High pressure Diels-Alder approach to hydroxy-substituted 6a-cyano-tetrahydro-6H-benzo[c]chromen-6-ones: A route to Δ6- cis-cannabidiol

Article abstract of DOI:10.1021/jo9005365

(Chemical Equation Presented) Diels-Alder cycloaddition reactions of 3-cyanocoumarin, hydroxy-substituted 3-cyanocoumarins and mesyl-substituted 3-cyano-coumarins with methyl-1,3-butadienes carried out under high pressure (11 kbar) are reported. Activatio

Full text of DOI:10.1021/jo9005365

High Pressure Diels-Alder Approach to Hydroxy-Substituted
6a-Cyano-tetrahydro-6H-benzo[c]chromen-6-ones: A Route to
∆6-Cis-Cannabidiol
Eleonora Ballerini, Lucio Minuti,* Oriana Piermatti, and Ferdinando Pizzo
Dipartimento di Chimica, UniVersita` degli Studi di Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy
lucio@unipg.it
ReceiVed March 16, 2009
Diels-Alder cycloaddition reactions of 3-cyanocoumarin, hydroxy-substituted 3-cyanocoumarins and
mesyl-substituted 3-cyano-coumarins with methyl-1,3-butadienes carried out under high pressure (11
kbar) are reported. Activation by high pressure allows these reactions to proceed satisfactorily under
mild conditions to produce 6a-cyano-hydroxy- and 6a-cyano-mesyl-tetrahydro-6H-benzo[c]chromen-6-
ones in moderate to excellent yield. The synthesis of cis-1-hydroxy-9-methyl-3-pentyl-6a,7,10,10a-
tetrahydro-benzo[c]chromen-6-one as precursor of ∆6-3,4-cis-cannabidiol (∆6-cis-CBD) and ∆8-cis-
tetrahydrocannabinol (∆8-cis-THC) is outlined.
Introduction
ZnCl2 as catalyst.3 In contrast, we have shown that HfCl4 ·2THF
is an efficient catalyst for Diels-Alder cycloadditions of
3-ethoxycarbonylcoumarins with 1,3-butadienes; the corre-
sponding cycloadducts can be prepared in satisfactory yields
under solvent-free conditions (SolFC) at 30-50 °C.2c Further-
more, we have reported that 3-nitrocoumarins react with isoprene
and 2,3-dimethyl-1,3-butadiene in water or under SolFC in good
yields, while the 6- and 7-hydroxy-substituted 3-nitrocoumarins
are deactivated by the hydroxy substituent and react only under
harsh conditions with moderate yields.2a These results highlight
the need to find a protocol that allows the cycloaddition reactions
of coumarins that have electron-donating groups in the 5-8-
positions to be performed under mild conditions. This would
provide a competitive, environmentally safe route to the
benzo[c]chromene skeleton.
Compounds based on a tetrahydrobenzo[c]chromene skeleton
are of great interest in the chemical community and are included
in the set of “privileged structures” due to their high incidence
in natural biologically active products and as precursors of
important molecules (e.g., functionalized biphenyls, cannabinoid
compounds).1 Recently, we focused on the development of new
environmentally friendly synthetic routes to obtain target
molecules that incorporate the chromane subunit by using the
Diels-Alder cycloaddition of 1,3-butadienes to various 3-sub-
stituted coumarins.2 Although the Diels-Alder reaction of
3-substituted coumarins with 1,3-butadienes permits the prepa-
ration of interesting synthetic targets, due to the low reactivity
of coumarin double bond, these reactions have been scarcely
successful. For example, 3-alkoxycarbonylcoumarins react at
room temperature in good yield only if a large amount of diene
(44 equiv) is used in combination with an excess (1.2 equiv) of
Recently, we reported the 9 kbar pressure (30-70 °C)
Diels-Alder reactions of coumarins substituted at C-3 position
with phenylsolfonyl-, carboxy-, ethoxycarbonyl-, nitro-, tiofe-
nyl-, and -pyridyl-groups. The corresponding tetrahydro-6H-
benzo[c]chromen-6-ones were prepared in excellent yields.
When carried out at atmospheric pressure, the reaction yields
and selectivities were greatly reduced.2d
* Corresponding author. Tel. +39.075.5855545. Fax: +39.075.5855560.
(1) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga,
S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939–9953.
(2) (a) Amantini, D.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. J.
Org. Chem. 2003, 68, 9263–9268. (b) Minuti, L.; Marrocchi, A.; Tesei, I.; Gacs-
Baitz, E. Tetrahedron Lett. 2005, 46, 8789–8792. (c) Fringuelli, F.; Girotti, R.;
Pizzo, F.; Zunino, E.; Vaccaro, L. AdV. Synth. Catal. 2006, 348, 297–300. (d)
Girotti, R.; Marrocchi, A.; Minuti, L.; Piermatti, O.; Pizzo, F.; Vaccaro, L. J.
Org. Chem. 2006, 71, 70–74. (e) Minuti, L.; Marrocchi, A.; Landi, S.; Mirko,
S.; Gacs-Baitz, E. Tetrahedron 2007, 63, 5477–5481.
(3) Ohkata, K.; Miyamoto, K.; Matsumara, S.; Akiba, K. Tetrahedron Lett.
1993, 34, 6575–6578.
10.1021/jo9005365 CCC: $40.75
Published on Web 04/29/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4311–4317 4311

Ballerini et al.
TABLE 1. Diels-Alder Reactions of Coumarin (1a) with
2,3-Dimethyl-1,3-butadiene (2x) and Isoprene (2y) under
Atmospheric and 11 kbar Pressure Conditions
SCHEME 1. Diels-Alder Reactions between
3-Cyanocoumarins 1 and 1,3-Butadienes 2
P
yield
entry dienea
mediumb
(kbar) T (°C) t (h) product (%)c
1
2
3
4
5
6
7
8
2x
PhMe
Atm 110 48 3ax
55 72 3ax
Atm 150
43d
55d
2xe SolFC/HfCl4 ·2THFe Atm
2x
2x
2x
2x
2x
2x
2y
H2O
3
4ax/5axf,g 65
CH2Cl2
MeCN
Me2CO
EtOAc
EtOH
11
11
11
11
11
55 16 3ax
55 16 3ax
55 16 3ax
55 36 3ax
55 36 3ax
90
85
80
50d
20d
38d
45d
9
PhMe
Atm 110 48 3ay
55 72 3ay
Atm 150
2ye SolFC/HfCl4 ·2THFe Atm
SCHEME 2. Proposed Synthesis of Tetrahydro-6H-
benzo[c]chromen-6-ones 4 and 5 and Cannabinoids 6 and 7
10
11
12
13
14
2y
2y
2x
2y
H2O
3
4ay/5ayf,h 60
CH2Cl2
MeCN
Me2CO
11
11
11
55 16 3ay
55 16 3ay
55 16 3ay
85
80
77
a Four equivalents of 1,3-diene were used. b Concn of coumarin 1a )
0.1 M. c Yield of isolated product. d Conversion. e Ten equivalents of
1,3-diene and 25 mol % of catalyst were used. f Diastereomeric ratio
was determined by GC and/or 1H NMR analyses. g Diastereomeric ratio
4ax/5ax ) 1:1.5. h Diastereomeric ratio 4ay/5ay ) 1:1.4.
SCHEME 3
for the synthesis of ∆6-3,4-cis-cannabidiol (∆6-cis-CBD) 6hy
(R ) 1′-OH, 3′-C5H11; R1 ) H), and ∆8-cis-tetrahydrocannabinol
(∆8-cis-THC) 7hy (R ) 1-OH, 3-C5H11; R1 ) H)5 (Scheme 2).
