An intramolecular pyranone Diels-Alder cycloaddition approach to cannabinol

Article abstract of DOI:10.1002/adsc.201301037

The natural product cannabinol was synthesized using an intramolecular pyranone Diels-Alder cycloaddition reaction as the key step. This strategy is well adapted to access cannabinol analogues.

Full text of DOI:10.1002/adsc.201301037

FULL PAPERS
DOI: 10.1002/adsc.201301037
An Intramolecular Pyranone Diels–Alder Cycloaddition
Approach to Cannabinol
Fangfang Fan,a Jingjing Dong,a Jinqian Wang,a Lina Song,a Chuanjun Song,a,*
and Junbiao Changa,*
a
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, Peopleꢀs Republic of China
E-mail: chjsong@zzu.edu.cn or changjunbiao@zzu.edu.cn
Received: November 20, 2013; Revised: January 4, 2014; Published online: March 20, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301037.
Abstract: The natural product cannabinol was syn- strategy is well adapted to access cannabinol ana-
thesized using an intramolecular pyranone Diels– logues.
Alder cycloaddition reaction as the key step. This
Keywords: cannabinol; cycloaddition; natural prod-
ucts; pyranones; total synthesis
Introduction
great interest. Besides oxidative aromatization of tet-
rahydrocannabinols,[7a,b,10] other strategies for the syn-
Cannabinoids comprise a class of more than 70 natu- thesis of cannabinols include formation of the biaryl
ral products isolated from the plant Cannabis sativa.[1] moiety by nucleophilic aromatic substitution or cross-
Besides the well-known recreational use of the canna- coupling reactions followed by pyran formation,[9,11]
bis plant as a psychotropic drug, other medicinal ap- and construction of the second phenyl ring starting
plications include antiemetic,[2] analgesic,[3] anticon- from a suitably substituted arene by various cycliza-
vulsant,[4] and antibiotic[1c,5] properties. The biological tion reactions including an Ru-catalyzed microwave-
activities of cannabinoids arise due to their interac- mediated [2+2+2]cyclotrimerization reaction[12] and
tion with two G-protein coupled cellular receptors,
the central cannabinoid receptor CB1 and the peri- Minuti and co-workers have developed a high pres-
ACHTUNGTRENNUNG
pheral cannabinoid receptor CB2.[6] Because CB1 and sure-promoted Diels–Alder reaction of 1-phenylbuta-
a
multicomponent domino reaction.[13] Recently,
CB2 show differences in their function, agonists that 1,3-dienes with methyl propiolate for the synthesis of
can selectively bind to one of the receptors are desira- phenylcyclohexadienes, which was also applied to the
ble.[7]
formal synthesis of cannabinol (2).[14] However, the
D9-Tetrahydrocannabinol (THC; 1) (Figure 1) has very high pressure (9ꢁ103 bar) required to secure
been identified as the primary active ingredient of a good yield of the products and the necessity for
Cannabis sativa. On aromatization of the cyclohexene a separate oxidation step to produce the biaryls is
ring, it gives cannabinol (CBN; 2) which has shown rather inconvenient. Herein, we report our strategy
potent antibacterial activity.[8] More importantly, de- for the synthesis of cannabinol (2), featuring an intra-
rivatives of 2 have been found to bind selectively to molecular pyranone Diels–Alder cycloaddition reac-
the CB2 receptor.[7b,9] Therefore, synthetic routes to- tion[15] of compound 4 as the key step to build up the
wards cannabinol and its derivatives have been of tricyclic motif 3 (Scheme 1).
Results and Discussion
Our synthesis started with regioselective acylation of
the known olivetol dimethyl ether 5[16] to produce
a,b-unsaturated ketone 6 (Table 1). Friedel–Crafts
acylation of 5 with crotonoyl chloride in DCM or tol-
Figure 1. D9-Tetrahydrocannabinol (1) and cannabinol (2).
uene gave a mixture of the desired 2-acylation prod-
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Fangfang Fan et al.
lithium and crotonoyl chloride were increased to 4.0
and 4.5 equivalents, respectively, and 6 was isolated in
81% yield.
