Efficient total synthesis of racemic bisabolane sesquiterpenes curcuphenol and xanthorrhizol starting from substituted acetophenones

Article abstract of DOI:10.1002/hlca.201000111

A total synthesis of natural bisabolane sesquiterpenes curcuphenol (1) and xanthorrhizol (2) was developed by using the substituted acetophenones 4 and 5, respectively, as starting materials. The acetyl group of the latter was activated through ethoxycarb

Full text of DOI:10.1002/hlca.201000111

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Efficient Total Synthesis of Racemic Bisabolane Sesquiterpenes Curcuphenol
and Xanthorrhizol Starting from Substituted Acetophenones
by Luisa E. Montiel, L. Gerardo Zepeda, and Joaquꢀn Tamariz*
´
´
´
Departamento de Quꢀmica Organica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico
´
Nacional. Prol. Carpio y Plan de Ayala, 11340 Mexico, D. F. Mexico
(phone/fax: þ52-55-57296300/46211; e-mail: jtamariz@woodward.encb.ipn.mx; jtamarizm@gmail.com)
A total synthesis of natural bisabolane sesquiterpenes curcuphenol (1) and xanthorrhizol (2) was
developed by using the substituted acetophenones 4 and 5, respectively, as starting materials. The acetyl
group of the latter was activated through ethoxycarbonylation to carry out the prenylation, which was
performed successfully to give their respective precursors 11a and 11b, and 21 that were converted into
the corresponding natural sesquiterpenes 1 and 2, respectively, over four steps and in high overall yields.
1. Introduction. – Curcuphenol (1) and xanthorrhizol (2) are naturally occurring
bioactive bisabolane sesquiterpenes isolated from diverse sources. For instance, while
compound (þ)-(S)-1 has been isolated from the marine sponges Didiscus flavus,
Didiscus aceratus, Didiscus oxeata, Epipolasis species, and Myrmekioderma styx [1],
among other genera [1d], or from the Taiwanese gorgonian coral Echinomuricea sp.
[2], its enantiomer (ꢀ)-(R)-1 has been extracted from the Caribbean gorgonian coral
Pseudopterogorgia rigida [3], and from the plant Lasianthaea podocephala [4]. In the
case of xanthorrhizol (2), only its enantiomer (ꢀ)-(R)-2 has been isolated from natural
sources, as constituent of rhizomes of Curcuma xanthorrhiza [5], and from the Mexican
medicinal plant Iostephane heterophylla [6]. These compounds have significant
biological activities. Curcuphenol (1) exhibits antibacterial activity against Staph-
ylococcus aureus, Candida albicans, and Vibrio anguillarum [1][3], is an inhibitor of
gastric H,K-ATPase, and has antitumor, antimalarial, antifungal, and antidiabetes
activities [1b][1c][7]. Xanthorrhizol (2) inhibits cytochrome P-450 [8], has anticancer
activity [9], potent antibacterial activity against a series of Gram-positive and Gram-
negative bacteria [10], and potent in vitro anticandidal activity [11], as well as
antioxidant and anti-inflammatory activities [12]. In accordance with their pharmaco-
logical potential, compounds 1 and 2 have attracted particular interest, and many
racemic [13]1) and asymmetric [14]2) total syntheses have been reported.
In a preliminary report, we described a novel synthetic method for the introduction
of the prenyl side chain of the bisabolane scaffold, which was applied in the total
synthesis of (ꢁ)-a-curcumene (3) [15]. With the aim of improving our methodology
and of establishing it as a new general synthetic approach to bisabolane compounds, we
1
)
)
For curcuphenol (1), see [13a – 13c], for xanthorrhizol (2), see [13d – 13f].
For curcuphenol (1), see [14a – 14f], for xanthorrhizol (2), see [14g – 14i].
2
ꢁ 2010 Verlag Helvetica Chimica Acta AG, Zꢂrich

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herein present the synthesis of racemic sesquiterpenes 1 and 2. This approach is based
on the direct prenylation of the properly activated 4-methylacetophenones 4 and 5, the
corresponding products of which, 6 and 7, were converted to the desired racemic
products 1 and 2, respectively (Scheme 1).
Scheme 1
2. Results and Discussion. – 2.1 Total Synthesis of (ꢁ)-Curcuphenol (1). To achieve
the appropriate functionalization of acetophenone 4, which is commercially available,
through the proposed strategy, the OH group had to be protected. We investigated two
common protecting groups that are resistant to the presence of strong bases,
nucleophiles, and hydrides: the Me and benzyl (Bn) groups. Thus, starting from 8a
and 8b, we evaluated the efficacy of the route in each case. These acetophenones were
readily prepared from 4 by reaction with KOH, and treatment either with MeI or BnBr
to afford ethers 8a and 8b, respectively, in high yields (> 90%; Scheme 2).
Since every attempt to directly introduce the prenyl (¼ 3-methylbut-2-en-1-yl) side
chain into these acetophenones under basic conditions failed to provide the desired
products, 6a or 6b, the Ac group had to be activated by ethoxycarbonylation. This is not
a straightforward functionalization process, because the treatment of the substrate with
a base and diethyl carbonate (CO(OEt)2) fails to give the desired product. That is the
reason why the procedure reported by Manjarrez et al. [16] was a very useful method.
Thus, the reaction between the acetophenone 8a and CO(OEt)2 was carried out in the
presence of NaH as the base, and a mixture of benzene/DMF/thiophene 2 :1:0.5 as the
solvent, affording b-keto ester 9a in a modest yield of ca. 50% (Scheme 2). Actually, the
yield was drastically improved (89%), when the reaction was carried out by heating the
mixture at 508 for 2 h, in contrast to our previous study in which the reaction took place

Helvetica Chimica Acta – Vol. 93 (2010)
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Scheme 2
at room temperature to give a moderate yield (51%) of the expected product [15].
Although the role of thiophene in the reaction has not yet been clearly understood, this
reagent is crucial for accomplishing the reaction, since, in its absence, the reaction does
not take place. A similar result was obtained for the derivative 8b, which provided the
b-keto ester 9b in 90% yield.
Once we had the activated derivatives 9 to conduct the prenylation reaction with
prenyl bromide (¼1-bromo-3-methylbut-2-ene; 10), every attempt to prepare com-
pounds 11a or 11b was unsuccessful under analogous conditions as previously used in
the synthesis of 3 [15], since the bis-prenylated products 12a or 12b, respectively, were
isolated as a single product (Scheme 2, and Table, Entries 1 and 2). Even by decreasing
the amount of 10, the crude reaction mixture was also largely contaminated by 12
(Table, Entries 3 and 4). The desired compounds 11a and 11b were finally obtained as
the main products by reducing the temperature to 08 (Table, Entries 5 and 6). Even
though the bis-prenyl derivatives 12a or 12b could never be avoided completely in the
reaction mixtures, they were easily separated by column chromatography.
Table. Reaction Conditions for the Prenylation of Substrates 9a and 9ba)
Entry
Substrate
10 [mol-equiv.]
NaH [mol-equiv.]
T [8]
Time [min]
11/12 [%]b)
1
2
3
4
5
6
9a
9b
9a
9b
9a
9b
2.0
2.0
1.2
1.2
1.2
1.2
2.5
2.5
1.5
1.5
1.0
1.0
50
50
20
20
0
45
45
30
30
60
60
11a (0)/12a (88)
11b (0)/12b (90)
11a (20)/12a (30)
11b (15)/12b (26)
11a (86)/12a (7)
11b (92)/12b (5)
0
a) Benzene/DMF 2 : 1, N2 atmosphere. b) Determined as isolated products after purification by column
chromatography.

