High-pressure-promoted Diels - Alder approach to biaryls: Application to the synthesis of the cannabinols family

Article abstract of DOI:10.1021/jo301203k

Diels - Alder reactions of a range of 1-(alkoxy/alkyl/halogen-substituted phenyl)buta-1,3-dienes with methyl propiolate carried out in a green ethanolic medium under 9 kbar pressure were investigated. The use of high pressure as activating method of the D

Full text of DOI:10.1021/jo301203k

Article
pubs.acs.org/joc
High-Pressure-Promoted Diels−Alder Approach to Biaryls:
Application to the Synthesis of the Cannabinols Family
Lucio Minuti,*,† Andrea Temperini,‡ and Eleonora Ballerini†
†Dipartimento di Chimica, Universita
̀
degli Studi di Perugia, via Elce di Sotto 8, 06123 Perugia, Italy
‡Dipartimento di Chimica e Tecnologia del Farmaco, Universita
̀
degli Studi di Perugia, via del Liceo 1, 06123 Perugia, Italy
S
* Supporting Information
ABSTRACT: Diels−Alder reactions of a range of 1-(alkoxy/alkyl/halogen-substituted phenyl)buta-1,3-dienes with methyl
propiolate carried out in a green ethanolic medium under 9 kbar pressure were investigated. The use of high pressure as
activating method of the Diels−Alder reactions allows efficient and regioselective generation of a series of cyclohexadienyl-
benzene cycloadducts that are oxidized to the corresponding biaryls. The alkoxy/alkyl/halogen-substituted biaryls produced are
useful precursors for accessing substituted 6H-benzo[c]chromen-6-ones and the cannabinols family.
for a metallic catalyst and/or high temperatures.12 Furthermore,
INTRODUCTION
■
this technique is also energy-economical because the energy
input is limited to the compression step at the onset of the
reaction, in sharp contrast with a classical heating that triggers
continuous energy consumption until completion.12 Instead,
the uncatalyzed synthesis of this class of compounds remains
little investigated,13 and to our knowledge, an energy-saving
high-pressure12 activation method for biaryls has never been
reported.
Although the Diels−Alder reaction might represent an
efficient method for the synthesis of functionalized biaryls,
there are only a few synthetic approaches to biaryls in the
literature that are based on the Diels−Alder reaction.11,14
Recently, the Carter group11 described a rapid and efficient
synthesis of a wide range of tetra-ortho-substituted biaryl
compounds utilizing the Diels−Alder reaction of phenyl-
acetylenes as dienophiles with oxygenated dienes.
One particular attraction to the powerful Carter’s strategy is
the ability to construct biaryl compounds possessing four
different atoms (N, Cl/Br, O and P) at the four ortho positions
that would not be readily accessible from the traditional
methods. However, because of the low reactivity of the alkyne
triple bond as a dienophile, the cycloaddition reactions required
harsh reaction conditions (80−155 °C), and they were only
successful using phenylacetylenes that have an electron-
withdrawing ortho-nitrophenyl moiety. This thus only allowed
the access of nitro-substituted biaryl compounds, strongly
limiting the flexibility of this approach.11
Biaryls represent a key structural motif in a wide variety of
natural products1 and pharmacologically active drugs,2 as well
as in high-performance molecules like organic semiconductors,
liquid crystals,3 and chiral auxiliaries.4 Thus, the construction of
the biaryl structure continues to generate considerable synthetic
attention. One of the main challenges in the construction of
this structural motif involves the palladium-catalyzed, cross-
coupling reaction of aryl halides with organometallics,5 such as
tin (Stille coupling),6 boron derivatives (Suzuki−Miyaura
coupling),7 and to a lesser extent, organozinc (Negishi
coupling), organomagnesium (Kumada coupling), and organo-
silicon (Hiyama) reagents.8 However, documented reports of
the significant cost of the necessary coupling partners (e.g., aryl
halide or boronic acid) for traditional metal-mediated
approaches to highly functionalized biaryls, and the limited
availability of the aryl halides and/or aryl metal species, have
made alternate strategies more attractive.9,10 Furthermore, the
methods reported are sometimes not attractive, as they can be
environmentally unsafe because of harsh reaction conditions
and toxic catalysts.9 Thus, considering also the profound need
to have this class of compounds as “ultra pure” material for
modern electronic application (e.g., metals and residual
halogens need to be in the low ppm to ppb levels), the
development of a nonmetal-mediated method for the
construction of biaryl compounds11 is desiderable. Relatedly,
high pressure technology could be a useful clean nondestructive
activation mode because it can markedly improve both reaction
yields and reaction selectivities (i.e., stereoselectivity, regiose-
lectivity) of organic reactions (particularly, the Diels−Alder
cycloadditions) under milder reaction conditions with no need
Received: June 11, 2012
Published: August 22, 2012
© 2012 American Chemical Society
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These results and the importance of this class of compounds
as precursors for accessing complex polyaromatic systems (i.e.,
the polyphenilenes family) and broadly substituted natural
products (i.e., the cannabinols family) prompted as to study
competitive, environmentally safe routes that allow the
synthesis of a wide range of broadly substituted biaryls.
Recently, we reported a high-yielding and eco-friendly synthetic
route to polysubstituted 6H-tetrahydro-benzo[c]chromene
templates (i.e., the tetrahydro-cannabinols family),15 which
was based on high-pressure Diels−Alder reactions. We
highlighted in our investigations the great benefit of using
high pressure as an activating method in the Diels−Alder key
step of the strategy, to access the cis- and trans-tetrahydro-
cannabinol (THC) families with excellent yields under milder
and noncatalytic reaction conditions,16 and in green solvents
(e.g., ethanol and water) as reaction medium.17 For example,
using hydroxy-substituted 3-cyano-coumarins or alkoxy-benzy-
lideneacetones as the dienophiles, we exploited this Diels−
Alder approach for the synthesis of Δ8-cis-THC and Δ8-trans-
THC 1 and their analogues.16d Instead, the Diels−Alder
reactions of 1-(alkoxy/alkyl-substituted phenyl)buta-1,3-dienes
with methyl vinyl ketone or methyl acrylate opened a route to
Δ9-cis-THC and Δ9-trans-THC 2 and their analogues.16e
Together with Δ8-THC 1 and Δ9-THC 2, another prominent
member of the natural cannabinoids family18 is cannabinol 3
(Figure 1). This deceptively simple natural product continues
to focus the attention of synthetic chemists, and new
approaches to this continue to appear.19
a wide range of ortho-substituted biaryls 7, which are useful
precursors for accessing 6H-benzo[c]chromen-6-ones 8 and
cannabinols 3 (Scheme 1).
In this report, we present (i) a study of the Diels−Alder
reaction of 3-methyl-1-(alkoxy/alkyl/halogen-substituted
phenyl)buta-1,3-dienes 4 with methyl propiolate (5); (ii)
oxidation of the cycloadducts 6 into their corresponding ortho-
substituted biaryls 7; and (iii) application of this approach to
the synthesis of important molecules, such as 6H-benzo[c]-
chromen-6-ones 8 and cannabinol 3 (Scheme 1).
