Synthesis and nmr structure determination of new linear geranylphenols by direct geranylation of activated phenols

Article abstract of DOI:10.4067/S0717-97072013000200033

The known geranylhydroquinone 2, geranylorcinol 4 and the derivative (E)-4-(3,7-dimethylocta-2,6-dienyl)-5-methylbenzene-1,3-diol 5, were prepared by Electrophilic Aromatic Substitution (EAS) reactions between the corresponding phenol derivatives containi

Full text of DOI:10.4067/S0717-97072013000200033

J. Chil. Chem. Soc., 58, Nº 2 (2013)
SYNTHESIS AND NMR STRUCTURE DETERMINATION OF NEW LINEAR GERANYLPHENOLS BY DIRECT
GERANYLATION OF ACTIVATED PHENOLS.
LAUTARO TABORGAa, ALEJANDRA VERGARAa, MARÍA JOSÉ FERNÁNDEZ a, MAURICIO OSORIOa,
MARCELA CARVAJALa, ALEJANDRO MADRIDa, FRANCISCO MARILAFa, HÉCTOR CARRASCOb AND LUIS
ESPINOZA CATALÁNa*.
aDepartamento de Química, Universidad Técnica Federico Santa María, Valparaíso, Chile.
bDepartamento de Ciencias Químicas, Universidad Andrés Bello, Viña del Mar, Chile.
(Received: August 22, 2012 - Accepted: January 23, 2013)
ABSTRACT
The known geranylhydroquinone 2, geranylorcinol 4 and the derivative (E)-4-(3,7-dimethylocta-2,6-dienyl)-5-methylbenzene-1,3-diol 5, were prepared
by Electrophilic Aromatic Substitution (EAS) reactions between the corresponding phenol derivatives containing electron-donor subtituents and geraniol using
BF3×OEt2 as a catalyst. In addition, spectroscopic NMR information for 4 and 5 is complemented. Furthermore, the new (E)-2-(3,7-dimethylocta-2,6-dienyl)
benzene-1,3,5-triol (geranylphloroglucinol) 13, (E)-2-(3,7-dimethylocta-2,6-dienyl)-1,3,5-trimethoxybenzene 14, (E)-2-(3,7-dimethylocta-2,6-dienyl)-6-
methoxyphenol 15, (E)-3-(3,7-dimethylocta-2,6-dienyl)-2-methoxyphenol 16, (E)-5-(3,7-dimethylocta-2,6-dienyl)-2-methoxyphenol 17, (E)-4-(3,7-dimethylocta-
2,6-dienyl)benzene-1,3-diol 18, (E)-3-(3,7-dimethylocta-2,6-dienyl)benzene-1,2-diol 19, (E)-4-(3,7-dimethylocta-2,6-dienyl)-5-isopropyl-2-methylphenol 20,
(E)-2-(3,7-dimethylocta-2,6-dienyl)-4-isopropyl-3-methylphenol 21, (E)-2-(3,7-dimethylocta-2,6-dienyl)-4-isopropyl-5-methylphenol 22, and(E)-2-tert-butyl-4-
(3,7-dimethylocta-2,6-dienyl)-5-methylphenol 23 were also prepared with this synthesis strategy. All the synthesized compounds were fully characterized and
their structures were established by IR, MS and mainly NMR spectroscopic dates.
Keywords: Linear geranylphenols, synthesis, NMR spectroscopy.
INTRODUCTION
The subgroups of linear geranylquinones or geranylhydroquinones
are represented by an important number of compounds, for example
2-geranylbenzoquinone (1) isolated from Ascindian Synoicum castellatum
[1] and 2-geranylhydroquinone (2) isolated from tree Cordia alliodora [2],
Phacelia crenulata [3-5], Aplidium antillense [6] and the tunicate Amaroucium
multiplicatum [7]. Both natural products are present in higher plants, but also
have been reported in marine urochordates [8].
2-geranylbenzoquinone (1) exhibits interesting biological activities
such as toxicity against Gambusia affinis and Artemia salina, antimicrobial
activity against Pseudomonas aeruginosa, Escherichia coli, Candida albicans,
Micrococcus luteus and Bacillus subtilis [9]. Also the compound 1 has been
reported as a potent skin sensitizer for guinea pigs, proving to be a fairly
reliable indicator of allergenicity against human skin [3]. In addition, it has
antimicrobial activity against Serratia marcescens, Morganella morganii,
Proteus mirabilis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas
Figure 1.Structure of some active linear geranylquinone and
aeruginosa, Streptococcus fecalis and antimicrobial activity against methicillin-
geranylphenols.
resistant Staphylococcus aureus [9]. Cytotoxicity against mouse P388 cells
and cytotoxicity against human KB cells has also been reported for this
On another hand, several factors highlight the urgent need for the
compound [6], as well as inhibition of soybean arachidonate 15-lipoxygenase
development of new strategies for the control of phytopathogen fungus Botrytis
and antioxidant activity in rat liver microsomes assessed as inhibition of
cinerea and other plagues affecting important Chilean agricultural crops. They
lipid peroxide formation [7]. Furthermore, 2-geranylhydroquinone (2) has
include the emergence of Botrytis strains resistant to fungicides, the high cost
been synthesized as a drug and it has been reported to have some value as
of chemical control and the limited availability of fungicides. In addition,
radioprotective and anti-cancer protective agents [10-11].
it should be considered the strong worldwide trend towards sustainable
Additionally, the evaluation of Cancer-Preventive Activity and Structure–
development and environmentally friendly substances. Therefore, our interest
Activity Relationships (SAR) of 3-demethylubiquinone Q2 (3), isolated from
the Ascidian Aplidium glabrum [12], and the geranylhydroquinone synthetic
is to gain a broader insight about the biological properties of these substances
against plant pathogens which are important for the local national industry.
analogues were informed. All the compounds tested were able to inhibit JB6
On the basis of previously described and considering the structure -activity
Cl41 cell transformation, to induce apoptosis, AP-1, and NF-KB activity, and
relationship with the derivatives 6-12, in this opportunity we report the synthesis
to inhibit p53 activity [13]. On the other hand, the geranylorcinol derivatives 4
of 2, 4-5 and the new 13-23 linear geranylmethoxyphenol derivatives (figure
and 5 (figure 1) showed antimicrobial and antifungal activities [14-15].
2) by direct geranylation reactions of activated phenols, between geraniol and
The geranylmethoxyphenol 6 (isolated from Piper crassinervium Kunth)
orcinol, phloroglucinol, guaiacol, resorcinol, catechol, carvacrol, 4-isopropyl-
showed antioxidant activity [16], whereas the linear geranylmethoxyphenol/
3-methylphenoland 2-tert-butyl-5-methylphenol using BF3∙Et2O as catalyst. In
acetates 7-9 (see figure 1), isolated from Phacelia ixodes [5], showed a
addition, the structural determinations of these new eleven compounds were
biological activity which allows to repel and in some cases, to kill phytophagous
established by chemical and spectroscopic properties and the effect in the
insects and plant pathogens [17].
inhibition of the growth of B. cinerea will be informed later.