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Ketone 13a was obtained in high yield by hydrolysis of compound 11a under basic
conditions (Scheme 3). Similarly, the preparation of derivative 13b was achieved
satisfactorily by carrying out the process according to the same procedure. The C¼O
group was transformed into the required Me group of the natural sesquiterpene by a
simple and efficient methodology: a) addition of the Grignard reagent; and b)
reduction of the benzylic alcohol with Et3SiH in the presence of BF3 · OEt2 [13a][17].
Under these conditions, hydrocarbon precursors 15a and 15b were obtained starting
from ketones 13a and 13b, respectively, in high overall yields (Scheme 3). Tertiary
alcohols 14a and 14b were isolated as stable intermediates after the addition of the
Grignard reagent.
Scheme 3
Finally, to carry out the deprotection of 15a, two methods were applied. The use of
BBr3 [18] at 08 for 12 h led to the natural product 1 in 70% yield. However, the
conversion was almost quantitative, when NaSEt was employed at high temperature
(1408) [5a][13a][14f][14g][14h] (Scheme 3). Curcuphenol (1) was also obtained by
deprotection of 15b through Pd-catalyzed hydrogenolysis in a slightly lower yield than
by the previous method. The structures of 1 and each intermediate were established by
1
IR, H- and 13C-NMR spectroscopy, assisted by 2D experiments, and high-resolution
mass spectrometry. Spectral data of 1 were in agreement with those reported for the
natural and synthetic compound [1b][3][14d][14h].
2.2 Total Synthesis of (ꢁ)-Xanthorrhizol (2). 2.2.1 Preparation of Acetophenone 5.
Since acetophenone 5 is not commercially available, we decided to develop an
alternative approach to that already reported [19] for the synthesis of 5, which resulted
in an economical and efficient starting material for the total synthesis of xanthorrhizol
(2). Actually, compound 5 is a natural product isolated from the red seaweed Laurencia
chilensis, which exhibits moderate antimicrobial activity [20]. The first step in its
preparation consisted of the nitration of 4-methylacetophenone (16), under typical
conditions by treatment with a mixture of HNO3 and H2SO4, to furnish the nitro

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derivative 17 [21] in moderate yield (Scheme 4). Although the reduction of the NO2
group with NaSH provided 3-aminoacetophenone 18 [21] in good yield (80%), the
reaction was improved (95%) by hydrogenation. The latter was converted into the
diazonium salt, followed by substitution with H2O, to yield the desired 3-hydroxy-
acetophenone 5 in 54% overall yield starting from 16.
Scheme 4
2.2.2 Synthesis of (ꢁ)-Xanthorrhizol (2). The approach using the protecting Me
group was slightly more efficient in the synthesis of 1 than that using the Bn group.
Moreover, the purification procedures were easier, and the loss of weight in the final
deprotection step was lower. Consequently, we chose this protecting group for the
synthesis of 2. Acetophenone 5 was protected with MeI to give 19 in good yield
(Scheme 4). The latter was ethoxycarbonylated to afford the b-keto ester 20, which was
prenylated under the optimal conditions found in the synthesis of 1, in order to avoid
the formation of the bis-alkylated compound. Thus, the mono-prenylated compound 21
was isolated as the major product in high yield (Scheme 5). Decarboxylation of the
latter under standard conditions led to ketone 22, which underwent addition of the
Grignard reagent to give alcohol 23. Final reduction of the tertiary alcohol and
deprotection, under the same conditions as those for 1, afforded the naturally occurring
xanthorrhizol (2) as a racemate over six steps and in 60% overall yield, starting from
acetophenone 19. Spectroscopic data of some precursors and the final product are in
agreement with those reported for the natural and synthetic compounds [4a][14h][14i]
(see Exper. Part).
3. Conclusions. – New total syntheses of the naturally occurring bisabolane
sesquiterpenes curcuphenol (1) and xanthorrhizol (2) as racemates in high overall
yields were described, starting from the properly substituted acetophenones, 8a and 8b,
and 19. The key step of this new approach was based on the activation of the latter
compounds with the ethoxycarbonyl group, in order to introduce the prenyl side chain.
The application of this strategy to the asymmetric synthesis of these and other natural
sesquiterpenes is currently under investigation, and the results will be described in due
course.
´
We thank Fabiola Jimenez and Alberto V. Jerezano for their help in spectrometric analyses, and Alan
Larsen for reviewing the English in the manuscript. J. T. is grateful to SIP/IPN (Grants 20070339,

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Scheme 5
20080527, 20090519, and 20100236) and CONACYT (Grants 43508-Q and 83446) for financial support.
L. E. M. thanks CONACYT for a scholarship, and SIP/IPN for a scholarship complement. L. G. Z. and
J. T. are fellows of the EDI-IPN and COFAA-IPN programs.
Experimental Part
General. Anal TLC: E. Merck silica-gel 60 F 254-coated plates were visualized by a long- and short-
wavelength UV lamp. All air moisture-sensitive reactions were carried out under N2 in oven-dried
glassware. Benzene and THF were freshly distilled over Na, and CH2Cl2 and DMF over CaH2. All other
reagents were used without further purification. M.p.: Electrothermal cap. melting-point apparatus;
uncorrected. IR Spectra: Perkin-Elmer 2000 spectrophotometer. 1H- (300 and 500 MHz) and 13C-NMR
(75.4 and 125 MHz) spectra: Varian Mercury-300 and VNMR-500 instruments in CDCl3, with Me4Si as
internal standard. MS: EI mode (70 eV); Thermo-Finnigan Polaris Q spectrometer. HR-MS: FAB
(mNBA) and CI (CH4), and EI (70 eV) modes; Jeol JMS-AX 505 HA and Jeol JSM-GCMateII
spectrometers.
1-(2-Methoxy-4-methylphenyl)ethanone (8a) [22]. To a stirred mixture of KOH (0.28 g, 5.0 mmol)
and 4 (0.50 g, 3.33 mmol) in THF (4 ml), at 208 under N2, MeI (1.18 g, 8.31 mmol) was added dropwise,
and the mixture was stirred for 12 h at the same temp. The mixture was diluted with CH2Cl2 (15 ml) and
washed with a sat. aq. NH4Cl soln. (2 ꢂ 8 ml) and H2O until neutral. The org. layer was dried (Na2SO4),
and the solvent was removed under vacuum. The residue was purified by CC (SiO2 (20 g); hexane/
AcOEt 98 :2) to give 8a (0.503 g, 92%). White solid. Rf (hexane/AcOEt 8 :2) 0.47. M.p. 37 – 388 ([23]:
35 – 368). IR (CH2Cl2): 1670, 1607, 1465, 1410, 1357, 1288, 1259, 1239, 1169, 1035, 815. 1H-NMR
(300 MHz, CDCl3): 2.38 (s, MeC6H3); 2.59 (s, MeCO); 3.89 (s, MeO); 6.76 (br. s, HꢀC(3’)); 6.80 (dm, J ¼
7.8, HꢀC(5’)); 7.68 (d, J ¼ 7.8, HꢀC(6’)). 13C-NMR (75.4 MHz, CDCl3): 21.8 (MeC6H3); 31.8 (MeCO);
55.3 (MeO); 112.2 (C(3’)); 121.3 (C(5’)); 125.3 (C(1’)); 130.5 (C(6’)); 144.8 (C(4’)); 159.1 (C(2’)); 199.2
(CO). EI-MS (70 eV): 165 (100, [M þ 1]þ), 164 (22, Mþ), 150 (12), 149 (36), 135 (4), 106 (4), 91 (7).
HR-EI-MS: 164.0838 (Mþ, C10H12O2þ ; calc. 164.0837).
1-[2-(Benzyloxy)-4-methylphenyl]ethanone (8b). Following the procedure as for 8a, with KOH
(0.28 g, 5.0 mmol), 4 (0.50 g, 3.33 mmol), and BnBr (1.71 g, 0.01 mol): 8b (0.72 g, 90%). White solid. Rf
(hexane/AcOEt 8 :2) 0.56. M.p. 56 – 578 ([22]: 538). IR (CH2Cl2): 1663, 1607, 1567, 1493, 1453, 1416, 1381,

