Facile total syntheses of two novel 4-alkenyloxy-2,6- dihydroxyacetophenones

Article abstract of DOI:10.1039/a807504b

Two novel acetophenones, 4-(1'-geranyloxy)-2,6-dihydroxyacetophenone 1 and 4-(1'-farnesyloxy)-2,6-dihydroxyacetophenone 2 isolated from the fruit of Evodia merrillii and from the aerial parts of Borronia ramosa respectively, have been synthesized starting from 2,4,6-trihydroxyacetophenone 3; the key step in their total synthesis is the regioselective alkenylation onto the intermediate 6 with alkenyl bromide.

Full text of DOI:10.1039/a807504b

View Article Online / Journal Homepage / Table of Contents for this issue
148 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 148±149$
Facile Total Syntheses of Two Novel
4-Alkenyloxy-2,6-dihydroxyacetophenones$
Chusheng Huang,a,b Zhe Zhang,a Shuhua Lia and Yulin Li*a
aNational Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry,
Lanzhou University, Lanzhou 730000, P.R. China
bInstitute of Applied Chemistry, Guangxi Teaching College, Nanning 530001, P.R. China
Two novel acetophenones, 4-(1'-geranyloxy)-2,6-dihydroxyacetophenone 1 and 4-(1'-farnesyloxy)-2,6-dihydroxy-
acetophenone 2 isolated from the fruit of Evodia merrillii and from the aerial parts of Borronia ramosa respectively, have
been synthesized starting from 2,4,6-trihydroxyacetophenone 3; the key step in their total synthesis is the regioselective
alkenylation onto the intermediate 6 with alkenyl bromide.
Phenols containing alkenyl units are potentially valuable
intermediates in the synthesis of chromenes, chromans,
¯avonoids and other complex natural products.1 Many
of these compounds and modi®cations of these structures
observed in nature possess a wide range of physiological
actions such as anti¯ammatory, antibacterial and anti-
oxidative activities.2 Two novel acetophenones were
recently isolated from the fruits of Evodia merrilli, a small
folk medicine tree widely distributed in Taiwan,3 and
the aerial pars of Borronia romosa in Australian genus
Boronia respectively.4 Their structures were elucidated as
4-(1'-geranyloxy)-4,6-dihydroxyacetophenone (1) and 4-(1'-
farnesyloxy)-2,6-dihydroxyacetophenone (2) by means of
spectral analysis. So far as we know, the synthesis of these
two compounds has not been reported yet. Herein, we wish
to report the ®rst total syntheses of 1 and 2 starting from
2,4,6-trihydroxyacetophenone and alkenyl bromide by ®ve
steps. Synthetic routes are outlined in Scheme 1.
Scheme 1 Reagents and conditions: i, BnCl, DMF, K2CO3,
80 8C, 1 h; ii, TsCl, K2CO3, acetone, reflux, 6 h; iii, H2±10% Pd/C,
MeOH, room temp., 20 h; iv, geranyl bromide (or farnesyl
bromide), K2CO3, acetone, reflux, 2 h; v, 30% aq. KOH±EtOH
(1:1), reflux, 1.5 h
Experimental
Melting points were measured on a Ko¯er hot stage and un-
corrected. IR spectra were obtained on a FT-170-SX spectrometer.
1H NMR spectra were recorded on a Varian FT-80 A instrument in
CDCl3 solution, and chemical shifts were recorded in ppm units
using SiMe4 as internal standard. MS were measured on a ZAB-HS
Compound 3 was treated with benzyl chloride and K2CO3
and MAT-44 S (EI, 70 eV).
4,6-Dibenzyloxy-2-hydroxyacetophenone (4).ÐA mixture of
in dry DMF at 80 8C for 1 h to give 4 in 85% yield.