RESULTS AND DISCUSSION
■
3-Methyl-1-(alkoxy/alkyl/halogen-substituted
phenyl)buta-1,3-dienes Synthesis. The synthesis of 1,3-
butadienes 4a−d was reported previously;16d,e according to the
same procedure, the novel dienes 4e and 4f were synthesized in
77 and 70% yields, respectively, using the Wittig reaction20 of
the corresponding (E)-benzylideneacetones.16d
Diels−Alder Reactions of 3-Methyl-1-(alkoxy/alkyl/
halogen-substituted phenyl)buta-1,3-dienes 4 with
Methyl Propiolate 5 under Atmospheric and High-
Pressure Conditions. The Diels−Alder reaction between 4
and 5 is the key step of our strategy, as this allows access to a
wide range of alkoxy/alkyl/halogen-substituted biaryls 7, which
are useful precursors for accessing substituted 6H-benzo[c]-
chromen-6-ones 8 and cannabinol 3 (see Scheme 1). There are
relatively few examples of Diels−Alder reactions of 1-aryl-1,3-
butadienes in the literature,21 and examples of cycloaddition
reactions of dienes of type 4 with methyl propiolate (5) are
particularly rare. For example, it has been reported that 4-aryl-
2-silyloxybuta-1,3-dienes react with methyl propiolate (5) and
other electron-deficient alkynes under thermal conditions (100
°C, for 20 h, in benzene), to give the adducts in low to
moderate yields (47−64%) after acidic workup.22 However, to
the best of our knowledge, no examples of Diels−Alder
reactions between 3-methyl-1-(alkoxy/alkyl/halogen-substi-
tuted phenyl)-1,3-butadienes 4 and methyl propiolate (5)
have been reported. Thus, it became clear that improving the
chemical and environmental efficiency of the Diels−Alder
reaction of 4 with 5 would not be a trivial task, and this was our
first aim.
Figure 1. Tetrahydrocannabinols (THC) and cannabinol.
Thus, in connection with our ongoing studies, as a flexible
method for accessing cannabinol 3 and its analogues, we
envisioned a strategy based on the Diels−Alder reaction of
substituted 1-aryl-3-methyl-1,3-butadienes with methyl propio-
late (5) (Scheme 1). This strategy allows uncatalyzed access to
First, the Diels−Alder reactions of (E)-3-methyl-1-(2′-
methoxyphenyl)buta-1,3-diene (4a) with methyl propiolate
(5) were chosen as representative, and they were investigated
Scheme 1. Diels−Alder Approach to Biaryls 7 and Its Application to the Synthesis of 6H-Benzo[c]chromen-6-ones 8 and
Cannabinols 3
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Table 1. Diels−Alder Reactions of (E)-3-Methyl-1-(2′-methoxyphenyl)buta-1,3-diene (4a) with Methyl Propiolate (5) under
Atmospheric and High-Pressure Conditions
ab
,
c
d
entry
medium
H2O
time (h)
pressure (bar)
temperature (°C)
products
yield (%)
e
1
2
24
150
100
56
27
1
1
100
50
6a/7a (4:1)
6a/7a (1.5:1)
6a/7a (19:1)
6a/7a (2.1:1)
6a/7a (9:1)
18, (27)
e
H2O
1
40, (65)
e
3
EtOH
1
80
44, (50)
e
4
EtOH/H2O (1:1)
PhMe
1
80
22, (41)
e
5
1
110
−10
−10
80
31, (38)
f
6
CH2Cl2
1
g
7
CH2Cl2
5
1
h
8
SolFC
15
40
40
1
6a/7a (1:0)
6a/7a (1:0)
6a/7a (1:0)
48
84
91
9
CH2Cl2
9 × 103
9 × 103
35
10
EtOH
35
a
b
c
d
1
Diene concentration, 0.1 M. 2 equiv of 5 were used. Ratio determined by gas chromatography and/or H NMR analysis. Yield of purified
e
f
g
cycloadduct 6a. Combined isolated yields of compounds 6a and 7a. In the presence of 0.5 equiv of EtAlCl2. In the presence of 0.5 equiv of
HfCl4·2THF. Performed in a sealed steel reactor using 6 equiv of 5.
h
Table 2. Diels−Alder Reactions of (E)-3-Methyl-1-(alkoxy/alkyl/halogen-substituted phenyl)buta-1,3-dienes 4b−f with Methyl
Propiolate (5) under Atmospheric and High-Pressure Conditions
ab
,
c
d
entry
diene
medium
time (h)
pressure (bar)
temperature (°C)
products
yield (%)
e
1
4b
4b
4b
4b
4b
4b
4b
4c
4c
4c
4d
4d
4d
4e
4e
4e
4f
H2O
30
95
1
100
50
80
110
80
40
40
80
40
40
80
40
40
80
45
45
80
45
45
6b/7b (9:1)
6b/7b (1.5:1)
6b/7b (9:1)
6b/7b (49:1)
6b/7b (1:0)
6b/7b (32:1)
6b/7b (49:1)
6c/7c (3:1)
6c/7c (49:1)
6c/7c (19:1)
6d/7d (3.2:1)
6d/7d (19:1)
6d/7d (24:1)
6e/7e (4:1)
6e/7e (19:1)
6e/7e (32:1)
6f/7f (4.9:1)
6f/7f (9:1)
23, (30)
e
2
H2O
1
39, (55)
e
3
EtOH
PhMe
100
32
1
50, (70)
4
1
30
43
76
85
f
5
SolFC
4
1
6
CH2Cl2
EtOH
EtOH
CH2Cl2
EtOH
EtOH
CH2Cl2
EtOH
EtOH
CH2Cl2
EtOH
EtOH
CH2Cl2
EtOH
44
9 × 103
9 × 103
1
7
44
e
8
120
44
43, (75)
9
9 × 103
9 × 103
1
9 × 103
9 × 103
1
9 × 103
9 × 103
1
9 × 103
9 × 103
90
92
10
11
12
13
14
15
16
17
18
19
44
e
120
48
45, (73)
77
83
48
e
120
48
37, (45)
60
70
48
e
120
52
27, (40)
4f
65
71
4f
52
6f/7f (16:1)
a
b
c
d
1
Diene concentration, 0.1 M. 2 equiv of 5 were used. Ratio determined by gas chromatography and/or H NMR analysis. Yield of purified
e
f
cycloadduct 6. Combined isolated yields of compounds 6 and 7. Performed in a sealed steel reactor using 6 equiv of 5.
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under various atmospheric and high-pressure conditions, in
methylene chloride, toluene and in green solvents (e.g., ethanol
and water) as reaction medium,17 and under solvent free
conditions, to search for high-yielding and eco-friendly
conditions for these transformations. All the Diels−Alder
reactions were carried out in the presence of a few crystals of
hydroquinone as radical scavenger, in order to prevent the
diene polymerization.16 The results of this optimization study
are summarized in Table 1.
between nitrophenyl-alkynes and oxygenated dienes, where
the strong directing ability of the ortho-nitrophenyl moiety in
the alkyne is able to guide the regiochemistry of the
cycloadditions even in the presence of additional electron-
withdrawing groups.