Helvetica Chimica Acta – Vol. 93 (2010)
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1289, 1252, 1242, 1171, 1137, 1020, 822. 1H-NMR (300 MHz, CDCl3): 2.34 (s, MeC6H3); 2.55 (s, MeCO);
5.10 (s, PhCH2); 6.78 – 6.81 (dm, J ¼ 8.1, HꢀC(5’)); 6.82 (br. s, HꢀC(3’)); 7.29 – 7.45 (m, 5 arom. H); 7.69
(d, J ¼ 8.1, HꢀC(6’)). 13C-NMR (75.4 MHz, CDCl3): 21.7 (MeC6H3); 31.9 (MeCO); 70.4 (PhCH2); 113.3
(C(3’)); 121.5 (C(5’)); 125.6 (C(1’)); 127.4 (2 arom. C); 128.0 (arom. C); 128.5 (2 arom. C); 130.4 (C(6’));
136.1 (arom. C); 144.6 (C(4’)), 158.1 (C(2’)); 198.9 (CO). EI-MS (70 eV): 241 (6, [M þ 1]þ), 240 (5, Mþ),
225 (12), 222 (14), 135 (18), 91 (100), 65 (18). HR-EI-MS: 240.1146 (Mþ, C16H16O2þ ; calc. 240.1150).
Ethyl 3-(2-Methoxy-4-methylphenyl)-3-oxopropanoate (9a). To a stirred mixture of NaH (0.183 g,
7.625 mmol) and CO(OEt)2 (0.719 g, 6.093 mmol) in a dry mixture of benzene/DMF/thiophene 2 :1:0.5
(5 ml), at 208 under N2, 8a (0.500 g, 3.048 mmol) was added dropwise, and the mixture was heated to 508
and kept for 2 h at this temp. The mixture was diluted with CH2Cl2 (20 ml), and washed with a sat. aq.
NH4Cl soln. (2 ꢂ 10 ml) and H2O until neutral. The org. layer was dried (Na2SO4), and the solvent was
removed under vacuum. The residue was purified by CC (SiO2 (20 g); hexane/AcOEt 98 :2) to give 9a
(0.642 g, 89%). Pale yellow oil. Rf (hexane/AcOEt 8 :2) 0.36. IR (film): 1739, 1668, 1607, 1496, 1465,
1410, 1325, 1263, 1197, 1168, 1125, 1034, 813. 1H-NMR (300 MHz, CDCl3): 1.23 (t, J ¼ 7.2, MeCH2O); 2.38
(s, MeC6H3); 3.87 (s, MeO); 3.93 (s, CH2(2)); 4.17 (q, J ¼ 7.2, MeCH2); 6.76 (br. s, HꢀC(3’)); 6.82 (dm,
J ¼ 8.1, HꢀC(5’)); 7.79 (d, J ¼ 8.1, HꢀC(6’)). 13C-NMR (75.4 MHz, CDCl3): 14.0 (MeCH2O); 21.8
(MeC6H3); 50.5 (C(2)); 55.0 (MeO); 60.7 (MeCH2O); 112.0 (C(3’)); 121.6 (C(5’)); 123.3 (C(1’)); 130.9
(C(6’)); 145.9 (C(4’)), 159.1 (C(2’)); 168.2 (CO2Et); 192.3 (ArCO). EI-MS (70 eV): 166 (70, [M ꢀ 70]þ),
151 (94), 149 (45), 135 (18), 123 (42), 121 (100), 108 (23), 91 (52), 77 (30). HR-EI-MS: 236.1045 (Mþ,
C13H16Oþ4 ; calc. 236.1049).
Ethyl 3-[2-(Benzyloxy)-4-methylphenyl]-3-oxopropanoate (9b). Following the procedure as for 9a,
with NaH (0.150 g, 6.250 mmol), 8b (0.500 g, 2.083 mmol), and CO(OEt)2 (0.491 g, 4.162 mmol): 9b
(0.585 g, 90%). Pale yellow oil. Rf (hexane/AcOEt 8 :2) 0.40. IR (CH2Cl2): 1738, 1668, 1606, 1496, 1415,
1325, 1259, 1195, 1169, 1024, 812, 735, 698. 1H-NMR (300 MHz, CDCl3): 1.17 (t, J ¼ 7.0, MeCH2O); 2.36
(s, MeC6H3); 3.95 (s, CH2(2)); 4.07 (q, J ¼ 7.0, MeCH2); 5.15 (s, PhCH2); 6.81 (br. s, HꢀC(3’)); 6.84 (dm,
J ¼ 8.1, HꢀC(5’)); 7.33 – 7.46 (m, 5 arom. H); 7.79 (d, J ¼ 8.1, HꢀC(6’)). 13C-NMR (75.4 MHz, CDCl3):
14.0 (MeCH2O); 21.9 (MeC6H3); 50.5 (C(2)); 60.8 (MeCH2); 70.6 (PhCH2); 113.4 (C(3’)); 122.0 (C(5’));
124.3 (C(1’)); 127.6 (arom. C); 128.3 (2 arom. C); 128.7 (2 arom. C); 131.2 (C(6’)); 135.9 (arom. C); 145.8
(C(4’)); 158.4 (C(2’)); 168.3 (CO2Et); 192.9 (ArCO). EI-MS (70 eV): 313 (1, [M þ 1]þ), 240 (4), 225
(12), 197 (8), 135 (18), 91 (100), 65 (22).
Ethyl 2-[(2-Methoxy-4-methylphenyl)carbonyl]-5-methylhex-4-enoate (11a) and Ethyl 2-[(2-Me-
thoxy-4-methylphenyl)carbonyl]-5-methyl-2-(3-methylbut-2-en-1-yl)hex-4-enoate (12a). To a stirred
suspension of NaH (0.061 g, 2.542 mmol) in a dry mixture of benzene/DMF 2 :1 (5 ml), at 08 under
N2, a soln. of 9a (0.600 g, 2.542 mmol) in dry benzene (2 ml) was added dropwise. After stirring at 08 for
10 min, 10 (0.455 g, 3.054 mmol) was added, and the mixture was stirred at 08 for 1 h. The mixture was
diluted with CH2Cl2 (10 ml), and washed with a sat. aq. NH4Cl soln. (2 ꢂ 10 ml) and H2O until neutral.
The org. layer was dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified
by CC (SiO2 (25 g); hexane/AcOEt 98 :2), to give 0.668 g (86%) of 11a and 0.066 g (7%) of 12a.
Data of 11a. Pale yellow oil. Rf (hexane/AcOEt 8 :2) 0.51. IR (CH2Cl2): 1736, 1672, 1608, 1572, 1496,
1464, 1409, 1256, 1168, 1126, 1035, 825. 1H-NMR (500 MHz, CDCl3): 1.18 (t, J ¼ 7.0, MeCH2); 1.60 (br. s,
MeC¼); 1.65 (br. s, MeC¼); 2.38 (s, MeC6H3); 2.57 – 2.68 (m, CH2CH¼); 3.86 (s, MeO); 4.08 – 4.17 (m,
MeCH2); 4.28 (t, J ¼ 7.3, CH2(2)); 5.09 – 5.14 (m, CH2CH¼); 6.74 (br. s, HꢀC(3’)); 6.81 – 6.83 (dm, J ¼
7.8, HꢀC(5’)); 7.67 (d, J ¼ 7.8, HꢀC(6’)). 13C-NMR (125 MHz, CDCl3): 14.1 (MeCH2O); 17.7 (MeC¼);
21.9 (MeC6H3); 25.7 (MeC¼); 27.6 (CH2CH¼); 55.1 (MeO); 58.6 (C(2)); 60.7 (MeCH2); 112.0 (C(3’));
121.1 (CH2CH¼); 121.7 (C(5’)); 124.5 (C(1’)); 131.2 (C(6’)); 133.6 (Me2C¼); 145.2 (C(4’)); 158.5 (C(2’));
170.5 (CO2Et); 195.9 (ArCO). EI-MS (70 eV): 305 (3, [M þ 1]þ), 225 (22), 222 (24), 197 (12), 135 (18),
91 (100), 65 (22). HR-EI-MS: 304.1676 (Mþ, C18H24O4þ ; calc. 304.1675).
Data of 12a. Pale yellow oil. Rf (hexane/AcOEt 8 :2) 0.60. IR (CH2Cl2): 1736, 1670, 1608, 1462, 1408,
1
1288, 1272, 1218, 1178, 1168, 1129, 1059, 1035, 938, 819. H-NMR (500 MHz, CDCl3): 1.13 (t, J ¼ 7.0,
MeCH2); 1.45 (br. s, 2 MeC¼); 1.62 (br. s, MeC¼); 2.36 (s, 2 MeC6H3); 2.56 (dd, J ¼ 15.5, 7.5, 2 H of
2 CH2CH¼); 2.74 (dd, J ¼ 15.5, 7.5, 2 H of 2 CH2CH¼); 3.77 (s, MeO); 4.07 (q, J ¼ 7.0, MeCH2O); 4.90 –
4.95 (m, 2 CH2CH¼); 6.69 (br. s, HꢀC(3’)); 6.79 (dm, J ¼ 8.0, HꢀC(5’)); 7.52 (d, J ¼ 8.0, HꢀC(6’)).
13C-NMR (125 MHz, CDCl3): 14.0 (MeCH2); 17.6 (2 MeC¼); 21.7 (MeC6H3); 26.0 (2 MeC¼); 30.7