Treatment of 4, K2CO3 and p-toluensulfonyl chloride in
acetone under re¯ux generated 5 in 85% yield. Compound 6
was obtained in 94% yield by selective hydrogenolysis of 5
using Pd/C as catalyst. Regioselective geranyl annexation
onto 6 with geranyl bromide a€orded compound 7a in
80% yield, similarly by farnesyl annexation onto 6 with
farnesyl bromide, 7b was obtained in 60% yield. Detoluen-
sulfonylation of 7a in 30% KOH ethanol solution gave the
desired natural product 13 in 75% yield, similarly hydrolysis
of 7b, 24 was obtained in 89% yield. The overall yields of
1 and 2 were 41 and 36% respectively.
3
(1.68 g, 10 mmol), benzyl chloride (2.66 g, 21 mmol) and anhydrous
K2CO3 (2.76 g, 20 mmol) in dry DMF (30 mL) was heated at 80 8C
for 1 h under vigorous stirring. After the solid was ®ltered o€,
the ®ltrate was poured into 20 mL water, and extracted with Et2O.
The extract was washed with water, brine, and dried over anhy-
drous MgSO4, and evaporated under reduced pressure to give a
solid residue that was puri®ed by ¯ash column chromatography on
silica gel (petroleum ether±EtOAc, 10:1) to a€ord 4 (2.96 g, 85%)
as colorless needles, mp 94±96 8C (lit.5 mp 96±98 8C).
2-Tolunesulfonyloxy-4,6-dibenzyloxyacetophenone (5).ÐA mixture
of 4 (1.15 g, 3.3 mmol), TsCl (0.940 g, 5.0 mmol) and anhydrous
K2CO3 (4.45 g, 32 mmol) in dry acetone (100 mL) was re¯uxed
under stirring for 6 h. After work-up, the residue was recrystallized
from EtOAc±petroleum ether to give a colorless powder 5 (1.41 g,
85%), mp 122±123 8C; IR ꢀ/max (KBr) 1696, 1616, 1575, 1497,
1432, 1374, 1159, 1055 cm 1; ꢁH 2.36 (3 H, s, C6H4Me), 2.47 (3 H,
s, COMe), 4.99 (2 H, s, ArCH2O), 5.04 (2 H, s, ArCH2O), 6.53
(2 H, s, H-3 and H-5), 7.27±7.43 (12 H, m, ArH), 7.78 (2 H, d,
*To receive any correspondence (e-mail: liyl@lzu.edu.cn).
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

View Article Online
J. CHEM. RESEARCH (S), 1999 149
‡
J ˆ 8.1 Hz); EIMS m/z (M ) 502 (5), 487 (12), 397 (11), 348 (2),
3134, 1655, 1626, 1560, 1287, 1165 cm 1; ꢁH 1.63, 1.70, 1.75 (3 H
each, s, Me-8', Me-9' Me-10'), 2.11 (4 H, m, 2 H-4', 2 H-5'), 2.64
(3 H, s, COMe), 4.57 (2 H, d, J ˆ 6.5 Hz, 2 H-1'), 5.09 (1 H, br s,
w1/2=7 Hz, H-6'), 5.44 (1 H, t, J ˆ 6.5 Hz, H-2'), 5.92, 5.99 (1 H
‡
347 (8), 181 (12), 91 (100); HREIMS m/z (M ) 504.1410
(C29H26O6S requires 502.1450).