Recently, our research group reported the synthesis and in vitro cytotoxic
activity against cells of PC-3 prostate cancer, MCF-7 and MDA-MB-231
breast carcinoma of compounds 1, 2 and some methoxylated geranylphenol
derivatives in µM concentrations.
These compounds were obtained by Electrophilic Aromatic Substitution
(EAS) reactions between geraniol and the phenols 1,4-hydroquinone and
p-methoxyphenols using BF3∙Et2O as catalyst. [18] [19].
e-mail: luis.espinozac@usm.cl.
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J. Chil. Chem. Soc., 58, Nº 2 (2013)
H-4 and H-6, confirming the unique possibility of aromatic mono-substitution.
Additionally, the signal at dH = 3.30 ppm to assigned at H-2’ (d, J = 6.9 Hz,
2H) shows 3JH-C coupling with C-1 and C-3 (dC = 155.7 ppm) and 2J coupling
with C-2 (dC = 106.3 ppm), these HMBC correlations are shown Hin-C figure 4.
In order to establish the E geometry in double bond position at C-2’-C-3’ of
the geranyl chain, selective 1D NOESY NMR experiments were registered for
the compound 13. These correlations are shown in figure 4, where the most
important of those correspond to the correlation observed between the H-2’
and the hydrogens of methyl group in C-3’ position. For the derivative 14, in
1H NMR spectra the two singlet signal at dH = 3.92 ppm (3H, OCH3) and dH =
3.79 ppm (6H, 2 x OCH3) confirm the presence of trimethoxylated derivative.
Figure 2.Structure of new linear geranylphenol derivatives.
Figure 4. Observed correlations 1D NOESY and 2D H-13C HMBC in
the NMR experiments for the compound 13, which confirm the position and
1
RESULTS AND DISCUSSION
geometrical orientation of double bond in the geranyl chain.
Our first objective was the preparation of compounds 2, 4-5, using the
coupling method previously described by us [18, 19] with geraniol and
commercially available hydroquinone and orcinol, respectively. In this
case, 2-geranylhydroquinone 2 was obtained with 28 % yield, whereas
the compounds 4 and 5 were obtained with 12.6 % and 27.6 % yields,
respectively. The physical and spectroscopic properties of compounds4 and
5 were consistent with those previously reported [14, 15]. In addition, for the
case of geranylorcinol structure derivatives, these were fully characterized by
our research group, where the position of geranyl chain was established by
selective 1D NOESY and 2D HMBC experiments, according to interactions
shown in figure 3.
The following step consisted in the preparation of compound 15.
Nevertheless, the regio-isomers 16 and 17 also were obtained according to
scheme 2.
Scheme 2: Synthesis of derivatives 15, 16 and 17 by direct geranylation
between geraniol and guaiacol (2-methoxyphenol) catalyzed by BF3.Et2O.
The substitution position of geranyl chain in aromatic ring was established
in base at NMR data spectra, mainly from the 2D HMBC and selective 1D
NOESY correlations. For the compound 15, the signal at dH = 3.39 ppm (d, J
= 6.6 Hz, 2H, H-1’) showed 3JH-C coupling with C-1 (dC = 143.3 ppm) and 2JH-C
coupling with C-2 (dC = 127.5 ppm), while other HMBC correlations are shown
in figure 5. In the compound 16, the signal at dH = 3.29 ppm (d, J = 7.2 Hz,
2H, H-1’) showed 3JH-C coupling with C-2 (d = 146.4 ppm) and 2JH-C coupling
with C-3 (dC = 133.7 ppm), additionally, othCer HMBC correlations are shown
in figure 5. In addition, for the compound 17 the signal at dH = 3.26 ppm (d, J =
7.2 Hz, 2H, H-1’) showed 3JH-C coupling with C-6 (dC = 114.6 ppm), with C-4
Figure 3. Observed correlations 1D NOESY and 2D 1H-13C HMBC in the
NMR experiments for the compounds 4 and 5, which confirm the position and
geometrical orientation of double bond in the geranyl chain.
2
(dC = 119.5 ppm) and JH-C coupling with C-5 (dC = 135.2 ppm), additionally,
other HMBC correlations are shown in figure 5.
In order to establish the E geometry in double bond position at C-2’-C-3’
of the geranyl chain, selective 1D NOESY NMR experiments were registered
for the compounds 15, 16 and 17. These correlations are shown in figure 5,
where the most important of those correspond to the observed between the
H-2’ of geranyl chain with the hydrogens of the CH3-C3’and between some
substituents in aromatic nucleus.
The synthesis of compound 13 (geranylphloroglucinol proposed name
by us in analogy with the name of geranylorcinol) was development by
direct geranylation reactions between phloroglucinol (benzene-1,3,5-triol)
and geraniol with a 4,2 % yield. Later, the compound 13 was methylated
with dimethylsulfate in acetone as was previously described by us for other
compounds [18]. The trimethoxylated derivative 14 was obtained with a 98.5
% yield.These reactions are shown in scheme 1.
On the other hand, the direct geranylation between resorcinol and geraniol
produced the compound 18 with 11.9 % yield. The structure and pattern of the
aromatic monosubstitution of this compound were established from NMR data
spectra. In 1H NMR spectrum, the signals at dH = 6.92 ppm (d, J = 8.8 Hz, 1H,
H-5) and dH = 6.37-6.35 ppm (m, 2H, H-2 and H-4) confirm the presence of a
tri-substituted aromatic system. The position of geranyl chain substitution in
the aromatic nucleus was determined from the 2D HMBC and selective 1D
NOESY techniques. The signal at d = 3.27 ppm (d, J = 7.2 Hz, 2H, H-1’)
showed heteronuclear JH-C coupling Hwith C-3 (dC = 154.8 ppm) and C-5 (dC
3
2
= 130.3 ppm) and JH-C coupling with C-4 (dC = 124.0 ppm). Other HMBC
correlations are shown in the figure 6. Additionally, the signal assigned at H-1’
(3.27 ppm, d, J = 7.2 Hz, 2H) showed long range NOE interaction with aromatic
H-5 (6.92 ppm, d, J = 8.8 Hz, 1H) confirming the geranyl chain position and
CH3-C3’ (1.72 ppm, s, 3H) that indicate the geometrical orientation of double
bond in C2’-C3’, as shown in figure 6.
Scheme 1: Synthesis of geranylphloroglucinol 13 and their trimethoxylated
derivative 14.