These results have proven that increased pressure promotes
efficiently the Diels-Alder cycloadditions of 3-substituted-
coumarins under milder condition with no need for a metallic
catalyst and/or high temperatures, thus promoting this technol-
ogy as a valuable tool in eco-friendly processes.2d,4
Results and Discussion
Diels-Alder Reactions of 3-Cyanocoumarins 1 with
1,3-Butadienes 2. The Diels-Alder cycloadditions of 3-cy-
anocoumarin (1a) with dienes 2 were initially investigated under
both atmospheric and high pressure. The results of this study
are summarized in Table 1.
Thus, in continuation of our research directed toward the
synthesis of compounds that incorporate the chromene subunit,
herein we report (i) the synthesis of 6a-cyano-tetrahydro-6H-
benzo[c]chromen-6-ones 3 based on the Diels-Alder cycload-
dition under high pressure of 3-cyano-coumarins 1 and 1,3-
butadienes 2 (Scheme 1) and (ii) the conversion of selected
cycloadducts 3 into their corresponding tetrahydro-6H-benzo-
[c]chromen-6-ones 4 and 5, under aqueous conditions. These
products are precursors of important molecules, such as iso-
propenyl-substituted tetrahydrobiaryl templates 6 and 6,6-
dimethyl-tetrahydro-6H-benzo[c]chromene derivatives 7 (Scheme
2).
Preliminary experiments showed that there was no reaction
between 1a and dienes 2 under atmospheric pressure, at low
temperature (55 °C) and for long period of time (72 h), neither
when toluene, methylene chloride or water, was used as solvent,
nor under SolFC. A moderate conversion of 1a to 3ax and 3ay
(55%, 45%) was obtained under SolFC at ambient pressure and
55 °C, by using 0.25 molar equivs of HfCl4′2THF (Table 1,
entries 2 and 10), or heating for 48 h 1a with dienes 2 in toluene
at 110 °C6 (Table 1, entries 1 and 9). However, under aqueous
conditions and an increase of reaction temperature from 55 to
150 °C the reactions of 1a with 2x and 2y gave better isolated
yields (65 and 60%, respectively) (Table 1, entries 3 and 11).
However, instead of the expected cycloadducts 3ax and 3ay,
under the given reaction conditions a mixture of 4ax/5ax2d or
4ay/5ay2d in ratios of 1:1.5 and 1:1.4, respectively were obtained
(Scheme 3).
Specifically, we have apllied this approach to the synthesis
of cis-tetrahydro-6H-benzo[c]chromen-6-one 4hy as precursor
(4) (a) Jurczak, J.; Gryko, D. T. In Chemistry Under Extreme or Non-
Classical Conditions; van Eldik, R., Hubbard, C. D., Eds.; Wiley: New York,
1997; Chapter 4. (b) Isaacs, N. S. In High-Pressure Techniques in Chemistry
and Physics; Harwood, L. M., Moody, C. J., Eds.; Oxford: New York, 1997;
Chapter 7. (c) Minuti, L.; Taticchi, A.; Costantini, L. Recent Res. DeV. Org.
Chem. 1999, 3, 105–116. (d) van Eldik, R.; Kla¨rner, F.-G. In High Pressure
Chemistry-Synthetic, Mechanistic, and Supercritical Applications; Wiley-Sons:
Weinheim, 2002. (e) Jenner, G. Tetrahedron 2002, 58, 5185–5202. (f) Matsu-
moto, K.; Hamana, H.; Iida, H. HelV. Chim. Acta 2005, 88, 2033–2234. (g)
Menichetti, S.; Faggi, C.; Lamanna, G.; Marrocchi, A.; Minuti, L.; Taticchi, A.
Tetrahedron 2006, 62, 5626–5631. (h) Minuti, L. In Eco-Friendly Processes
and Procedures for the Synthesis of Fine Chemicals; RSC Green Chemistry
series; The Royal Society of Chemistry: Cambridge (UK); Chapter 7. In press.
(5) Handrick, G. R.; Razdan, R. K.; Uliss, D. B.; Dalzell, H. C.; Boger, E.
J. Org. Chem. 1977, 42, 2563–2568, The authors have not reported the yield
obtained in the reaction to lactone 4hy.
(6) Taylor, E. C.; Strojny, E. J. J. Am. Chem. Soc. 1960, 82, 5198–5292.
4312 J. Org. Chem. Vol. 74, No. 11, 2009

Route to ∆6-Cis-Cannabidiol
TABLE 2. Diels-Alder Reactions of Coumarins (1b-g) with
2,3-Dimethyl-1,3-butadiene (2x) and Isoprene (2y) under 11 kbar
Pressure at 55 °C
SCHEME 4
entry coumarina dieneb medium t (h) product yield (%)c
1
2
3
4
5
6
7
8
1b
1b
1b
1b
1b
1b
1c
1c
1d
1d
1e
1e
1f
2x
2x
2x
2y
2y
2y
2x
2y
2x
2y
2x
2y
2x
2y
2x
2y
CH2Cl2
Me2CO
MeCN
CH2Cl2
Me2CO
MeCN
Me2CO
Me2CO
MeCN
Me2CO
Me2CO
Me2CO
MeCN
Me2CO
MeCN
Me2CO
36
36
48
48
36
48
48
60
48
36
15
15
20
24
20
24
3bx
3bx
3bx
3by
3by
3by
3cx
3cy
3dx
3dy
3ex
3ey
3fx
25d
60
65
30d
60
65
30
10d
12d
5d
75
65
75
70
76
60
9
10
11
12
13
14
15
16
1f
1g
1g
3fy
3gx
3gy
these substrates by the hydroxy group in the 6- and 7-positions,
respectively.
a Concn of coumarins 1b-g ) 0.1 M. b Four equivalents of 1,3-diene
were used. c Yields of isolated cycloadducts. d Conversion determined
1
by H NMR of crude reaction mixture.
In view of these unsatisfactory results, we converted cou-
marins 1c and 1d to the corresponding methanesulfonic acid
3-cyano-2-oxo-2H-chromen-6-yl and 7-yl esters 1f and 1g
following the usual procedure.7 These dienophiles were then
submitted to Diels-Alder reaction with dienes 2x, y.
The electron-withdrawing capacity of the mesyl group
allowed the Diels-Alder reaction of 1f and 1g with 2x to occur
with improved yields (75 and 76%, respectively) (Table 2,
entries 13 and 15) when performed in acetonitrile solution.8 With
diene 2y (Table 2, entries 14 and 16), the 11 kbar pressure
cycloadditions in acetone solution were totally regioselective,
producing cycloadducts 3fy and 3gy in 70 and 60% yield,
respectively (Scheme 4).
Application to the Synthesis of Cannabinoids. Cannab-
inoids are a well-known group of about 60 structurally related
compounds, that have been isolated from Indian hemp (Cannabis
satiVa Var. indica). These compounds, along with their non-
natural analogues, have been gaining the attention of synthetic
and medicinal chemists because of their important bioactivities
and the effect that structural modifications of their skeleton can
play on their biological role.9 In the past decade, the need for
further studies has created an increased demand for analogues
and metabolites.10
The low yields obtained under harsh reaction conditions (high
temperature, long reaction time) and the need to have a metal
catalyst in order for the reactions to occur at atmospheric
pressure, makes the procedure unattractive. Thus, considering
the powerful pressure-induced acceleration of the Diels-Alder
reaction,4 we studied the cycloadditions of coumarin 1a with
dienes 2 under high pressure.
When a mixture of coumarin 1a and 2,3-dimethyl-1,3-
butadiene (2x) in methylene chloride was compressed to 11 kbar
for 16 h at 55 °C, an isolated yield of 90% of 3ax was obtained
(Table 1, entry 4). Similarly, isoprene (2y) under identical
conditions gave 3ay in high yield (85%) (Table 1, entry 12).