At normal pressure (1 bar), heating at high temperatures
(50−110 °C) for long reaction times (30−95 h), (E)-3-methyl-
1-(2′, 4′-dimethoxyphenyl)buta-1,3-diene (4b) with 5 in water
and in toluene solution led to mixtures of cycloadduct 6b and
biaryl 7b, from which 6b was isolated in low yields (23−39%)
by column chromatography on silica gel (Table 2, entries 1, 2,
4). As with 4a, the same reaction at ambient pressure under
SolFC gave the cycloadduct 6b selectively in a shorter reaction
time (4 h), although the isolated yield of 6b still remained
unsatisfactory (43%) (Table 2, entry 5). At normal pressure,
the best isolated yield (70%) of a 9:1 mixture of 6b/7b was
obtained when ethanol was used as the reaction medium, at 80
°C for 100 h (Table 2, entry 3). Similarly, the thermal
cycloadditions of dienes 4c and 4d with 5 in ethanol as the
reaction medium at 80 °C for 120 h provided mixtures of 6c/7c
and 6d/7d in 75 and 73% yields, respectively (Table 2, entries
8, 11). Analogous to previous reports on the cycloadditions of
dienes 4 with methyl vinyl ketone or methyl acrylate,16e the
higher electron-donating character of the phenyl moiety of
diene 4b−d with respect to 4a (due to the introduction of a
second methoxy electron-donating-group) did not translate
into higher yields at normal pressure.
The unsatisfactory results obtained under thermal conditions
(low−moderate yields of mixtures 6/7, at high reaction
temperatures for long reaction times) prompted us to study
the cyloaddition of dienes 4b−d with 5 under hyperbaric
conditions, to investigate more efficient and eco-friendly
conditions for all of these transformations. Thus, as with
diene 4a, using hyperbaric conditions (9 × 103 bar), the
cycloadditions of 4b−d with 5 occurred in methylene chloride
at low temperature (40 °C), to give the corresponding
cycloadducts 6b−d selectively in 76−90% isolated yields
(Table 2, entries 6, 9, 12). When the reaction medium was
changed from methylene chloride to ethanol under identical
conditions, the same cycloadditions gave again slightly better
isolated yields of the cycloadducts 6b−d (83−92%) (Table 2,
entries 7, 10, 13).
Under atmospheric (1 bar) or high-pressure conditions (9 ×
103 bar), the cycloadditions of 4a with 5 were always totally
regioselective.
When the cycloaddition of diene 4a with 5 was performed at
normal pressure and high temperature (50−110 °C) in toluene,
water and ethanol, this always led to mixtures of cycloadduct 6a
and the biaryl product 7a, which was derived from 6a by the
dehydrogenation reaction23 (Table 1, entries 1−5). In water, at
100 °C and at 50 °C, mixtures of the cycloadduct 6a and the
aromatic product 7a were obtained in low yields in the ratios of
4:1 and 1.5:1, respectively (Table 1, entries 1, 2); separation by
chromatography on silica gel led to pure cycloadducts 6a in 18
and 40% yields, respectively.
Under ambient pressure in ethanol and toluene solutions,
and under solvent free conditions, the cycloadditions of 4a with
5 were more selective, producing mixtures of 6a/7a in the
ratios of 19:1, 9:1 and 1:0, respectively, although they again
gave low yields of the isolated cycloadduct 6a (31−48%)
(Table 1, entries 3, 5, 8). However, attempted cycloadditions
between 4a and 5 with conventional and mild Lewis acids, such
as EtAlCl2 and HfCl4·2THF, at low temperature (−10 °C)
produced complex mixtures in which compounds 6a and 7a
were not detected at all (Table 1, entries 6, 7).
Thus, on the basis of our experience in the high-pressure
field,12e,g,16a−e and in view of the excellent results achieved
recently in our laboratory using high pressure as an activation
method for the Diels−Alder reactions of diene 4a,16e we
studied the cycloaddition of 4a with methyl propiolate (5)
under high-pressure conditions.
Accordingly, cycloadduct 6a was obtained with total
selectivity and in high isolated yield (84%) when a solution
of 4a and methyl propiolate (5) in methylene chloride was
treated for 35 h under 9 × 103 bar pressure at low temperature
(35 °C). Changing the solvent from methylene chloride to
ethanol improved the yield to 91%, again at reduced
temperature (35 °C) (Table 1, entries 9, 10).
This study was then extended to the Diels−Alder reactions
of other 3-methyl-1-(alkoxy/alkyl/halogen-substituted phenyl)-
buta-1,3-dienes 4b−f with methyl propiolate (5), to determine
the flexibility of this approach to biaryls and the cannabinols
family. The results of the optimized thermal and high-pressure
reaction conditions are reported in Table 2.
As with 4a, the [4 + 2] cycloadditions reactions of dienes
4b−f with 5 carried out under normal and high-pressure
conditions were always totally regioselective (Table 2), showing
to proceed exclusively to [1,3] adducts.24 This regiochemical
bias was expected because it is the normal path in the Diels−
Alder reactions of electron-rich 1,3-substituted-1,3-dienes with
electron−deficient alkenes and alkynes, in accord with frontier
molecular orbital theory.24 Thus, for example, this regiochem-
ical bias has been maintained for the reactions of 2-
cyclohexenones with 2-methyl-1,3-pentadiene,24 for those of
4-aryl-2-silyloxybuta-1,3-dienes with methyl propiolate,22 and
for all the cycloadditions reactions, studied by Carter,11
Next, we extended the study to halogenated dienes, such as
3-methyl-1-(2′,6′-dichlorophenyl)buta-1,3-diene (4e) and 3-
methyl-1-(2′-chloro-6′-fluoro-phenyl)buta-1,3-diene (4f), to
explore the potential of our approach in the synthesis of
halogenated biaryls, which are versatile precursors for the
construction of complex molecules (e.g., organic semi-
conductors, natural products) (Table 2, entries 14−19). The
cycloadditions of 4e and 4f with 5 under normal and high-
pressure conditions always gave reduced yields with respect to
dienes 4a−d. This was the result of the deactivation of the
dienic components 4e and 4f with respect to 4a−d, due to the
electron-withdrawing character of the two halogens in the
phenyl moiety.
However, we observed that the 9 × 103 bar pressure
cycloadditions of 4e and 4f with 5 in methylene chloride again
proceeded well, selectively yielding cycloadducts 6e and 6f in
reasonable isolated yields (60 and 65%, respectively) (Table 2,
entries 15, 18). Furthermore, under the same reaction
conditions, use of the ethanol as reaction medium improved
the isolated yields of 6e and 6f to 70 and 71%, respectively
(Table 2, entries 16, 19), thus showing that electron-
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withdrawing substituents on the phenyl moiety of the dienes
were also well tolerated under high-pressure conditions.
Thus, the comparison across the data reported in Tables 1
and 2 indicates once again that high pressure was a very
efficient and eco-friendly method of activation. Indeed, under 9
× 103 bar pressure in methylene chloride and in ethanol as
reaction media we always obtained remarkably superior yields
of purified cyclohexadienylbenzenes cycloadduct 6, by cyclo-
addition of both electron-rich and electron-poor dienes. In
addition, it should be noted that reaction temperatures and/or
reaction times were reduced compared with the thermal
conditions, and that the cycloadducts 6 were obtained
selectively without any consistent contamination of the
aromatic compounds 7 (Figure 2). This thus allowed for easily
purified 6, obtained in excellent yields, using short column
chromatography on silica gel.