The determination of structure of 13 was mainly established by the NMR
aromatic signal at dH = 5.93 ppm, where was observed a singlet for two hydrogen
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Scheme 3: Synthetic route for the obtaining of derivatives 20-23 by direct
geranylation reaction between, carvacrol, 4-i-propil-3-methylphenol and
2-t-butil-5-methylphenol and geraniol in Et2O catalyzed by BF3.Et2O.
The structural determination of these compounds was mainly established
by NMR data spectra. Thus, for compound 20, the signals at dH = 6.88 ppm (s,
1H, H-3) and 6.69 ppm (s, 1H, H-6) indicate the aromatic substitution pattern,
confirming that the geranyl fragment was incorporated in para orientation
Figure 5. Main 2D HMBC and 1D NOESY observed correlations that
allowed differentiate and determine the regio-isomer structures 15, 16 and 17.
3
with respect to hydroxyl group. Additionally, J HMBC correlations were
observed between H-1’ (d = 3.27 ppm, d, J = 6H.8-C Hz) with C-3 (d = 131.9
ppm), C-5 (dC = 146.1 ppHm) and C-3’ (dC = 135.3 ppm) on the otCher hand,
2JH-C correlation with C-4 (dC = 130.8 ppm) and C-2’ (dC = 124.1 ppm) also
were observed (to see figure 8). Additionally, long range interactions (NOE)
between H-1’ with H-3 (dH = 6.88 ppm, s, 1H) and CH3-C-3’ (d = 1.71 ppm,
s, 3H) were observed which confirmed the geometrical E orientHations around
of double bond C2’-C3’ and geranyl fragment position in the aromatic nuclei
(to see figure 8)
Figure 6. 2D 1H-13C HMBC and 1D NOESY observed correlations
in the NMR experiments for the compound 18, which confirm the aromatic
substitution position and geometrical orientation of double bond in the geranyl
chain.
For the synthesis of compound 19, pyrocatechol and geraniol were used. In
this opportunity, the geranyl chain was substituted in ortho position respect to
hydroxyl group at the aromatic nucleus; as in the previous cases, the structure
of compound 19 and geranyl chain position were confirmed by NMR data
Figure 8. Main 2D 1H-13C HMBC and 1D NOESY observed correlations
in the NMR experiments for the compound 20, these confirm the aromatic
substitution position and geometrical orientation of double bond in the geranyl
chain.
1
spectra. In H NMR spectrum the signals at dH = 6.79 – 6.72 (m, 2H, H-5
and H-6) and 6.66 (d, J = 7.0 Hz, 1H, H-4) ppm confirm the presence of a
tri-substituted aromatic system. From 2D HMBC spectrum, the signal at dH =
3
3.37 ppm (d, J = 7.1 Hz, 2H, H-1’) showed heteronuclear JH-C coupling with
2
C-2 (dC = 141.9 ppm) and C-4 (d = 121.4 ppm) and JH-C coupling with C-3
(dC = 127.4 ppm). HMBC correlatCions are shown in the figure 7. Additionally,
the signal to assigned at H-1’ (3.37 ppm, d, J = 7.1 Hz, 2H) showed long range
NOE interaction with aromatic H-4 (6.66 ppm, d, J = 7.0 Hz, 1H) confirming
the geranyl chain position and with single signal CH3-C3’ (1.78 ppm, s, 3H)
that indicate the geometrical orientation of double bond in C2’-C3’, as shown
in figure 7.
When 4-i-propil-3-methylphenol was reacted with geraniol catalyzed by
BF3.Et2O under ethereal solution, the compounds 21 and 22 were obtained. After
work-up and posterior flash conventional C.C. purification and separation, only
the compound 21 was accessible in pure form with a 4.2 % yield. However, the
mixture of compounds 21-22 was mainly obtained with a 25.2 % yield. The
proportion of compounds 21/22= 1:1 present in the mixture was determined
from 1H NMR spectrum, considering the average values of integration area for
signal assigned to the aromatic hydrogens. H-1’ and CH(CH3)2 signals were
clearly identified in the 1H NMR spectrum onto the mixture.
The structure of compound 21 was easily identified due to the pattern of
1
aromatic substitution shown in the spectrum of H RMN. Two doublet signal
at d = 7.01 ppm (d, J = 8.4 Hz, 1H, H-5) and d = 6.67 ppm (d, J = 8.4 Hz,
1H,HH-6) confirmed that the geranyl chain was to iHncorporated in ortho position
with respect to hydroxyl group, specifically, in C-2. Additionally, 3JH-C HMBC
correlations were observed between H-1’ (dH = 3.41 ppm, d, J = 6.6 Hz) with
C-1 (dC = 151.1 ppm) and C-3 (dC = 131.7 ppm). Additionally, 2JH-C correlation
with C-2 (dC = 125.9 ppm) and C-2’ (dC = 122.1 ppm) were also observed (to
see figure 9).
Figure 7. Principal 2D 1H-13C HMBC and 1D NOESY observed
correlations in the NMR experiments for the compound 19, these confirm the
aromatic substitution position and geometrical orientation of double bond in
the geranyl chain.
Later, the compounds 20, 21, 22 and 23 were obtained by direct
geranylation between carvacrol, 4-i-propyl-3-methylphenol, 2-t-butyl-5-
methylphenol and geraniol under identical conditions for the three cases.
Nevertheless, in the latter case, ethyl ether was used as dissolvent instead of
dioxane (to see scheme 3). These compounds were obtained with 21.7 %, 4.2
% and 17.7 % yield, respectively. In addition, the 21-22 mixture was obtained
with a 25.2 % yield, when the 4-i-propyl-3-methylphenol reacted with geraniol
according to the scheme 3.
1
Figure 9. Main 2D H-13C HMBC observed correlations in the NMR
spectrum for the compound 21, which confirm the aromatic substitution
position of the geranyl chain.
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J. Chil. Chem. Soc., 58, Nº 2 (2013)
The structural assignation of compound 22 was established by comparison
3.35 ppm (d, J = 7.1 Hz, 2H); 3.06 ppm (sept. J = 6.8 Hz, 1H); 2.27 ppm (s,
3H); 1.79 ppm (s, 3H); 1.70 ppm (s, 3H); 1.61 ppm (s, 3H) and 1.25 ppm (d, J
= 6.8 Hz; 6H) were assigned to the OH, H-1’, CH(CH3) , CH3-Ar, CH3-C3’,
CH3-8, CH3-C7’ and (CH3)2CH respectively, as shown in2Figure 10.
