Efficient and general method for the synthesis of benzopyrans by ethylenediamine diacetate-catalyzed reactions of resorcinols with α,β-unsaturated aldehydes. One step synthesis of biologically active (±)-confluentin and (±)-daurichromenic acid

Article abstract of DOI:10.1016/j.tetlet.2005.08.159

An efficient and general synthesis of benzopyrans is achieved by ethylenediamine diacetate-catalyzed reactions of resorcinols with α,β-unsaturated aldehydes in moderated yields. As an application of this methodology, biologically interesting confluentin, which was known to have an inhibitory effect on histamine release is synthesized in one step. Also, natural daurichromenic acid, which has highly potent anti-HIV activity, is successfully synthesized in one step.

Full text of DOI:10.1016/j.tetlet.2005.08.159

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7539–7543
Efficient and general method for the synthesis of benzopyrans
by ethylenediamine diacetate-catalyzed reactions of resorcinols
with a,b-unsaturated aldehydes. One step synthesis of
biologically active ( )-confluentin and ( )-daurichromenic acid
Yong Rok Lee,* Jung Hyun Choi and Sang Heum Yoon
School of Chemical Engineering and Technology, Yeungnam University, Gyeongsan 712-749, Republic of Korea
Received 9 June 2005; revised 30 August 2005; accepted 31 August 2005
Available online 15 September 2005
Abstract—An efficient and general synthesis of benzopyrans is achieved by ethylenediamine diacetate-catalyzed reactions of resor-
cinols with a,b-unsaturated aldehydes in moderated yields. As an application of this methodology, biologically interesting conflu-
entin, which was known to have an inhibitory effect on histamine release is synthesized in one step. Also, natural daurichromenic
acid, which has highly potent anti-HIV activity, is successfully synthesized in one step.
Ó 2005 Published by Elsevier Ltd.
The compounds containing benzopyran moiety (chrom-
enes) are widely distributed in nature.1 They have shown
many biological activities2 and are used as versatile
intermediates in organic and natural product synthesis.3
Several synthesis of benzopyran nuclei have been re-
ported using the Claisen rearrangement of propargyl
ethers4 and Lewis acid-catalyzed condensation of phe-
nols with acetals or ketals.5 These reactions have been
limited due to harsh reaction conditions, long reaction
steps, unsatisfactory yields, and stoichiometric amounts
of catalysts. As a useful strategy for the synthesis of
benzopyrans, cycloaddition of phenols to a,b-unsatu-
rated aldehydes have been reported in refluxing pyri-
dine.6 These reactions have limitations such as low
yields and difficulty of isolation of the products. In order
to overcome limitations of this process, metal-catalyzed
reactions have been developed by several groups.7
compounds, cycloaddition using a,b-unsaturated imin-
ium salts has been also reported by Hsung and co-work-
ers.9 However, ethylenediamine diacetate-catalyzed
reactions of substituted resorcinols instead of 1,3-dicar-
bonyl compounds to a,b-unsaturated aldehydes have
not been reported. We report herein an efficient and con-
venient procedure for the synthesis of benzopyrans
starting from resorcinol in the presence of ethylenedi-
amine diacetate.
Reaction of orcinol (1) with 3-methyl-2-butenal was
investigated under several catalysts (Table 1). Both in-
dium(III) chloride (10 mol %) and ytterbium(III) triflate
(10 mol %) as Lewis acid catalysts in refluxing acetoni-
trile gave no adducts. With pyridine as a reactant and
solvent, no products were obtained. Treatment of 1
3-methyl-2-butenal in the presence of 20 mol % of
Ca(OH)2 according to Shigemasa condition10 gave no
products. Interestingly, with ethylenediamine diacetate
(10 mol %) as a catalyst, products 2 and 3 were ob-
tained. Upon raising the temperature to 80–140 °C by
using the several solvents, the best yields of 2 (55%)
and 3 (5%) were obtained in toluene. The two com-
pounds were easily separated by column chromato-
graphy and assigned by spectroscopic analyses.11
Ethylenediamine diacetate-catalyzed reactions of 1,3-
dicarbonyl compounds with enals have received consid-
erable attention due to their highly catalytic activity.8
These reactions provided a rapid entry to versatile het-
erocycles by tandem Knoevenagel-electrocyclic reaction.
In order to increase reactivity and yields of tandem
Knoevenagel-electrocyclic reactions of 1,3-dicarbonyl
Additional reactions of several types of resorcinols with
a,b-unsaturated aldehydes were carried out in the pres-
ence of ethylenediamine diacetate (10 mol %) in toluene
Keywords: Benzopyrans; Ethylenediamine diacetate.
*
Corresponding author. Tel.: +82 538 102529; fax: +82 538 104631;
e-mail: yrlee@yu.ac.kr
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.08.159