The effect of pressure on the reactions of 1a with 2 was also
explored in other organic solvents. The use of acetonitrile or
acetone led to cycloadducts 3ax and 3ay (Table 1, entries 5, 6,
13, and 14) in yields that were slightly lower than those obtained
with methylene chloride (Table 1, entries 4 and 12). When ethyl
acetate or ethanol were used the conversions to adduct 3ax were
very low (Table 1, entries 7 and 8).
The study was then extended to the hydroxy-substituted-3-
cyanocoumarins 1b-e to determine the scope of the reaction
(Table 2).
To demonstrate the practical utility of our Diels-Alder
approach to 6a-cyano-tetrahydro-benzo[c]chromenones 3 in the
synthesis of cannabinoids, we first studied the conversion of
cycloadducts 3bx, 3cx and 3ex into the corresponding hydroxy-
The electron-donating hydroxy group in positions 5-8 of
coumarins 1b-e lowered the dienophilicity of coumarins 1b-e
toward dienes 2 and reduced their solubility in methylene
chloride. Thus, optimized reaction conditions for the reactions
of 1a only gave low yields of the corresponding adducts when
applied to the reactions of coumarin 1b with dienes 2 (Table 2,
entries 1 and 4). When acetone was used as solvent, the
cycloadditions of 1b and 1e with 2x occurred under homoge-
neous condition and gave the corresponding cycloadducts 3bx
and 3ex (Scheme 4) in satisfactory yields (60 and 75%,
respectively) (Table 2, entries 2 and 11). In the case of isoprene
(2y), the cycloadditions with 1b and 1e in acetone were always
totally regioselective and produced adducts 3by and 3ey in 60
and 65% yields, respectively (Table 2, entries 5 and 12). The
reaction of 1b with 2x and 2y in acetonitrile gave 65% yields
(Table 2, entries 3 and 6).
(7) Carnahan, J. C.; Closson, W. D.; Ganson, J. R.; Juckett, D. A.; Ouaal,
K. S. J. Am. Chem. Soc. 1976, 98, 2526–2531.
(8) The same reactions occur in 70% yield when performed in acetone
solution.
(9) (a) Crombie, L. Pure Appl. Chem. 1986, 58, 693–700. (b) Crombie, L. W.;
Crombie, M. L.; Firth, D. F. J. Chem. Soc., Perkin Trans. 1 1988, 1263–1270.
(c) Toyota, M.; Kinugawa, Y. Phytochemistry 1944, 37, 859–862. (d) Matsuda,
L. A.; Lolait, S. J.; Brownstein, M. J.; Young, A. C.; Bonner, T. I. Nature 1990,
346, 561–564. (e) Devane, W. A.; Hanus, L.; Breuer, A.; Pertwee, R. G.;
Stevenson, L. A.; Griffin, G.; Gibson, D.; Mandelbaum, A.; Etinger, A.;
Mechoulam, R. Science 1992, 258, 1946–1949. (f) Munro, S.; Thomas, K. L.;
Abu-Shaar, M. Nature 1993, 365, 61–65. (g) Mechoulam, R.; Hanus, L. Chem.
Phys. Lipids 2002, 121, 35–43. (h) Mechoulam, R.; Parker, L. A.; Gallily, R. J.
J. Clin. Pharmacol. 2002, 42, 11S–19S.
(10) (a) Tchilibon, S.; Mechoulam, R. Org. Lett. 2000, 2, 3301–3303. (b)
William, A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67, 8771–8782. (c)
Nadipuram, A. K.; Krishnamurthy, M.; Ferreira, A. M.; Li, W.; Moore, B. M.
Bioorg. Med. Chem. 2003, 11, 3121–3132. (d) Kobayashi, Y.; Takeuchi, A.;
Wang, Y.-G. Org. Lett. 2006, 8, 2699–2702. (e) Trost, B. M.; Dogra, K. Org.
Lett. 2007, 9, 861–863. (f) Song, Y.; Hwang, S.; Gong, P.; Kim, D.; Kim, S.
Org. Lett. 2008, 10, 269–271.
Under homogeneous conditions reactions between coumarins
1c and 1d with both dienes 2 gave low conversions (Table 2,
entries 7-10). This result is due to the strong deactivation of
J. Org. Chem. Vol. 74, No. 11, 2009 4313

Ballerini et al.
TABLE 3. Diels-Alder Reactions of Coumarin (1h) with 2,3-Dimethyl-1,3-butadiene (2x) and Isoprene (2y) under Atmospheric and 11 kbar
Pressure Conditions
entry
diene (eq.)
mediuma
P (kbar)
T (°C)
t (h)
product
yield (%)b
1
2
3
4
5
6
7
8
2x (4)
2x (4)
2y (3)
2y (3)
2y (7)
2y (7)
2y (4)
2y (4)
MeCN
CH2Cl2
H2O
11
11
55
55
20
16
2
6
2
5
24
24
3hx
3hx
3hy
4hy
3hy
4hy
3hy
3hy
70
68
30
25
31
22
80
60
Atm.
Atm.
Atm
Atm
11
150
150
150
150
55
H2O
SolFC
SolFC
MeCN
CH2Cl2
11
55
a Concn of coumarin 1h ) 0.1 M;. b Yield of isolated cycloadduct.
SCHEME 5. Synthesis of Hydroxy-substituted-tetrahydro-
benzo[c]chromenones 4 and 5
Finally, cycloadduct 3hy in aqueous solution of NaHCO3 was
heated at 150 °C for 2 h and produced the expected chromenone
4hy in 60% yield.5 Methylation of 4hy and subsequent
dehydratation to ∆6-cis-CBD 6hy and/or cyclization to (∆8-cis-
THC) 7hy (Scheme 6) have been reported in the literature.5
Structural Analysis. All of the 6a,7,10,10a-tetrahydro-6H-
benzo[c]chromen-6-ones 3, 4 and 5 prepared in this work are
new compounds except 3ay,6 4ax,2d 5ax,2d 4ay,2d 5ay2d and
5
1
4hy. However, for compounds 3ay and 4hy incomplete H
NMR characterization has been reported. The structure and
stereochemistry of the products were assigned by analyzing the
1H and 13C NMR spectra. The structures of all the new 6a-
cyano-benzo[c]chromenones 3 have been assigned based on the
comparison of their NMR data with those of similar 6a-
substituted-benzo[c]chromen-6-ones.2d
benzo[c]chromenones 4 and 5 (Scheme 5). Heating cycloadduct
3bx in an aqueous solution of NaHCO3 at 150 °C for 6 h
selectively gave cis-tetrahydrobenzo[c]chromenone 4bx in 55%
yield (Scheme 5). Similar to the results obtained in the
Diels-Alder reactions of 3-cyanocoumarin 1a in water (Table
1, entries 3 and 11), adducts 3cx and 3ex led to a mixture of
chromenones 4cx/5cx and 4ex/5ex in ratios of 1.8:1 and 2.2:1,
respectively (Scheme 5).
We then explored the cycloadditions of 5-hydroxy-7-pentyl-
3-cyanocoumarin (1h) with dienes 2x,y to exploit our Diels-Alder
approach to the synthesis of cis-tetrahydro-6H-benzo[c]chromen-
6-one 4hy, as precursor5 for the synthesis of cannabinoids ∆6-
cis-CBD 6hy and ∆8-cis-THC 7hy.