Application to the Synthesis of Ortho-Substituted
Biaryls, 6H-Benzo[c]chromenones, and the Cannabinols
Family. With the alkoxy/halogen-substituted cyclohexadienyl-
benzenes 6 in hand, we then turned our attention to the
synthesis of biaryls 7, and their conversion into the
corresponding 6H-benzo[c]chromenones 8 and cannabinol 3.
Thus, aromatization of the pure cycloadducts 6a−f (or the
thermal Diels−Alder reaction mixtures 6/7) with 1.5 mol equiv
of DDQ in toluene solution at room temperature for 1 h
resulted in the formation of the corresponding biaryls 7a−f in
excellent yields (Scheme 2).
Scheme 2. Oxidation Reactions of Cycloadducts 6 to Biaryls
7
Then, with biaryl esters 7 in hand, it appeared useful to
synthesize the corresponding 6H-benzo[c]chromen-6-one
derivatives 8, which are useful precursors of important
molecules, such as the cannabinoids (i.e., cannabinol 3 and
its analogues).
Thus, in agreement with the literature,19h,26 demethylative
lactonization of selected biaryls 7a−d with 57% aqueous
hydrogen iodide in acetic anhydride at reflux temperatures for 1
h gave the corresponding 6H-benzo[c]chromenones 8a
(85%),25 8b (81%), 8c (80%) and 8d (81%)19h,26 (Scheme
3). The synthesis of cannabinol 3 from chromenone 8d
Scheme 3. Synthesis of 6H-Benzo[c]chromenones 8a−d and
Cannabinol 3
Figure 2. Diels−Alder cycloadducts 6 and biaryls 7.
On the basis of the above findings (e.g., the presence of
aromatized compounds 7 in the Diels−Alder reaction
mixtures), it was expected that performing the Diels−Alder
reactions between dienes 4 and dienophile 5 in the presence of
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) as an oxidant
would directly favor the formation of aromatized products 7.
Despite our considerable efforts with a wide range of conditions
(e.g., 1−10 mol equiv of DDQ at normal and high pressure),
we were not able to effect a one-step Diels−Alder reaction/
oxidation to biaryls 7a−f. However, it is worth noting that the
selective access to cyclohexadienylbenzenes cycloadduct 6 with
two carbon−carbon double bonds with different chemical
reactivities (one isolated and the other conjugated to the
carbomethoxyl function) remains valuable and promising, as
these compounds would be useful molecular scaffolds for
additional functionalizations.
through methylation with methylmagnesium iodide and the
subsequent treatment of the crude product with p-TsOH has
been described in the literature19h,26 (Scheme 3).
Structural Analysis. The structures of all of the
1
compounds were inferred from the analysis of their H NMR
and 13C NMR spectra. The pertinent data are given in the
Experimental Section. The (E)-configurations of the carbon−
carbon double bond for the 3-methyl-1-(2′,6′-dichlorophenyl)-
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synthesis of aryl buta-1,3-dienes 4e,f was achieved according a previous
procedure using the Wittig reaction of the corresponding (E)-
benzylideneacetones.16d,e,20 Dienophile 5 was purchased and used
without further purification. The products were purified by column
chromatography carried out on silica gel (230−400 mesh), using
petroleum ether−ethyl acetate or petroleum ether−diethyl ether
mixtures as eluent.
The complete NMR structure assignments for all of the new
compounds were based on the relevant JH,H coupling constant values
and on COSY, NOESY and HETCOR experiments.
2′,6′-Dichloro-1-((E)-3-methylbuta-1,3-dienyl)benzene (4e).
Light yellow oil: 2.21 g, (13.5 mmol) 77% yield; IR (CHCl3) 1560,
915 cm−1; 1H NMR (CDCl3) δ 2.04 (s, 3H, CH3), 5.19 (s broad, 2H,
Hs-4), 6.58 (d, 1H, J = 16.5 Hz, H-2), 6.92 (d, 1H, J = 16.5 Hz, H-1),
7.10 (t, 1H, J = 8.0 Hz, H-4′), 7.33 (d, 2H, J = 8.0 Hz, H-3′, H-5′); 13C
NMR (CDCl3) δ18.2, 119.0, 122.7, 127.9, 128.4, 132.0, 134.4 (2C),
134.8, 139.8, 141.7; MS m/e (rel intensity) 70 (10), 75 (10), 115 (15),
141 (58), 142 (110), 143 (12), 162 (22), 177 (44), 179 (14), 212
(M+, 12). Anal. Calcd for C11H10Cl2: C, 62.00; H, 4.73. Found: C,
62.05; H, 4.70.
buta-1,3-diene (4e) and the 3-methyl-1-(2′-chloro,6′fluoro-
phenyl)buta-1,3-diene (4f) were confirmed from the 16.5 Hz
coupling constants measured for J1,2.
3
All of the cycloadducts 6, biaryl compounds 7, and
chromenones 8 prepared in this study were new compounds,
except 8a25 and 8d.19h The structures of all of the new
compounds were assigned mainly on the basis of the
comparison of their NMR data with those of similar
compounds.11a,25 The regiochemistry of the methyl group at
C-4 of all of the compounds was confirmed by two-dimensional
correlation spectroscopy, COSY, NOESY and HMQC experi-
1
ments performed on 6d and 7d. Inspection of the H−1H and
1H−13C connectivities of compounds 6d and 7d, together with
the presence of NOESY correlation peaks between the H-5, H-
6 and 4-Me protons for 6d and between the H-5 and 4-Me
protons for 7d, revealed the regiochemistry of the methyl group
at C-4. Confirmation of the structures assigned to adducts 6
followed also from the conversion of 6a and 6d into the known
chromenones 8a25 and 8d,19h,26 respectively.
2′-Chloro-6′-fluoro-1-((E)-3-methylbuta-1,3-dienyl)benzene
(4f). Yellow oil: 1.86 g, (13.5 mmol) 70% yield; IR (CHCl3) 1566, 905
cm−1; 1H NMR (CDCl3) δ 2.02 (m, 3H, CH3), 5.19 (s broad, 2H, Hs-
4), 6.66 (d, 1H, J = 16.5 Hz, H-2), 7.00 (m, 1H, H-3′), 7.07−7.14 (m,
2H, H-1, H-5′), 7.19 (m, 1H, H-4′); 19F NMR (CDCl3) δ −111,41
(dd, 1F, J = 10.9, 5.64 Hz, F-6′); 13C NMR (CDCl3) δ 18.1, 114.5
(2JCF = 24.1 Hz), 119.2, 119.4, 124.3 (2JCF = 14.1 Hz), 125.5, 127.8
CONCLUSIONS
■
A novel high-yielding strategy for the synthesis of a range of
ortho-substituted biaryls was developed via the Diels−Alder
reaction of 1-(alkoxy/alkyl/halogen-substituted phenyl)buta-
1,3-dienes with methyl propiolate. The results described in this
report show that activation by high pressure allows the [4 + 2]
cycloaddition reactions to occur in excellent yields in a green
ethanolic medium, under mild reaction temperatures, and
without any metal catalyst, thus making this approach to the
biaryls chemically efficient and environmentally friendly.