Having 6 in hand, we then finished our total syn-
thesis of cannabinol (2) (Scheme 2). Michael addition
of 6 with diethyl malonate provided 8 in excellent
yield. Ester hydrolysis followed by decarboxylation in
refluxing pyridine afforded keto acid 9, which cyclized
on treatment with acetic anhydride to give dihydro-
pyranone 10. Subsequent oxidation of 10 with DDQ
gave pyranone 11 in excellent yield. Next, in order to
get access to precursor 4 (R=CH3) for the key intra-
molecular pyranone Diels–Alder cycloaddition reac-
tion, one of the methyl protecting groups of 11
Scheme 1. Retrosynthetic analysis of cannabinol (2).
uct 6 and the isomeric 4-acylation product 7 in a ratio needed to be replaced with a propargyl group. Quite
of 1:2, from which only a disappointing 20% yield of a number of methods for the monodeprotection of
6 was isolated (entries 1 and 2). The ratio of 6 to 7 aryl dimethyl ethers have been developed in the liter-
could be improved to 2:3 by subjecting 5 to crotonic ature and applied in natural product synthesis.[19]
acid in the presence of TFAA and FeCl3 (entry 3).[17] However, this proved to be difficult in our hands.
Addition of 1,10-phenanthroline to the reaction mix- Usually, the dideprotection product 12 itself or a mix-
ture to reduce the reactivity of FeCl3 in the hope that ture with the desired monodeprotection product
the 2-acylation product 6 could be obtained in im- (structure not shown) was obtained. Finally, we decid-
proved yield resulted, however, in exclusive formation ed to remove both methyl protecting groups and react
of compound 7 (in 58% isolated yield) (entry 4). Al- the resulting bis-phenol 12 with propargyl bromide to
though the desired product 6 was not obtained, the obtain the dipropargyl ether 13. The extra propargyl
high regioselectivity was noteworthy. We then treated group could be removed later at a suitable stage after
5 with n-butyllithium (1.2 equiv.) in the presence of the cycloaddition reaction had been carried out. The
TMEDA to effect ortho-lithiation[11c,18] and subse- dideprotection with BBr3 proceeded as expected to
quently treated the resulting organolithium with cro- give 12 in 69% isolated yield. After dipropargylation,
tonoyl chloride (1.4 equiv.) (entry 5). To our delight, 6 13 was ready for the key intramolecular pyranone
was the only product formed although the reaction Diels–Alder cycloaddition reaction, which proceeded
was not complete. After stirring the reaction mixture smoothly in refluxing toluene and delivered pyran 14
at ambient temperature for 3 h, 6 was isolated in 10% in excellent yield. Next, selective oxidation of the
yield together with substantial amount of the unreact- benzylic methylene group with PCC furnished pyra-
ed 5 recovered. The quantity of reactants was then ex- none 15 in 86% isolated yield. Finally, addition of
plored. After some experiments, it was found that the CH3Li followed by treatment of the crude reaction
reaction was complete when the amounts of n-butyl- mixture with TFA furnished the natural product can-
Table 1. Regioselective acylation of olivetol dimethyl ether 5.
Entry
Reagents and conditions
6/7[a]
Yield [%] of 6[b]
1
2
3
4
5
crotonoyl chloride, AlCl3, CH2Cl2, reflux
crotonoyl chloride, AlCl3, toluene, reflux
crotonic acid, TFAA, FeCl3, DCM, r.t.
33:67
33:67
40:60
0:100
100:0
20
20
35
0
crotonic acid, TFAA, FeCl3, 1,10-phenanthroline, DCM, r.t.
(a) n-BuLi (1.2 equiv.), TMEDA, Et2O, À788C to r.t.;
(b) crotonoyl chloride (1.4 equiv.), À788C to r.t.
(a) n-BuLi (4.0 equiv.), TMEDA, Et2O, À788C to r.t.;
(b) crotonoyl chloride (4.5 equiv.), À788C to r.t.
10
6
100:0
81
[a]
1
Determined by H NMR integration of the crude reaction mixture.
Isolated yield.
[b]
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An Intramolecular Pyranone Diels–Alder Cycloaddition
Scheme 2. Total synthesis of cannabinol (2).
nabinol (2) with simultaneous removal of the proparg- ment. Mass spectra were recorded on a Micromass Q-TOF
mass spectrometer.
yl protecting group, so that an extra deprotection step
was not necessary. A separate study on phenyl prop-
argyl ether indicated that the propargyl deprotection
reaction was effected by MeLi rather than TFA. A
number of methods for propargyl ether deprotection
have been reported.[20] However, there is no literature
precedent involving an organolithium reagent as de-
propargylation agent. Thus, our work has provided
a new entry to propargyl ether deprotection. Detailed
studies are currently underway and the results will be
published elsewhere.