The assignment of cis/trans stereochemistry at the C(6a)-
C(10a) ring junction of compounds 4bx,cx,ex,hy and 5cx,ex
was based on the relevant JH,H coupling constant values. The
3
10.9-13.4 Hz and the 5.4-5.8 Hz measured for J10a,10R and
3J10a,10ꢀ respectively, revealed a pseudoaxial orientation of
H(10a) with respect to the cyclohexene ring in all the com-
3
pounds. Thus, in accord with the J6a,10a values previously
reported2d for 4ax,ay and 5ax,ay, the 5.5-5.8 Hz coupling
constant values between H(10a) and H(6a) for 4bx,cx,ex,hy
indicate their cis-relationship, whereas the 10.9 and 10.8 Hz
coupling constant values between H(10a) and H(6a) for 5cx
and 5ex respectively, indicate their trans stereochemistry (Table
4).
The cycloaddition of 1h with 2x in acetonitrile or methylene
chloride solutions occurred in good yields (70 and 68%,
respectively) under 11 kbar pressure at 55 °C (Table 3, entries
1 and 2).
The Diels-Alder cycloaddition between 1h and isoprene (2y)
was then studied in water and under SolFC at atmospheric
pressure and in organic solvent under high pressure. In aqueous
conditions, the cycloaddition of 1h with 2y at 150 °C for 2 h
(Table 3, entry 3) gave a low yield (30%) affording the
cycloadduct 3hy. When the reaction time was increased to 6 h
chromenone 4hy was obtained in 25% yield (Table 3, entry 4).
Similar results were obtained when this reaction was carried
out under SolFC at 150 °C for 2 and 5 h, respectively (Table 3,
entries 5 and 6). Previously, lactone 4hy was prepared from
isoprene (2y) and 3-carboxy-5-hydrox-7-pentylcoumarin in
xylene solution by Diels-Alder cycloaddition accompanied by
a decarboxylation reaction at 180 °C for 18 h.5 When the
reaction between coumarin 1h and isoprene (2y) was carried
out in acetonitrile, under 11 kbar pressure, cycloadduct 3hy was
regioselectively produced in good yield (80%) under mild
reaction temperature (55 °C) (Table 3, entry 7).
Conclusions
Even though hydroxy-substituted 3-cyano-coumarins 1b-e,h,
behave as poor dienophiles in [4 + 2] cycloaddition, under 11
kbar of pressure they react with 1,3-dienes 2x,y under milder
reaction temperature and without any metal catalyst to produce
6a-cyano-hydroxy-substituted benzo[c]chromenones 3 in good-
to-high yields. This protocol, is the first high-yielding synthetic
approach to this important class of heterocyclic compounds.
This approach has been applied to the synthesis hydroxy-
substituted-tetrahydro-benzo[c]chromenones 4 and 5, includ-
ing cis-1-hydroxy-9-methyl-3-pentyl-6a,7,10,10a-tetrahydro-
benzo[c]chromen-6-one(4hy), precursor of cannabinoids ∆6-cis-
CBD 6hy and ∆8-cis-THC 7hy, by performing a decyanation
reaction of the cycloadducts 3 in aqueous solution of NaHCO3.
4314 J. Org. Chem. Vol. 74, No. 11, 2009

Route to ∆6-Cis-Cannabidiol
SCHEME 6. Synthesis of ∆6-cis-CBD 6hy and ∆8-cis-THC 7hy
TABLE 4. 3JH,H Coupling Constant Values (Hz) of H(10a) of
mixture was purified by column chromatography on silica gel
followed by recrystallization, to give cycloadducts 3.
Compounds 4 and 5
3J6a,10a
3J10a,10R
3J10a,10ꢀ
3ax. White solid, mp 84-85 °C (n-exane/chloroform); IR (KBr)
compound
1
ν: 2241 (CN), 1782 (CdO) cm-1; H NMR (200 MHz, CDCl3) δ
4ax2d
4bx
4cx
5.5
5.6
5.5
5.5
5.0
11.0
11.3
10.9
10.9
10.9
11.5
13.0
12.3
13.4
11.8
5.5
5.6
5.5
5.5
5.9
5.8
5.4
5.6
5.6
5.5
1.65 (s, 6H, 2 CH3), 2.21 (dd broad, 1H, J ) 17.6, 8.6 Hz, H-10R),
2.48 (dd broad, 1H, J ) 17.6, 6.0 Hz, H-10ꢀ), 2.55 (d broad, 1H,
J ) 17.3 Hz, H-7R), 2.85 (d broad, 1H, J ) 17.3 Hz, H-7ꢀ), 3.45
(dd, 1H, J ) 8.6, 6.0 Hz, H-10a), 7.10-7.39 (m, 4H, H-1, H-2,
H-3, H-4); 13C NMR (50.3 MHz, CDCl3) δ 18.1, 18.5 (8-Me, 9-Me),
32.9, 34.4 (C-7, C-10), 37.6 (C-10a), 41.9 (C-6a), 116.8 (C-4), 117.3
(CN), 121.1, 123.1, 123.9 (C-8, C-9, C-10b), 125.4, 126.8 (C-2,
C-3), 129.2 (C-1), 150.0 (C-4a), 162.4 (C-6); MS, m/e (relative
intensity) 253 (M+, 45), 121 (15), 120 (100), 115 (15), 82 (83), 77
(17), 67 (70). Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N,
5.53. Found: C, 75.83; H, 5. 99; N, 5.51.
4ex
4ay2d
4hy
5.8
5ax2d
5ay2d
5cx
10.6
11.8
10.9
10.8
5ex
Considering that 3-cyano-hydroxy-substituted-coumarins 1
can be readily prepared by Knoevenagel condensation between
salicylic aldehydes and malonitrile,11by using water as reaction
medium, our proposed strategy to hydroxy-tetrahydro-benzo[c]-
chromen-6-ones nucleous 3, 4 and 5 is also a new environ-
mentally friendly synthetic route to non natural cannabinoids
6 and 7.
3ay. White solid, mp 97-98 °C (n-exane/ethyl acetate) (lit.7 mp
93-95 °C); IR (KBr) ν: 2241 (CN), 1787 (CdO) cm-1; 1H NMR
(200 MHz, CDCl3) δ 1.66 (s, 3H, CH3), 2.17 (dd broad, 1H, J )
18.3, 8.0 Hz, H-10R), 2.36-2.64 (m, 2H, H-7R, H-10ꢀ), 2.85 (dddd,
1H, J ) 17.6, 7.6, 3.7, 1.9 Hz, H-7ꢀ), 3.47 (dd, 1H, J ) 8.0, 6.0
Hz, H-10a), 5.30 (s broad, 1H, H-8), 7.00-7.40 (m, 4H, H-1, H-2,
H-3, H-4); 13C NMR (50.3 MHz, CDCl3) δ 23.0 (9-Me), 29.1 (C-
10), 31.1 (C-7), 37.3 (C-10a), 41.0 (C-6a), 115.8, 116.9 (C-4, C-8),
117.3 (CN), 123.6 (C-10b), 125.5, 126.7 (C-2, C-3), 129.4 (C-1),
131.4 (C-9), 150.1 (C-4a), 162.6 (C-6); MS, m/e (relative intensity)
239 (M+, 97), 210 (24), 172 (16), 120 (100), 77 (13), 68 (75). Anal.
Calcd for C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C, 75.39;
H, 5. 45; N, 5.83.
Experimental Section
General Procedure for the Diels-Alder Reaction of 3-Cy-
anocoumarins 1a-h with Dienes 2x,y. The cycloadditions of 1
with 2 were accomplished (A) in water, toluene and SolFC at
normal pressure and (B) under 11 kbar pressure conditions. Details
are listed in Tables 1-3.
Conditions (A). Diene 2 (3 or 4 equiv) and few crystals of
hydroquinone (1-2 mg) were added to a metal reactor containing
coumarin 1 (0.3 mmol) and 3 mL of solvent (0.1 M). In the case
of experiments without solvent (SolFC), diene 2 (7 or 10 equiv)
and 1-2 mg of hydroquinone were added directly to coumarin 1.