1
1
from H NMR spectrum of pure 21 with the mixture 21/22. Thus, in the H
NMR spectrum of mixture the signals at d = 6.96 ppm (s, 1H) and 6.62 ppm
(s, 1H) were assigned to the H-3 and H-6, rHespectively, indicating the aromatic
substitution pattern. Additionally, the 1H NMR signal at dH = 5.04 ppm (s, 1H);
Figure 10. 1HNMR spectrum of the mixture compounds 21/22 and identification of the signals corresponding to the compound 22.
EXPERIMENTAL
The structure of compound 22 was unequivocally assigned from 2D
HSQC and HMBC spectra data of the mixture of compounds 21/22. Thus, for
compound 22, the signals at dH = 3.35 ppm (d, J = 7.1 Hz, 2H, H-1’) showed
3JH-C HMBC correlations with C-1 (d = 151.9 ppm), C-3 (dC = 126.3 ppm) and
C-3’ (dC = 138.1 ppm) and 2JH-C correClation with C-2 (dC = 123.8 ppm) and C-2’
(d = 122.2 ppm) also were observed. In addition other 3JH-C and 2JH-C HMBC
coCrrelations are shown in figure 11.
General
Unless otherwise stated, all chemical reagents purchased (Merck or
Aldrich) were of the highest commercially available purity and were used
without previous purification. IR spectra were recorded as thin films in a FT-IR
Nicolet 6700 spectrometer and frequencies are reported in cm-1. Low resolution
mass spectra were recorded on an Agilent 5973 spectrometer at 70eV ionising
voltage in a DB-5 m, 30 m x 0.25 mm x 0.25 um column, and dates are given
as m/z (% rel. int.). 1H, 13C, 13C DEPT-135, sel. gs1D 1H NOESY, gs 2D HSQC
and gs 2D HMBC spectra were recorded in CDCl3 solutions and are referenced
to the residual peaks of CHCl3 at δ = 7.26 ppm and δ = 77.0 ppm for 1H and 13C,
respectively, on a Bruker Avance 400 Digital NMR spectrometer, operating
at 400.1 MHz for 1H and 100.6 MHz for 13C. For selective 1D NOESY
experiment the selnogp.3 with Z-PFG pulse program was used, obtained from
Bruker Library and optimizedparameter at ns = 32, ds = 4, d1 = 2.0sec, TD =
16k, sp2 = 73.0dB, p12 = 80msec, d8 = 600ms, and gradient ratios: gpz3 = 40,
gpz4 = -40. For gs 2D HSQC experiment invigpph pulse program was used and
optimized parameter at ns = 4, ds = 16, d1 = 1.0sec, TD = 1k, p16 = 1.0msec,
d16 = 500msec, gradient ratios: gpz1 = 80, gpz2 = 30 and gpz3 = 20.1. For gs
2D HMBC experiment invi4gplplrndqf with 1JHC filter (low-pass J-filter) pulse
program was used and optimized parameter at ns = 4, ds = 16, d1 = 1.0sec, TD
= 1k, p16 = 1.0msec, d16 = 500msec, gradient ratios: gpz1 = 50, gpz2 = 30 and
gpz3 = 40.1. Chemical shifts are reported in δ ppm and coupling constants (J)
are given in Hz. Silica gel (Merck 200-300 mesh) was used for C.C. and silica
gel plates HF-254 for TLC. TLC spots were detected by heating after spraying
with 25% H2SO4 in H2O.
1
Figure 11. Major 2D H-13C HMBC observed correlations in the NMR
spectrum for the compound 22.
On the other hand, from the 1D selective NOE NMR experiments was
possible to determinate the long range interactions between the H-1’ with
aromatic H-3, olefinic H-2’, OH and CH3-C3’. In addition to this information,
was possible to confirm the geometric orientation around the C2’-C3’ double
bond. These interactions are shown in Figure 12.
( E ) - 2 - ( 3 , 7 - d i m e t h y l o c t a - 2 , 6 - d i e n y l ) b e n z e n e - 1 , 4 - d i o l
(1,4-geranylhydroquinone) 2
To a solution of 1,4-hydroquinone (0,601 g, 5,5 mmol) and geraniol (0,8
g, 5,5 mmol) in 1,4-dioxane (30 mL) BF3.OEt2(0,23 g, 1.6 mmol) was slowly
added dropwise with stirring at room temperature and under a N2 atmosphere,.
After the addition was completed, the stirring was continued overnight. When
the end of the reaction was verified by TLC, the mixture was poured onto
crushed ice (app. 30 g) and it was extracted with diethyl ether (3 x 30 mL).
Then the ethereal layer was washed with 5% NaHCO3 (30 mL), water (2 x 15
mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced
pressure. The crude was redissolved in CH Cl (5 mL) and chromatographed
on silicagel with petroleum ether/EtOAc2 m2ixtures of increasing polarity
(19.8:0.2→13.0:7.0) to obtain the title compound as a brownish oil 0.373
g, 28%). Spectroscopic data of compound 2 were consistent with those of
literature.
(E)-2-(3,7-dimethylocta-2,6-dienyl)-5-methylbenzene-1,3-diol 4 and (E)-
4-(3,7-dimethylocta-2,6-dienyl)-5-methylbenzene-1,3-diol 5
1
Figure 12. Bottom: normal H-NMR spectrum of mixture 21/22; Top:
To a solution of 5-methylbenzene-1,3-diol (1,21 g, 9,8 mmol) and BF3.
OEt2 (1.4 g, 9.8 mmol) in freshly distilled 1,4-dioxane (5 mL) was slowly
added dropwise, with stirring at room temperature and under a N2 atmosphere,
selective gs 1D NOESY irradiation at = 3.35 ppm for compound 22 in the
mixture, which long-range interactions can clearly be seen between H-1’ with
H-3, OH, H-2’ and CH3-C3’.
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J. Chil. Chem. Soc., 58, Nº 2 (2013)
a solution of geraniol (1.5 g, 9.8 mmol) in 1,4-dioxane (5 mL). After the
addition was complete, the stirring was continued overnight. When the end
of the reaction was verified by TLC, the mixture was poured onto crushed
ice (app. 30 g) and it was extracted with diethyl ether (3 x 30 mL). Then, the
ethereal layer was washed with 5% NaHCO (30 mL), water (2 x 20 mL), dried
over Na2SO4, filtered and the solvent was e3vaporated under reduced pressure.
The crude was redissolved in CH2Cl2 (5 mL) and the mixture was subjected to
silica gel flash column chromatography with petroleum ether/EtOAc mixtures
of increasing polarity (19.8:0.2→0.2:19.8) as the mobile phase. Two fractions
were obtained. Fraction I: 0.320 g (12.6% yields) of viscous brownish oil
(E)-2-(3,7-dimethylocta-2,6-dienyl)-6-methoxyphenol 15, (E)-3-(3,7-
dimethylocta-2,6-dienyl)-2-methoxyphenol 16 and (E)-5-(3,7-dimethylocta-
2,6-dienyl)-2-methoxyphenol 17.
