Facile synthesis of 1,3,7-trihydroxyxanthone and its regioselective coupling reactions with prenal: Simple and efficient access to osajaxanthone and nigrolineaxanthone F

Article abstract of DOI:10.1021/jo0606655

A facile five-step synthesis of naturally occurring 1,3,7- trihydroxyxanthone has been described starting from 1,3,5-trimethoxybenzene via NBS-induced nuclear bromination, lithiation followed by an in situ benzoylation with methyl 2,5-dibenzyloxybenzoate, selective deprotection of the two benzyl groups, base-catalyzed intramolecular cyclization, and demethylations pathway with 62% overall yield. The regioselective coupling reactions of 1,3,7-trihydroxyxanthone with prenal in the presence of calcium hydroxide at room temperature and under thermal conditions at 140-150 °C have been demonstrated to exclusively obtain the natural products osajaxanthone in 15% yield and nigrolineaxanthone F in 98% yield, respectively.

Full text of DOI:10.1021/jo0606655

all the available sites on these hydroxy-substituted xanthones
for remarkable regioselective coupling reactions with the
naturally occurring prenal, citral, and farnesal to design a vast
array of corresponding pyranoxanthones and also to generate
their complex structural architectures with the help of further
intramolecular cyclizations.1-4 The 1,3,7-trihydroxyxanthone (6)
has been isolated from Athyrium mesosorum, and it possesses
xanthine oxidase inhibitor activity.5 The xanthone 6 has been
synthesized earlier in good yield using the intramolecular
oxidative coupling reaction of suitably substituted benzophenone
derivatives.6 In nature, xanthone 6 produces two structural
analogues, osajaxanthone (7a) and nigrolineaxanthone F (8a),
via two different regioselective coupling reactions with prenal.
Osajaxanthone (7a) has been isolated from Calophyllum ener-
Vosum, and it possesses antimicrobial and antifish poison
activities.3 Nigrolineaxanthone F (8a) has been isolated from
the Garcinia nigrolineata species.4 Two multistep total syntheses
of osajaxanthone (7a) have been reported using two different
synthetic strategies.7 To date, exclusive synthesis of Nigro-
lineaxanthone F is not known in the literature. All the reported
attempts to condense xanthone 6 with prenal have resulted in
the formation of a mixture of xanthones 7a and 8a.8 Now we
herein report a short and efficient synthesis of xanthone 6 and
the regioselective coupling reactions of 6 with prenal to
exclusively design osajaxanthone (7a) and nigrolineaxanthone
F (8a) in high yield (Scheme 1).
Facile Synthesis of 1,3,7-Trihydroxyxanthone and
Its Regioselective Coupling Reactions with
Prenal: Simple and Efficient Access to
Osajaxanthone and Nigrolineaxanthone F†
Mukulesh Mondal,‡ Vedavati G. Puranik,§ and
Narshinha P. Argade*,‡
DiVision of Organic Chemistry (Synthesis),
Centre for Material Characterization,
National Chemical Laboratory, Pune 411 008, India
np.argade@ncl.res.in
ReceiVed March 28, 2006
1,3,5-Trimethoxybenzene (1) on treatment with NBS (1.0
equiv) in refluxing CCl4 furnished 2-bromo-1,3,5-trimethoxy-
benzene (2) in quantitative yield. Bromobenzene 2 on n-BuLi
(1.0 equiv) induced lithiation, followed by the benzoylation of
the lithiated species with methyl 2,5-dibenzyloxybenzoate gave
the corresponding dibenzyloxytrimethoxybenzophenone 3 in
75% yield. The benzophenone 3, when subjected to catalytic
hydrogenation, yielded the desired dihydroxytrimethoxyben-
zophenone 4 in nearly 100% yield. The benzophenone 4 on
base-catalyzed intramolecular cyclization9 via the oxa-Michael
addition, followed by the elimination pathway, furnished the
dimethoxyhydroxyxanthone 5 in quantitative yield. The BBr3
(6.0 equiv) induced demethylations of xanthone 5 gave the
naturally occurring 1,3,7-trihydroxyxanthone (6) in 82% yield.