The reactor was sealed and poured into an oil bath under magnetic
stirring at the indicated reaction temperature and time. After cooling,
the mixture was evaporated under vacuo and the residue was
purified by column chromatography on silica gel followed by
recrystallization.
Conditions (B). A solution of compound 1 (1.5 mmol), diene 2
(4 molar equiv) and a few crystals of hydroquinone in 10 mL of
the appropriate solvent were placed in a 15 mL Teflon vial that
was then filled with the solvent. The vial was closed and kept at
11 kbar at the indicated temperature for the appropriate time. After
depressurizing, the solvent was removed in vacuo. The crude
3bx. White solid, mp 173-174 °C (n-exane/ethyl acetate); IR
1
(CHCl3) ν: 2242 (CN), 1780 (CdO) cm-1; H NMR [400 MHz,
(CD3)2CO] δ 1.62 (s, 3H, CH3), 1.72 (s, 3H, CH3), 1.84 (m broad,
1H, H-10R), 2.41 (dd, 1H, J ) 18.2, 6.2 Hz, H-10ꢀ), 2.80 (d broad,
1H, J ) 17.6 Hz, H-7R), 3.05 (d broad, 1H, J ) 17.6 Hz, H-7ꢀ),
3.85 (dd, 1H, J ) 11.4, 6.2 Hz, H-10a), 6.69 (dd, 1H, J ) 8.2, 0.9
Hz, H-2), 6.83 (d, 1H, J ) 8.2 Hz, H-4), 7.22 (t, 1H, J ) 8.2 Hz,
H-3), 9.26 (s broad, 1H, OH); 13C NMR [100.6 MHz, (CD3)2CO]
δ 17.5, 17.6 (8-Me, 9-Me), 33.0 (C-10a), 33.3, 35.1 (C-7, C-10),
41.1 (C-6a), 107.7, 112.01 (C-2, C-4), 113.1 (C-10b), 117.5 (CN),
121.4, 123.0 (C-8, C-9), 129.3 (C-3), 151.4 (C-4a), 154.5 (C-1),
162.1 (C-6); MS, m/e (relative intensity) 269 (M+, 79), 226 (12),
188 (15), 159 (10), 136 (873), 82 (100), 67 (54). Anal. Calcd for
C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C, 70.83; H, 5. 99;
N, 5.31.
1
3by. Oil, IR (KBr) ν: 1776 (CdO) cm-1; H NMR [400 MHz,
(CD3)2CO] δ 1.67 (s, 3H, CH3), 1.83 (m broad, 1H, H-10R), 2.45
(dd, 1H, J ) 17.8, 5.8 Hz, H-10ꢀ), 2.80 (d broad, 1H, J ) 18.4
Hz, H-7ꢀ), 3.19 (d broad, 1H, J ) 18.4 Hz, H-7ꢀ), 3.90 (dd, 1H,
J ) 11.5, 6.2 Hz, H-10a), 5.45 (s broad, 1H, H-8),), 6.69 (d, 1H,
J ) 9.2 Hz, H-2), 6.84 (d, 1H, J ) 9.2 Hz, H-4), 7.24 (t, 1H, J )
8.2 Hz, H-3),), 9.26 (s broad, 1H, OH); 13C NMR [100.6 MHz,
(11) Brufola, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles 1996,
43, 1257–1266.
J. Org. Chem. Vol. 74, No. 11, 2009 4315

Ballerini et al.
(CD3)2CO] δ 22.9 (9-Me), 30.7 (C-10), 32.7 (C-7), 33.8 (C-10a),
41.2 (C-6a), 108.7, 113.0 (C-2, C-4), 114.2 (C-10b), 117.2 (C-8),
118.6 (CN), 130.3 (C-3), 132.2 (C-9), 152.3 (C-4a), 155.4 (C-1),
162.6 (C-6); MS, m/e (relative intensity) 255 (M+, 100), 226 (10),
212 (10), 187 (55), 159 (20), 136 (46), 68 (77). Anal. Calcd for
C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.39; H, 5. 45;
N, 5.63.
(CD3)2CO] δ 1.76 (s, 3H, CH3), 2.45 (dd broad, 1H, J ) 18.0, 6.6
Hz, H-10R), 2.64 (m, 2H, H-10ꢀ, H-7R), 2.73 (d broad, 1H,, J )
16.5 Hz, H-7ꢀ), 3.31 (s, 3H, SCH3), 3.98 (t, 1H, J ) 6.4 Hz, H-10a),
5.38 (s broad, 1H, H-8), 7.29 (d, 1H, J ) 8.8 Hz, H-4), 7.42 (dd,
1H, J ) 8.8, 2.7 Hz, H-3), 7.49 (d, 1H, J ) 2.7 Hz, H-1); 13C
NMR [100.6 MHz, (CD3)2CO] δ 23.2 (9-Me), 29.6, 30.7 (C-7,
C-10), 37.3 (OSO2CH3), 37.6 (C-10a), 42.0 (C-6a), 116.7 (C-4),
118.2 (CN), 119.1, 122.1, 124.2 (C-1, C-3, C-8), 126.7, 132.6 (C-
9, C-10b), 147.4 (C-4a), 149.9 (C-2), 163.4 (C-6); MS, m/e (relative
intensity) 333 (M+, 100), 254 (78), 226 (47), 214 (59), 199 (52),
186 (23), 128 (18), 68 (28). Anal. Calcd for C16H15NO5S: C, 57.65;
H, 4.54; N, 4.20; S, 9.62. Found: C, 57.77; H, 4. 65; N, 4.31; S,
9.35.
3cx. White solid, mp 174-175 °C (n-exane/ethyl acetate); IR
1
(CHCl3) ν: 2242 (CN), 1772 (CdO) cm-1; H NMR [400 MHz,
(CD3)2CO] δ 1.65 (s, 3H, CH3), 1.68 (s, 3H, CH3), 2.23 (dd broad,
1H, J ) 18.7, 7.9 H-10R), 2.53 (dd broad, 1H, J ) 18.7, 6.1 Hz,
H-10ꢀ), 2.56 (d, 1H, J ) 16.6 Hz, H-7R), 2.74 (d, 1H, J ) 16.6
Hz, H-7ꢀ), 3.67 (dd, 1H, J ) 7.9, 6.1 Hz, H-10a), 6.85 (dd, 1H, J
) 8.6, 2.8 Hz, H-3), 6.88 (d, 1H, J ) 2.8 Hz, H-1), 7.00 (d, 1H,
J ) 8.6 Hz, H-3), 8.62 (s broad, 1H, OH); 13C NMR [100.6 MHz,
(CD3)2CO] δ 17.5, 17.9 (8-Me, 9-Me), 32.5, 34.4 (C-7, C-10),
37.2 (C-10a), 42.2 (C-6a), 113.5 (C-3), 115.5 (C-1), 117.5 (C-4),
117.7 (CN), 121.2, 1234, 125.6 (C-8, C-9, C-10b), 143.4 (C-4a),
154.7 (C-2), 162.9 (C-6); MS, m/e (relative intensity) 269 (M+,
52), 240 (20), 226 (11), 187 (28), 159 (9), 136 (100), 82 (23). Anal.
Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C, 70.95;
H, 5. 89; N, 5.42.