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(2 CH2CH¼); 54.2 (MeO); 60.4 (MeCH2); 62.5 (C(2)); 111.7 (C(3’)); 118.7 (2 CH2CH¼); 121.6 (C(5’));
125.1 (C(1’)); 131.3 (C(6’)); 134.3 (2 Me2C¼); 143.9 (C(4’)); 157.0 (C(2’)); 171.7 (CO2Et); 198.9 (ArCO).
EI-MS (70 eV): 373 (2, [M þ 1]þ), 303 (26), 257 (16), 181 (14), 149 (100), 135 (38), 109 (18), 91 (20), 77
(6). HR-FAB-MS: 373.2362 ([M þ 1]þ, C23H33O4þ ; calc. 373.2379).
Ethyl 2-{[2-(Benzyloxy)-4-methylphenyl]carbonyl}-5-methylhex-4-enoate (11b) and Ethyl 2-{[2-
(Benzyloxy)-4-methylphenyl]carbonyl}-5-methyl-2-(3-methylbut-2-en-1-yl)hex-4-enoate (12b). Follow-
ing the procedure as for 11a/12a, with NaH (0.046 g, 1.917 mmol), 9b (0.600 g, 1.923 mmol), and 10
(0.346 g, 2.322 mmol), 0.67 g (92%) of 11b and 0.045 g (5%) of 12b were obtained.
Data of 11b. Pale yellow oil. Rf 0.52 (hexane/AcOEt 8 :2). IR (CH2Cl2): 1734, 1671, 1606, 1496, 1454,
1414, 1240, 1169, 1123, 1019, 821, 732, 696. 1H-NMR (500 MHz, CDCl3): 1.11 (t, J ¼ 7.0, MeCH2); 1.54 (br.
s, MeC¼); 1.58 (br. s, MeC¼); 2.34 (s, MeC6H3); 2.57 (tm, J ¼ 7.5, CH2CH¼); 3.99 – 4.09 (m, MeCH2);
4.46 (t, J ¼ 7.5, CH2(2)); 4.90 – 4.95 (m, CH2CH¼); 5.15 (s, PhCH2); 6.78 (br. s, HꢀC(3’)); 6.81 (dm, J ¼
8.0, HꢀC(5’)); 7.32 – 7.44 (m, 5 arom. H); 7.61 (d, J ¼ 8.0, HꢀC(6’)). 13C-NMR (125 MHz, CDCl3): 14.0
(MeCH2); 17.6 (MeC¼); 21.9 (MeC6H3); 25.7 (MeC¼); 27.6 (CH2CH¼); 58.2 (C(2)); 60.7 (MeCH2O);
70.5 (PhCH2); 113.4 (C(3’)); 120.9 (CH2CH¼); 121.9 (C(5’)); 125.3 (C(1’)); 127.5 (2 arom. C); 128.2
(arom. C); 128.6 (2 arom. C); 131.1 (C(6’)); 133.6 (Me2C¼); 136.1 (arom. C); 144.8 (C(4’)); 157.5 (C(2’));
170.3 (CO2Et); 196.8 (ArCO). EI-MS (70 eV): 308 (12, [M ꢀ C3H4O2]þ), 223 (24), 217 (56), 135 (100),
121 (40), 105 (16). HR-FAB-MS: 381.2064 ([M þ 1]þ, C24H29O4þ ; calc. 381.2066).
Data of 12b. Pale yellow oil. Rf 0.46 (hexane/AcOEt 8 :2). IR (CH2Cl2): 1733, 1695, 1608, 1496, 1454,
1413, 1378, 1289, 1272, 1219, 1177, 1129, 1059, 1027, 938, 818, 735, 697. 1H-NMR (500 MHz, CDCl3): 1.09
(t, J ¼ 7.0, MeCH2); 1.45 (br. s, 2 MeC¼); 1.60 (br. s, 2 MeC¼); 2.66 (s, MeC6H3); 2.60 (dd, J ¼ 15.5, 7.5,
2 H of 2 CH2CH¼); 2.76 (dd, J ¼ 15.5, 7.5, 2 H of 2 CH2CH¼); 4.12 (q, J ¼ 7.0, MeCH2); 4.93 – 4.97 (m,
2 CH2CH¼); 5.19 (s, PhCH2); 6.65 (br. s, HꢀC(3’)); 6.75 (dm, J ¼ 8.0, HꢀC(5’)); 7.26 – 7.30 (m, 1 arom.
H); 7.34 – 7.39 (m, 5 arom. H). 13C-NMR (125 MHz, CDCl3): 13.9 (MeCH2); 17.7 (2 MeC¼); 21.7
(MeC6H3); 26.0 (2 MeC¼); 31.0 (2 CH2CH¼); 60.7 (MeCH2); 62.8 (C(2)); 69.8 (PhCH2); 113.5 (C(3’));
118.7 (2 CH2CH¼); 121.6 (C(5’)); 126.3 (C(1’)); 126.7 (2 arom. C); 127.7 (arom. C); 128.6 (2 arom. C);
130.1 (C(6’)); 134.5 (2 Me2C¼); 136.8 (arom. C); 143.1 (C(4’)); 156.2 (C(2’)); 171.8 (CO2Et); 200.1
(ArCO). EI-MS (70 eV): 357 (2, [M ꢀ 91]þ), 303 (20), 257 (14), 225 (8), 181 (22), 149 (100), 135 (52),
109 (26), 91 (36). HR-FAB-MS: 449.2687 ([M þ 1]þ, C29H37O4þ ; calc. 449.2692).
1-(2-Methoxy-4-methylphenyl)-5-methylhex-4-en-1-one (13a). A stirred mixture of KOH (0.368 g,
6.571 mmol) and 11a (0.500 g, 1.645 mmol) in MeOH/H2O 85 :15 (8 ml), under N2, was heated to reflux
for 3 h. The mixture was diluted with CH2Cl2 (10 ml), and washed with a sat. aq. NH4Cl soln. (2 ꢂ 10 ml)
and H2O until neutral. The org. layer was dried (Na2SO4), and the solvent was removed under vacuum.
The residue was purified by CC (SiO2 (20 g); hexane/AcOEt 98 :2) to give 13a (0.364 g, 95%). Pale
yellow oil. Rf (hexane/AcOEt 8 :2) 0.65. IR (CH2Cl2): 1669, 1607, 1495, 1464, 1409, 1285, 1255, 1168, 1124,
1035, 813. 1H-NMR (500 MHz, CDCl3): 1.61 (br. s, MeC¼); 1.68 (br. s, MeC¼); 2.33 – 2.38 (m,
CH2CH¼); 2.38 (s, MeC6H3); 2.97 (dd, J ¼ 8.0, 7.5, CH2CO); 3.88 (s, MeO); 5.12 – 5.17 (m, CH2CH¼);
6.75 (br. s, HꢀC(3’)); 6.80 (dm, J ¼ 7.5, HꢀC(5’)); 7.61 (d, J ¼ 7.5, HꢀC(6’)). 13C-NMR (125 MHz,
CDCl3): 17.6 (MeC¼); 21.8 (MeC6H3); 23.2 (CH2CH¼); 25.7 (MeC¼); 43.8 (CH2CO); 55.4 (MeO);
112.2 (C(3’)); 121.4 (C(5’)); 123.6 (CH2CH¼); 125.7 (C(1’)); 130.5 (C(6’)); 132.1 (Me2C¼); 144.3
(C(4’)); 158.7 (C(2’)); 201.8 (ArCO). EI-MS (70 eV): 233 (13, [M þ 1]þ), 232 (6, Mþ), 217 (6), 164 (32),
149 (100), 135 (7), 105 (9), 91 (28). HR-EI-MS: 232.1461 (Mþ, C15H20O2þ ; calc. 232.1463).
1-[2-(Benzyloxy)-4-methylphenyl]-5-methylhex-4-en-1-one (13b). Following the procedure as for
13a, with KOH (0.237 g, 4.232 mmol) and 11b (0.400 g, 1.053 mmol) in MeOH/H2O 85 :15 (6 ml): 13b
(0.310 g, 95%). Colorless oil. Rf (hexane/AcOEt 8 :2) 0.64. IR (CH2Cl2): 1670, 1606, 1497, 1454, 1414,
1378, 1287, 1255, 1169, 1123, 1022, 812, 732, 696. 1H-NMR (500 MHz, CDCl3): 1.54 (br. s, MeC¼); 1.63
(br. s, MeC¼); 2.26 – 2.32 (m, CH2CH¼); 2.36 (s, MeC6H3); 2.95 – 2.99 (m, CH2CO); 4.97 – 5.02 (m,
CH2CH¼); 5.13 (s, PhCH2); 6.81 – 6.83 (m, HꢀC(3’), HꢀC(5’)); 7.32 – 7.44 (m, 5 arom. H); 7.63 (d, J ¼
8.5, HꢀC(6’)). 13C-NMR (125 MHz, CDCl3): 17.5 (MeC¼); 21.8 (MeC6H3); 23.1 (CH2CH¼); 27.6
(MeC¼); 44.0 (CH2CO); 70.6 (PhCH2); 113.4 (C(3’)); 121.8 (C(5’)); 123.4 (CH2CH¼); 126.1 (C(1’));
127.6 (2 arom. C); 128.1 (arom. C); 128.6 (2 arom. C); 130.5 (C(6’)); 132.0 (Me2C¼); 136.3 (arom. C);
144.2 (C(4’)); 157.8 (C(2’)); 201.9 (ArCO). EI-MS (70 eV): 232 (30, [M ꢀ C6H4]þ), 162 (54), 149 (100),
147 (48), 135 (32), 95 (30), 91 (44).