Starting from the symmetrical trimethoxybenzene 1, the xan-
thone 6 was obtained in five steps with 62% overall yield. The
analytical and spectral data obtained for xanthone 6 was in
A facile five-step synthesis of naturally occurring 1,3,7-
trihydroxyxanthone has been described starting from 1,3,5-
trimethoxybenzene via NBS-induced nuclear bromination,
lithiation followed by an in situ benzoylation with methyl
2,5-dibenzyloxybenzoate, selective deprotection of the two
benzyl groups, base-catalyzed intramolecular cyclization, and
demethylations pathway with 62% overall yield. The regio-
selective coupling reactions of 1,3,7-trihydroxyxanthone with
prenal in the presence of calcium hydroxide at room tem-
perature and under thermal conditions at 140-150 °C have
been demonstrated to exclusively obtain the natural products
osajaxanthone in 75% yield and nigrolineaxanthone F in 98%
yield, respectively.
The natural and unnatural xanthones are an important class
of compounds.1 Several hydroxy and multiple-hydroxy-substi-
tuted xanthones exist in nature.2 Nature very smartly explores
(3) (a) Taher, M.; Idris, M. S.; Ahmad, F.; Arbain, D. Phytochemistry
2005, 66, 723. (b) Lopes, J. L. C.; Lopes, J. N. C.; Gilbert, B.; Bonini, S.
E. Phytochemistry 1977, 16, 1101. (c) Wolfrom, M. L.; Dickey, E. E.;
McWain, P.; Thompson, A.; Looker, J. H.; Windrath, O. M.; Komitsky, F.
J. Org. Chem. 1964, 29, 689.
(4) Rukachaisirikul, V.; Ritthiwigrom, T.; Pinsa, A.; Swangchote, P.;
Taylor, W. C. Phytochemistry 2003, 64, 1149.
† NCL Communication No. 6693.
‡ Division of Organic Chemistry.
§ Centre for Material Characterization.
(1) (a) Hay, A. E.; Aumond, M. C.; Mallet, S.; Dumontet, V.; Litaudon,
M.; Rondeau, D.; Richomme, P. J. Nat. Prod. 2004, 67, 707. (b) Matsumoto,
K.; Akao, Y.; Kobayashi, E.; Ohguchi, K.; Ito, T.; Tanaka, T.; Iinuma, M.;
Nozawa, Y. J. Nat. Prod. 2003, 66, 1124. (c) Rukachaisirikul, V.; Kamkaew,
M.; Sukavisit, D.; Phongpaichit, S.; Sawangchote, P.; Taylor, W. C. J. Nat.
Prod. 2003, 66, 1531. (d) Gopalakrishnan, G.; Banumathi, B.; Suresh, G.
J. Nat. Prod. 1997, 60, 519. (e) Marston, A.; Hamburger, M.; Sordat-
Diserens, I.; Msonthi, J. D.; Hostettmann, K. Phytochemistry 1993, 33, 809.
(f) Bo, T.; Liu, H. J. Chromatogr., B 2004, 812, 165 and references therein.
(2) (a) Nicolaou, K. C.; Xu, H.; Wartmann, M. Angew. Chem., Int. Ed.
2005, 44, 756. (b) Dharmaratne, H. R.; Piyasena, K. G.; Tennakooan, S. B.
Nat. Prod. Res. 2005, 19, 239. (c) Sukpondma, Y.; Rukachaisirikul, V.;
Phongpaichit, S. J. Nat. Prod. 2005, 68, 1010 and references therein.
(5) Noro, T.; Ueno, A.; Mizutani, M.; Hashimoto, T.; Miyase, T.;
Kuroyanagi, M.; Fukushima, S. Chem. Pharm. Bull. 1984, 32, 4455.