2-Toluenesulfonyloxy-4,6-dihydroxyacetophenone (6).ÐA well
stirred mixture of 5 (1.00 g, 2.0 mmol) and 10% Pd/C (100 mg) in
MeOH (20 mL) was passed through H2 at room temperature for
20 h. The residual black solid and evaporated solution was puri®ed
by silica gel column chromatography eluting with petroleum ether±
EtOAc (10:1 to 4:1) to give 6 as colorless needles (565 mg, 94%),
mp 150±152 8C; IR ꢀ/max (KBr) 3407, 3259, 1631, 1595, 1447,
1372, 1265, 1179, 1036 cm 1; ꢁH 2.39 (3 H, s, C6H4Me), 2.51 (3 H,
s, COMe), 6.10, 6.25 (1 H each, d, J ˆ 2 Hz, H-3, H-5), 7.35, 7.70
(2 H each, d, J ˆ 8 Hz, p-MeC6H4SO2), 13.80 (1 H, s, OH); EIMS
‡
each, d, J ˆ 2.4 Hz, H-3, H-5), 13.98 (1 H, s, OH); EIMS m/z [M ]
304 (7), 181 (5), 168 (100), 153 (91), 137 (32), 121 (7), 81 (33), 69
(68); HREIMS m/z (M ) 304.1695 (C18H24O4 requires 304.1674).
‡
The spectral data of 1 are essentially identical with those of natural
1 as reported in ref. 4.
4-(1'-Farnesyloxy)-2,6-dihydroxyacetophenone (2).ÐLikewise treat-
ment of 7b (90 mg, 0.17 mmol) in KOH±EtOH, gave compound 2
(57 mg, 89%) as a white gum. IR ꢀ/max 3124±2966, 2927, 2845,
1710, 1624, 1550, 1463, 1371, 1287, 1257, 1165, 1072, 947, 820,
800 cm 1; ꢁH 1.60 (6 H, s, 2 Me), 1.67, 1.73 (3 H each, s, 2 me),
1.94±2.25 (8 H, m, 2 H-4', 2 H-5', 2 H-8', 2 H-9'), 2.61 (3 H,
s, COMe), 4.54 (2 H, d, J ˆ 6.5 Hz, 2 H-1'), 5.09 (2 H, br s,
w1/2=7.0 Hz, H-10', H-6'), 5.46 (1 H, t, J ˆ 6.2 Hz, H-2'), 5.92 (2 H,
‡
‡
m/z [M ] 322 (16), 280 (10), 258 (27), 155 (76), 91 (100); HREIMS
m/z [M ] 322.0483 (C15H14O6S requires 322.0511).
2-Toluensulfonyloxy-6-hydroxy-4-(1'-geranyloxy)acetophenone (7a).
ÐA mixture of 6 (322 mg, 1 mmol), geranyl bromide (217 mg,
1 mmol) and anhydrous K2CO3 (276 mg, 2 mmol) in acetone
(20 mL) was well stirred at room temperature for 2 h. After work-
up, 7a (385 mg, 84%) was obtained by silica gel column chromatog-
raphy, eluting with petroleum ether±EtOAc (10:1 to 4:1), as a color-
less gum. IR ꢀ/max (KBr) 1694, 1573, 1429, 1379, 1180, 1154, 1079.
ꢁH 1.62, 1.70, 1.72 (3 H each, s, Me-8', Me-9', Me-10'), 1.95±2.15
(4 H, m, 2 H-4', 2 H-5'), 2.45 (3 H, s, C6H4Me), 2.60 (3 H, s,
COMe), 4.48 (2 H, d, J ˆ 6.5 Hz, 2 H-1'), 5.10 (1 H, app. t, H-6'),
5.42 (1 H, app. f, H-2'), 6.40 (2 H, s, H-3, C6H4 H-5), 7.35, 7.81
(2 H each, d, J ˆ 8.1 Hz, p-MeC6H4SO2), 13.27 (1 H, OH); EIMS
‡
s, H-2, H-5), 13.97 (1 H, s, OH); EIMS m/z [M ] 372 (5), 357 (1),
303 (8), 235 (8), 204 (7), 168 (22), 153 (30), 137 (12), 123 (7), 121
(12), 119 (8), 93 (15), 81 (51), 69 (100), Calc. for C23H32O4: C, 74.16;
H, 8.66. Found: C, 74.14; H 8.66%. The spectral data of 2 are
essentially identical with those of natural as reported in ref. 5.
This research was ®nancially supported by the National
Natural Science Foundation of China (No. 29560003) and
the Natural Science Foundation of Guangxi.