Another particular attraction to this strategy is the efficient
high pressure activation of the Diels−Alder reactions of 1-aryl-
3-methyl-1,3-butadienes with both electron-donating (e.g.,
alkoxy/alkyl groups) and electron-withdrawing (e.g., halogen)
substituents. This allows access to highly functionalized biaryl
compounds that are not readily accessible from the traditional
palladium-catalyzed cross-coupling reactions. This also provides
an ideal complement to the powerful Diels−Alder approach of
Carter et al.,11 which remains useful for the synthesis of nitro-
substituted biaryls.
(4JCF = 10.1 Hz), 134.4, 138.8 (3JCF = 12.9 Hz), 142.3, 161.1 (1JCF
=
252.5 Hz); MS m/e (rel intensity) 99 (15), 133 (33), 145 (22), 146
(100), 147 (17), 159 (26),160 (M+, 16), 161 (100), 162 (15), 196
(M+, 36). Anal. Calcd for C11H10ClF: C, 67.18; H, 5.13. Found: C,
67.45; H, 5.17.
General Procedure for the Diels−Alder Reaction of 1-
Arylbuta-1,3-dienes (4a−f) with Methyl Propiolate (5). The
cycloaddition reactions of 1-arylbuta-1,3-dienes 4 with 5 were
accomplished (A) at normal pressure and (B) under 9 kbar pressure
conditions. The details are given in Tables 1 and 2.
Condition (A). Methyl propiolate (5) (3 mmol) and a few crystals
of hydroquinone were added to a solution of arylbutadiene 4 (1.5
mmol) in 15 mL of the solvent, and the resulting mixture was poured
into an oil bath under magnetic stirring at the indicated reaction
temperature and for the indicated reaction time. The cooled mixture
was then poured into saturated brine (15 mL) and extracted twice with
diethyl ether. The dried extract (Na2SO4) was evaporated under a
vacuum and chromatographed over silica gel. Elution with 10−20%
mixtures of ethyl acetate/petroleum ether gave the pure cycloadducts
6.
Condition (B). A solution of arylbutadiene 4 (1.5 mmol) in 10 mL
of solvent was placed in a 15 mL Teflon vial. Dienophile 5 (3 mmol)
and a few crystals of hydroquinone were then added, and the vial was
filled with the solvent. The vial was closed and kept at 9 kbar at the
indicated temperature for the appropriate time. After depressurizing,
the mixture was worked up and purified as above, giving the pure
cycloadducts 6.
Methyl 6-(2′-methoxyphenyl)-4-methylcyclohexa-1,4-diene-
1-carboxylate (6a). White solid: mp 42−43 °C (n-hexane); 0.352 g,
91% yield; IR (CHCl3) 1713 (CO) cm−1; 1H NMR (CDCl3) δ 1.67
(s, 3H, CH3), 2.84 (m, 2H, Hs-3), 3.59 (s, 3H, OCH3), 3.89 (s, 3H,
OCH3), 4.84 (s broad, 1H, H-6), 5.52 (s, 1H, H-5), 6.84 (dd, 1H, J =
1.0, 7.5 Hz H-3′), 6.86 (t, 1H, J = 8.0 Hz, H-5′), 6.94 (dd, 1H, J = 1.8,
7.6 Hz, H-6′), 7.15 (dt, 1H, J = 1.8, 7.9 H-4′), 7.21 (dt, 1H, J = 0.9, 4.5
Hz, H-2); 13C NMR (CDCl3) δ 22.6, 31.9, 35.2, 51.5, 55.7, 110.8,
120.8, 123.3, 127.1, 127.4, 127.6, 130.9, 132.9, 137.8, 156.5, 167.1; MS
m/e (rel intensity) 59 (18), 65 (15), 77 (28), 91 (37), 108 (20), 128
(20), 139 (16), 152 (38), 153 (22), 165 (39), 166 (15), 167 (18), 168
(29), 169 (18), 181 (24), 183 (41), 184 (23), 195 (46), 196 (28), 199
(21), 210 (23), 211 (100), 225 (59), 226 (84), 227 (18), 258 (M+, 9).
Anal. Calcd for C16H18O3: C, 74.39; H, 7.02. Found: C, 74.35; H, 7.08.
Methyl 6-(2′,4′-dimethoxyphenyl)-4-methylcyclohexa-1,4-
diene-1-carboxylate (6b). White solid: mp 86−87 °C (n-hexane);
Furthermore, in connection with our ongoing studies on the
synthesis of Δ8-THCs and Δ9-THCs, this chemistry has been
applied to the synthesis of a series of 6H-benzo[c]-
chromenones, including the synthesis of the benzo[c]chromene
natural product cannabinol. However, our proposed strategy for
the construction of the 6H-benzo[c]chromenes-based priv-
ileged15,16 structures can also be applied to the synthesis of
other naturally occurring derivatives for use in bioassays or SAR
studies. Extension of this methodology to the synthesis of other
natural products is under active investigation.
EXPERIMENTAL SECTION
■
General Methods. All of the compounds were purified by column
chromatography or by recrystallization. NMR spectra were recorded at
400 MHz for protons, 376.3 MHz for fluorine and 100.6 MHz for
carbon nuclei. Gas chromatography−mass spectrometry (GC−MS)
analysis was carried out using a 70 eV electron energy EI. GC analysis
was performed with an SPB-5 fused silica capillary column (30 m, 0.25
mm diameter) on an “on column” injector system and with a flame
ionization detector with hydrogen as the carrier gas. Infrared (IR)
spectra were recorded with a FT-IR instrument, using CHCl3 as
solvent. Melting points are uncorrected. The aryl buta-1,3-dienes 4a−
d16e were prepared previously in our laboratory. Hyperbaric
experiments were conducted on a Unipress LV30/16 apparatus. The
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The Journal of Organic Chemistry
Article
0.367 g, 85% yield; IR (CHCl3) 1714 (CO) cm−1; 1H NMR
(CDCl3) δ 1.67 (s, 3H, CH3), 2.83 (m, 2H, Hs-3), 3.60 (s, 3H,
OCH3), 3.76 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 4.74 (s, 1H, H-6),
5.50 (s, 1H, H-5), 6.38 (dd, 1H, J = 2.4, 8.4 Hz, H-5′), 6.46 (d, 1H, J =
2.4 Hz, H-3′), 6.83 (d, 1H, J = 8.4 Hz, H-6′), 7.18 (t broad, 1H, H-2);
13C NMR (CDCl3) δ 22.6, 31.8, 34.7, 51.4, 55.2, 55.7, 98.7, 104.4,
extracted twice with diethyl ether. The dried extract (Na2SO4) was
concentrated under a vacuum and purified by silica gel column
chromatography (20% diethyl ether/petroleum ether) to give biaryls 7.