3gx. Pale-yellow oil; IR (CHCl3) ν: 2244 (CN), 1787 (CdO)
1
cm-1; H NMR [400 MHz, (CD3)2CO] δ 1.64 (s, 3H, CH3), 1.70
(s, 3H, CH3), 2.39 (m broad, 1H, H-10R), 2.59 (m, 2H, H-10ꢀ,
H-7R), 2.72 (d broad, 1H, J ) 18.3 Hz, H-7ꢀ), 3.36 (s, 3H,
OSO2CH3), 3.88 (t, 1H, J ) 6.7 Hz, H-10a), 7.22 (d, 1H, J ) 2.4
Hz, H-4), 7.26 (dd, 1H, J ) 8.4, 2.4 Hz, H-2), 7.58 (d, 1H, J ) 8.4
Hz, H-1); 13C NMR [100.6 MHz, (CD3)2CO] δ 17.4, 17.8 (8-Me,
9-Me), 31.8, 33.9 (C-7, C-10), 36.4 (C-10a), 36.9 (OSO2CH3), 42.1
(C-6a), 111.1 (C-4), 117.3 (CN), 119.1 (C-2), 121.0, 123.3 (C-8,
C-9, C-10b), 128.5 (C-1), 149.5 (C-4a), 150.8 (C-3), 162.2 (C-6);
MS, m/e (relative intensity) 347 (M+, 24), 214 (94), 187 (13), 135
(6), 82 (100), 67 (42). Anal. Calcd for C17H17NO5S: C, 58.78; H,
4.93; N, 4.03; S, 9.23. Found: C, 59.03; H, 5. 19; N, 4.13; S, 9.15.
3gy. Pale-yellow solid; mp 134-135 °C (n-exane/ethyl acetate);
IR (CHCl3) ν: 2244 (CN), 1789 (CdO) cm-1; 1H NMR [400 MHz,
(CD3)2CO] δ 1.76 (s, 3H, CH3), 2.46 (dd broad, 1H, J ) 18.3, 6.1
Hz, H-10R), 2.61 (d broad, 2H, J ) 17.3 Hz, H-10ꢀ, H-7R), 2.71
(d broad, 1H, J ) 15.7 Hz, H-7ꢀ), 3.36 (s, 3H, OSO2CH3), 3.97 (t,
1H, J ) 6.1 Hz, H-10a), 5.38 (s broad, 1H, H-8), 7.23 (d, 1H, J )
2.3 Hz, H-4), 7.27 (dd, 1H, J ) 8.4, 2.3 Hz, H-2), 7.60 (d, 1H, J
) 8.4 Hz, H-1); 13C NMR [100.6 MHz, (CD3)2CO] δ 22.4 (9-Me),
28.8, 29.9 (C-7, C-10), 36.2 (C-10a), 37.0 (OSO2CH3), 41.4 (C-
6a), 111.2 (C-4), 115.8 (C-2), 117.4 (CN), 119.3 (C-8), 123.1 (C-
10b), 128.5 (C-1), 131.7 (C-9), 149.7 (C-4a), 151.0 (C-3), 162.4
(C-6); MS, m/e (relative intensity) 333 (M+, 59), 265 (26), 214
(59), 187 (64), 68 (100). Anal. Calcd for C16H15NO5S: C, 57.65;
H, 4.54; N, 4.20; S, 9.62. Found: C, 57.77; H, 4. 65; N, 4.31; S,
9.35.
3ex. White solid, mp 141-142 °C (n-exane/ethyl acetate); IR
1
(CHCl3) ν: 2242 (CN), 1778 (CdO) cm-1; H NMR [400 MHz,
(CD3)2CO] δ 1.65 (s, 3H, CH3), 1.67 (s, 3H, CH3), 2.25 (dd broad,
1H, 18.3, 8.0 Hz, H-10R), 2.52 (dd broad, 1H, J ) 18.3, 6.1 Hz,
H-10ꢀ), 2.59 (d, 1H, J ) 17.3 Hz, H-7R), 2.77 (d, 1H, J ) 17.3
Hz, H-7ꢀ), 3.72 (dd, 1H, J ) 8.0, 6.1 Hz, H-10a), 6.89 (dd, 1H, J
) 7.6, 1.5 Hz, H-3), 6.97 (dd, 1H, J ) 8.2, 1.5 Hz, H-1), 7.08 (t,
1H, J ) 8.1 Hz, H-2), 8.80 (s broad, 1H, OH); 13C NMR [100.6
MHz, (CD3)2CO] δ 17.5, 17.9 (8-Me, 9-Me), 32.7, 34.4 (C-7, C-10),
37.4 (C-10a) 42.2 (C-6a), 116.8, 117.5 (C-1, C-3), 117.6 (CN),
121.1, 123.5, (C-8, C-9), 125.6 (C-2), 125.7 (C-10b), 138.4 (C-
4a), 144.9 (C-4), 162.4 (C-6); MS, m/e (relative intensity) 269 (M+,
71), 240 (18), 226 (29), 187 (13), 136 (100), 82 (39), 67 (23). Anal.
Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C, 71.73;
H, 5. 29; N, 5.15.
3ey. White solid, mp 190-191 °C (n-exane/ethyl acetate), IR
(CHCl3) ν: 1775 (CdO) cm-1; 1H NMR [400 MHz, (CD3)2CO] δ
1.73 (s, 3H, CH3), 2.30 (dd broad, 1H, J ) 18.3, 7.4 Hz H-10R),
2.54 (dd broad, 1H, J ) 18.3, 6.0 Hz, H-10ꢀ), 2.62 (d broad, 1H,
J ) 17.6 Hz, H-7ꢀ), 2.81 (d broad, 1H, J ) 18.4 Hz, H-7ꢀ), 3.80
(dd, 1H, J ) 7.4, 6.0 Hz, H-10a), 5.37 (s broad, 1H, H-8),), 6.90
(dd, 1H, J ) 8.9, 1.5 Hz, H-3), 6.98 (dd, 1H, J ) 8.2, 1.5 Hz,
H-1), 7.09 (t, 1H, J ) 7.9 Hz, H-2), 8.77 (s broad, 1H, OH); 13C
NMR [100.6 MHz, (CD3)2CO] δ 23.2 (9-Me), 30.4, 31.7 (C-7,
C-10), 38.0 (C-10a), 42.2 (C-6a), 116.8, 117.7, 118.2 (C-1, C-3,
C-8), 118.6 (CN), 126.4 (C-10b), 126.6 (C-2), 132.7 (C-9), 139.1
(C-4a), 145.8 (C-4), 163.2 (C-6); MS, m/e (relative intensity) 255
(M+, 100), 226 (35), 212 (32), 187 (39), 159 (15), 136 (84), 68
(21). Anal. Calcd for C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found:
C, 70.22; H, 5. 11; N, 5.48.
3fx. Pale-yellow solid, mp 112-113 °C (n-exane/ethyl acetate);
IR (CHCl3) ν: 2244 (CN), 1784 (CdO) cm-1; 1H NMR [400 MHz,
(CD3)2CO] δ 1.64(s, 3H, CH3), 1.70 (s, 3H, CH3), 2.38 (dd broad,
1H, J ) 18.1, 6.7 Hz, H-10R), 2.62 (m, 2H, H-10ꢀ, H-7R), 2.70 (d
broad, 1H, J ) 17.3 Hz, H-7ꢀ), 3.31 (s, 3H, SCH3), 3.90 (t, 1H, J
) 6.7 Hz, H-10a), 7.29 (d, 1H, J ) 8.8 Hz, H-4), 7.42 (dd, 1H, J
) 8.8, 2.8 Hz, H-3), 7.47 (d, 1H, J ) 2.8 Hz, H-1); 13C NMR
[100.6 MHz, (CD3)2CO] δ 18.3, 18.7 (8-Me, 9-Me), 32.6, 34.9 (C-
7, C-10), 37.5 (OSO2CH3), 37.6 (C-10a), 42.9 (C-6a), 118.2 (CN),
119.1 (C-4), 122.0, 124.2, 126.9 (C-8, C-9, C-10b), 122.1 (C-3),
124.1 (C-1), 147.3 (C-4a), 149.9 (C-2), 163.2 (C-6); MS, m/e
(relative intensity) 347 (M+, 44), 268 (21), 240 (17), 214 (100),
135 (26), 82 (52), 79 (12), 67 (25). Anal. Calcd for C17H17NO5S:
C, 58.78; H, 4.93; N, 4.03; S, 9.23. Found: C, 58.83; H, 5. 09; N,
4.22; S, 9.33.