(6) (a) Patel, G. N.; Trivedi, K. N. Synth. Commun. 1989, 19, 1641. (b)
Ellis, R. C.; Whalley, B.; Ball, K. J. Chem. Soc., Perkin Trans. 1 1976,
1377. (c) Findlay, J. W. A.; Gupta, P.; Lewis, J. R. J. Chem. Soc. C 1969,
2761 and references therein.
(7) (a) Wolfrom, M. L.; Koos, E. W.; Bhat, H. B. J. Org. Chem. 1967,
32, 1058. (b) Jain, A. C.; Khanna, V. K.; Seshadri, T. R. Tetrahedron 1969,
25, 2787. (c) Tisdale, E. J.; Kochman, D. A.; Theodorakis, E. A. Tetrahedron
Lett. 2003, 44, 3281.
(8) (a) Wolfrom, M. L.; Komitsky, F.; Looker, J. H. J. Org. Chem. 1965,
30, 144. (b) Lewis, J. R.; Reary, J. B. J. Chem. Soc. C 1970, 1662.
(9) Horne, S.; Rodrigo, R. J. Org. Chem. 1990, 55, 4520.
10.1021/jo0606655 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/20/2006
4992
J. Org. Chem. 2006, 71, 4992-4995

SCHEME 1 a
a Key: (i) CCl4, NBS (1.0 equiv), reflux, 6 h (∼100%); (ii) THF, -78 °C, n-BuLi (1.0 equiv), 45 min, methyl 2,5-dibenzyloxybenzoate, 30 min (75%);
(iii) H2, 10% Pd-C, methanol, rt, 6 h (∼100%); (iv) (a) KOH (5.0 equiv), MeOH, reflux, 12 h, (b) H+/2 N HCl (∼100%); (v) DCM, BBr3 (6.0 equiv), -78
°C to room temperature, 36 h (82%); (vi) prenal/crotonaldehyde/citral (5 equiv), Ca(OH)2 (2.0 equiv), methanol, rt, 36 h (7a, 75%; 7b, 66%; 7c, 81%); (vii)
prenal/crotonaldehyde/citral (10.0 equiv), 140-150 °C, 6 h (8a, 98%; 8b, 86%; 8c, 80%); (viii) pyridine, Ac2O, rt, 12 h (∼100%).
complete agreement with the reported data.5,6 We feel that our
present simple and efficient approach to xanthone 6 using two
different protecting groups, selective deprotections, and in-
tramolecular cyclization is noteworthy.
tion of xanthone 6 and its condensation with prenal at room
temperature exclusively furnished the osajaxanthone (7a) in 75%
yield. We surmise that the complexation of the Ca2+ ion with
xanthone could be responsible for the present observed selectiv-
ity. The reaction of xanthone 6 with prenal under thermody-
namic conditions (heat, 140-150 °C), with the generation of a
stable carbanion at the 4-position, exclusively furnished the
nigrolineaxanthone F (8a) in 98% yield. The osajaxanthone (7a)
and nigrolineaxanthone F (8a) were further characterized as their
respective diacetyl derivatives 93b and 10. The analytical and
spectral data obtained for xanthones 7a and 8a were in complete
agreement with the reported data.3,4,7,8 As expected, the linear
product osajaxanthone (7a) had a higher melting point than the
corresponding angular nigrolineaxanthone F (8a), but the con-
firmatory structural discrimination of these two natural products
Theoretically, the xanthone 6 can undergo coupling reactions
with the R,â-unsaturated aldehydes at the 2-, 4-, 6-, and
8-position to generate the corresponding benzopyrans via an
aldol-type condensation, followed by SN2′-dehydrative ring-
closure reactions. The order of thermodynamic stability for these
in situ-generated carbanions will be 4 > 2 > 8 > 6 as a result
of the flanking of the 4-position carbanion between carbonyl
and R,â-unsaturated carbonyl, flanking of the 2-position car-
banion between 1,3-dicarbonyl system (on conversion of enol
to keto form), electron-withdrawing inductive effect of xanthone
carbonyl on the 8-position carbanion, and formation of simple
R-carbanion at the 6-position. Because, in xanthone 6, the ring
A is doubly activated, the regioselective coupling reactions of
xanthone 6 at the 2- and 4-position with the R,â-unsaturated
aldehydes to exclusively generate, respectively, the linear and
angular pyranoxanthones under kinetic and thermodynamic
conditions is a practical and challenging task of current interest.