To a solution of 2-methoxyphenol (1.50 g, 12.1 mmol) and BF3.OEt (2.25
g, 15.8 mmol) in freshly distilled 1,4-dioxane (5 mL) was added dro2pwise,
with stirring at room temperature and under a N2 atmosphere, a solution of
geraniol (2.44 g, 15.8 mmol) in 1,4-dioxane (5 mL). After the addition was
complete, the stirring was continued overnight. When the end of the reaction
was verified by TLC, the mixture was poured onto crushed ice (app. 30 g) and
it was extracted with diethyl ether (3 x 30 mL). Then, the ethereal layer was
washed with 5% NaHCO3 (30 mL), water (2 x 20 mL), dried over Na2SO4,
filtered and the solvent was evaporated under reduced pressure. The crude
was redissolved in CH2Cl2 (5 mL) and the mixture was subjected to silica
gel flash column chromatography with petroleum ether/EtOAc mixtures of
increasing polarity (19.8:0.2→0.2:19.8) as the mobile phase. Three fractions
1
compound 4. H NMR: 6.26 (s, 1H, H-6); 6.22 (s, 2H, H-2); 5.60 (brs, 2H,
OH); 5.13 (t, J = 6.8 Hz, 1H, H-2’); 5.05 (t, J = 6.7 Hz, 1H, H-6’); 3.28 (d, J
= 6.7 Hz, 2H, H-1’); 2.21 (s, 3H, CH3-Ar); 2.09-2.06 (m, 2H, H-5’); 2.04-2.00
(m, 2H, H-4’); 1.78 (s, 3H, CH3-3’); 1.67 (s, 3H, H-8’); 1.60 (s, 3H, CH3-C7’);
13C NMR: 155.2 (C-3); 154.1 (C-1); 138.6 (C-5); 137.2 (C-3’); 131.8 (C-7’);
123.9 (C-6’); 122.2 (C-2’); 118.1 (C-4); 109.7 (C-6); 101.0 (C-2); 39.6 (C-
4’); 26.4 (C-5’); 25.6 (C-8’); 25.0 (C-1’); 20.0 (CH3-Ar); 17.6 (CH3-C7’);
16.1 (CH3-C3’); IR (cm−1): 3393, 2975, 2925, 2859, 1602; MS (m/z, %): M+
260 (21.7), 191 (26.9), 177 (13.9), 137 (100), 123 (10.5). Fraction II: 0.704
1
were obtained. Fraction I: compound 15 as a yellow oil (0.09 g, 2.5%). H
NMR: 6.81-6.74 (m, 3H, H-3, H-4 and H-5); 5.72 (s, 1H, OH); 5.37 (t, J =
7,2Hz, 1H, H-2’); 5.13 (t, J = 6.6Hz, 1H, H-6’); 3.90 (s, 3H, OCH3); 3.39 (d, J
= 7.2Hz, 2H, H-1’); 2.14-2.11 (m, 2H, H-5’); 2.09-2.05 (m, 2H, H-4’); 1.74 (s,
3H, CH -C3’); 1.70 (s, 3H, H-8’); 1.62 (s, 3H, CH3-C7’); 13C NMR: 146.3 (C-
6); 143.34 (C-1); 136.3 (C-3’); 131.4 (C-7’); 127.5 (C-2); 124.4 (C-6’); 122.1
(C-2’); 121.8 (C-3); 119.2 (C-4); 108.3 (C-5); 56.0 (OCH3); 39.8 (C-4’); 27.8
(C-1’); 26.6 (C-5’); 25.7 (C-8’); 17.7 (CH -C7’); 16.0 (CH3-C3’); IR (cm−1):
3545, 2964, 2923, 2853, 1616, 1592, 1478,31442, 1376, 1356, 1270, 1217; MS
(m/z, %): M+ 260 (53.8%),191 (29.4), 137 (100), 123 (78.7), 69 (36.7) Fraction
II: compound 16 as aviscous yellow oil (0.12 g, 4.1%); 1H NMR: 6.83 (d, J =
8.5Hz, 1H, H-6); 6.68 (d, J = 6.8Hz, 2H, H-4 and H-5); 5.47 (s, 1H, OH); 5.33
(t, J = 7.2Hz, 1H, H-2’); 5.12 (t, J = 6.4Hz, 1H, H-6’); 3.87 (s, 3H, OCH ); 3.29
(d, J = 7.2Hz, 2H, H-1’); 2.13-2.10 (m, 2H, H-5’); 2.07-2.06 (m, 2H,3H-4’);
1.17 (s, 3H, CH3-C3’); 1.68 (s, 3H, H-8’); 1.60 (s, 3H, CH -C3’); 13C NMR:
146.4 (C-2); 143.6 (C-1); 136.0 (C-3’); 133.7 (C-3); 131.4 3(C-7’); 124.2 (C-
6’); 123.4 (C-2’); 120.8 (C-5); 114.2 (C-6); 110.8 (C-4); 55.8 (OCH3); 39.7 (C-
4’); 33.8 (C-1’); 26.7 (C-5’); 25.7 (C-8’); 17.7 (C-10’); 16.1 (C-9’); IR (cm−1):
3443, 2963, 2924, 2853, 1676, 1600, 1512, 1451, 1432, 1376, 1267, 1230; MS
(m/z, %): M+ 260 (84.3%), 159 (100), 137 (89.9), 123 (42.0), 69 (40.4) Fraction
1
g (27.6% yields) of viscous yellow oil, compound 5. H NMR: 6.26 (s, 1H,
H-6); 6.22 (s, 2H, H-2); 5.60 (brs, 2H, OH); 5.13 (t, J = 6.8 Hz, 1H, H-2’);
5.05 (t, J = 6.7 Hz, 1H, H-6’); 3.28 (d, J = 6.7 Hz, 2H, H-1’); 2.21 (s, 3H, CH -
Ar); 2.09-2.06 (m, 2H, H-5’); 2.04-2.00 (m, 2H, H-4’); 1.78 (s, 3H, CH3-C3’3);
1.67 (s, 3H, H-8’); 1.60 (s, 3H, CH3-C3’); 13C NMR: 155.2 (C-3); 154.1 (C-1);
138.6 (C-5); 137.2 (C-3’); 131.8 (C-7’); 123.9 (C-6’); 122.2 (C-2’); 118.1 (C-
4); 109.7 (C-6); 101.0 (C-2); 39.6 (C-4’); 26.4 (C-5’); 25.6 (C-8’); 25.0 (C-1’);
20.0 (CH3-Ar); 17.6 (CH3-C7’); 16.1 (CH3-C3’); IR (cm−1): 3393, 2975, 2925,
2859, 1602; MS (m/z, %): M+ 260 (21.7), 191 (26.9), 177 (13.9), 137 (100),
123 (10.5).
