Facile synthesis of polyhydroxycoumaronochromones with quinones: Synthesis of alkylpolyhydroxy- and alkoxycoumaronochromones from 2′-hydroxyisoflavones

Article abstract of DOI:10.1016/S0040-4039(01)01234-5

4′,5,7-Trihydroxy- or 8-alkyl-4′,5,7-trihydroxycoumaronochromones were synthesized by oxidative cyclization of the corresponding 2′-hydroxyisoflavones with o-chloranil under mild conditions. By contrast, alkoxycoumaronochromones were synthesized by oxidative cyclization of the corresponding 2′-hydroxyisoflavones with DDQ.

Full text of DOI:10.1016/S0040-4039(01)01234-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6163–6166
Facile synthesis of polyhydroxycoumaronochromones with
quinones: synthesis of alkylpolyhydroxy- and
alkoxycoumaronochromones from 2%-hydroxyisoflavones
Masao Tsukayama,* Akihiro Oda, Yasuhiko Kawamura, Masaki Nishiuchi and Kazuyo Yamashita
Department of Chemical Science and Technology, Faculty of Engineering, The University of Tokushima, Minamijosanjima,
Tokushima 770-8506, Japan
Received 10 April 2001; revised 2 July 2001; accepted 6 July 2001
Abstract—4%,5,7-Trihydroxy- or 8-alkyl-4%,5,7-trihydroxycoumaronochromones were synthesized by oxidative cyclization of the
corresponding 2%-hydroxyisoflavones with o-chloranil under mild conditions. By contrast, alkoxycoumaronochromones were
synthesized by oxidative cyclization of the corresponding 2%-hydroxyisoflavones with DDQ. © 2001 Elsevier Science Ltd. All
rights reserved.
Coumaronochromones
(=benzofuro[2,3-b][1]benzo-
molecule. For the synthesis of coumaronochromones, it
is also necessary to investigate the suitable oxidants for
the biogenetic-like dehydrocyclization of 2%-hydroxy-
isoflavones. Quinones have been applied occasionally as
dehydrogenating reagents under mild conditions; high-
potential quinones such as 2,3-dichloro-5,6-dicyanoben-
zoquinone (DDQ) or tetrachloro-1,2-benzoquinone
(o-chloranil) reacted with hydroaromatic compounds,
benzylic alcohols, and o-(3,3-dialkylallyl)phenols under
mild conditions to give the corresponding dehydro-
genated aromatic compounds, carbonyl compounds,
and chromenes in good yields, respectively.1a,5 Our
interest in high dehydrogenation of the phenol com-
pounds by the quinones under mild conditions encour-
aged us to apply this methodology to the preparation of
C-alkyl-orC-alkenylpolyhydroxycoumaronochromones
from the corresponding 2%-hydroxyisoflavones.
pyran-11-ones) occur along with isoflavones in nature,
and lisetin was known as the single example of these
compounds for many years, although, recently, the
structures of many coumaronochromones have been
characterized by spectroscopic studies.1 Lisetin [4%,5,7-
trihydroxy-5%-methoxy-3%-(3-methyl-2-butenyl)coumaro-
nochromone] was synthesized by oxidative cyclization
of piscerythrone (2%-hydroxyisoflavone) with K3[Fe-
(CN)6] in low yield,1b and other unsubstituted or O-
alkylated coumaronochromones, albeit in generally low
yields, were synthesized by oxidation of the correspond-
ing 2%-hydroxyisoflavones with oxidants such as
Ag2CO3, lead(IV) acetate, and SeO2.2 Recently, new
and unique alkyl- or alkenylpolyhydroxycou-
maronochromones such as lupiltin, lupinalubin B, etc.