The DBU-induced generation of kinetic carbanion on 3,5-
dihydroxyphthalide10a and Ca(OH)2-induced generation of
kinetic carbanion on methyl 2,4-dihydroxybenzoate10b and their
condensation with R,â-unsaturated aldehydes are known in the
literature.10 The DBU-induced coupling of xanthone 6 with
prenal in acetonitrile at room temperature was slow and gave
7a in only 11% yield after a 72 h reaction time. The same
reaction on heating lost its selectivity and furnished a mixture
of 7a and 8a in good yield. However, the Ca(OH)2-induced
regioselective generation of the kinetic carbanion at the 2-posi-
1
on the basis of H and 13C NMR data was a difficult task.
Finally, the structures of these nice yellow crystalline linear and
angular pyranoxanthones 7a and 8a were confirmed by using
X-ray crystallographic data.11 The X-ray data revealed that the
intramolecular O-H‚‚‚O hydrogen bonding is seen for the
compound 7a in addition to intermolecular O-H‚‚‚O hydrogen
bondings. The molecules of 7a pack in a zigzag manner when
viewed down the “a” axis (Figure 1). Compound 8a initially
forms a dimer by intramolecular O-H‚‚‚O hydrogen bonding
and intermolecular O-H‚‚‚O hydrogen bondings in the packing
of the molecules when viewed down the “c” axis (Figure 2).
The present approach to these xanthones is general in nature,
and we could also very selectively condense crotonaldehyde
and citral with xanthone 6 to obtain the compounds 7b,c and
8b,c in very good yields.
In summary, we have demonstrated a facile access to 1,3,7-
trihydroxyxanthone and its two different regioselective cou-
(10) (a) Mondal, M.; Argade, N. P. Synlett 2004, 1243. (b) Saimoto, H.;
Yoshida, K.; Murakami, T.; Morimoto, M.; Sashiwa, H.; Shigemasa, Y. J.
Org. Chem. 1996, 61, 6768.
(11) For all the details related to X-ray crystallographic data, please see
the Supporting Information.
J. Org. Chem, Vol. 71, No. 13, 2006 4993

FIGURE 1. Intra- and intermolecular hydrogen bonding in 7a and packing of 7a in a zigzag manner when viewed down the “a” axis.
FIGURE 2. Dimeric 8a with intra- and intermolecular hydrogen bonding and packing of 8a when viewed down the “c” axis.
6H), 6.14 (s, 2H); 13C NMR (CDCl3, 50 MHz) δ 55.3, 56.1, 91.4,
91.6, 157.2, 160.3; MS (m/z) 271, 269, 249, 247, 224, 119; IR
(Nujol) 1589, 1574, 1462, 1377, 1346, 1229, 1207, 1155, 1128
cm-1. Anal. Calcd for C9H11BrO3: C, 43.75; H, 4.49; Br, 32.34.
Found: C, 43.69; H, 4.53; Br, 32.59.
pling reactions with prenal to obtain osajaxanthone and nigro-
lineaxanthone F. Our present approach to these three natural
products has several advantages over other known approaches
in the literature.