(E)-2-(3, 7-dimethylocta-2, 6-dienyl)benzene-1, 3, 5-triol
(geranylphloroglucinol) 13
To a solution of phloroglucinol (1.21 g, 7.5 mmol) and BF .OEt2 (1.06
g, 7.5 mmol) in freshly distilled 1,4-dioxane (5 mL), a solution3of geraniol
(1.15 g, 7.5 mmol) in 1,4-dioxane (5 mL) was added dropwise, with stirring
at room temperature and under a N atmosphere. After the addition was
complete, the stirring was continued o2vernight. When the end of the reaction
was verified by TLC, the mixture was poured onto crushed ice (app. 30 g) and
it was extracted with diethyl ether (3 x 30 mL). Then, the ethereal layer was
washed with 5% NaHCO (30 mL), water (2 x 20 mL), dried over Na2SO4,
filtered and the solvent wa3s evaporated under reduced pressure. The crude was
redissolved in CH2Cl2 (5 mL) and the mixture was subjected to silica gel flash
column chromatography with petroleum ether/EtOAc mixtures of increasing
polarity (19.8:0.2→0.2:19.8) as the mobile phase to afford the compound 13 as
a viscous brownish oil (0.832 g, 4,2 % yield). 1H NMR: 5.99 (brs, 2H, -OH);
5.93 (s, 2H, H-4 and H-6); 5.22 (t, J = 6.8 Hz, 1H, H-2’); 5.03 (t, J = 5.9
Hz, 1H, H-6’); 3.30 (d, J = 6.9 Hz, 2H, H-1’); 208-2.05 (m, 2H, H-5’); 2.03-
2.02 (m, 2H, H-4’); 1.76 (s, 3H, CH3-C7’); 1.66 (s, 3H, H-8’); 1.57 (s, 3H,
CH3-C3’); 13C NMR: 155.7 (C-1 and C-3), 154.7 (C-5), 138.7 (C-3’), 131.9
(C-7’), 123.7 (C-6’), 122.0 (C-2’), 106.3 (C-2), 96.1 (C-4 and C-6), 39.6 (C-
4’), 26.3 (C-5’), 25.6 (C-8’), 21.9 (C-1’), 17.6 (CH3-C7’), 16.0 (CH3-C3’); IR
(cm−1): 3397, 2967, 2925, 1706, 1620, 1515, 1463, 1377; MS (m/z, %): M+ 262
(0.2%), 191 (100), 175 (52.7), 137 (49.8), 123 (47.8), 69 (22.1).
1
III: compound 17 as aviscous yellow oil (0.01 g, 0.3%); H NMR: 6.78 (d,
J = 8.3Hz, 1H, H-3); 6.76 (d, J = 1.7Hz, 1H, H-6); 6.66 (dd, J = 8.3-1.7Hz,
1H, H-4); 5.55 (s, 1H, OH); 5.31 (t, J = 7.2Hz, 1H, H-2’); 5.10 (t, J = 6.7Hz,
1H, H-6’); 3.86 (s, 3H, OCH ); 3.26 (d, J = 7.2Hz, 2H, H-1’); 2.12-2.08 (m,
2H, H-5’); 2.05-2.03 (m, 2H,3H-4’); 1.69 (s, 6H, CH3-C3’ and H-8’); 1.60 (s,
3H, CH3-C7’); 13C NMR: 145.5 (C-1); 144.7 (C-2); 136.0 (C-3’); 135.2 (C-
5); 131.4 (C-7’); 124.3 (C-6’); 123.2 (C-2’); 119.5 (C-4); 114.6 (C-6); 110.6
(C-3); 56.0 (OCH3); 39.7 (C-4’); 33.5 (C-1’); 26.6 (C-5’); 25.7 (C-8’); 17.7
(CH3-C7’); 16.1 (CH3-C3’); IR (cm−1): 3443, 2923, 2853, 1591, 1509, 1442,
1377, 1270, 1212, 1128.
(E)-4-(3,7-dimethylocta-2,6-dienyl)benzene-1,3-diol 18
To a solution of resorcinol (1.00 g, 9.1 mmol) and BF . OEt2 (1.29 g,
9.1 mmol) in freshly distilled 1,4-dioxane (5 mL) was ad3 ded dropwise,
with stirring at room temperature and under a N2 atmosphere, a solution of
geraniol (2.80 g, 18.1 mmol) in 1,4-dioxane (5 mL). After the addition was
complete, the stirring was continued overnight. When the end of the reaction
was verified by TLC, the mixture was poured onto crushed ice (app. 30 g) and
it was extracted with diethyl ether (3 x 30 mL). Then, the ethereal layer was
washed with 5% NaHCO (30 mL), water (2 x 20 mL), dried over Na2SO4,
filtered and the solvent wa3s evaporated under reduced pressure. The crude was
redissolved in CH2Cl2 (5 mL) and the mixture was subjected to silica gel flash
column chromatography with petroleum ether/EtOAc mixtures of increasing
polarity (19.8:0.2→0.2:19.8) as the mobile phase to afford the compound 18 as
a viscous yellow oil (0.268 g, 11.9%); 1H NMR: 6.92 (d, J = 8.8Hz, 1H, H-5);
6.37 (d, J = 2.4Hz, 1H, H-2); 6.36 (dd, J = 2.4 and 8.8Hz, 1H, H-6); 5.30 (t, J =
7.0Hz, 1H, H-2’); 5.09 (t, J = 6.1Hz, 1H, H-6’); 3.27 (d, J = 7.0Hz, 2H, H-1’);
2.12-2.09 (m, 2H, H-5’); 2.08-2.06 (m, 2H, H-4’); 1.72 (s, 3H, CH3-C3’); 1.69
(s, 3H, H-8’); 1.60 (s, 3H, CH3-C7’); 13C NMR: 154.8 (*C-1); 154.7 (*C-3);
137.6 (C-3’); 131.7 (C-7’); 130.3 (C-5); 124.0 (C-6’); 122.1 (C-2’); 119.4 (C-
4); 107.6 (C-6); 103.2 (C-2); 39.6 (C-4’); 28.3 (C-1’); 26.4 (C-5’); 25.6 (C-8’);
17.6 (CH3-C7’); 16.0 (CH3-C3’); IR (cm−1): 3387, 2927, 1702, 1620, 1508,
1455, 1377, 1297, 1152; MS (m/z, %): M+ 246 (16.8%), 177 (43.5), 161 (28.5),
123 (100), 69 (29.0) * interchangeable signs.