have been isolated as a small amount of the compo-
nents along with several new isoflavones from the roots
of white lupin (Lupinus albus L.) and the structures
have been identified by spectroscopic studies.3 The total
synthesis of these coumaronochromones has not been
achieved yet, although a biosynthetic pathway of cou-
maronochromones from isoflavone precursors has been
proposed by Ollis and his colleagues.4 The reason seems
to be due to difficulty in introducing regioselectively an
alkyl or alkenyl group into the isoflavone or cou-
maronochromone nucleus and the selectivity of protec-
tion and deprotection of the hydroxy groups in the
We have examined for the first time the simple and
general applicability of DDQ or o-chloranil to the
synthesis of polyhydroxycoumaronochromones from
the corresponding 2%-hydroxyisoflavones and report
here on the first syntheses of lupilutin (1,3,8-trihydroxy-
4-(3-hydroxy-3-methylbutyl)benzofuro[2,3-b][1]benzo-
pyran-11-one) (1),6 4%,5,7-trihydroxy-4-(3-methyl-2-
butenyl)benzofuro[2,3-b][1]benzopyran-11-one)
lupinalbin (4%,5,7-trihydroxycoumaronochromone)
(3),3
and
(2),
A
4%,5,7-trihydroxy-5%-methoxycoumarono-
chromone (4), alkoxycoumaronochromones 51b and 6.
Compounds 2, 4, 5 and 6 have yet to be isolated from
natural sources.
Keywords: coumaronochromones; 2%-hydroxyisoflavones; oxidative
cyclization; o-chloranil.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01234-5

6164
M. Tsukayama et al. / Tetrahedron Letters 42 (2001) 6163–6166
Condensation of 2%-(methoxymethoxy)acetophenone
127 with benzaldehyde 13 in the presence the of KOH
at 85°C in ethanol gave the corresponding 2%-
(methoxymethoxy)chalcone, which was converted into
2%-acetoxychalcone 14 (mp 115–116°C, 68% overall) by
demethoxymethylation with hydrochloric acid and the
subsequent acetylation of the resulting 2%-hydroxychal-
cone by the acetic anhydride/pyridine method (Scheme
1). Oxidative rearrangement of 14 with thallium(III)
nitrate trihydrate (TTN), followed by cyclization of the
resulting crude acetal 15 with aqueous NaOH gave
isoflavone 16 (mp 178–179°C), which was converted
into tetrahydroxyisoflavone 88 (mp 254–256°C) by cata-
lytic hydrogenation over Pd/C.7 8-Iodoisoflavone 20
(mp 151–152°C) also was synthesized via condensation
of 3%-iodoacetophenone 177 with 13, followed by oxida-
tive rearrangement of the resulting 3%-iodochalcone 18
(mp 82–83°C, 72% overall) and the subsequent cycliza-
tion of acetal 19 by the same procedure as that used to
prepare 16. Coupling reaction of 20 with 2-methyl-3-
butyn-2-ol in the presence of Pd(0)9 gave easily the
8-(3-hydroxy-3-methylbutynyl)isoflavone 21 (mp 221–
223°C), which was hydrogenated over Pd/C to give
8-(3-hydroxy-3-methylbutyl)isoflavone 7.6,7 Oxidative
rearrangement of 5%-benzyloxy-2%-methoxyacetophe-
none with a mixture of m-chloroperbenzoic acid and
trifluoroacetic acid in dichloromethane at 0°C to room
temperature, followed by hydrolysis of the resulting
crude acetate with 10% aqueous NaOH in methanol/
dioxane gave 5-benzyloxy-2-methoxyphenol (mp 106–
108°C, 72% overall), which was converted into
2,4-bis(benzyloxy)-1-methoxybenzene (95%) by using