2,5-Dibenzyloxyphenyl 2′,4′,6′-Trimethoxyphenyl Methanone
(3). To a stirring solution of 2 (10.00 g, 40.45 mmol) in THF (60
mL) at -78 °C was added n-BuLi (27.00 mL, 40.45 mmol)
dropwise. After stirring at -78 °C for 45 min, this reaction mixture
was added slowly to a stirring solution of methyl 2,5-dibenzyloxy-
benzoate (16.90 g, 48.55 mmol) in THF (80 mL) at -78 °C and
stirred for an additional 30 min. A saturated solution of NH4Cl
was then added to the reaction mixture at -78 °C, and the reaction
mixture was allowed to reach room temperature. THF was removed
in vacuo. To the reaction mixture was added ethyl acetate (150
mL), and the organic layer was washed with water and brine and
dried over Na2SO4. Removal of the solvent in vacuo followed by
silica gel column chromatographic purification of the residue using
30% ethyl acetate in petroleum ether afforded 3 (14.6 g, 75%) as
Experimental Section
Methyl 2,5-Dibenzyloxybenzoate. To a stirring mixture of
methyl 2,5-dihydroxybenzoate (10.00 g, 59.52 mmol) and anhy-
drous potassium carbonate (41.10 g, 297.62 mmol) in acetone (100
mL) was added benzylbromide (17.70 mL, 148.80 mmol), and the
reaction mixture was refluxed for 6 h. After cooling, the reaction
mixture was filtered, and concentration of the filtrate under vacuum
followed by silica gel column chromatographic purification of the
residue using 15% ethyl acetate in petroleum ether afforded methyl
2,5-dibenzyloxybenzoate (20.23 g, 98%) as a colorless oil. 1H NMR
(CDCl3, 200 MHz) δ 3.90 (s, 3H), 5.03 (s, 2H), 5.12 (s, 2H), 6.94
(d, J ) 9.1 Hz, 1H), 7.05 (dd, J ) 9.1 and 3.2 Hz, 1H), 7.25-7.55
(m, 11H); 13C NMR (CDCl3, 50 MHz) δ 51.7, 70.2, 71.3, 115.9,
117.0, 119.9, 121.3, 126.7-128.2 (7 carbons) 136.5, 136.8, 152.3,
166.0; MS (m/z) 387, 371, 349, 317, 281, 257, 224, 181, 143; IR
(Nujol) 1722, 1504 cm-1. Anal. Calcd for C22H20O4: C, 75.84; H,
5.79. Found: C, 76.02; H, 5.67.
1
a white solid. Mp 123-125 °C; H NMR (CDCl3, 200 MHz) δ
3.57 (s, 6H), 3.77 (s, 3H), 4.86 (s, 2H), 5.04 (s, 2H), 5.97 (s, 2H),
6.88 (d, J ) 9.0 Hz, 1H), 7.00-7.15 (m, 2H), 7.20-7.45 (m, 10H);
13C NMR (CDCl3, 50 MHz) δ 55.1, 55.7, 70.5, 71.3, 90.7, 114.5,
115.0, 116.3, 120.1, 127.2, 127.4, 127.5, 127.8, 128.0, 128.4, 130.8,
136.7, 136.9, 152.5, 152.6, 158.7, 162.0, 192.9; MS (m/z) 485, 391,
317, 261, 185; IR (Nujol) 1643, 1605, 1585, 1491, 1462, 1416,
1377 cm-1. Anal. Calcd for C30H28O6: C, 74.36; H, 5.82. Found:
C, 74.29; H, 5.90.
2-Bromo-1,3,5-trimethoxybenzene (2). To a solution of 1 (10.00
g, 59.46 mmol) in CCl4 (100 mL) was added NBS (10.58 g, 59.46
mmol), and the reaction mixture was refluxed gently for 3 h. After
cooling, the reaction mixture was filtered, and concentration of the
filtrate under vacuum followed by silica gel column chromato-
graphic purification of the residue using 25% ethyl acetate in
petroleum ether gave 212 (14.6 g, ∼100%) as a white solid. Mp
2,5-Dihydroxyphenyl 2′,4′,6′-Trimethoxyphenyl Methanone
(4). To a stirring solution of 3 (10.00 g, 20.66 mmol) in methanol
(100 mL) at room temperature was added 10% Pd/C (500 mg),
and the reaction mixture was subjected to hydrogenation at 65-psi
hydrogen pressure for 24 h. The reaction mixture was filtered
1
84-86 °C; H NMR (CDCl3, 200 MHz) δ 3.79 (s, 3H), 3.85 (s,
(12) Higgs, D. E.; Nelen, M. I.; Detty, M. R. Org. Lett. 2001, 3, 349.