Methyl 2′-methoxy-4-methyl-1′,6-biphenyl-1-carboxylate
(7a). Yellow oil: 80.6 mg, 90% yield; IR (CHCl3) 1717 (CO)
1
cm−1; H NMR (CDCl3) δ 2.42 (s, 3H, CH3), 3.64 (s, 3H, OCH3),
3.72 (s, 3H, OCH3), 6.90 (d, 1H, J = 8.0 Hz, H-3), 7.04 (t, 1H, J = 7.5
Hz, H-5′), 7.15 (s, 1H, H-5), 7.20 (d broad, 1H, J = 7.5 H-6′), 7.24
(dd, 1H, J = 1.6, 7.5 Hz, H-3′), 7.33 (dt, 1H, J = 1.6, 7.5 H-4′), 7.80
(d, 1H, J = 8.0 Hz, H-2); 13C NMR (CDCl3) δ 21.4, 51.5, 55.2, 110.0,
120.6, 127.8, 128.6, 128.7, 129.6, 129.7, 130.8, 132.0, 138.9, 142.0,
156.1, 168.4; MS m/e (rel intensity) 115 (19), 139 (18), 151 (18), 152
(62), 153 (37), 163 (43), 165 (38), 181 (100), 182 (56), 195 (41),
210 (100), 225 (100), 226 (66), 256 (M+, 100). Anal. Calcd for
C16H16O3: C, 74.98; H, 6.29. Found: C, 74.93; H, 6.23.
123.6, 125.4, 127.1, 128.1, 131.0, 137.4, 157.4, 159.0, 167.2; MS m/e
(rel intensity) 91 (13), 115 (15), 138 (16), 153 (14), 165 (18), 197
(23), 198 (20), 213 (57), 214 (26), 225 (37), 226 (39), 227 (32), 228
(29), 229 (26), 241 (100), 255 (47), 256 (79), 288 (M+, 56). Anal.
Calcd for C17H20O4: C, 70.81; H, 6.99. Found: C, 70.76; H, 7.03.
Methyl 6-(2′,6′-dimethoxyphenyl)-4-methylcyclohexa-1,4-
diene-1-carboxylate (6c). White solid: mp 90−91 °C (n-hexane);
0.397 g, 92% yield; IR (CHCl3) 1710 (CO) cm−1; 1H NMR
(CDCl3) δ 1.69 (s, 3H, CH3), 2.81 (m, 2H, Hs-3), 3.56 (s, 3H,
OCH3), 3.76 (s, 6H, OCH3, OCH3), 4.99 (s, 1H, H-6), 5.30 (s, 1H,
H-5), 6.53 (d, 2H, J = 8.3 Hz, H-3′, H-5′), 7.04 (s broad, 1H, H-2),
7.11 (t, 1H, J = 8.3 Hz, H-4′); 13C NMR (CDCl3) δ 22.6, 32.2, 32.2.
51.2, 56.2 (2C), 104.9 (2C), 120.0, 121.6, 127.2, 128.4, 130.4, 136.4,
158.7 (2C), 167.3; MS m/e (rel intensity) 77 (19), 91 (28), 115 (29),
128 (21), 138 (33), 139 (18), 141 (17), 152 (27), 153 (28), 165 (31),
169 (18), 181 (36), 183 (17), 197 (42), 198 (42), 199 (19), 210 (22),
213 (51), 225 (100), 226 (100), 227 (20), 240 (50), 241 (100), 242
(28), 255 (100), 256 (100), 288 (M+, 18). Anal. Calcd for C17H20O4:
C, 70.81; H, 6.99. Found: C, 70.78; H, 6.93.
Methyl 2′,4′-dimethoxy-4-methyl-1′,6-biphenyl-1-carboxy-
late (7b). White solid: mp 59−60 °C (n-hexane); 93.1 mg, 93%
1
yield; IR (CHCl3) 1713 (CO) cm−1; H NMR (CDCl3) δ 2.40 (s,
3H, CH3), 3.66 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.85 (s, 3H,
OCH3), 6.48 (d, 1H, J = 2.3 Hz, H-3′), 6.56 (dd, 1H, J = 2.3, 8.3 Hz,
H-5′), 7.11 (s, 1H, H-5), 7.16 (d, 1H, J = 8.3 Hz, H-6′), 7.17 (d, 1H, J
= 7.9 Hz, H-3), 7.76 (d, 1H, J = 7.9 Hz, H-2); 13C NMR (CDCl3) δ
21.4, 51.5, 55.2, 55.3, 98.2, 104.2, 123.6, 127.5, 128.7, 129.5, 130.1,
132.2, 138.6, 141.9, 157.1, 160.4, 168.7; MS m/e (rel intensity) 115
(16), 139 (11), 163 (21), 169 (11), 197 (28), 225 (13), 240 (61), 255
(100), 256 (19), 286 (M+, 86). Anal. Calcd for C17H18O4: C, 71.31; H,
6.34. Found: C, 71.38; H, 6.29.
Methyl 6-(2′,6′-dimethoxy-4′-pentylphenyl)-4-methylcyclo-
hexa-1,4-diene-1-carboxylate (6d). Light yellow solid: mp 60−61
°C (n-hexane); 0.446 g, 83% yield; IR (CHCl3) 1711 (CO) cm−1;
1H NMR (CDCl3) δ 0.89 (t, 3H, J = 6.9 Hz, CH3), 1.28−1.36 (m, 4H,
Methyl 2′,6′-dimethoxy-4-methyl-1′,6-biphenyl-1-carboxy-
late (7c). White solid: mp 93−94 °C (n-hexane); 87.1 mg, 87%
1
yield; IR (CHCl3) 1724 (CO) cm−1; H NMR (CDCl3) δ 2.42 (s,
CH2CH2), 1.58−1.65 (m, 2H, CH2), 1.69 (s, 3H, CH3), 2.53 (t, 2H, J
= 7.8 Hz, CH2), 2.79 (m, 2H, Hs-3), 3.58 (s, 3H, OCH3), 3.78 (s, 6H,
OCH3, OCH3), 4.95 (s broad, 1H, H-6), 5.31 (s broad, 1H, H-5), 6.36
(s, 2H, H-3′, H-5′), 7.03 (s broad, 1H, H-2); 13C NMR (CDCl3) δ
14.0 (C-5″), 22.5 (C-4″), 22.6 (4-CH3), 30.9 (C-2″), 31.7 (C-3″),
32.0 (C-6), 32.2 (C-3), 36.4 (C-1″), 51.1 (CH3OCO), 56.2 (2′-
OCH3, 6′-OCH3), 105.1 (C-3′, C-5′), 117.2 (C-1′), 121.9 (C-5),
128.2 (C-1), 130.5 (C-4′), 136.3 (C-2), 142.3 (C-4), 158.5 (C-2′, C-
6′), 167.3 (CO); MS m/e (rel intensity) 91 (30), 152 (92), 153
(26), 165 (44), 181 (27), 195 (45), 211 (40), 213 (41), 225 (100),
240 (40), 254 (44), 267 (33), 295 (100), 311 (100), 325 (100), 326
(73), 358 (M+, 43). Anal. Calcd for C22H30O4: C, 73.71; H, 8.44.
Found: C, 73.75; H, 8.41.
3H, CH3), 3.63 (s, 3H, OCH3), 3.71 (s, 6H, OCH3, OCH3), 6.64 (d,
2H, J = 8.3 Hz, H-3′, H-5′), 7.13 (s, 1H, H-5), 7.20 (d, 1H, J = 7.9 Hz,
H-3), 7.28 (t, 1H, J = 8.3 Hz, H-4′), 7.88 (d, 1H, J = 7.9 Hz, H-2); 13C
NMR (CDCl3) δ 21.5, 51.4, 55.9 (2C), 104.0 (2C), 119.3, 127.8,
128.5, 129.9, 132.9, 135.2, 141.6 (2C), 157.1 (2C), 167.9; MS m/e (rel
intensity) 115 (16), 163 (41), 169 (16), 181 (15), 197 (17), 225 (12),
240 (30), 255 (100), 256 (16), 286 (M+, 50). Anal. Calcd for
C17H18O4: C, 71.31; H, 6.34. Found: C, 71.29; H, 6.30.