Helvetica Chimica Acta – Vol. 93 (2010)
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2-(2-Methoxy-4-methylphenyl)-6-methylhept-5-en-2-ol (14a) [13a]. To a stirred suspension of
MeMgBr (0.616 g, 5.176 mmol; 3m in Et2O) in dry THF (3 ml), at 08 under N2, a soln. of 13a (0.400 g,
1.724 mmol) in dry THF (3 ml) was added dropwise. After stirring at r.t. for 2 h, a sat. aq. NH4Cl soln.
(5 ml) was added at 08; then, the mixture was diluted with CH2Cl2 (10 ml), and washed with sat. aq.
NH4Cl soln. (2 ꢂ 10 ml) and H2O until neutral. The org. layer was dried (Na2SO4), and the solvent was
removed under vacuum. The residue was purified by CC (SiO2 (20 g); hexane/AcOEt 98 :2) to give 14a
(0.385 g, 90%). Pale yellow oil. Rf (hexane/AcOEt 8 :2) 0.60. IR (CH2Cl2): 3470, 2965, 2922, 1612, 1502,
1455, 1406, 1376, 1286, 1251, 1169, 1065, 1037, 928, 814. 1H-NMR (500 MHz, CDCl3): 1.52 (br. s, MeC¼);
1.55 (s, MeC(OH)); 1.64 (br. s, MeC¼); 1.81 – 2.01 (m, CH2CH¼); 2.33 (s, MeC6H3); 3.86 (s, MeO); 3.99
(br. s, OH); 5.05 – 5.10 (m, CH2CH¼); 6.72 (br. s, HꢀC(3’)); 6.75 (dm, J ¼ 7.8, HꢀC(5’)); 7.61 (d, J ¼ 7.8,
HꢀC(6’)). 13C-NMR (125 MHz, CDCl3): 17.5 (MeC¼); 21.2 (MeC6H3); 23.3 (CH2CH¼); 25.6 (MeC¼);
27.4 (MeC(OH)); 42.1 (CH2C(OH)); 55.2 (MeO); 74.9 (MeC(OH)); 112.2 (C(3’)); 121.3 (C(5’)); 124.6
(CH2CH¼); 126.6 (C(6’)); 131.3 (Me2C¼); 131.8 (C(1’)); 137.9 (C(4’)); 156.7 (C(2’)). EI-MS (70 eV):
248 (2, Mþ), 231 (22), 187 (24), 165 (100), 147, (50), 119 (56), 91, (36). HR-EI-MS: 248.1776 (Mþ,
C16H24Oþ2 ; calc. 248.1776).
2-[2-(Benzyloxy)-4-methylphenyl]-6-methylhept-5-en-2-ol (14b). Following the procedure as for 14a,
with MeMgBr (0.348 g, 2.924 mmol) and 13b (0.300 g, 0.974 mmol): 14b (0.282 g, 89%). Pale yellow oil.
Rf (hexane/AcOEt 8 :2) 0.59. IR (CH2Cl2): 3523, 2965, 2919, 1611, 1501, 1453, 1378, 1288, 1248, 1171,
1063, 1023, 814, 732, 696. 1H-NMR (500 MHz, CDCl3): 1.49 (br. s, MeC¼); 1.56 (s, MeC(OH)); 1.63 (br.
s, MeC¼); 1.80 – 2.05 (m, CH2CH2CH¼); 2.33 (s, MeC6H3); 3.94 (s, OH); 5.05 – 5.08 (m, CH2CH¼); 5.10
(s, PhCH2); 6.78 (br. d, J ¼ 8.0, HꢀC(5’)); 6.80 (br. s, HꢀC(3’)); 7.21 (d, J ¼ 8.0, HꢀC(6’)); 7.32 – 7.44 (m,
5 arom. H). 13C-NMR (125 MHz, CDCl3): 17.5 (MeC¼); 21.2 (MeC6H3); 23.3 (CH2CH¼); 25.7
(MeC¼); 27.6 (MeC(OH)); 42.1 (CH2CH2CH¼); 70.5 (PhCH2); 75.0 (MeC(OH)); 113.2 (C(3’)); 121.6
(C(5’)); 124.6 (CH2CH¼); 126.8 (C(6’)); 127.6 (2 arom. C); 128.2 (arom. C); 128.8 (2 arom. C); 131.4
(Me2C¼); 132.1 (C(1’)); 136.4 (arom. C); 137.9 (C(4’)); 155.9 (C(2’)). HR-FAB-MS: 325.2166 ([M þ
H]þ, C22H29Oþ2 ; calc. 325.2168).
2-Methoxy-4-methyl-1-(6-methylhept-5-en-2-yl)benzene (15a) [13a]. To a stirred soln. of 14a (0.300 g,
1.210 mmol) in dry CH2Cl2 (4 ml), at ꢀ 788 under N2, Et3SiH (0.169 g, 1.457 mmol) was added dropwise.
After stirring for 10 min, BF3 · Et2O (0.257 g, 1.810 mmol) was added dropwise, and the mixture was
stirred at the same temp. for 1 h. The mixture was diluted with CH2Cl2 (15 ml) and washed with a sat. aq.
NaHCO3 soln. (2 ꢂ 10 ml) and H2O until neutral. The org. layer was dried (Na2SO4), and the solvent was
removed under vacuum. The residue was purified by CC (SiO2 (18 g); hexane/AcOEt 98 :2): to give 15a
(0.258 g, 92%). Colorless oil. Rf (hexane/AcOEt 8 :2) 0.83. IR (CH2Cl2): 2959, 2923, 2855, 1611, 1578,
1
1505, 1463, 1411, 1285, 1259, 1157, 1043, 809. H-NMR (500 MHz, CDCl3): 1.17 (d, J ¼ 7.0, MeCHAr);
1.47 – 1.55 (m, 1 H of CH2CHAr); 1.53 (br. s, MeC¼); 1.60 – 1.67 (m, 1 H of CH2CHAr); 1.66 (br. s,
MeC¼); 1.83 – 1.98 (m, CH2CH¼); 2.32 (s, MeC6H3); 3.12 (sext, J ¼ 7.0, MeCHAr); 3.79 (s, MeO); 5.09 –
5.14 (m, CH2CH¼); 6.66 (d, J ¼ 1.0, HꢀC(3’)); 6.73 (dd, J ¼ 8.0, 1.0, HꢀC(5’)); 7.04 (d, J ¼ 8.0,
HꢀC(6’)). 13C-NMR (125 MHz, CDCl3): 17.6 (MeC¼); 21.1 (MeCHAr); 21.4 (MeC6H3); 25.7 (MeC¼);
26.3 (CH2CH¼); 31.4 (MeCHAr); 37.2 (CH2CHAr); 55.3 (MeO); 111.5 (C(3’)); 121.1 (C(5’)); 124.9
(CH2CH¼); 126.6 (C(6’)); 131.1 (Me2C¼); 132.9 (C(1’)); 136.2 (C(4’)); 157.0 (C(2’)). EI-MS (70 eV):
233 (32, [M þ 1]þ), 232 (100, Mþ), 162 (24), 149 (98), 147 (40), 95 (28), 91 (20). HR-EI-MS: 232.1823
(Mþ, C16H24Oþ; calc. 232.1827).
2-(Benzyloxy)-4-methyl-1-(6-methylhept-5-en-2-yl)benzene (15b). Following the procedure as for
15a, with 14b (0.200 g, 0.617 mmol), Et3SiH (0.086 g, 0.741 mmol), and BF3 · Et2O (0.131 g, 0.923 mmol):
15b (0.171 g, 90%). Colorless oil. Rf (hexane/AcOEt 8 :2) 0.83. IR (CH2Cl2): 2960, 2919, 1610, 1504 1452,
1377, 1257, 1125, 1026, 810, 733, 695. 1H-NMR (500 MHz, CDCl3): 1.19 (d, J ¼ 7.0, MeCHAr); 1.49 – 1.56
(m, 1 H of CH2CHAr); 1.51 (br. s, MeC¼); 1.62 (br. s, MeC¼); 1.63 – 1.71 (m, 1 H of CH2CHAr); 1.86 –
1.98 (m, CH2CH¼); 2.31 (s, MeC6H3); 3.24 (sext, J ¼ 7.0, MeCHAr); 5.04 (s, PhCH2); 5.08 – 5.11 (m,
CH2CH¼); 6.74 (br. s, HꢀC(3’)); 6.76 (br. d, J ¼ 7.5, HꢀC(5’)); 7.07 (d, J ¼ 7.5, HꢀC(6’)); 7.30 – 7.33 (m,
1 arom. H); 7.36 – 7.40 (m, 2 arom. H); 7.43 – 7.46 (m, 2 arom. H). 13C-NMR (125 MHz, CDCl3): 17.6
(MeC¼); 21.0 (MeCHAr); 21.4 (MeC6H3); 25.7 (MeC¼); 26.3 (CH2CH¼); 31.4 (MeCHAr); 37.3
(CH2CHAr); 70.0 (PhCH2); 112.8 (C(3’)); 121.5 (C(5’)); 124.8 (CH2CH¼); 126.7 (C(6’)); 127.1 (2 arom.
C); 127.6 (arom. C); 128.5 (2 arom. C); 131.1 (Me2C¼); 133.2 (C(1’)); 136.2 (C(4’)); 137.7 (arom. C);