(E)-1-(2’,6’-Dimethoxy-4’-pentylphenyl)but-2-en-1-
one (6)
To
a solution of olivetol dimethyl ether 5 (337 mg,
1.62 mmol) and TMEDA (0.3 mL, 1.94 mmol) in dry THF
(10 mL) at À788C under nitrogen, was added n-butyllithium
(1.6M solution in hexane, 4 mL, 6.47 mmol). After addition,
the mixture was allowed to warm to ambient temperature
and stirred for 0.5 h before being cooled to À788C again.
Crotonoyl chloride (0.7 mL, 7.29 mmol) was added drop-
wise. The resulting mixture was allowed to warm to ambient
temperature and stirred for a further 0.5 h, and then
quenched with saturated aqueous ammonium chloride
(30 mL). The mixture was extracted with ethyl acetate (3ꢁ
30 mL). The combined organic extracts were dried
(Na2SO4), filtered and evaporated under vacuum. The resi-
due was purified by column chromatography on silica gel
(10% ethyl acetate in petroleum ether) to give 6 as an
orange oil; yield: 362 mg (81%). 1H NMR (300 MHz,
CDCl3): d=0.90 (t, J=6.9 Hz, 3H), 1.30–1.35 (m, 4H),
1.56–1.64 (m, 2H), 1.89 (dd, J=6.9 Hz and 1.5 Hz, 3H), 2.58
Conclusions
In summary, we have developed a novel approach to
the total synthesis of the natural product cannabinol.
The key step involves an intramolecular pyranone
Diels–Alder cycloaddition reaction to build up the
benzo[c]chromene framework. This strategy is well
adapted to access broadly substituted C-ring ana-
logues of cannabinol by using other a,b-unsaturated (t, J=7.8 Hz, 2H), 3.75 (s, 6H), 6.32 (dq, J=15.6, 1.5 Hz,
1H), 6.37 (s, 2H), 6.62 (dq, J=15.6, 6.9 Hz, 1H); 13C NMR
acyl chlorides or propargyl bromide derivatives.
(75 MHz, CDCl3): d=14.1, 18.4, 22.6, 31.1, 31.5, 36.7, 55.9,
104.2, 116.0, 134.1, 145.9, 146.3, 157.2, 195.7 ppm; IR (neat):
nmax =1658, 1606, 1578, 1455, 1414, 1235, 1126 cmÀ1; HR-MS
(ESI): m/z=277.1802, calcd. for C17H25O3 [M+H]+:
Experimental Section
277.1804.
General
Diethyl 2-[4’-(2’’,6’’-Dimethoxy-4’’-pentylphenyl)-4’-
oxobutan-2’-yl]malonate (8)
Solvents were dried according to standard procedures where
needed. Melting points were determined on a XT4A hot-
stage apparatus and are uncorrected. IR spectra were ob-
tained using an IFS25 FT-IR spectrometer. 1H and 13C NMR
spectra were obtained on a Bruker AV300 or AV400 instru-
To a solution of ketone 6 (4.5 g, 16.4 mmol) in dry ethanol
(100 mL) was added diethyl malonate (5.3 g, 32.8 mmol) and
anhydrous K2CO3 (0.5 g, 3.3 mmol). The resulting mixture
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was heated to 808C for 4 h, then cooled and quenched with
2M aqueous HCl (10 mL). The bulk of ethanol was evapo-
rated under vacuum. The residue was partitioned between
H2O (100 mL) and ethyl acetate (30 mL). The separated
aqueous phase was extracted with ethyl acetate (2ꢁ30 mL).