(E)-2-(3,7-dimethylocta-2,6-dienyl)-1,3,5-trimethoxybenzene 14
A solution of compound 13 (0.36 g, 1.4 mmol), dimethyl sulphate (0.58
g, 4.6 mmol) and potassium carbonate (0.58 g, 4.2 mmol) in dry acetone (50
mL) was refluxed for 6 h. in presence of. Later the mixture was filtered, and
the inorganic salts washed with acetone (2 x 10 mL). The combined acetone
solutions were evaporated under reduced pressure, the residue macerated with
crushed ice, extracted with ethyl acetate (2 x 40 mL). Then, the organic layer
was washed with sodium hydroxide solution (5%), water, dried under Na SO4,
filtered and the solvent was evaporated under reduced pressure to affor2d the
compound 14 as a brownish oil (0.42 g, 98.5 %). 1H NMR: 6.14 (s, 2H, H-4 and
H-6); 5.19 (t, J = 6.9Hz, 1H, H-2’); 5.09 (t, J = 6.3Hz, 1H, H-6’); 3.92 (s, 3H,
OCH3); 3.79 (s, 6H, 2xOCH ); 3.29 (d, J = 7.0 Hz, 2H, H-1’); 2.08-2.05 (m,
2H, H-5’); 1.99-1.95 (m, 2H,3H-4’); 1.78 (s, 3H, CH3-C3’); 1.66 (s, 3H, H-8’);
1.59 (s, 3H, CH3-C7’); 13C NMR: 159.0 (C-5); 158.4 (C-1 and C-3); 133.6
(C-3’); 130.6 (C-7’); 124.3 (C-6’); 123.2 (C-2’); 110.5 (C-2); 90.4 (C-4 and
C-6); 55.3 (2xOCH3); 54.9 (OCH3); 39.6 (C-4’); 26.5 (C-5’); 25.3 (C-8’); 21.4
(C-1’); 17.3 (CH3-C7’); 15.6 (CH3-C3’); IR (cm−1): 2935, 2836, 1726, 1608,
1596, 1496, 1455, 1437, 1417, 1377, 1322; MS (m/z, %): M+ 304 (10.9%), 235
(23.8), 181 (100), 167 (15.0), 69 (12.9)
(E)-3-(3,7-dimethylocta-2,6-dienyl)benzene-1,2-diol 19
To a solution of pyrocatechol (1.00 g, 9.1 mmol) and BF3.OEt2 (1.3 g,
9.1 mmol) in freshly distilled 1,4-dioxane (5 mL) was added dropwise, with
1794

J. Chil. Chem. Soc., 58, Nº 2 (2013)
stirring at room temperature and under a N2 atmosphere, a solution of geraniol
(1.4 g, 9.1 mmol) in 1,4-dioxane (5 mL). After the addition was complete,
the stirring was continued overnight. When the end of the reaction was
verified by TLC, the mixture was poured onto crushed ice (app. 30 g) and
it was extracted with diethyl ether (3 x 30 mL). Then, the ethereal layer was
washed with 5% NaHCO (30 mL), water (2 x 20 mL), dried over Na2SO4,
filtered and the solvent wa3s evaporated under reduced pressure. The crude was
redissolved in CH2Cl2 (5 mL) and the mixture was subjected to silica gel flash
column chromatography with petroleum ether/EtOAc mixtures of increasing
polarity (19.8:0.2→0.2:19.8) as the mobile phase to afford the compound 19
as a viscous brown oil (0.108 g, 4.8 %); 1H NMR: 6.79-6.72 (m, 2H, H-5 and
H-6); 6.66 (d, J = 7.0Hz, 1H, H-4); 5.38 (s, 1H, OH); 5.33-5.31 (m, 2H, OH
and H-2’); 5.05–5.04 (m, 1H, H-6’); 3.37 (d, J = 7.1Hz, 2H, H-1’); 2.14–2.12
(m, 2H, H-5’); 2.11-2.09 (m, 2H, H-4’); 1.78 (s, 3H, CH3-C3’); 1.69 (s, 3H,
H-8’); 1.60 (s, 3H, CH3-C7’); 13C NMR: 144.3 (C-1);141.9 (C-2); 138.9 (C-
3’); 132.2 (C-7’); 127.4 (C-3); 123.7 (C-6’); 121.7 (C-2’); 121.4 (C-4); 120.7
(C-5); 113.2 (C-6); 39.6 (C-4’); 29.9 (C-1’); 26.3 (C-5’); 25.7 (C-8’); 17.7
(CH3-C7’); 16.1 (CH3-C3’); IR (cm-1): 3588, 3418, 2967, 2922, 2845, 1620,
1595, 1475, 1375, 1278.
5.17-5.07 (m, 1H, H-6’); 5.04 (s, 1H, OH); 3.35 (d, J = 7.0Hz, 2H, H-1’); 3.06
(sept. J = 6.8 Hz, 1H CH(CH3)2); 2.27 (s, 3H, CH3-Ar); 2.14-2.08 (m, 2H,
H-5’); 2.05–2.04 (m, 2H, H-4’); 1.79 (s, 3H, CH3-C3’); 1.70 (s, 3H, H-8’);
1.61 (s, 3H, CH3-C7’); 1.25 (d, J = 6.8 Hz, 6H, (CH3)2CH); 13C NMR:151.9
(C-1); 138.9 (C-4); 138.1 (C-3’); 131.6 (C-7’); 126.3 (C-3); 126.0 (C-5); 124.0
(C-6’); 123.8 (C-2); 122.2 (C-2’); 117.5 (C-6); 39.7 (C-4’); 29.9 (C-1’); 28.6
(CH(CH )2); 26.5 (C-5’); 25.6 (C-8’); 23.5 ((CH3)2CH); 18.8 (CH3-Ar); 17.6
(CH3-C73’); 16.2 (CH3-C3’).
(E)-2-tert-butyl-4-(3,7-dimethylocta-2,6-dienyl)-5-methylphenol 23
To a solution of 2-tert-butyl-5-methylphenol (0.25 g, 1.52 mmol) and BF3.