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Y. R. Lee et al. / Tetrahedron Letters 46 (2005) 7539–7543
Table 1. Reaction of 1 with 3-methyl-2-butenal under several catalysts
OH
OH
O
O
H
+
catalyst
OH
O
1
O
2
3
Catalyst (mol %)
Condition
Yield (%)
2
3
InCl3 (10)
Yb(OTf)3 (10)
Pyridine (excess)
Ca(OH)2 (20)
Ethylenediamine diacetate (10)
Ethylenediamine diacetate (10)
Ethylenediamine diacetate (10)
Ethylenediamine diacetate (10)
Acetonitrile, reflux, 5 h
Acetonitrile, reflux, 5 h
Reflux, 5 h
0
0
0
0
11
36
55
33
0
0
0
0
0
6
5
8
Rt, 12 h
CH2Cl2, rt, 12 h
Benzene, reflux, 5 h
Toluene, reflex, 5 h
Xylene, reflux, 5 h
or xylene. The results are collected in Table 2. Reaction
of resorcinol (1) with 3-methyl-2-butenal in refluxing xy-
lene for 5 h afforded adducts 7 and 8 in 23% and 12%
yields, respectively (Table 2, entry 1). In the case of res-
orcinols with substituent on the ring, a higher yield of
products was produced. For example, reaction of orci-
nol (1) with citral under 10 mol % of ethylenediamine
diacetate in refluxing toluene for 5 h gave both 9 and
10 in 47% and 8% yields, respectively (entry 2). With
other a,b-unsaturated aldehydes including cyclic ring,
cycloaddition reactions were successful. Reactions of 1
with 1-cyclohexene-1-carboxaldehyde and (À)-myrtenal
provided adducts 11 (62%) and 12 (78%) as a single
compound, respectively (entries 3 and 4), whereas treat-
ment with (À)-perillaldehyde in refluxing xylene gave
both 13 and 14 in 53% and 21% yields (entry 5). On
the other hand, in reaction with a long chain on the res-
orcinol ring, reaction was also successful. Reaction of 5
with 3-methyl-2-butenal in refluxing toluene afforded
adduct 15 in 48% yield (entry 6). In order to extend
the utility of this methodology, further reactions with
other types of substituted resorcinol were examined
(entries 7–9). Reaction of ethyl 2,4-dihydroxy-6-meth-
ylbenzoate (6) with 3-methyl-2-butenal in refluxing
xylene afforded 16 in 60% yield. Similarly, with citral
and (À)-myrtenal in refluxing toluene or xylene, adducts
17 and 18 were obtained in 51% and 75% yields, respec-
tively. These reactions provide a rapid route for the syn-
thesis of benzopyran derivatives with a variety of
substituents on the benzopyran ring.
highly potent anti-HIV activity in acutely infected H9
cells with an EC50 of 0.00567 lg/mL and a therapeutic
index (TI) of 3710. Rhododaurichromanic acid A (21)
has also shown potent anti-HIV activity with an EC50
value of 0.37 lg/mL and a TI of 91.9.14 Interestingly,
although natural confluentin and daurichromenic acid
have been isolated from same sources, their absolute
configurations of C-2 are different. The absolute config-
uration of 19 is known as R from its circular dichroism
spectrum by Kitanaka and co-workers.12 The absolute
stereochemistry of 20 was confirmed as S from X-ray
crystallographic analysis and photochemical conversion
by Kashiwada et al.14
The one-step synthesis of confluentin (19) is outlined in
Scheme 1. Reaction of orcinol (1) with trans,trans-farne-
sal in the presence of 10 mol % of ethylenediamine diac-
etate at refluxing xylene for 5 h gave adduct 19 in 65%
yield. The spectroscopic data of our synthetic material
19 are in agreement with those reported in the
literature.15
Recently, the total synthesis of daurichromenic acid
(20), rhododaurichromanic acid A (21), and rhododau-
richromanic acid B (22) has been reported by three
groups. Hsung and co-workers have reported on total
synthesis of methyl ester of 20 starting from 5-methyl-
1,3-cyclohexanedione in three steps (22%, overall
yields).16 Subsequent photochemical reaction and
hydrolysis of methyl ester of 20 gave rhododaurichro-
manic acid A (21) and rhododaurichromanic acid B
(22) as a mixture. Other synthetic approach of dauri-
chromenic acid (20) was accomplished by Jin and co-
workers starting from orcinol in five steps (49%, overall
yields).17 Compound 20 provided 21 (40%) and 22 (20%)
by irradiation with a low-pressure mercury lamp. More
recently, another concise synthesis of 20 has been re-
ported by Wilson and co-workers from ethyl acetoace-
tate in four steps (6%, overall yields).18 Although there
are currently several methods available to synthesize
daurichromenic acid (20), rhododaurichromanic acid
A (21), and rhododaurichromanic acid B (22), general
and efficient concise synthetic routes are still more
required. Our one-step synthetic approach to dauri-
As an application of this methodology, total synthesis of
confluentin (19) and daurichromenic acid (20) was next
attempted. Confluentin (19) was recently isolated from
Rhododendron dauricum, a plant found in areas of north-
ern China, eastern Siberia, Mongolia, and Hokkaido,
Japan (Fig. 1).12 The dried leaves of this plant are
known as ÔManshanfongÕ in China and are used in med-
icines for treatment of an expectorant and an acute-
chronic bronchitis.13 Confluentin (19) has shown an
inhibitory effect on histamine release.12 Daurichromenic
acid (20), rhododaurichromanic acid A (21), and rho-
dodaurichromanic acid B (22) were also isolated from
the same plant.14 Daurichromenic acid (20) has shown