‡
m/z (M ) 458 (3), 323 (33), 303 (5), 281 (23), 258 (47), 181(3), 155
(99), 91(100), 69 (71). HREIMS m/z [M ] 458.1745 (C25H30O6S
requires 458.1763).
‡
Received, 28th September 1998; Accepted, 18th November 1998
Paper E/8/07504B
2-Toluensulfonyloxy-6-hydroxy-4-(1'-farnesyloxy)acetophenone (7b).
ÐSimilar to the reaction of 6 and geranly bromide, treatment of 6
(1 mmol) with farnesyl bromide (1 mmol) gave a colorless gum 7b
(316 mg, 60%). IR ꢀ/max (KBr) 1627, 1575, 1480, 1380, 1204, 1184,
1157, 1089 cm 1. ꢁH 1.61, 1.0 (12 H, s, 4 Me), 1.95±2.15 (8 H, m,
2 H-4', 2 H-5', 2 H-8', 2 H-9'), 2.47 (3 H, s, C6H4Me), 2.60 (3 H,
s, COMe), 4.47 (2 H, d, J ˆ 6.5 Hz, 2 H-1'), 5.12 (2 H, m, H-6',
H-10'), 5.41 (1 H, d, J ˆ 6.5 Hz, H-2'), 6.17, 6.32 (1 H each, br s,
References
1 G. P. Ellis, Chromenes, Chromanones and Chromones, John Wiley
and Sons, New York, 1977; J. B. Harborne, The Flavonoids:
Advances in Research since 1980, Chapman and Hall, New York,
1988.
2 H. Fukui, H. Egawa, K. Koshimizu and T. Mitsui, Agric. Biol.
Chem., 1973, 37, 417; W. S. Bowers, T. Ohta, J. S. Cleere and
P. A. Marseilla, Science, 1976, 193, 542; W. R. Phillips, N. J. Baj,
A. A. L. Gunatilaka and D. G. I. Kingston, J. Nat. Prod., 1996,
59, 495; M. L. Barrett, A. M. Scott and F. J. Evans, Experientia,
1986, 42, 452; R. K. Razdan, W. R. Thompson, H. G. Parks and
F. E. Gramchelli, Tetrahedron Lett., 1967, 3405.
3 C. J. Chou, I. C. Lin and C. F. Chen, J. Nat. Prod., 1992, 55,
795.
4 A. Monira, I. G. Alexander and G. W. Peter, J. Nat. Prod., 1994,
57, 673.
5 M. Tsukayama, K. Fujimoto, T. Horie, M. Masumura and
M. Nakayama, Bull. Chem. Soc. Jpn, 1985, 58, 1.
w1/2=2 Hz, H-3, H-5), 7.36, 7.78 (2
H
each, d, J ˆ 7.9 Hz,
‡
p-MeC6H4SO2, 13.26 (1 H, s, OH). EIMS m/z [M ] 526 (4), 483 (1),
419 (1), 371 (5), 323 (33), 281 (30), 258 (28), 204 (20), 155 (63), 91
(64), 69 (100). Calc. for C30H38O6S: C, 68.41; S, 6.09; H, 7.27.
Found: C, 68.48; S, 6.10; H, 7.25%.
2-(1'-Geranyloxy)-4,6-dihydroxyacetophenone (1).ÐCompound 7a
(229 mg, 0.5 mmol) was hydrolyzed with 30% KOH (2 mL) and
EtOH (2 mL) under re¯ux and stirring for 1.5 h. Dilute HCl was
then added to pH 3, and the solution extracted with Et2O. The
extract was washed with water, brine, and dried over anhydrous
MgSO4, then puri®ed by silica gel column chromatography (eluting
with petroleum ether±EtOAc 6:1) to a€ord 1 (114 mg, 75%) as a
colorless powder, mp 147±148 8C (lit.3 147±150 8C). IR ꢀ/max (KBr)