4994 J. Org. Chem., Vol. 71, No. 13, 2006

through Celite, and the filtrate was concentrated in vacuo. Silica
gel column chromatographic purification of the residue using 40%
ethyl acetate in petroleum ether furnished 4 (6.20 g, ∼100%) as a
yellow solid. Mp 232-234 °C; 1H NMR (DMSO-d6, 200 MHz) δ
3.69 (s, 6H), 3.85 (s, 3H), 6.34 (s, 2H), 6.66 (d, J ) 2.9 Hz, 1H),
6.83 (d, J ) 8.8 Hz, 1H), 7.00 (dd, J ) 9.0 and 3.0 Hz, 1H), 9.10
(s, 1H), 11.45 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 55.8,
56.1, 91.2, 109.1, 116.8, 118.4, 120.9, 125.4, 149.6, 154.8, 157.8,
162.6, 200.6; MS (m/z) 305, 279, 187, 155, 109; IR (Nujol) 3234,
1611, 1582, 1568, 1483, 1458 cm-1. Anal. Calcd for C16H16O6:
C, 63.15; H, 5.30. Found: C, 63.19; H, 5.42.
7-Hydroxy-1,3-dimethoxy-xanthen-9-one (5). To an ice-cooled
stirring solution of 4 (5.00 g, 16.45 mmol) in methanol (30 mL), a
solution of KOH (4.60 g, 82.24 mmol) in methanol (30 mL) was
added slowly. The reaction mixture was refluxed gently for 12 h.
After cooling to 0 °C, the reaction mixture was acidified with 2 N
HCl, and the solid compound obtained was filtered, washed with
cold water, and dried to provide 5 (4.40 g, ∼100%) as a faint yellow
solid. Mp 290-292 °C; 1H NMR (DMSO-d6, 200 MHz) δ 3.83 (s,
3H), 3.84 (s, 3H), 6.39 (d, J ) 2.3 Hz, 1H), 6.54 (d, J ) 2.3 Hz,
1H), 7.16 (dd, J ) 9.0 and 2.9 Hz, 1H), 7.33 (d, J ) 9.0 Hz, 1H),
7.38 (d, J ) 2.9 Hz, 1H), 9.82 (s, 1H); 13C NMR (DMSO-d6, 50
MHz) δ 56.1, 56.3, 93.0, 95.2, 106.1, 109.2, 118.5, 123.1, 123.3,
148.1, 153.9, 159.3, 161.6, 164.7, 173.7; MS (m/z) 273, 253, 205,
185, 155, 149, 125, 114, 109; IR (Nujol) 3391, 1638, 1632, 1593,
1460 cm-1. Anal. Calcd for C15H12O5: C, 66.17; H, 4.44. Found:
C, 65.98; H, 4.58.
Hz, 1H), 7.47 (d, J ) 9.1 Hz, 1H), 10.07 (s, 1H), 13.26 (s, 1H);
13C NMR (DMSO-d6, 100 MHz) δ 28.3, 78.8, 94.9, 103.1, 104.0,
108.2, 114.7, 119.5, 120.6, 125.2, 128.8, 149.4, 154.4, 157.0 (2
carbons), 160.4, 180.5; MS (m/z) 311, 301, 268, 239, 204, 188,
172, 126; IR (Nujol) 3227, 1651, 1632, 1609 cm-1. Anal. Calcd
for C18H14O5: C, 69.67; H, 4.55. Found: C, 69.55; H, 4.73.