Y. R. Lee et al. / Tetrahedron Letters 46 (2005) 7539–7543
Table 2. Reaction of resorcinols with a,b-unsaturated aldehydes
7541
Entry
Starting material
a,b-Unsaturated aldehyde
Condition
Product (yield)
OH
OH
O
O
H
1
B
O
23%
OH
O
4
7
8
12%
OH
OH
O
O
H
2
A
O
47%
OH
O
1
9
10
8%
OH
OH
O
H
3
4
B
B
62%
78%
O
OH
1
11
OH
OH
O
H
O
12
OH
1
OH
O
H
OH
O
5
B
OH
O
53%
1
13
O
14
21%
OH
OH
O
H
6
7
8
9
A
B
B
A
48%
O
15
OH
5
O
O
O
OH
O
O
O
OH
O
H
EtO
EtO
EtO
EtO
60%
O
O
OH
OH
OH
6
16
OH
OH
OH
O
H
EtO
EtO
51%
75%
6
17
O
H
OH
O
18
6
Condition A: ethylenediamine diacetate (10 mol %), toluene, reflux, 5 h.
Condition B: ethylenediamine diacetate (10 mol %), xylene, reflux, 5 h.
chromenic acid (20) is shown in Scheme 2. Reaction of 6
with trans,trans-farnesal in the presence of 10 mol % of
ethylenediamine diacetate at refluxing benzene for 5 h
gave adduct 20 in 59% yield. The spectroscopic data of
our synthetic material 20 are in agreement with those
reported in the literature.14

7542
Y. R. Lee et al. / Tetrahedron Letters 46 (2005) 7539–7543
O
OH
OH
HO
H3C
O
H3C
O
20
19
daurichromenic acid
confluentin
H3C
H
H
O
OH
H
O
OH
H
HO
H3C
H
HO
H3C
H
O
CH3
O
CH3
21
22
rhododaurichromanic acid B
rhododaurichromanic acid A
Figure 1.
OH
O
OH
H
ethylenediamine diacetate
xylene, reflux
H3C
O
H3C
OH
65%
19
1
5 h
Scheme 1.
O
OH
O
O
OH
HO
H3C
H
HO
H3C
ethylenediamine diacetate
benzene, reflux
5 h
O
OH
20
6
59%
Scheme 2.
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In conclusion, we have described here the formation of
benzopyrans starting from resorcinols with a,b-unsatu-
rated aldehydes in the presence of ethylenediamine di-
acetate. This methodology has been applied to the
total synthesis of naturally occurring confluentin (19)
and daurichromenic acid (20).
Acknowledgment
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