3hx. Oil; IR (KBr) ν: 2260 (CN), 1780 (CdO) cm-1; 1H NMR
[200 MHz, (CDCl3] δ 0.89 (s, 3H, CH3), 1.10-1.45 (m, 4H,
CH2CH2), 1.45-1.75 (m, 2H CH2), 1.59 (s, 3H, CH3), 1.71 (s, 3H,
CH3), 1.86 (dd broad, 1H, J ) 18.3, 11.4 Hz H-10R), 2.39 (dd,
1H, J ) 18.3, 6.2 Hz, H-10ꢀ), 2.52 (t, 2H, J ) 7.3 Hz, ArCH2),
2.66 (d broad, 1H, J ) 17.5 Hz, H-7R), 3.14 (d broad, 1H, J )
17.5 Hz, H-7ꢀ), 3.72 (dd, 1H, J ) 11.4, 6.2 Hz, H-10a), 5.75 (s
broad, 1H, OH), 6.45 (d, 1H, J ) 1.3 Hz, H-4), 6.55 (d, 1H, J )
1.3 Hz, H-2); 13C NMR (50.3 MHz, CHCl3) δ 13.9 (C-5′), 18.3,
18.6 (8-Me, 9-Me), 22.4 (C-4′), 30.5, 31.4 (C-2′, C-3′), 33.4 (C-
10a), 33.8 (C-10), 35.7 (C-1′, C-7), 41.3 (C-6a), 109.2 (C-4), 110.3
(C-10b), 112.2 (C-2), 117.7 (CN), 121.4, 123.4 (C-8, C-9), 145.2
(C-3), 151.2 (C-4a), 152.6 (C-1), 162.5 (C-6); MS, m/e (relative
intensity) 339 (M+, 39), 338 (31), 258 (20), 206 (26), 201 (56), 82
(100), 77 (9), 67 (33). Anal. Calcd for C21H25NO3: C, 74.31; H,
7.42; N, 4.13. Found: C, 74.64; H, 7. 99; N, 4.31.
3hy. White solid; mp 139-140 °C (n-exane/ethyl acetate); IR
1
(KBr) ν: 2400 (CN), 1772 (CdO) cm-1; H NMR [200 MHz,
(CDCl3] δ 0.94 (s, 3H, CH3), 1.10-1.50 (m, 4H, CH2CH2),
1.50-2.00 (m, 3H, CH2, H-10R), 1.66 (s, 3H, CH3), 2.41 (dd broad,
1H, J ) 18.1, 6.2 Hz, H-10ꢀ), 2.54 (t, 2H, J ) 7.3 Hz, ArCH2),
2.68 (d broad, 1H, J ) 17.9 Hz, H-7R), 3.29 (d broad, 1H, J )
17.9 Hz, H-7ꢀ), 3.76 (dd, 1H, J ) 11.4, 6.2 Hz, H-10a), 5.40 (m,
1H, H-8), 5.64 (s broad, 1H, OH), 6.47 (d, 1H, J ) 1.3 Hz, H-4),
6.57 (d, 1H, J ) 1.3 Hz, H-2); 13C NMR (50.3 MHz, CHCl3) δ
13.9 (C-5′), 22.4 (C-4′), 22.8 (9-Me), 30.2, 30.5, 31.4, 32.3 (C-2′,
C-3′, C-7, C-10), 33.1 (C-10a), 35.6 (C-1′), 40.4 (C-6a), 109.0 (C-
4), 110.2 (C-10b), 112.3 (C-2), 116.0 (C-8), 117.7 (CN), 131.6 (C-
3fy. Pale-yellow solid, mp 100-101 °C (n-exane/ethyl acetate);
IR (CHCl3) ν: 2244 (CN), 1782 (CdO) cm-1; 1H NMR [400 MHz,
4316 J. Org. Chem. Vol. 74, No. 11, 2009

Route to ∆6-Cis-Cannabidiol
9), 145.2 (C-3), 151.1 (C-4a), 152.8 (C-1), 162.4 (C-6); MS, m/e
(relative intensity) 325 (M+, 38), 269 (27), 257 (23), 201 (100),
173 (6), 150 (8), 77 (10), 68 (37). Anal. Calcd for C20H23NO3: C,
73.82; H, 7.12; N, 4.30. Found: C, 74.04; H, 6. 99; N, 4.31.
General Procedure for the Decyanation Reaction of 3bx,cx,
ex,hy. Cycloadduct 3 (0.15 mmol) was added to a 0.05 M aqueous
solution of NaHCO3 (3 mL) in a metal reactor and the mixture
was heated at 150 °C (6 h for 3bx,cx,ex and 2 h for 3hy) under
stirring. After cooling to room temperature, the mixture was then
transferred into a separatory funnel and extracted with ethyl acetate.
The combined organic layers were dried (Na2SO4) and evaporated
under reduced pressure. The residue was purified by column
cromatography (silica gel, 4:1 petroleum ether-ethyl acetate), to
give tetrahydro-benzo[c]chromen-6-ones 4 and 5.
1.60 (s, 3H, CH3), 1.69 (s, 3H, CH3), 1.90-2.40 (m, 3H, H-7R,
H-10R, H-10ꢀ), 2.68 (d broad, 1H, J ) 17.6 Hz, H-7ꢀ), 3.02 (t
broad, 1H, J ) 5.5 Hz, H-6a), 3.13 (ddd, 1H, J ) 10.9, 5.5, 5.5
Hz, H-10a), 5.90 (s broad, 1H, OH), 6.70 (dd, 1H, J ) 7.3, 1.8
Hz, H-3), 6.88 (dd, 1H, J ) 8.2, 1.8 Hz, H-1), 6.98 (dd, 1H, J )
8.2, 7.3 Hz, H-2); 13C NMR [50.3 MHz, CDCl3] δ 18.7, 18.9 (8-
Me, 9-Me), 30.0 (C-10), 34.6 (C-6a), 35.1 (C-7), 38.8 (C-10a),
115.0, 117.9 (C-1, C-3), 123.3, 123.5 (C-8, C-9), 124.7 (C-2), 128.9
(C-10b), 138.4 (C-4a), 143.8 (C-4), 169.5 (C-6); MS, m/e (relative
intensity) 244 (M+, 46), 216 (19), 162 (100), 134 (15), 94 (10), 77
(12). Anal. Calcd for C15H16O3: C, 73.75; H, 6.60. Found: C, 73.68;
H, 6. 51.
