 mmol) in anhydrous THF (1.0 L); yield:
76% (46.3 g); white solid; mp 63–64 ЊC (lit.,18 mp 64 ЊC).
2
2
2
98.3% incorporation of H3), 288 (1.5% H2), 287 (0.1% H1)
and 286 (0.1% 2H0).
ꢀ9-[2Ј,2Ј,3Ј,3Ј,3Ј-2H5]Tetrahydrocannabivarin 5b
1,3-Dimethoxy-5-[2Ј,2Ј,3Ј,3Ј,3Ј-2H5]propylbenzene 3b
The synthesis was carried out analogous to the preparation of
5a starting from 4b (5.0 g, 31.8 mmol), (ϩ)-trans-p-mentha-2,8-
dien-1-ol (5.32 g, 35.03 mmol), MgSO4 (4.2 g) and BF3ؒEt2O
(2.0 mL) in anhydrous CH2Cl2 (200 mL). Yield: 2.70 g (29%);
pale yellow gum; δH (CDCl3) 1.09 (3H, s, 6α-Me), 1.44–1.37
(4H, m, 7-H, 6β-Me, especially 1.41, s, 6β-Me), 1.72–1.63 (4H,
m, 6a-H, 11-H, especially 1.68, br s, 11-H), 1.93–1.88 (1H, m,
7-H), 2.18–2.16 (2H, m, 8-H), 2.40 (2H, s, 1Ј-H), 3.19 (1H, br d,
J 11.0, 10a-H), 4.83 (1H, s, OH), 6.13 (1H, d, J 1.4, 2-H), 6.27
(1H, d, J 1.4, 4-H), 6.30 (1H, m, 10-H); δC 12.9 (septet, J 19.1,
C-3Ј), 19.4 (6α-Me), 23.1 (qt, J 19.3, C-2Ј), 23.5 (9-Me), 25.2
(C-7), 27.7 (6β-Me), 31.3 (C-8), 33.8 (C-10a), 37.5 (C-1Ј), 46.0
(C-6a), 77.5 (C-6), 107.9 (C-2), 109.3 (C-10b), 110.1 (C-4),
124.0 (C-10), 134.3 (C-9), 142.7 (C-3), 154.7 and 154.4 (C-1,
C-4a); m/z (EI) 291.2247 (Mϩ, C19H21D5O2 requires 291.2247,
86%), 276 (96), 248 (54), 208 (100), 170 (15); m/z (FI) 291 (Mϩ,
98.6% incorporation of 2H5), 290 (1.4% 2H4), 289 (0% 2H3), 288
(0% 2H2).
Dilithium tetrachlorocuprate solution (0.1 M). The solution
was prepared by reacting anhydrous LiCl (1.26 g, 30 mmol) and
CuCl2 (2.01 g, 15 mmol) in anhydrous THF (150 mL).
Preparation of [1,1,2,2,2-2H5]Ethylmagnesium bromide. The
title compound was prepared by the method described for
2a using C2H3C2H2Br (33.0 g, 289.5 mmol) and Mg turnings
(6.96 g, 286.4 mmol) in anhydrous Et2O (580 mL).
Coupling reaction. The solution of Grignard reagent was
diluted with anhydrous THF (700 mL) cooled to Ϫ78 ЊC, and
Li2CuCl4 (138 mL, 0.1 M solution in THF) was added under
an argon atmosphere. The mixture was stirred for 5 min and a
solution of 3,5-dimethoxybenzyl toluene-p-sulfonate 6 (44.4 g,
137.9 mmol) in anhydrous THF (600 mL) was added over a
period of 15 min. The reaction was warmed to rt, stirred for
1.5 h and quenched by adding sat. aqueous NH4Cl. Workup
of the reaction was performed in the usual manner as
described for 2a. Purification by flash column chromatography
on silica gel (Et2O–petroleum ether; 6 : 94) afforded 3b as a
colorless liquid in 81% yield (20.6 g); δH (CDCl3) 2.51 (2H, s,
1Ј-H), 3.78 (6H, s, OMe), 6.30 (1H, t, J 2.1, 2-H), 6.34 (2H, d,
J 2.1, 4-H, 6-H); δC 13.1 (septet, J 19.1, C-3Ј), 23.5 (qt, J 19.0,
C-2Ј), 38.3 (C-1Ј), 55.4 (OMe), 97.8 (C-2), 106.7 (C-4, C-6),
145.4 (C-5), 160.9 (C-1, C-3); m/z (EI) 185.1466 (Mϩ,
C11H11D5O2 requires 185.1464, 60%), 167 (12), 153 (100), 138
(8), 122 (10), 91 (18), 77 (23); m/z (FI) 185 (Mϩ, 98.7%
incorporation of 2H5), 184 (1.3% 2H4), 183 (0% 2H3), 182
(0% 2H2).