The combined organic extracts were washed with brine (3ꢁ
40 mL), then dried (Na2SO4), filtered and evaporated under
vacuum. The residue was purified by column chromatogra-
phy on silica gel (15% ethyl acetate in petroleum ether) to
give 8 as an orange oil; yield: 6.97 g (97%). 1H NMR
(300 MHz, CDCl3): d=0.90 (t, J=6.9 Hz, 3H), 1.10 (d, J=
6.9 Hz, 3H), 1.25 (t, J=7.2 Hz, 6H), 1.29–1.36 (m, 4H),
1.55–1.65 (m, 2H), 2.56 (t, J=7.5 Hz, 2H), 2.72–2.99 (m,
3H), 3.45 (d, J=6.3 Hz, 1H), 3.76 (s, 6H), 4.18 (q, J=
7.5 Hz, 4H), 6.34 (s, 2H); 13C NMR (75 MHz, CDCl3): d=
14.1, 14.2, 17.4, 22.6, 29.3, 31.1, 31.6, 36.8, 49.0, 55.8, 56.4,
61.1, 61.2, 104.1, 117.8, 146.5, 156.7, 168.7, 168.9, 203.7; IR
(neat): nmax =1749, 1731, 1706, 1607, 1580, 1457, 1416,
due was purified by column chromatography on silica gel
(10% ethyl acetate in petroleum ether) to give dihydropyra-
none 10 as an orange oil; yield: 3.0 g (100%). 1H NMR
(300 MHz, CDCl3): d=0.90 (t, J=6.9 Hz, 3H), 1.17 (d, J=
6.9 Hz, 3H), 1.28–1.35 (m, 4H), 1.57–1.64 (m, 2H), 2.41 (m,
1H), 2.57 (t, J=7.8 Hz, 2H), 2.72–2.84 (m, 2H), 3.78 (s,
6H), 5.23 (d, J=3.3 Hz, 1H), 6.36 (s, 2H); 13C NMR
(75 MHz, CDCl3): d=14.1, 20.2, 22.6, 26.4, 31.1, 31.6, 36.9,
36.9, 56.1, 104.2, 109.6, 113.3, 144.0, 146.4, 158.7, 170.1; IR
(neat): nmax =1763, 1688, 1607, 1577, 1459, 1416, 1236, 1128,
1023 cmÀ1
;
HR-MS (ESI): m/z=319.1901, calcd. for
C19H27O4 [M+H]+: 319.1909.
6-(2’,6’-Dimethoxy-4’-pentylphenyl)-4-methyl-2H-
pyran-2-one (11)
DDQ (5.8 g, 19.1 mmol) was added to a solution of dihydro-
pyranone 10 (4.1 g, 12.7 mmol) in dry 1,4-dioxane (100 mL).
The resulting mixture was heated to reflux for 1 h and
cooled. The bulk of solvent was evaporated under vacuum.
The residue was diluted with DCM (40 mL), and then fil-
tered. The filter cake was washed with DCM (20 mL). The
filtrate was washed successively with saturated aqueous
sodium bicarbonate (3ꢁ40 mL) and brine (3ꢁ40 mL), and
then dried (Na2SO4), filtered and evaporated under vacuum.
The residue was purified by column chromatography on
silica gel (17% ethyl acetate in petroleum ether) to give pyr-
anone 11 as a yellow solid; yield: 3.9 g (96%); mp 91–948C.
1H NMR (300 MHz, CDCl3): d=0.90 (t, J=6.9 Hz, 3H),
1.28–1.38 (m, 4H), 1.57–1.67 (m, 2H), 2.17 (d, J=1.5 Hz,
3H), 2.58 (t, J=7.8 Hz, 2H), 3.76 (s, 6H), 6.02 (m, 1H),
6.10 (d, J=1.5 Hz, 1H), 6.38 (s, 2H); 13C NMR (75 MHz,
CDCl3): d=14.1, 21.6, 22.6, 31.0, 31.6, 36.9, 56.0, 104.1,
108.8, 111.1, 111.6, 147.6, 155.9, 156.0, 158.5, 164.1; IR
(KBr): nmax =1720, 1649, 1608, 1577, 1561, 1468, 1418, 1238,
1128 cmÀ1
;
HRMS (ESI): m/z=459.2350, calcd. for
C24H36NaO7 [M+Na]+: 459.2359.
5-(2’,6’-Dimethoxy-4’-pentylphenyl)-3-methyl-5-oxo-
pentanoic Acid (9)
A mixture of diethyl malonate 8 (7.5 g, 17.2 mmol) and
sodium hydroxide (6.8 g, 172 mmol) in ethanol (100 mL)
and water (57 mL) was refluxed for 1 h, and then cooled.