6,9-Dihydroxy-3,3-dimethyl-3H,7H-pyrano[2,3-c]xanthen-7-
one (8a). A stirring mixture of 6 (250 mg, 1.02 mmol) and
3-methyl-2-butenal (prenal; 1.00 mL, 10.24 mmol) was heated at
140-150 °C for a period of 6 h. After cooling, the obtained residue
on silica gel column chromatographic purification using 15% ethyl
acetate in petroleum ether gave 8a (310 mg, 98%) as a yellow solid.
Mp 244-245 °C (EtOH); 1H NMR (DMSO-d6, 400 MHz) δ 1.43
(s, 6H), 5.77 (d, J ) 10.2 Hz, 1H), 6.19 (s, 1H), 6.79 (d, J ) 10.1
Hz, 1H), 7.31 (d, J ) 9.0 Hz, 1H), 7.39 (s, 1H), 7.53 (d, J ) 9.0
Hz, 1H), 10.06 (s, 1H), 12.98 (s, 1H); 13C NMR (DMSO-d6, 100
MHz) δ 28.1, 78.6, 98.4, 100.7, 103.0, 108.1, 114.5, 119.4, 120.5,
125.0, 127.8, 149.2, 151.6, 154.4, 160.3, 162.4, 180.4; MS (m/z)
311, 229, 167; IR (Nujol) 3381, 1645, 1466 cm-1. Anal. Calcd for
C18H14O5: C, 69.67; H, 4.55. Found: C, 69.58; H, 4.49.
5,8-Diacetoxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-
one (9). To a stirring solution of 7a (100 mg, 0.32 mmol) in pyridine
(5 mL) was added acetic anhydride (5 mL), and the reaction mixture
was kept in the dark at room temperature for 24 h. The reaction
mixture was poured into ice-cold water and extracted with ethyl
acetate (15 mL × 5). The combined organic layer was washed with
10% aq CuSO4 solution, water, and brine and dried over Na2SO4.
Concentration of the organic layer under vacuum followed by silica
gel column chromatographic purification of the residue using 25%
ethyl acetate in petroleum ether gave 9 (125 mg, ∼100%) as a white
1,3,7-Trihydroxyxanthen-9-one (6). To a stirring suspension
of 5 (4.00 g, 14.71 mmol) in dichloromethane (80 mL) at -78 °C
was added borontribromide (8.40 mL, 88.24 mmol) quickly, and
the reaction mixture was allowed to attain room temperature slowly.
After stirring for 36 h at room temperature, the reaction mixture
was cooled to 0 °C and very slowly quenched with water.
Dichloromethane was removed in vacuo, and ethyl acetate (100
mL) was added to the reaction mixture. The organic layer was
washed with water and brine and dried over Na2SO4. Removal of
the solvent under vacuo followed by silica gel column chromato-
graphic purification of the residue using 30% ethyl acetate in
petroleum ether afforded 6 (3.65 g, 82%) as a yellow solid. Mp
1
solid. Mp 197-199 °C; H NMR (CDCl3, 400 MHz) δ 1.49 (s,
6H), 2.31 (s, 3H), 2.50 (s, 3H), 5.75 (d, J ) 10.1 Hz, 1H), 6.50 (d,
J ) 10.0 Hz, 1H), 6.73 (s, 1H), 7.35-7.45 (m, 2H), 7.89 (s, 1H);
13C NMR (CDCl3, 100 MHz) δ 20.9, 21.0, 28.5, 78.4, 102.1, 108.7,
112.1, 115.0, 118.5, 118.6, 122.7, 128.2, 131.5, 145.5, 146.6, 152.7,
158.0, 159.0, 169.2 (2 carbons), 174.2; MS (m/z) 395, 375, 353,
300, 239; IR (Nujol) 1759, 1749, 1659, 1643, 1614, 1470 cm-1
.
Anal. Calcd for C22H18O7: C, 67.00; H, 4.60. Found: C, 67.15; H,
4.52.