Acknowledgements
This work was supported by grants from the National Institute
of Drug Abuse (DA03801, DA07215, and DA09158). We are
thankful to Dr Steven Mullen from the School of Chemical
Sciences, University of Illinois at Urbana-Champaign for
recording low,high resolution mass spectra and isotopic ratio
analysis.
References and notes
1 H. Hoellinger, N. H. Nam, J. F. Decauchereux and L. Pichat,
J. Labelled Compd. Radiopharm., 1977, 13, 401.
2 (a) M. A. Tius and G. S. K. Kannangara, Tetrahedron, 1992, 48,
9173; (b) B. Schmidt, I. Franke, F. J. Witteler and M. Binder, Helv.
Chim. Acta, 1983, 66, 2564; (c) E. Pop, B. Rachwal, S. Rachwal,
J. Vlasak, M. E. Brewster and L. Prokai, J. Labelled Compd.
Radiopharm., 1998, 41, 885.
1,3-Dihydroxy-5-[2Ј,2Ј,3Ј,3Ј,3Ј-2H5]propylbenzene 4b
The synthesis was carried out analogous to the preparation
of 4a starting from 3b (18.2 g, 98.4 mmol) and BBr3 (246 mL,
1.0 M solution in CH2Cl2) in anhydrous CH2Cl2 (984 mL);
yield: 96% (14.8 g); white solid; mp 85–86 ЊC; δH (CDCl3) 2.45
(2H, s, 1Ј-H), 4.95 (2H, s, OH), 6.17 (1H, t, J 2.1, 2-H), 6.24
(2H, d, J 2.1, 4-H, 6-H); δC (CDCl3 ϩ DMSO-d6) 12.8 (septet,
J 18.9, C-3Ј), 23.2 (qt, J 18.9, C-2Ј), 37.8 (C-1Ј), 100.5 (C-2),
108.3 (C-4, C-6), 146.2 (C-5), 156.6 (C-1, C-3); m/z (EI)
157.1154 (Mϩ, C9H7D5O2 requires 157.1151, 73%), 139 (22),
125 (100), 77 (7), 69 (17).
3 H. H. Seltzman, M. K. Begum and C. D. Wyrick, J. Labelled
Compd. Radiopharm., 1991, 29, 1009.
4 (a) A. R. Banijamali, N. Abou-Taleb, C. J. Van der Schyf,
A. Charalambous and A. Makriyannis, J. Labelled Compd.
Radiopharm., 1987, 25, 73; (b) M. Szirmai, M. M. Halldin and
A. Ohlsson, J. Labelled Compd. Radiopharm., 1991, 31, 131; (c)
S. Feng and M. A. ElSohly, J. Labelled Compd. Radiopharm., 2000,
43, 655; (d ) R. Mechoulam, P. Braun and Y. Gaoni, J. Am. Chem.
Soc., 1972, 94, 6159; (e) R. A. Driessen and C. A. Salemink, Recl:
J. R. Neth. Chem. Soc., 1981, 100, 342.
5 M. Lane, C. L. Vogel, J. Ferguson, S. Krasnow, J. L. Saiers,
J. Hamm, K. Salva, P.H. Wiernik, C. P. Holroyde and S. Hammill,
J. Pain Symptom Manage., 1991, 6, 352.
6 J. E. Bill, R. Olson, L. Lefkowitz, L. Laubenstein, P. Bellman,
B. Yangco, J. O. Morales, R. Murphy, W. Powderly, T. F. Plasse,
K. W. Mosdell and K. V. Shepard, J. Pain Symptom Manage., 1997,
14, 7.