The bulk of the ethanol was evaporated under vacuum. The
residue was partitioned between 2M aqueous HCl (60 mL)
and ethyl acetate (50 mL). The separated aqueous phase
was extracted with ethyl acetate (2ꢁ50 mL). The combined
organic extracts were dried (Na2SO4), filtered and evaporat-
ed under vacuum. The residue was dissolved in pyridine
(172 mL). The resulting mixture was heated to reflux for
12 h, and then cooled. The bulk of pyridine was evaporated
under vacuum. The residue was partitioned between 2M
aqueous HCl (60 mL) and ethyl acetate (60 mL). The sepa-
rated aqueous phase was extracted with ethyl acetate (2ꢁ
60 mL). The combined organic extracts were dried
(Na2SO4), filtered and evaporated under vacuum to give
1129 cmÀ1
;
HR-MS (ESI): m/z=339.1554, calcd. for
C19H24NaO4 [M+Na]+: 339.1572.
6-(2’,6’-Dihydroxy-4’-pentylphenyl)-4-methyl-2H-
pyran-2-one (12)
1
keto acid 9 as an orange oil; yielkd: 4.9 g (90%), H NMR
(300 MHz, CDCl3): d=0.90 (t, J=6.9 Hz, 3H), 1.05 (d, J=
6.6 Hz, 3H), 1.29–1.35 (m, 4H), 1.57–1.65 (m, 2H), 2.24 (m,
1H), 2.50–2.86 (m, 6H), 3.76 (s, 6H), 6.35 (s, 2H); 13C NMR
(75 MHz, CDCl3): d=14.1, 19.9, 22.6, 26.3, 31.0, 31.5, 36.7,
40.7, 51.1, 55.7, 104.1, 117.7, 146.6, 156.7, 179.1, 204.4; IR
(neat): nmax =1705, 1608, 1582, 1463, 1416, 1369, 1282, 1230,
To a solution of pyranone 11 (3.4 g, 10.9 mmol) in dry DCM
(20 mL) at À788C under argon, was added boron tribromide
(1.0M solution in DCM, 11.4 mL, 11.4 mmol). After addi-
tion, the mixture was allowed to warm to ambient tempera-
ture and stirred for 15 h before being quenched with ice-
cooled water (50 mL). The bulk of DCM was evaporated
under vacuum. The residue was extracted with ethyl acetate
(3ꢁ30 mL). The combined organic extracts were washed
successively with saturated aqueous sodium bicarbonate (3ꢁ
40 mL) and brine (3ꢁ40 mL), and then dried (Na2SO4), fil-
tered and evaporated under vacuum. The residue was puri-
fied by column chromatography on silica gel (3% methanol
in DCM) to give pyranone 12 as a colorless solid; yield:
2.2 g (69%); mp 191–1938C. 1H NMR (300 MHz, DMSO-
d6): d=0.87 (t, J=6.9 Hz, 3H), 1.25–1.34 (m, 4H), 1.47–1.56
(m, 2H), 2.15 (s, 3H), 2.40 (t, J=7.8 Hz, 2H), 6.01 (s, 1H),
6.20 (s, 3H), 9.54 (s, 2H); 13C NMR (100 MHz, CD3OD):
d=14.4, 21.6, 23.6, 31.8, 32.5, 36.9, 108.0, 111.2 112.8, 148.4,
157.8, 158.3, 159.7, 166.8; IR (KBr): nmax =3392, 1685, 1630,
1565, 1524, 1451, 1200, 1174, 1049 cmÀ1; HR-MS (ESI):
m/z=311.1248, calcd. for C17H20NaO4 [M+Na]+: 311.1259.
1130 cmÀ1
;
HR-MS (ESI): m/z=359.1833, calcd. for
C19H28NaO5 [M+Na]+: 359.1834.
6-(2’,6’-Dimethoxy-4’-pentylphenyl)-4-methyl-3,4-di-
hydro-2H-pyran-2-one (10)
A solution of keto acid 9 (3.2 g, 9.51 mmol) in acetic anhy-
dride (50 mL) was heated to reflux for 5 h. The cooled mix-
ture was evaporated under vacuum. The residue was parti-
tioned between water (100 mL) and ethyl acetate (40 mL).