1
318-319 °C; H NMR (DMSO-d6, 200 MHz) δ 6.18 (d, J ) 2.1
6,9-Diacetoxy-3,3-dimethyl-3H,7H-pyrano[2,3-c]xanthen-7-
one (10). Compound 10 was prepared from 8a using the same
procedure described for 9. 10: White solid (126 mg, ∼100% yield);
mp 185-187 °C; 1H NMR (CDCl3, 400 MHz) δ 1.50 (s, 6H), 2.31
(s, 3H), 2.46 (s, 3H), 5.70 (d, J ) 10.0 Hz, 1H), 6.47 (s, 1H), 6.88
(d, J ) 10.3 Hz, 1H), 7.40 (dd, J ) 8.8 and 2.7 Hz, 1H), 7.44 (d,
J ) 8.5 Hz, 1H), 7.90 (d, J ) 2.7 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 20.9, 21.2, 28.4, 78.5, 107.3, 108.5, 108.6, 114.9, 118.5,
118.6, 122.6, 128.3, 129.4, 146.7, 150.7, 152.5, 152.9, 158.4, 169.2,
169.6, 174.2; MS (m/z) 395, 353, 301, 282, 260, 204, 149; IR
(Nujol) 1763, 1751, 1653, 1464 cm-1. Anal. Calcd for C22H18O7:
C, 67.00; H, 4.60. Found: C, 66.89; H, 4.66.
Hz, 1H), 6.35 (d, J ) 1.9 Hz, 1H), 7.27 (dd, J ) 9.0 and 3.0 Hz,
1H), 7.40 (d, J ) 2.9 Hz, 1H), 7.45 (d, J ) 9.1 Hz, 1H), 10.00 (s,
1H), 11.04 (s, 1H), 12.88 (s, 1H); 13C NMR (DMSO-d6, 50 MHz)
δ 93.9, 98.0, 102.1, 108.2, 119.1, 120.6, 124.6, 149.2, 154.1, 157.7,
162.7, 163.0, 179.9; MS (m/z) 291, 267, 259, 245, 224, 204, 191,
161, 127; IR (Nujol) 3368, 3207, 1651, 1614, 1582, 1464 cm-1
.
Anal. Calcd for C13H8O5: C, 63.94; H, 3.30. Found: C, 64.06; H,
3.35.
5,8-Dihydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-
one (7a). To a stirring mixture of 6 (250 mg, 1.02 mmol) and
Ca(OH)2 (15 mg, 2.05 mmol) in methanol (10 mL) at room
temperature was added 3-methyl-2-butenal (prenal; 0.5 mL, 5.12
mmol). After stirring for 36 h at room temperature, methanol was
removed at room temperature under vacuo, and the reaction mixture
was diluted with ethyl acetate (30 mL). The organic layer was
washed with 2 N HCl, water, and brine and dried over Na2SO4.
Removal of the solvent under vacuo followed by silica gel column
chromatographic purification of the residue using 12% ethyl acetate
in petroleum ether gave 7a (235 mg, 75%) as a yellow solid. Mp
266-268 °C (MeOH/EtOH ) 1:1); 1H NMR (DMSO-d6, 400 MHz)
δ 1.43 (s, 6H), 5.77 (d, J ) 10.1 Hz, 1H), 6.40 (s, 1H), 6.60 (d, J
) 9.9 Hz, 1H), 7.29 (dd, J ) 9.0 and 2.8 Hz, 1H), 7.40 (d, J ) 2.6
Acknowledgment. M.M. thanks UGC, New Delhi, for the
award of a research fellowship.
Supporting Information Available: 1H NMR spectra of 3-6,
7a-c, and 8a-c and 13C NMR spectra of 4-6, 7a-c, and 8a. X-ray
crystallographic data in CIF format and ORTEP diagrams for
compounds 7a and 8a. Preparation details and tabulated analytical
and spectral data of compounds 7b, 7c, 8b, and 8c. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO0606655
J. Org. Chem, Vol. 71, No. 13, 2006 4995