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Helvetica Chimica Acta – Vol. 93 (2010)
156.1 (C(2’)). EI-MS (70 eV): 217 (2, [M ꢀ 91]þ), 149 (100), 135 (32), 91 (28), 77 (8). HR-FAB-MS:
308.2136 (Mþ, C22H28Oþ; calc. 308.2140).
Curcuphenol (¼(1,5-Dimethylhex-4-en-1-yl)-5-methylphenol; 1). Method A. To a stirred soln. of 15a
(0.100 g, 0.431 mmol) in dry CH2Cl2 (3 ml), at ꢀ 788 under N2, BBr3 (0.032 g, 1.280 mmol) was added
dropwise. After stirring at 08 for 30 min, the mixture was stirred at r.t. for 1.5 h, and icy H2O (3 ml) was
added. The mixture was stirred for 30 min, then diluted with CH2Cl2 (12 ml), and washed with a sat. aq.
NaHCO3 soln. (2 ꢂ 5 ml) and H2O until neutral. The org. layer was dried (Na2SO4), and the solvent was
removed under vacuum. The residue was purified by CC (SiO2 (18 g); hexane/AcOEt 98 :2), to give 1
(0.066 g, 70%). Colorless oil.
Method B. To a suspension of NaH (0.083 g, 3.458 mmol) in dry DMF (2 ml), at 08 under N2, EtSH
(0.190 g, 3.065 mmol) was added dropwise. After stirring at r.t. for 2 h, 15a (0.100 g, 0.430 mmol) in dry
DMF was added, and the mixture was heated to reflux for 3 h. A 10% aq. soln. of HCl (3 ml) and CH2Cl2
(12 ml) were added, and the mixture washed with H2O (2 ꢂ 3 ml). The org. layer was dried (Na2SO4) and
the solvent was removed under vacuum. The residue was purified by CC (SiO2 (18 g); hexane/AcOEt
98 :2): to give 1 (0.091 g, 97%). Colorless oil. Rf (hexane/AcOEt 8 :2) 0.57.
Method C. Under H2 (25 psi), a suspension of 15b (0.070 g, 0.227 mmol) and 0.007 g (0.006 mmol) of
Pd/C (10%) in MeOH (3 ml) was stirred at r.t. for 1.5 h. The mixture was filtered over Celite, and the
solvent was removed under vacuum. The residue was purified by CC (SiO2 (18 g); hexane/AcOEt 98 :2)
to give 1 (0.045 g, 90%). Colorless oil. Rf (hexane/AcOEt 8 :2) 0.57. IR (CH2Cl2): 3425, 2962, 2923, 2856,
1619, 1583, 1517, 1451, 1419, 1376, 1287, 1221, 1152, 1121, 904, 809. 1H-NMR (500 MHz, CDCl3): 1.22 (d,
J ¼ 7.0, MeCHAr); 1.54 (br. s, MeC¼); 1.56 – 1.67 (m, CH2CHAr); 1.68 (br. s, MeC¼); 1.87 – 1.99 (m,
CH2CH¼); 2.26 (s, MeC6H3); 2.96 (sext., J ¼ 7.0, MeCHAr); 4.66 (s, OH); 5.10 – 5.15 (m, CH2CH¼); 6.58
(br. s, HꢀC(3’)); 6.72 (br. d, J ¼ 7.5, HꢀC(5’)); 7.03 (d, J ¼ 7.5, HꢀC(6’)). 13C-NMR (125 MHz, CDCl3):
17.7 (MeC¼); 20.9 (MeC6H3); 21.1 (MeCHAr); 25.7 (CH2CH¼); 26.1 (MeC¼); 31.4 (MeCHAr); 37.3
(CH2CHAr); 116.2 (C(3’)); 121.7 (C(5’)); 124.6 (CH2CH¼); 126.8 (C(6’)); 129.9 (C(1’)); 132.0
(Me2C¼); 136.5 (C(4’)); 152.8 (C(2’)). EI-MS (70 eV): 218 (4, Mþ), 148 (100), 121 (22), 107 (16), 91
(14). HR-FAB-MS: 218.1672 (Mþ, C15H22Oþ; calc. 219.1671).
1-(4-Methyl-3-nitrophenyl)ethanone (17). At 08, a mixture of H2SO4 (0.441 g, 4.50 mmol) and HNO3
(0.236 g, 3.746 mmol) was added dropwise to 16 (0.500 g, 3.753 mmol). The mixture was stirred at r.t. for
6 h, then poured into a beaker containing icy H2O (20 ml). The precipitate was filtered and dissolved with
CH2Cl2 (10 ml). The org. layer was dried (Na2SO4), and the solvent was removed under vacuum. The
residue was purified by CC (SiO2 (45 g); hexane/AcOEt 95 :5) to give 17 (0.436 g, 65%). Yellow solid. Rf
(hexane/AcOEt 7:3) 0.48. M.p. 60 – 618 ([21]: MeOH) (628). IR (CH2Cl2): 1692, 1617, 1531, 1348, 1282,
1251, 833, 803. 1H-NMR (500 MHz, CDCl3): 2.65 (s, MeCO); 2.67 (s, MeC6H3); 7.47 (d, J ¼ 8.0,
HꢀC(5’)); 8.08 (dd, J ¼ 8.0, 1.5, HꢀC(6’)); 8.52 (d, J ¼ 1.5, HꢀC(2’)). 13C-NMR (125 MHz, CDCl3): 20.6
(MeC6H3); 26.5 (MeCO); 124.6 (C(2’)); 131.9 (C(6’)); 133.3 (C(5’)); 136.1 (C(1’)); 138.6 (C(4’)); 149.2
(C(3’)); 195.5 (CO). EI-MS (70 eV): 179 (4, Mþ), 164 (84), 162 (100), 147 (66), 120 (34), 118 (35), 106
(14), 90 (50), 89 (60), 77 (27). HR-FAB-MS: 180.0673 ([M þ 1]þ, C9H10NO3þ ; calc. 180.0661).
1-(3-Amino-4-methylphenyl)ethanone (18). Method A. A mixture of 17 (0.400 g, 2.235 mmol) in
THF (5 ml) and Na2S2O4 (2.333 g, 13.408 mmol) in H2O (5 ml) was stirred at 508 for 12 h. The mixture
was diluted with CH2Cl2 (15 ml) and washed with cold H2O (2 ꢂ 8 ml). The org. layer was dried
(Na2SO4), and the solvent was removed under vacuum. The residue was purified by CC (SiO2 (25 g);
hexane/AcOEt 95 :5) to give 18 (0.266 g, 80%). Brown solid. Rf (hexane/AcOEt 8 :2) 0.24.
Method B. Under an H2 (30 psi), a suspension of 17 (0.400 g, 2.235 mmol) and 0.040 g (0.034 mmol)
of Pd/C (10%) in MeOH (8 ml) was stirred at r.t. for 1.0 h. The mixture was filtered over Celite, and the
solvent was removed under vacuum. The residue was purified by CC (SiO2 (25 g); hexane/AcOEt 95 :5)
to give 18 (0.316 g, 95%). Brown solid. Rf (hexane/AcOEt 8 :2) 0.24. M.p. 80 – 818 ([21]: 828; [24]: 83 –
1
848). IR (CH2Cl2): 3367, 1672, 1573, 1422, 1356, 1291, 1237, 1199. H-NMR (500 MHz, CDCl3): 2.21 (s,
MeC6H3); 2.54 (s, MeCO); 3.77 (br., NH2); 7.12 (d, J ¼ 7.5, HꢀC(5’)); 7.27 (d, J ¼ 2.0, HꢀC(2’)); 7.28 (dd,
J ¼ 7.5, 2.0, HꢀC(6’)). 13C-NMR (125 MHz, CDCl3): 17.5 (MeC6H3); 26.5 (MeCO); 113.8 (C(2’)); 119.1
(C(6’)); 128.0 (C(4’)); 130.4 (C(5’)); 136.2 (C(1’)); 144.8 (C(3’)); 198.3 (CO). EI-MS (70 eV): 149 (80,
Mþ), 134 (100), 106 (80), 79 (42), 77 (50). HR-FAB-MS: 150.0929 ([M þ 1]þ, C9H12NOþ; calc.
150.0919).