The separated aqueous phase was extracted with ethyl ace-
tate (2ꢁ40 mL). The combined organic extracts were
washed successively with saturated aqueous sodium bicar-
bonate (5ꢁ50 mL) and brine (3ꢁ50 mL), and then dried
(Na2SO4), filtered and evaporated under vacuum. The resi-
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An Intramolecular Pyranone Diels–Alder Cycloaddition
(400 MHz, CDCl3): d=0.90 (t, J=7.0 Hz, 3H), 1.31–1.38
(m, 4H), 1.63–1.70 (m, 2H), 2.53 (s, 3H), 2.63 (t, J=2.4 Hz,
1H), 2.67 (t, J=7.8 Hz, 2H), 4.92 (d, J=2.4 Hz, 2H), 6.76
(d, J=1.3 Hz, 1H), 6.88 (d, J=1.3 Hz, 1H), 7.34 (dd, J=8.1
and 0.9 Hz, 1H), 8.30 (d, J=8.1 Hz, 1H), 8.80 (s, 1H);
13C NMR (100 MHz, CDCl3): d=14.1, 22.6, 22.7, 30.6, 31.5,
36.0, 56.7, 76.3, 78.0, 106.5, 108.8, 111.0, 118.2, 127.5, 129.0,
130.2, 134.5, 145.6, 145.7, 152.7, 156.0, 161.7; IR (KBr):
nmax =3310, 1716, 1621, 1502, 1293, 1111 cmÀ1; HR-MS
(ESI): m/z=335.1642, calcd. for C22H23O3 [M+H]+:
335.1647.
4-Methyl-6-[4’-pentyl-2’,6’-bis(prop-2’’-yn-1’’-yloxy)-
phenyl]-2H-pyran-2-one (13)
To a solution of pyranone 12 (230 mg, 0.8 mmol) in acetone
(20 mL) were added potassium carbonate (442 mg,
3.2 mmol) and propargyl bromide (0.33 mL, 4.4 mmol). The
resulting mixture was heated to reflux for 12 h and cooled.
The bulk of solvent was evaporated under vacuum. The resi-
due was partitioned between ethyl acetate (20 mL) and
water (40 mL). The separated aqueous phase was extracted
with ethyl acetate (2ꢁ20 mL). The combined organic ex-
tracts were washed with brine (3ꢁ30 mL), and then dried
(Na2SO4), filtered and evaporated under vacuum. The resi-
due was purified by column chromatography on silica gel
(25% ethyl acetate in petroleum ether) to give pyranone 13
as an orange solid; yield: 234 mg (90%); mp 95–978C.
1H NMR (400 MHz, CDCl3): d=0.89 (t, J=6.9 Hz, 3H),
1.31–1.36 (m, 4H), 1.58–1.66 (m, 2H), 2.17 (s, 3H), 2.49 (t,
J=2.4 Hz, 2H), 2.60 (t, J=7.8 Hz, 2H), 4.66 (d, J=2.4 Hz,
4H), 6.02 (s, 1H), 6.13 (s, 1H), 6.58 (s, 2H); 13C NMR
(100 MHz, CDCl3): d=14.1, 21.6, 22.6, 30.8, 31.4, 36.7, 56.8,
76.0, 78.5, 106.9, 110.4, 111.4, 111.8, 147.4, 155.0, 156.0,
156.5, 163.8; IR (KBr): nmax =3290, 2123, 1732, 1612, 1582,
1565, 1454, 1402 cmÀ1; HR-MS (ESI): m/z=387.1552, calcd.
for C23H24NaO4 [M+Na]+: 387.1572.