5ex. White solid, mp 192-194 °C (CHCl3); IR (KBr) ν: 3555
(OH), 1762 (CdO) cm-1; 1H NMR (200 MHz, CDCl3)] δ 1.72 (s,
6H, 2 CH3), 2.10-2.75 (m, 5H, H-7R, H-7ꢀ, H-6a, H-10R, H-10ꢀ),
3.01 (ddd, 1H, J ) 11.8, 10.8, 5.5 Hz, H-10a), 5.83 (s broad, 1H,
OH), 6.78 (d, 1H, J ) 7.5 Hz, H-3), 6.91 (d, 1H, J ) 7.7 Hz,
H-1), 7.04 (t, 1H, J ) 7.6 Hz, H-2); 13C NMR [50.3 MHz, CDCl3]
δ 18.7, 18.8 (8-Me, 9-Me), 32.4 (C-10), 33.4 (C-6a), 36.0 (C-7),
39.6 (C-10a), 115.0, 116.4 (C-1, C-3), 123.6, 124.4 (C-8, C-9),
124.8 (C-2), 127.2 (C-10b), 138.5 (C-4a), 143.7 (C-4), 169.6 (C-
6); MS, m/e (relative intensity) 244 (M+, 46), 216 (19), 162 (100),
134 (15), 94 (10), 77 (12). Anal. Calcd for C15H16O3: C, 73.75; H,
6.60. Found: C, 73.70; H, 6. 68.
4bx. White solid, mp 208-210 °C (n-exane/ethyl acetate); IR
1
(KBr) ν: 3270 (OH), 1764 (CdO) cm-1; H NMR (200 MHz,
(CD3)2CO)] δ 1.58 (s, 3H, CH3), 1.67 (s, 3H, CH3), 1.75 (m, 1H,
H-10R), 2.10-2.45 (m, 2H, H-7R, H-10ꢀ), 2.66 (d broad, 1H, J )
17.8 Hz, H-7ꢀ), 3.03 (t broad, 1H, J ) 5.6 Hz, H-6a), 3.46 (ddd,
1H, J ) 11.3, 5.6, 5.6 Hz, H-10a), 6.50 (dd, 1H, J ) 8.1, 1.1 Hz,
H-4), 6.68 (dd, 1H, J ) 8.1, 1.1 Hz, H-2), 7.06 (t, 1H, J ) 8.1 Hz,
H-3), 8.89 (s broad, 1H, OH); 13C NMR [50.3 MHz, (CD3)2CO] δ
18.0, 18.1 (8-Me, 9-Me), 28.7 (C-10a), 30.0 (C-10), 33.6 (C-7),
38.0 (C-6a), 107.6, 110.9 (C-2, C-4), 116.0 (C-10b), 123.0, 123.4
(C-8, C-9), 128.0 (C-3), 146.0 (C-4a), 154.2 (C-1), 169.6 (C-6);
MS, m/e (relative intensity) 244 (M+, 45), 201 (21), 162 (100),
134 (25), 77 (16), 67 (70). Anal. Calcd for C15H16O3: C, 73.75; H,
6.60; N, 5.20. Found: C, 73.80; H, 5. 21.
4hy. White solid, mp 112-113 °C (lit.6 115-117 (n-hexane/
1
ethyl acetate); IR (CHCl3) ν: 3270 (OH), 1754 (CdO) cm-1; H
NMR [400 MHz, (CD3)2CO)] δ 0.89 (t, 3H, J ) 6.9 Hz, CH3),
1.29-1.35 (m, 4H, CH2CH2), 1.57-1.72 (m, 3H, CH2, H-10R),
1.63 (s, 3H, CH3), 2.22 (dd, 1H, J ) 5.8, 17.4, H-10ꢀ), 2.36 (d
broad, 1H, H-7R), 2.51 (t broad, 2H, J ) 7.6 HZ, ArCH2), 2.78 (d
broad, 1H, J ) 19.8 Hz, H-7ꢀ), 3.02 (t broad, 1H, J ) 5.8 Hz,
H-6a), 3.46 (ddd, 1H, J ) 11.5, 5.8, 5.8 Hz, H-10a), 5.41 (s broad,
1H, H-8), 6.40 (d, 1H, J ) 2.6 Hz, H-4), 6.68 (d, 1H, J ) 2.6 Hz,
H-2), 9.07 (s broad, 1H, OH); 13C NMR [100.6 MHz, (CD3)2CO]
δ 13.4 (C-5′), 22.2 (C-4′), 22.6 (9-Me), 24.0 (C-3′), 28.2 (C-10a),
30.7, 31.2, 32.2, 35.3 (C-1′, C-2′, C-7, C-10), 36.9 (C-6a), 107.6
(C-4), 110.8 (C-2), 113.1 (C-10b), 118.8 (C-8), 131.2 (C-9), 143.4
(C-3), 152.2 (C-4a), 153.7 (C-1), 169.6 (C-6); MS, m/e (relative
intensity) 300 (M+, 29), 232 (68), 190 (18), 176 (100), 147 (7), 91
(7). Anal. Calcd for C19H24O3: C, 75.97; H, 8.05. Found: C, 75.88;
H, 8. 13.
4cx. White solid, mp 155-156 °C (diethyl ether); IR (KBr) ν:
1
3596 (OH), 1758 (CdO) cm-1; H NMR (200 MHz, CDCl3)] δ
1.58 (s, 3H, CH3), 1.66 (s, 3H, CH3), 1.87-2.37 (m, 3H, H-7R,
H-10R, H-10ꢀ), 2.65 (d broad, 1H, J ) 17.7 Hz, H-7ꢀ), 2.97 (t
broad, 1H, J ) 5.5 Hz, H-6a), 3.04 (ddd, 1H, J ) 10.9, 5.5, 5.5
Hz, H-10a), 6.50 (s broad, 1H, OH), 6.71 (s broad, 1H, H-1), 6.74
(dd, 1H, J ) 8.7, 2.8 Hz, H-3), 6.88 (d, 1H, J ) 8.7 Hz, H-4); 13
C
NMR [50.3 MHz, CDCl3] δ 18.7, 18.9 (8-Me, 9-Me), 29.9 (C-10),
34.5 (C-6a), 34.9 (C-7), 38.5 (C-10a), 113.6, 114.7, 117.6 (C-1,
C-3, C-4), 123.2, 123.6 (C-8, C-9), 129.2 (C-10b), 144.5 (C-4a),
152.6 (C-2), 171.7 (C-6); MS, m/e (relative intensity) 244 (M+,
36), 216 (12), 162 (100), 134 (30), 94 (7), 77 (10). Anal. Calcd for
C15H16O3: C, 73.75; H, 6.60. Found: C, 73.80; H, 6. 55.
5cx. White solid, mp 195-196 °C (diethyl ether); IR (KBr) ν:
1
3596 (OH), 1758 (CdO) cm-1; H NMR [200 MHz, (CD3)2CO)]
δ 1.69 (s, 6H, 2 CH3), 2.00-2.75 (m, 5H, H-7R, H-7ꢀ, H-6a,
H-10R, H-10ꢀ), 2.94 (ddd, 1H, J ) 13.4, 10.9, 5.6 Hz, H-10a),
6.67-6.87 (m, 3H, H-1, H-3, H-4); 13C NMR [50.3 MHz,
(CD3)2CO3] δ 18.9 (8-Me, 9-Me), 33.3 (C-10), 34.0 (C-6a), 36.6
(C-7), 39.8 (C-10a), 112.9, 115.3, 117.7 (C-1, C-3, C-4), 124.4,
125.0 (C-8, C-9), 128.8 (C-10b), 145.1 (C-4a), 154.9 (C-2), 170.6
(C-6); MS, m/e (relative intensity) 244 (M+, 36), 216 (12), 162
(100), 134 (30), 94 (7), 77 (10). Anal. Calcd for C15H16O3: C, 73.75;
H, 6.60. Found: C, 73.68; H, 6.66.
Acknowledgment. We thank the Fondazione Cassa Ris-
parmio Perugia and the Ministero dell’Istruzione dell’Universita`
e della Ricerca (MIUR) for financial support.
Supporting Information Available: General experimental
procedures and analytical data for all new compounds, as well
as 1H and 13C NMR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
4ex. White solid, mp 155-156 °C (diethyl ether); IR (KBr) ν:
1
3555 (OH), 1762 (CdO) cm-1; H NMR (200 MHz, CDCl3)] δ
JO9005365
J. Org. Chem. Vol. 74, No. 11, 2009 4317