7 (a) M. A. ElSohly, H. DeWit, S. R. Wachtel, S. Feng and
T. P. Murphy, J. Anal. Toxicol., 2001, 25, 565; (b) M. A. ElSohly,
S. Feng, T. P. Murphy, S. A. Ross, A. Nimrod, Z. Mehmedic and
N. Fortner, J. Anal. Toxicol., 1999, 23, 222.
8 S. P. Nikas, G. A. Thakur and A. Makriyannis, Synth. Commun.,
2002, 32, 1751.
ꢀ9-[3Ј,3Ј,3Ј-2H3]Tetrahydrocannabivarin 5a
To a stirred suspension of resorcinol 4a (1.0 g, 6.5 mmol),
(ϩ)-trans-p-mentha-2,8-dien-1-ol (1.1 g, 7.1 mmol) and MgSO4
(0.8 g) in anhydrous CH2Cl2 (41 mL) at Ϫ3 ЊC under an argon
atmosphere was added BF3ؒEt2O (0.4 mL). Stirring was con-
tinued for 2.5 h at 0 ЊC and anhydrous sodium bicarbonate
(2.1 g) was added. The mixture was warmed to rt,stirred
vigorously for 30 min and filtered through Florisil. The filtrate
was evaporated under reduced pressure to give a pale yellow
gum. Purification by repeated flash column chromatography
(three times) on silica gel using 10% Et2O in hexane as eluent
afforded 0.52 g (28% yield) of the title compound in 98–99%
purity as confirmed by 1H-NMR; δH (CDCl3) 1.09 (3H, s,
9 S. P. Nikas, G. A. Thakur and A. Makriyannis, J. Labelled Compd.
Radiopharm., 2002, 45, 1065.
J. Chem. Soc., Perkin Trans. 1, 2002, 2544–2548
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10 K. Kobayashi, P. K. Jadhav, T. M. Zydowsky and H. G. Floss, J. Org.
Chem., 1983, 48, 3510.
11 (a) E. W. Garbisch, Jr., L. Schreader and J. J. Frankel, J. Am. Chem.
Soc., 1967, 89, 4233; (b) K. Ofosu-Asante and L. M. Stock, J. Org.
Chem., 1986, 51, 5452; (c) K. Ofosu-Asante and L. M. Stock, J. Org.
Chem., 1987, 52, 2938.
12 (a) T. Sakai, K. Miyata, M. Utaka and A. Takeda, Tetrahedron Lett.,
1987, 28, 3817; (b) E. Ghera, R. Maurya and A. Hassner,
Tetrahedron Lett., 1989, 30, 4741.
13 M. E. Jung and P. L. Ornstein, Tetrahedron Lett., 1977, 31, 2659.
14 G. A. Olah, S. C. Narang, B. G. B. Gupta and R. Malhotra, J. Org.
Chem., 1979, 44, 1247.
15 Formation of alkenes during deoxygenation of closely related
benzylic alcohols using TMSCl–NaI has been reported (see ref. 12b).
16 D. N. Kursanov, Z. N. Parnes and N. M. Loim, Synthesis, 1974,
633.
17 (a) M. Tamura and J. Kochi, Synthesis, 1971, 303; (b) G. Fouquet
and M. Schlosser, Angew. Chem., Int. Ed. Engl., 1974, 13, 82.
18 S. Combes and J.-P. Finet, Synth. Commun., 1997, 27, 3769.
19 E. W. Gill, J. Chem. Soc., 1971, 579.
20 A. R. Banijamali, C. J. Van der Schyf and A. Makriyannis,
J. Labelled Compd. Radiopharm., 1998, 41, 121.
21 R. K. Razdan, H. C. Dalzell and G. R. Handrick, J. Am. Chem.
Soc., 1974, 96, 5860.
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