benzyl chloride and K2CO3 in DMF at 80°C. Formyla-
tion of the 1-methoxybenzene with DMF–phosphoryl
chloride in 1,2-dichloroethane gave 5-methoxybenzalde-
hyde 22.10 The condensation of 12 with 22 gave chal-
cone 23 (mp 111–112°C, 76% overall), which was
converted into tetrahydroxy-5%-methoxyisoflavone
9
(mp 267°C, decomposition) via acetal 24 and the subse-
quent isoflavone 25 (mp 152–154°C) by the same proce-
dure as that used to prepare 8. The reaction of
2,4-dihydroxy-5-methoxybenzaldehyde, prepared from
R1
BnO
OMOM
Ac
BnO
O
BnO
OBn
R2
12 R1=H
17 R1=I
13 R2=H
22 R2=OMe
26
OMe
OBn
OHC
OHC
R2
R1
R1
R1
MeO OMe
OAc
R2
OBn
BnO
OAc
BnO
O
BnO
OBn
ii
i
OBn
OBn
OBn
OBn O
OBn O
R2
OBn
O
OBn
16 R1=R2=H
20 R1=I, R2=H
21 R1=
14 R1=R2=H
18 R1=I, R2=H
23 R1=H, R2=OMe
15 R1=R2=H
19 R1=I, R2=H
v
, R2=H
24 R1=H, R2=OMe
OH
25 R1=H, R2=OMe
R1
R1
1
OH
OH
8
HO
O
O
R3O 7
O
2
O
iii
iv
2'
3'
OH
6
OR3
5
4
4'
OH
OR3
O
6'
R2
5'
R2
8 R1=R2=H
7 R1=
3
R1=R2=R3=H
27 R1=R2=H, R3=Ac
, R2=H
9 R1=H, R2=OMe
1
R1=
, R2=R3=H
OH
OH
OH
MeO
O
MeO
O
O
28 R1=
, R2=H, R3=Ac
iv
O
OMe
OH
O
R1=
R1=R3=H, R2=OMe
, R2=R3=H
O
OMeO
OMe
2
4
OMe
10
5
MeO
O
MeO
O
O
29 R1=H, R2=OMe, R3=Ac
O
iv
O
O
HO
HO
O
O
O
11
6
Scheme 1. Reagents and conditions: (i) CHCl3/MeOH, TTN (2 equiv.), 40°C, 2 h, each crude solid; (ii) THF/MeOH, 10% NaOH,
35°C, 2 h, 75–80% from (i); (iii) 1,4-dioxane/MeOH, H2, 5% Pd/C, rt, 8 h, 81–92%; (iv) 1,4-dioxane, DDQ or o-chloranil; (v)
2-methyl-3-butyn-2-ol, PdCl2 (3 mol%), PPh3 (6 mol%), CuI (3 mol%), NEt3/DMF, 85°C, 2 h, 77%.

M. Tsukayama et al. / Tetrahedron Letters 42 (2001) 6163–6166
6165
Table 1. Oxidative cyclization of 2%-hydroxyisoflavones to coumaronochromones by DDQ or o-chloranil
Isoflavone
Quinone (equiv.)
Solvent
Temp. (°C)
Time (h)
Product (yield %)a
7
DDQ (2.2)
o-Chloranil (2.3)
THF
Dioxane
50
80
0.5
2
Decomposed
1 (71)
2 (73)b
8
9
DDQ (2.2)
o-Chloranil (2.3)
DDQ (1.2)
o-chloranil (2.3)
DDQ (1.2)
DDQ (1.2)
THF
50
80
25
80
25
25
0.5
2
0.5
2
2
2
3 (63)
Dioxane
Dioxane
Dioxane
THF
3 (50)c
Decomposed
4 (49)
5 (78)
10
11
THF
6 (82)
a Isolated yields.
b Overall yield from 28 via dehydration and hydrolysis.
c Overall yield from 8 via 27.
22 in 94% yield by debenzylation, with 2-methyl-3-
buten-2-ol in the presence of BF3·OEt2 in dioxane gave
2,4-dihydroxy-5-methoxy-3-(3-methyl-2-butenyl)benzal-
dehyde (40%), whose cyclization with HCl, followed by
benzylation of the resulting crude 6-formyl-5-hydroxy-
8-methoxy-2,2-dimethylchroman, afforded 5-benzyloxy-
2,2-dimethylchroman 26 (mp 164–165°C, overall 20%).
Condensation of 4%,6%-dimethoxy-2%-methoxymethoxy-
acetophenone with 26 gave 2%-hydroxydihydropyra-
noisoflavone 10 (mp 235–237°C, 27% overall) by the
same procedure as that used to prepare 8.
contain free hydroxy groups, which are highly suscepti-
ble to oxidation with DDQ, the oxidation of these
compounds would not lead to decomposition.
On the basis of the above results, the oxidative cycliza-
tion of alkoxy-2%-hydroxyisoflavones with DDQ gave
the desired coumaronochromones in high yields, while
alkylpolyhydroxyisoflavones were shown to be easily
oxidized to the corresponding coumaronochromones by
o-chloranil.