Helvetica Chimica Acta – Vol. 93 (2010)
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1-(3-Hydroxy-4-methylphenyl)ethanone (5). To 18 (0.300 g, 2.013 mmol), at r.t. and under N2,
H2SO4 (0.986 g, 10.061 mmol) in icy H2O (4 ml) was added, and the mixture was vigorously stirred at 458
for 30 min. The mixture was cooled to 08, and NaNO2 (0.167 g, 2.420 mmol) dissolved in H2O (3 ml) was
added, and the mixture was stirred for 10 min and then heated to reflux for 5 h. The mixture was poured
into icy H2O (20 ml), the precipitate was filtered and dissolved with CH2Cl2 (10 ml). The org. layer was
dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by CC (SiO2
(20 g); hexane/AcOEt 95 :5) to give 5 (0.267 g, 88%). White solid. Rf (hexane/AcOEt 7:3) 0.39. M.p.
110 – 1118 ([20]: 105 – 1078) IR (CH2Cl2): 3412, 1663, 1606, 1582, 1418, 1350, 1289, 1241, 898, 812.
1H-NMR (500 MHz, CDCl3): 2.32 (s, MeC6H3); 2.58 (s, MeCO); 6.50 (br., OH); 7.20 (d, J ¼ 8.0,
HꢀC(5’)); 7.42 (dd, J ¼ 8.0, 1.5, 1 HꢀC(6’)); 7.54 (d, J ¼ 1.5, HꢀC(2’)). 13C-NMR (125 MHz, CDCl3):
16.2 (MeC6H3); 26.6 (MeCO); 113.9 (C(2’)); 121.3 (C(6’)); 131.0 (C(5’)); 131.1 (C(4’)); 136.2 (C(1’));
154.5 (C(3’)); 198.8 (CO). EI-MS (70 eV): 150 (28, Mþ), 135 (100), 107 (30), 79 (26), 77 (52), 51 (10).
HR-CI-MS: 151.0753 ([M þ 1]þ, C9H11Oþ2 ; calc. 151.0759).
1-(3-Methoxy-4-methylphenyl)ethanone (19) [19]. Following the procedure as for 8a, with KOH
(0.112 g, 2.00 mmol), 5 (0.250 g, 1.667 mmol), and MeI (0.473 g, 3.331 mol). After stirring at r.t. for 6 h,
19 (0.246 g, 90%) was obtained. Colorless oil. Rf (hexane/AcOEt 8 :2) 0.48. IR (CH2Cl2): 1681, 1605,
1579, 1501, 1407, 1270, 1226, 1037, 876. 1H-NMR (500 MHz, CDCl3): 2.27 (s, MeC6H3); 2.59 (s, MeCO);
3.89 (s, MeO); 7.20 (d, J ¼ 8.0, HꢀC(5’)); 7.44 (d, J ¼ 1.0, HꢀC(2’)); 7.45 (dd, J ¼ 8.0, 1.0, HꢀC(6’)).
13C-NMR (125 MHz, CDCl3): 16.5 (MeC6H3); 26.5 (MeCO); 55.4 (MeO); 108.4 (C(2’)); 121.4 (C(6’));
130.4 (C(5’)); 133.0 (C(4’)); 136.3 (C(1’)); 157.9 (C(3’)); 197.9 (CO). EI-MS (70 eV): 165 (100, [M þ
1]þ), 164 (22, Mþ), 150 (12), 149 (36), 135 (4), 106 (4), 91 (7). HR-EI-MS: 164.0838 (Mþ, C10H12Oþ2 ;
calc. 164.0837).
Ethyl 3-(3-Methoxy-4-methylphenyl)-3-oxopropanoate (20). Following the procedure as for 9a, with
NaH (0.073 g, 3.042 mmol), 19 (0.200 g, 1.220 mmol), and CO(OEt)2 (0.288 g, 2.441 mmol): 20 (0.259 g,
90%). Pale yellow oil. Rf (hexane/AcOEt 8 :2) 0.39. IR (CH2Cl2): 1736, 1680, 1603, 1576, 1504, 1455,
1
1406, 1314, 1230, 1138, 1031, 872, 800. H-NMR (500 MHz, CDCl3): 1.26 (t, J ¼ 7.0, MeCH2); 2.27 (s,
MeC6H3); 3.88 (s, MeO); 3.97 (s, CH2(2)); 4.21 (q, J ¼ 7.0, MeCH2); 7.21 (d, J ¼ 7.5, HꢀC(5’)); 7.41 (dd,
J ¼ 7.5, 1.5, HꢀC(6’)); 7.40 (d, J ¼ 1.5, HꢀC(2’)). 13C-NMR (125 MHz, CDCl3): 14.0 (MeCH2); 16.5
(MeC6H3); 45.9 (C(2)); 55.4 (MeO); 61.4 (MeCH2); 108.6 (C(2’)); 121.4 (C(6’)); 130.5 (C(5’)); 133.9
(C(4’)); 135.1 (C(1’)), 158.0 (C(3’)); 167.6 (CO2Et); 192.1 (ArCO). EI-MS (70 eV): 149 (40, [M ꢀ 87]þ),
123 (100), 94 (52), 91 (32), 77 (14), 65 (12). HR-CI-MS: 237.1113 ([M þ 1]þ, C13H17O4þ ; calc. 237.1127).
Ethyl 2-[(3-Methoxy-4-methylphenyl)carbonyl]-5-methylhex-4-enoate (21). Following the procedure
as for 11a/12a, with NaH (0.020 g, 0.833 mmol), 20 (0.200 g, 0.847 mmol), and prenyl bromide (0.152 g,
1.020 mmol): 21 (0.237 g, 92%). Pale yellow oil. Rf (hexane/AcOEt 8 :2) 0.53. IR (CH2Cl2): 1736, 1682,
1
1603, 1578, 1504, 1463, 1408, 1258, 1210, 1150, 1038, 855. H-NMR (500 MHz, CDCl3): 1.18 (t, J ¼ 7.0,
MeCH2); 1.64 (br. s, MeC¼); 1.66 (br. s, MeC¼); 2.27 (s, MeC6H3); 2.62 – 2.76 (m, 2 CH2CH¼); 3.88 (s,
MeO); 4.14 (qd, J ¼ 7.0, 0.5, MeCH2); 4.28 (dd, J ¼ 7.8, 6.8, HꢀC(2)); 5.09 – 5.14 (m, CH2CH¼); 7.21 (d,
J ¼ 8.0, HꢀC(5’)); 7.46 (d, J ¼ 1.5, HꢀC(2’)); 7.50 (dd, J ¼ 8.0, 1.5, HꢀC(6’)). 13C-NMR (125 MHz,
CDCl3): 14.0 (MeCH2); 16.5 (MeC6H3); 17.8 (MeC¼); 25.7 (MeC¼); 27.8 (CH2CH¼); 54.5 (C(2)); 55.4
(MeO); 61.2 (MeCH2); 109.0 (C(3’)); 120.3 (CH2CH¼); 121.3 (C(6’)); 130.4 (C(5’)); 133.5 (C(4’)); 134.6
(Me2C¼); 135.4 (C(1’)); 158.0 (C(3’)); 170.0 (CO2Et); 194.5 (ArCO). EI-MS (70 eV): 231 (2, [M ꢀ
73]þ), 193 (56), 164 (46), 149 (100), 121 (30), 91 (56), 77 (22). HR-CI-MS: 305.1758 ([M þ 1]þ,
C18H25Oþ4 ; calc. 305.1753).
1-(3-Methoxy-4-methylphenyl)-5-methylhex-4-en-1-one (22). Following the procedure as for 13a,
with KOH (0.110 g, 1.964 mmol) and 21 (0.150 g, 0.493 mmol) in MeOH/H2O 85 :15 (4 ml): 22 (0.109 g,
95%). Colorless oil. Rf (hexane/AcOEt 8 :2) 0.62. IR (CH2Cl2): 1681, 1604, 1579, 1503, 1454, 1407, 1263,
1249, 1155, 1038, 877. 1H-NMR (500 MHz, CDCl3): 1.64 (br. s, MeC¼); 1.69 (br. s, MeC¼); 2.26 (s,
MeC6H3); 2.41 (br. q, J ¼ 7.5, CH2CH¼); 2.97 (t, J ¼ 7.5, CH2CO); 3.88 (s, MeO); 5.15 – 5.21 (m,
CH2CH¼); 7.18 (d, J ¼ 7.5, HꢀC(5’)); 7.44 (d, J ¼ 1.5, HꢀC(2’)); 7.45 (dd, J ¼ 7.5, 1.5, HꢀC(6’)).
13C-NMR (125 MHz, CDCl3): 16.5 (MeC6H3); 17.6 (MeC¼); 23.1 (CH2CH¼); 25.7 (MeC¼); 38.6
(CH2CO); 55.4 (MeO); 108.5 (C(2’)); 120.9 (C(6’)); 123.0 (CH2CH¼); 130.3 (C(5’)); 132.6 (C(4’)); 132.7
(Me2C¼); 136.2 (C(1’)), 157.9 (C(3’)); 199.7 (ArCO). EI-MS (70 eV): 233 (20, [M þ 1]þ), 232 (40, Mþ),