Cannabinol (2)[12]
Methyllithium (1.6M solution in diethyl ether, 1.2 mL,
1.9 mmol) was added dropwise to a solution of benzo[c]-
chromenone 15 (63 mg, 0.19 mmol) in dry diethyl ether
(10 mL) at À108C under argon. The resulting mixture was
stirred for 1 h at À108C, before being allowed to warm to
ambient temperature and stirred for a further 3 h. The reac-
tion was then cooled to 08C. Saturated aqueous ammonium
chloride (30 mL) was added and the resulting mixture ex-
tracted with ethyl acetate (3ꢁ30 mL). The combined organic
extracts were washed with brine (3ꢁ30 mL), and then dried
(Na2SO4), filtered and evaporated under vacuum. The resi-
due was dissolved in DCM (20 mL). TFA (3 drops) was
added and the reaction stirred at ambient temperature for
12 h before being quenched with ice-cooled water. The bulk
of DCM was evaporated under vacuum. The residue was
partitioned between ethyl acetate (20 mL) and water
(30 mL). The separated aqueous phase was extracted with
ethyl acetate (2ꢁ20 mL). The combined organic extracts
were washed successively with saturated aqueous sodium bi-
carbonate (3ꢁ30 mL) and brine (3ꢁ30 mL), and then dried
(Na2SO4), filtered and evaporated under vacuum. The resi-
due was purified by column chromatography on silica gel
(6% ethyl acetate in petroleum ether) to give cannabinol (2)
9-Methyl-3-pentyl-1-(prop-2’-yn-1’-yloxy)-6H-
benzo[c]chromene (14)
A solution of pyranone 13 (666 mg, 1.83 mmol) in dry tolu-
ene (35 mL) was heated to reflux for 12 h and cooled. The
bulk of toluene was evaporated under vacuum. The residue
was partitioned between ethyl acetate (40 mL) and water
(50 mL). The separated aqueous phase was extracted with
ethyl acetate (2ꢁ40 mL). The combined organic extracts
were washed with brine (3ꢁ50 mL), and then dried
(Na2SO4), filtered and evaporated under vacuum. The resi-
due was purified by column chromatography on silica gel
(5% ethyl acetate in petroleum ether) to give benzo[c]chro-
mene 14 as an orange oil; yield: 507 mg (87%). 1H NMR
(400 MHz, CDCl3): d=0.92 (t, J=6.9 Hz, 3H), 1.34–1.38
(m, 4H), 1.62–1.69 (m, 2H), 2.41 (s, 3H), 2.57–2.61 (m, 3H),
4.82 (d, J=2.4 Hz, 2H), 4.96 (s, 2H), 6.58 (s, 2H), 7.03–7.08
(m, 2H), 8.19 (s, 1H); 13C NMR (100 MHz, CDCl3): d=
14.2, 21.9, 22.7, 30.8, 31.6, 36.2, 56.6, 68.9, 75.7, 78.7, 107.3,
111.0, 111.1, 124.3, 127.1, 127.5, 128.8, 128.9, 137.7, 144.6,
155.6, 156.8; IR (neat): nmax =3290, 2124, 1613, 1582, 1561,
1
as an orange oil; yield: 52 mg (89%); H NMR (300 MHz,
CDCl3): d=0.89 (t, J=6.9 Hz, 3H), 1.29–1.34 (m, 4H),
1.56–1.65 (m, 8H), 2.38 (s, 3H), 2.50 (t, J=7.8 Hz, 2H), 5.22
(br s, 1H), 6.29 (d, J=1.2 Hz, 1H), 6.44 (d, J=1.2 Hz, 1H),
7.07 (d, J=7.8 Hz, 1H), 7.14 ( d, J=7.8 Hz, 1H), 8.16 (s,
1H); MS (ESI): m/z (%)=333 (100) [M+Na]+, 311 (95)
[M+H]+.
1454 cmÀ1
;
HR-MS (ESI): m/z=343.1652, calcd. for
Acknowledgements
C22H24NaO2 [M+Na]+: 343.1674.
We are grateful to the National Natural Science Foundation
of China (#20902085; #21172202; #81330075) for financial
support.
9-Methyl-3-pentyl-1-(prop-2’-yn-1’-yloxy)-6H-
benzo[c]chromen-6-one (15)
To a solution of benzo[c]chromene 14 (78 mg, 0.25 mmol) in
dry DCM (10 mL) were added PCC (436 mg, 2.0 mmol) and
celite (436 mg). The resulting mixture was heated to reflux References
for 12 h, and then cooled and filtered. The filter cake was
washed with DCM (15 mL). The filtrate was washed with
brine (3ꢁ30 mL), and then dried (Na2SO4), filtered and
evaporated under vacuum. The residue was purified by
column chromatography on silica gel (10% ethyl acetate in
petroleum ether) to give benzo[c]chromenone 15 as a color-
less solid; yield: 72 mg (86%); mp 138–1418C. 1H NMR
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