To a THF solution of 2%-hydroxyisoflavone 8, DDQ
(1.2 equiv.) was added under mild conditions and
stirred for 10 min, and subsequently DDQ (1.0 equiv.)
was again added into the solution, and the reaction was
completed in 30 min. The reaction mixture was purified
by silica-gel column chromatography to give the desired
coumaronochromone 311 in good yield as shown in
Table 1. Oxidative cyclization of 8 with o-chloranil [the
reduction potential (0.83 V) is lower than that (1.0 V)
of DDQ]5 in dioxane at 80°C, followed by acetylation
of the resulting crude compound 311 gave triacetate 273
(mp 256–258°C, 55%), which was hydrolyzed to 3.
References
1. (a) Dewick, P. M. In The Flavonoids: Advances in
Research Since 1986; Harborne, J. B., Ed.; Chapman &
Hall: London, 1994; pp. 193–195; (b) Falshaw, C. P.;
Ollis, W. D.; Moore, J. A.; Magnus, K. Tetrahedron,
Suppl. 1966, 7, 333–348.
2. (a) Antus, S.; Nogradi, M. Acta Chim. Acad. Sci. Hung.
1979, 100, 179–182; Chem. Abstr. 1980, 92, 59169; (b)
Kurosawa, K.; Araki, F. Bull. Chem. Soc. Jpn. 1979, 52,
529–532; (c) Chubachi, M.; Hamada, M.; Kawano, E.
Agric. Biol. Chem. 1983, 47, 619–621.
3. Tahara, S.; Ingham, J. H.; Mizutani, J. Agric. Biol. Chem.
1985, 49, 1775–1783.
4. Falshaw, C. P.; Harmer, R. A.; Ollis, W. D.; Wheeler, R.
E. J. Chem. Soc. (C) 1969, 374–382.
5. (a) Becker, H.-D. In The Chemistry of the Quinoid Com-
pounds, Part 1; Patai, S., Ed.; John Wiley & Sons:
London, 1974; pp. 335–423; (b) Becker, H.-D.; Bjo¨rk, A.;
Adler, E. J. Org. Chem. 1980, 45, 1596–1600.
6. Hashidoko, Y.; Tahara, S.; Mizutani, J. Agric. Biol.
Chem. 1986, 50, 1797–1807.
7. Tsukayama, M.; He, L.; Tsurumoto, K.; Nishiuchi, M.;
Kawamura, Y. Bull. Chem. Soc. Jpn. 1998, 71, 2673–
2680.
Oxidation of 8-alkylisoflavone
K3[Fe(CN)6] led to decomposition and the desired cou-
maronochromone was not obtained. Oxidative
7 with DDQ or
1
decomposition of compound 7 with DDQ would take
place via the formation of a 5,8-quinomethide struc-
ture. Oxidative cyclization of 7 with o-chloranil gave
easily the desired compound 1,11 which was converted
into triacetate 28 (mp 202–204°C). Dehydration of 28
with BF3·OEt2 in CH2Cl2 at 20°C, followed by hydroly-
sis of the resulting crude 8-prenylcoumaronochromone
gave easily trihydroxy-8-prenylcoumaronochromone
2.11 Oxidation of 5%-methoxyisoflavone 9 with DDQ
also led to decomposition and the desired cou-
maronochromone 4 was not obtained, because oxida-
tive decomposition would probably proceed via the
4%,5%-quinoid formation. Oxidative cyclization of 9 with
o-chloranil, however, gave compound 4,11 which was
converted into triacetate 29 (mp 250–252°C). Oxidative
cyclization of alkoxyisoflavone 10 and 6-alkylisoflavone
1112 with DDQ gave the corresponding cou-
maronochromones 511 and 611 in high yields, respec-
tively. Because alkoxyisoflavones 10 and 11 do not
8. Biggs, R. Aust. J. Chem. 1975, 28, 1389–1392.
9. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467–4470.
10. Compound 22: Colorless needles; mp 112–114°C (94%);
1H NMR (400 MHz, CDCl3): l 3.88 (3H, s, OCH3), 5.04
and 5.18 (each 2H, s, OCH2), 6.55 (1H, s, 3-H), 7.34–7.39
(11H, m, Ar-H), 10.35 (1H, s, CHO). Found: C, 75.92; H,
5.91; calcd for C22H20O4: C, 75.84; H, 5.79%.