Methyl 2′,6′-dimethoxy-4-methyl-4′-pentyl-1′,6-biphenyl-1-
carboxylate (7d). Light yellow solid: mp 48−49 °C (n-hexane);
1
122.1 mg, 98% yield; IR (CHCl3) 1723 (CO) cm−1; H NMR
(CDCl3) δ 0.94 (t, 3H, J = 7.0 Hz, CH3), 1.34−1.44 (m, 4H,
CH2CH2), 1.67−1.73 (m, 2H, CH2), 2.40 (s, 3H, CH3), 2.65 (t, 2H, J
= 7.8 Hz, CH2), 3.62 (s, 3H, OCH3), 3.69 (s, 6H, OCH3, OCH3), 6.46
(s, 2H, H-3′, H-5′), 7.13 (s, 1H, H-5), 7.17 (d, 1H, J = 7.9 Hz, H-3),
7.85 (d, 1H, J = 7.9 Hz, H-2); 13C NMR (CDCl3) δ 14.1 (C-5″), 21.5
(4-CH3), 22.6 (C-4″), 31.1 (C-2″), 31.6 (C-3″), 36.7 (C-1″), 51.4
(CH3OCO), 55.8 (2′-OCH3, 6′-OCH3), 104.3 (C-3′, C-5′), 116.6
(C-1′), 127.6 (C-5), 128.7 (C-1), 129.8 (C-3), 133.2 (C-2), 135.3 (C-
4′), 141.4 (C-6), 143.8 (C-4), 156.8 (C-2′, C-6′), 168.1 (CO); MS
m/e (rel intensity) 152 (10), 163 (15), 165 (14), 181 (14), 225 (21),
237 (21), 253 (75), 254 (20), 268 (100), 269 (18), 299 (17), 325
(31), 356 (M+, 62). Anal. Calcd for C22H28O4: C, 74.13; H, 7.92.
Found: C, 74.17; H, 7.90.
Methyl 6-(2′,6′-dichlorophenyl)-4-methylcyclohexa-1,4-
diene-1-carboxylate (6e). Light yellow solid: mp 76−77 °C (n-
1
hexane); 0.312 g, 70% yield; IR (CHCl3) 1717 (CO) cm−1; H
NMR (CDCl3) δ 1.72 (s, 3H, CH3), 2.86 (m, 2H, Hs-3), 3.61 (s, 3H,
OCH3), 5.0 (s, 1H, H-6), 5.34 (s, 1H, H-5), 6.88 (t, 1H, J = 9.2 Hz, H-
2), 7.03−7.10 (m, 1H, H-4′), 7.15 (m, 2H, H-3′, H-5′); 13C NMR
(CDCl3) δ 22.5, 32.1, 51.5, 114.6, 119.3(2C), 127.8, 128.3, 130.3,
132.1, 134.9, 138.5, 142.8, 158.6, 166.6; MS m/e (rel intensity) 91
(27), 165 (65), 166 (43), 170 (41), 221 (33), 233 (27), 245 (100),
265 (23), 280 (34). Anal. Calcd for C15H14Cl2O2: C, 60.62; H, 4.75.
Found: C, 60.66; H, 4.78.
Methyl 6-(2′-chloro-6′-fluorophenyl)-4-methylcyclohexa-
1,4-diene-1-carboxylate (6f). Light yellow oil: 0.299 g, 71% yield;
Methyl 2′,6′-dichloro-4-methyl-1′,6-biphenyl-1-carboxylate
1
IR (CHCl3) 1717 (CO) cm−1; H NMR (CDCl3) δ 1.72 (s, 3H,
(7e). Light yellow oil: 85.5 mg, 83% yield; IR (CHCl3) 1726 (CO)
1
cm−1; H NMR (CDCl3) δ 2.45 (s, 3H, CH3), 3.69 (s, 3H, OCH3),
CH3), 2.87 (m, 2H, 3-CH2), 3.61 (s, 3H, OCH3), 4.99 (s broad, 1H,
H-6), 5.33 (s broad, 1H, H-5), 6.88 (t, 1H, J = 9.2 Hz, H-2), 7.05−
7.11 (m, 1H, H-5′), 7.15 (m, 2H, H-3′, H-4′); 19F NMR (CDCl3) δ
−113,94 (s broad, 1F, F-6′); 13C NMR (CDCl3) δ 22.5 (2C), 32.1,
51.5, 114.6 (2JCF = 22.33 Hz), 119.4, 125.6, 127.8 (3JCF = 10.06 Hz),
128.3, 130.4, 134.9 (2C), 138.5, 162.1 (1JCF = 267.59 Hz), 166.6; MS
m/e (rel intensity) 59 (48), 91 (43), 119 (21), 143 (21), 165 (94), 166
(52), 170 (54), 183 (68), 186 (37), 221 (35), 233 (25), 245 (100),
265 (22), 280 (M+, 30). Anal. Calcd for C15H14ClFO2: C, 64.18; H,
5.03. Found: C, 64.13; H, 5.00.
7.03−7.09 (m, 1H, H-4′), 7.1 (s broad, 1H, H-5), 7.24−7.29 (m, 2H,
H-3′, H-5′), 7.31 (m, 1H, H-3), 8.03 (d, 1H, J = 8.0 Hz, H-2); 13C
NMR (CDCl3) δ 21.5, 51.9, 113.5, 113.7, 124.7, 127.1, 129.1, 130.8,
132.1, 134.1, 142.8 (2C), 158.6, 161.0, 166.5; MS m/e (rel intensity)
157 (15), 181 (17), 183 (100), 184 (65), 199 (32), 200 (16), 228
(93), 229 (15), 243 (100), 244 (80), 247 (31). Anal. Calcd for
C15H12Cl2O2: C, 61.04; H, 4.10. Found: C, 61.01; H, 4.07.
Methyl 2′-chloro-6′-fluoro-4-methyl-1′,6-biphenyl-1-car-
boxylate (7f). Light yellow solid: 82.9 mg, 85% yield; mp 67−68
°C (n-hexane); IR (CHCl3) 1727 (CO) cm−1; 1H NMR (CDCl3) δ
2.44 (s, 3H, CH3), 3.69 (s, 3H, OCH3), 7.02−7.08 (m, 1H, H-5′), 7.1
(s, 1H, H-5), 7.26 (m, 2H, H-3′, H-4′), 7.31 (d broad, 1H, J = 8.4 Hz,
H-3), 8.02 (d, 1H, J = 8.4 Hz, H-2); 19F NMR (CDCl3) δ −111,64 (s
Oxidation of Cycloadducts 6 to Biaryls 7. To a solution of the
cycloadducts 6 (0.35 mmol) in toluene (4.35 mL) was added DDQ
(0.118 g, 0.521 mmol). The mixture was stirred at room temperature
for 1 h and then poured into saturated aqueous NaHCO3 and
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broad, 1F, F-6′);13C NMR (CDCl3) δ 21.5, 51.9, 113.6 (2JCF = 22.94
Hz), 124.7, 127.2, 128.9 (3JCF = 9.35 Hz), 129.3, 130.8, 132.2, 134.2,
142.9 (2C), 159.7, 160.4 (1JCF = 246.84 Hz), 166.5; MS m/e (rel
intensity) 183 (23), 184 (13), 199 (6), 228 (19), 243 (100), 244 (16).