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Helvetica Chimica Acta – Vol. 93 (2010)
217 (10), 164 (100), 149 (57), 122 (44), 121 (25), 91 (34). HR-CI-MS: 233.1530 ([M þ 1]þ, C15H21O2þ ;
calc. 233.1542).
2-(3-Methoxy-4-methylphenyl)-6-methylhept-5-en-2-ol (23) [13a]. Following the procedure as for
14a, with MeMgBr (0.154 g, 1.294 mmol) and 22 (0.100 g, 0.431 mmol): 23 (0.095 g, 89%). Pale yellow oil.
Rf (hexane/AcOEt 8 :2) 0.59. IR (CH2Cl2): 3433, 2966, 2924, 1612, 1580, 1504, 1463, 1405, 1252, 1133,
1041, 857, 815. 1H-NMR (300 MHz, CDCl3): 1.51 (br. s, MeC¼); 1.53 (s, MeC(OH)); 1.65 (br. s, MeC¼);
1.78 – 2.05 (m, CH2CH2CH ¼ , OH); 2.20 (s, MeC6H3); 3.85 (s, MeO); 3.99 (br. s, OH); 5.05 – 5.15 (m,
CH2CH¼); 6.85 (dd, J ¼ 7.5, 1.8, HꢀC(6’)); 6.97 (d, J ¼ 1.8, HꢀC(2’)); 7.08 (d, J ¼ 7.5, HꢀC(5’)).
13C-NMR (75.4 MHz, CDCl3): 15.8 (MeC¼); 17.7 (MeC6H3); 23.0 (CH2CH¼); 25.6 (MeC¼); 30.6
(MeC(OH)); 43.6 (CH2C(OH)); 55.3 (MeO); 75.0 (MeC(OH)); 106.8 (C(2’)); 116.5 (C(6’)); 124.2
(CH2CH¼); 124.6 (C(4’)); 130.2 (C(5’)); 132.1 (Me2C¼); 147.0 (C(1’)), 157.5 (C(3’)). EI-MS (70 eV):
248 (8, Mþ), 230 (31), 187 (100), 172 (34), 166 (54), 165 (28), 151 (20), 91 (17). HR-CI-MS: 249.1851
([M þ 1]þ, C16H25Oþ2 ; calc. 249.1855).
4-(1,5-Dimethylhex-4-en-1-yl)-2-methoxy-1-methylbenzene (24) [13a]. Following the procedure as
for 15a, with 23 (0.100 g, 0.403 mmol), Et3SiH (0.056 g, 0.483 mmol), and BF3 · Et2O (0.086 g,
0.606 mmol): 24 (0.084 g, 90%). Colorless oil. Rf (hexane/AcOEt 8 :2) 0.80. IR (CH2Cl2): 2953, 2923,
1
2853, 1612, 1586, 1456, 1376, 1256, 1134, 1045, 850, 813. H-NMR (300 MHz, CDCl3): 1.23 (d, J ¼ 7.2,
MeCHAr); 1.53 (br. s, MeC¼); 1.56 – 1.64 (m, CH2CHAr); 1.68 (br. s, MeC¼); 1.82 – 1.98 (m,
CH2CH¼); 2.18 (s, MeC6H3); 2.65 (sext., J ¼ 7.2, MeCHAr); 3.82 (s, MeO); 5.05 – 5.14 (m, CH2CH¼);
6.66 (br. s, HꢀC(2’)); 6.68 (dd, J ¼ 7.5, 1.5, HꢀC(6’)); 7.04 (d, J ¼ 7.5, HꢀC(5’)). 13C-NMR (75.4 MHz,
CDCl3): 15.8 (MeC¼); 17.7 (MeCHAr); 22.5 (MeC6H3); 25.7 (MeC¼); 26.2 (CH2CH¼); 38.4
(MeCHAr); 39.5 (CH2CHAr); 55.2 (MeO); 108.9 (C(2’)); 118.7 (C(6’)); 123.8 (CH2CH¼); 124.5
(C(4’)); 130.3 (C(5’)); 131.4 (Me2C¼); 146.7 (C(1’)); 157.6 (C(3’)). EI-MS (70 eV): 232 (30, Mþ), 162
(27), 150 (69), 149 (30), 135 (100), 91 (25). HR-CI-MS: 233.1916 ([M þ 1]þ, C16H25Oþ; calc. 233.1905).
Xanthorrhizol (¼ 5-(1,5-Dimethylhex-4-en-1-yl)-2-methylphenol; 2). Following the procedure as for
1, with 24 (0.100 g, 0.430 mmol), EtSH (0.190 g, 3.065 mmol), and NaH (0.083 g, 3.458 mmol): 2 (0.089 g,
95%). Colorless oil. Rf (hexane/AcOEt 8 :2) 0.55. IR (CH2Cl2): 3392, 2960, 2923, 1589, 1505, 1454, 1421,
1375, 1258, 1121, 812. 1H-NMR (300 MHz, CDCl3): 1.20 (d, J ¼ 7.2, MeCHAr); 1.53 (br. s, MeC¼); 1.56 –
1.58 (m, CH2CHAr); 1.67 (br. s, MeC¼); 1.84 – 1.93 (m, CH2CH¼); 2.22 (s, MeC6H3); 2.61 (sext., J ¼ 7.2,
MeCHAr); 4.61 (s, OH); 5.03 – 5.15 (m, CH2CH¼); 6.61 (d, J ¼ 7.5, HꢀC(2’)); 6.68 (dd, J ¼ 7.5, 1.8,
HꢀC(6’)); 7.03 (d, J ¼ 7.5, HꢀC(5’)). 13C-NMR (125 MHz, CDCl3): 15.3 (MeC6H3); 17.7 (MeC¼); 22.4
(MeCHAr); 25.7 (MeC¼); 26.1 (CH2CH¼); 38.4 (CH2CHAr); 39.0 (MeCHAr); 113.5 (C(2’)); 119.4
(C(6’)); 120.8 (C(4’)); 124.5 (CH2CH¼); 130.7 (C(5’)); 131.4 (Me2C¼); 147.2 (C(1’)); 153.6 (C(3’)). EI-
MS (70 eV): 218 (30, Mþ), 148 (58), 136 (58), 121 (100), 91 (24), 77 (13). HR-CI-MS: 219.1744 ([M þ
1]þ, C15H23Oþ; calc. 219.1749).
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Received March 18, 2010