6166
M. Tsukayama et al. / Tetrahedron Letters 42 (2001) 6163–6166
11. Compound 3: Colorless needles; mp >300°C; 1H NMR
(400 MHz, (CD3)2CO): l 6.37 (1H, d, J=2.4 Hz, 6-H),
6.60 (1H, d, J=2.4 Hz, 8-H), 7.02 (1H, dd, J=2.0 and
8.3 Hz, 5%-H), 7.14 (1H, d, J=2.0 Hz, 3%-H), 7.81 (1H, d,
J=8.3 Hz, 6%-H), 8.90 and 9.77 (each 1H, s, OH), 12.99
(1H, s, 5-OH). Found: C, 61.72; H, 3.31; calcd for
m/z (EI): 352 (M+, 100). Found: C, 64.80; H, 4.82; calcd
for C20H16O6·H2O: C, 64.86; H, 4.90%. Compound 4:
Colorless needles; mp>300°C; 1H NMR (400 MHz,
DMSO-d6): l 3.87 (3H, s, OCH3), 6.30 (1H, s, 6-H), 6.56
(1H, s, 8-H), 7.18 (1H, s, 3%-H), 7.36 (1H, s, 6%-H), 9.53
(1H, s, OH), 10.94 (1H, br s, OH), 12.91 (1H, s, 5-OH).
Found: C, 61.15; H, 3.21; calcd for C16H10O7: C, 60.95;
H, 3.48%. Compound 5: Colorless needles; mp 277–
279°C; 1H NMR (400 MHz, CDCl3): l 1.44 (6H, s,
CH3×2), 1.90 (2H, t, J=6.8 Hz, 2%%-H), 2.98 (2H, t, J=6.8
Hz, 1%%-H), 3.91, 3.93 and 3.98 (each 3H, s, OCH3), 6.46
(1H, d, J=2.4 Hz, 6-H), 6.60 (1H, d, J=2.4 Hz, 8-H),
7.52 (1H, s, 6%-H). Found: C, 67.07; H, 5.39; calcd for
C23H22O7: C, 67.31; H, 5.40%. Compound 6: Colorless
C15H8O6·1/2H2O: C, 61.44; H, 3.10%. Compound 1: Col-
7
orless needles; mp 286–288°C (lit.
284–286°C); 1H
NMR (400 MHz, (CD3)2CO): l 1.31 (6H, s, CH3×2), 1.78
(2H, m, 2%%-H), 2.92 (2H, m, 1%%-H), 3.65 (1H, br s,
3%%-OH), 6.43 (1H, s, 6-H), 7.01 (1H, dd, J=8.3 and 2.0
Hz, 5%-H), 7.14 (1H, d, J=2.0 Hz, 3%-H), 7.80 (1H, d,
J=8.3 Hz, 6%-H), 8.99 and 9.98 (each 1H, br s, OH),
12.93 (1H, s, 5-OH). IR (KBr): 3450, 1650, 1600, 1500,
1420, 1320, 1210, 1130, 1100 cm−1. Found: C, 64.94; H,
4.96; calcd for C20H18O7: C, 64.86; H, 4.90%. Compound
2: Colorless needles; mp 259–261°C; 1H NMR (400 MHz,
CDCl3): l 1.67 and 1.87 (each 3H, s, CH3), 3.51 (2H, d,
J=7.3 Hz, 1%%-H), 5.28 (1H, t, J=7.3 Hz, 2%%-H), 6.44
(1H, s, 6-H), 7.02 (1H, dd, J=8.3 and 2.0 Hz, 5%-H), 7.15
(1H, d, J=2.0 Hz, 3%-H), 7.81 (1H, d, J=8.3 Hz, 6%-H),
8.88 and 9.75 (each 1H, br s, OH), 12.94 (1H, s, 5-OH).
1
needles; mp 237–239°C; H NMR (400 MHz, CDCl3): l
1.32 (6H, s, CH3×2), 1.82 (2H, m, 2%%-H), 2.81 (2H, m,
1%%-H), 3.97 (3H, s, OCH3), 6.05 (2H, s, OCH2O), 6.96,
7.05, 7.26 and 8.11 (each 1H, s, Ar-H). Found: C, 66.55;
H, 5.65; calcd for C22H22O7: C, 66.34; H, 5.57%.
12. Tsukayama, M.; He, L.; Nishiuchi, M.; Takahashi, M.;
Kawamura, Y. J. Chem. Res. (M) 1998, 1181–1196.
.