Anal. Calcd for C15H12ClFO2: C, 64.64; H, 4.34. Found: C, 64.65; H,
4.37.
Demethylative Lactonization of Biaryls 7a−d to Benzo[c]-
chromenones 8a−d. To a hot solution of 7a−d (0.184 mmol) in
acetic anhydride (1 mL) was added dropwise 57% aq HI (1 mL), and
the mixture was refluxed for 1 h. This was then cooled to room
temperature, poured into water, and extracted with diethyl ether. The
combined extracts were washed successively with 20% aqueous
Na2SO3, 1 M aqueous solution of NaHCO3, and water and dried
over Na2SO4. Then, the solvent was evaporated, and the residue was
purified by two crystallizations (n-hexane and chloroform) to give
chromenones 8a,25 8b, 8c and 8d.19h,26
(2) (a) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M.
J.; Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384−
5427. (b) Bringmann, G.; Gunther, C.; Ochse, M.; Schupp, O.; Tasler,
S. In Progress in the Chemistry of Organic Natural Products; Herz, W.,
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3-Hydroxy-9-methyl-6H-benzo[c]chromen-6-one (8b). White
solid: mp 245−246 °C (n-hexane); 33.7 mg, 85% yield; IR (CHCl3)
1
3425 (OH), 1733 (CO) cm−1; H NMR ((CD3)2CO) δ 2.52 (s,
3H, CH3), 6.78 (m, 1H, H-2), 6.88 (m, 1H, H-4), 7.36 (m, 1H, H-8),
8.03 (m, 1H, H-1), 8.12 (m, 1H, H-10), 9.17 (d, 1H, J = 5.1 Hz, H-7);
13C NMR ((CD3)2CO) δ 21.2, 103.3, 110.3, 112.9, 117.4, 121.5,
124.6, 128.8, 129.7, 135.4, 146.1, 153.0, 159.8, 160.6. Anal. Calcd for
C14H10O3: C, 74.33; H, 4.46. Found: C, 74.29; H, 4.42.
1-Hydroxy-9-methyl-6H-benzo[c]chromen-6-one (8c). White
solid: mp 242−243 °C (n-hexane); 33.3 mg, 80% yield; IR (CHCl3)
1
3349 (OH), 1732 (CO) cm−1; H NMR ((CD3)2CO) δ 2.52 (s,
3H, CH3), 6.86 (d, 1H, J = 8.2 Hz, H-4), 6.92 (d, 1H, J = 8.2 Hz, H-2),
7.33 (t, 1H, J = 8.2 Hz, H-3), 7.44 (d, 1H, J = 8.1 Hz, H-8), 8.22 (d,
1H, J = 8.1 Hz, H-7), 9.03 (s, 1H, H-10); 13C NMR ((CD3)2CO) δ
21.6, 106.8, 108.6, 111.9, 118.5, 127.7, 129.0, 129.7, 129.9, 134..9,
145.6, 153.5, 156.4, 160.4. Anal. Calcd for C14H10O3: C, 74.33; H,
4.46. Found: C, 74.38; H, 4.45.
1-Hydroxy-9-methyl-3-pentyl-6H-benzo[c]chromen-6-one
(8d).26 White solid: mp 183−184 °C (n-hexane) (lit.26 191−192 °C);
44.1 mg, 81% yield; IR (CHCl3) 3358 (OH), 1732 (CO) cm−1; 1H
NMR ((CD3)2CO) δ 0.87 (t, 3H, J = 8.3 Hz, CH3), 1.34 (m, 4H,
−CH2CH2−), 1.65 (m, 2H, −CH2−), 2.51 (s, 3H, CH3), 2.61 (t, 2H,
J = 7.5 Hz, −CH2−), 6.73 (d, 1H, J = 1.6 Hz, H-4), 6.78 (d, 1H, J =
1.6 Hz, H-2), 7.39 (d, 1H, J = 8.0 Hz, H-8), 8.19 (d, 1H, J = 8.0 Hz, H-
7), 8.97 (s, 1H, H-10); 13C NMR ((CD3)2CO) δ 13.4, 21.6, 22.3, 30.4,
31.3, 35.2, 104.5, 108.4, 112.0, 118.1, 127.3, 128.5, 129.7, 135.1, 145.5,
145.7, 153.0, 156.1, 160.6. Anal. Calcd for C19H20O3: C, 77.00; H,
6.80. Found: C, 76.96; H, 6.76.
(8) Campeau, L. C.; Fagnou, K. Chem. Commun. 2006, 1253−1264.
(9) Rouhi, A. M. Chem. Eng. News 2004, 82 (36), 66−67.
(10) Yoshida, H.; Honda, Y.; Shirakawa, E.; Hiyama, T. Chem.
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ASSOCIATED CONTENT
■
S
* Supporting Information
(12) (a) Ibata, T. In Organic Synthesis at High Pressures; Matsumoto,
K., Achenson, R. M., Eds.; Wiley: Toronto, 1991; Chapter 9.
1H NMR and 13C NMR spectra of all of the new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(b) Klarner, F.-G.; Diedrich, M. K.; Wigger, A. E. In Chemistry
̈
Under Estreme or Non-Classical Conditions; van Eldik, R., Hubbard, C.
D., Eds.; Wiley: New York, 1997; Chapter 3. (c) Jurczak, J.; Gryko, D.
T. In Chemistry Under Estreme or Non-Classical Conditions; van Eldik,
R., Hubbard, C. D., Eds.; Wiley: New York, 1997; Chapter 4.
(d) Isaacs, N. S. In High-Pressure Techniques in Chemistry and Physics;
Harwood, L. M., Moody, C. J., Eds.; Oxford: New York, 1997; Chapter
7. (e) Minuti, L.; Taticchi, A.; Costantini, L. Recent Res. Dev. Org.
Chem. 1999, 3, 105−116. (f) Matsumoto, K.; Hamana, H.; Iida, H.
Helv. Chim. Acta 2005, 88, 2033−2234. (g) Minuti, L. In Eco-Friendly
Processes and Procedures for the Synthesis of Fine Chemicals; The Royal
Society of Chemistry: Cambridge, U.K., 2009; Chapter 7. (h) Rulev, A.
Ju.; Kotsuki, H.; Maddaluno, J. Green Chem. 2012, 14, 503−508.
(13) Becht, J.-M.; Gissot, A.; Wagner, A.; Miosikowki, C. Chem.
Eur. J. 2003, 9, 3209−3215.
AUTHOR INFORMATION
Corresponding Author
*E-mail: lucio@unipg.it.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the Fondazione Cassa Risparmio Perugia
and the Ministero dell'Istruzione dell'Universita
(MIUR) for financial support.
■
̀
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