Et O (0.2 mL, 1.59 mmol) in freshly distilled ethyl ether (10 mL) a solution of
ge2raniol (0.308 g, 2.00 mmol) in ethyl ether (5 mL) was added dropwise with
stirring at room temperature and under a N atmosphere,. After the addition was
complete, the stirring was continued over2night. When the end of the reaction
was verified by TLC, the mixture was poured onto crushed ice (app. 30 g) and
it was extracted with ethyl acetate (3 x 20 mL). Then, the organic layer was
washed with 5% NaHCO3 (30 mL), water (2 x 20 mL), dried over Na2SO4,
filtered and the solvent was evaporated under reduced pressure. The crude
was redissolved in CH2Cl2 (5 mL) and the mixture was subjected to silica gel
flash column chromatography with petroleum ether/ethyl acetate mixtures of
increasing polarity as the mobile phase to afford the compound 23 as a brown
viscous oil (123.4 mg, , 17.7%) 1H NMR: 7.03 (s, 1H, H-3); 6.48 (s, 1H, H-6);
5.23 (t, J = 7.0Hz, 1H, H-2’); 5.10 (t, J = 6.3 Hz, 1H, H-6’); 4.59 (s, 1H, OH);
3.23 (d, J = 7.0Hz, 2H, H-1’); 2.18 (s, 3H, CH3-Ar); 2.11-2.08 (m, 2H, H-5’);
2.05–2.02 (m, 2H, H-4’); 1.71 (s, 3H, CH3-C3’); 1.67 (s, 3H, H-8’); 1.60 (s, 3H,
CH3-C7’); 1.39 (s, 9H, (CH3)3C); 13C NMR:152.0 (C-1); 135.5 (C-3’); 134.8
(C-4); 133.2 (C-2); 131.6 (C-7’ + C-5); 127.5 (C-3); 124.3 (C-6’); 123.2 (C-2);
118.3 (C-6); 39.7 (C-4’); 34.2 (C(CH3)3); 31.6 (C-1’); 29.7 ((CH3)3C); 26.8
(C-5’); 25.7 (C-8’); 18.6 (CH3-Ar); 17.7 (CH3-C7’); 16.1 (CH3-C3’) IR (cm-
1): 3526, 2958, 2916, 2862, 1618, 1576, 1514, 1483, 1449, 1410, 1389, 1295,
1182, 1136, 1080, 949, 808; MS (m/z, %): M+ 300 (87.5%), 206 (41.6), 192
(100), 163 (75), 57 (25).
(E)-4-(3,7-dimethylocta-2,6-dienyl)-5-isopropyl-2-methylphenol 20
To a solution of carvacrol (0.25 g, 1.67 mmol) and BF3.Et2O (0.2 mL, 1.59
mmol) in freshly distilled ethyl ether (10 mL) a solution of geraniol (0.308 g,
2.00 mmol) in ethyl ether (5 mL) was added dropwise with stirring at room
temperature and under a N atmosphere. After the addition was complete, the
stirring was continued over2night. When the end of the reaction was verified by
TLC, the mixture was poured onto crushed ice (app. 30 g) and it was extracted
with ethyl acetate (3 x 20 mL). Then, the organic layer was washed with 5%
NaHCO3 (30 mL), water (2 x 20 mL), dried over Na2SO4, filtered and the
solvent was evaporated under reduced pressure. The crude was redissolved
in CH Cl2 (5 mL) and the mixture was subjected to silica gel flash column
chrom2atography with petroleum ether/ethyl acetate mixtures of increasing
polarity as the mobile phase to afford the compound 20 as a dark yellow
1
viscous oil (86.6 mg, 21.7%); H NMR: 6.88 (s, 1H, H-3); 6.69 (s, 1H, H-6);
5.20 (t, J = 6.9Hz,1H, H-2’); 5.10 (t, J = 6.7Hz, 1H, H-6’); 4.49 (s, 1H, OH);
3.27 (d, J = 6.8Hz, 2H, H-1’); 3.08 (sext. J = 6.8 Hz, 1H CH(CH )2); 2.19 (s,
3H, CH -Ar); 2.19-2.08 (m, 2H, H-5’); 2.06-2.02 (m, 2H, H-4’); 31.71 (s, 3H,
CH3-C33’); 1.67 (s, 3H, H-8’); 1.59 (s, 3H, CH3-C7’); 1.19 (d, J = 6.8 Hz, 6H,
(CH ) CH); 13C NMR: 152.4 (C-1); 146.1 (C-5); 135.3 (C-3’); 131.9 (C-3);
130.382(C-4); 124.6 (C-7’); 124.3 (C-6’); 124.1 (C-2’); 111.8 (C-6); 39.7 (C-4’);
30.7 (C-1’); 28.6 (CH(CH3)2); 26.6 (C-5’); 25.7 (C-8’); 23.8 ((CH3)2CH); 17.7
(CH3-C7’); 16.2 (CH3-C3’); 15.2 (CH3-Ar); IR (cm-1): 3398, 3418, 2962, 2925,
2845, 1620, 1589, 1496, 1456, 1380, 1278, 1107, 889, 813; MS (m/z, %): M+
285 (81%), 257 (14.9), 256 (22.3), 255 (14), 191 (13.5), 177 (100), 163 (40).
CONCLUSIONS
In summary we have prepared fourteen compounds, the known
geranylhydroquinone 2, geranylorcinol 4 and the derivative geranylorcinol
5 and the new geranylphenol derivatives 13-23. All these compounds were
obtained by direct geranylation reactions using BF ∙Et2O as a catalyst between
geraniol and commercially available activated phe3nols hydroquinone, orcinol,
phloroglucinol, guaiacol, resorcinol, catechol, pyrocatechol, carvacrol,
4-isopropyl-3-methylphenol and 2-tert-butyl-5-methylphenol. Additionally,
all the synthesized compounds were fully characterized by spectroscopic data,
especially by NMR techniques.
(E)-2-(3,7-dimethylocta-2,6-dienyl)-4-isopropyl-3-methylphenol 21 and
(E)-2-(3,7-dimethylocta-2,6-dienyl)-4-isopropyl-5-methylphenol 22
On the other hand, the orientation in electrophilic aromatic substitution
of geranyl chain was directed in ortho and/or para position according to the
location the OH or OCH groups in the aromatic system. Also, for the same
reason, mixtures of regi3o-isomers were obtained in some cases. The low
yields were observed due to that during the reaction time, part of geraniol
was transformated into unidentified products and unreacted starting material
(arenes nuclei) was recovered.
We are currently investigating the effect of a second catalyst in the
geranylation reactions and we have found better results in yields for these
reactions. These results, together with biological activity assay against plant
pathogens will be informed soon.
To a solution of 4-isopropyl-3-methylphenol (0.25 g, 1.67 mmol) and
BF3.Et O (0.2 mL, 1.59 mmol) in freshly distilled ethyl ether (10 mL) was
added 2dropwise with stirring at room temperature and under a N2 atmosphere,
a solution of geraniol (0.308 g, 2.00 mmol) in ethyl ether (5 mL). After the
addition was complete, the stirring was continued overnight. When the finish
of the reaction was verified by TLC, the mixture was poured onto crushed
ice (app. 30 g) and it was extracted with ethyl acetate (3 x 20 mL). Then, the
organic layer was washed with 5% NaHCO3 (30 mL), water (2 x 20 mL), dried
over Na2SO4, filtered and the solvent was evaporated under reduced pressure.
The crude was redissolved in CH2Cl2 (5 mL) and the mixture was subjected to
silica gel flash column chromatography with petroleum ether/EtOAc mixtures
of increasing polarity (19.8:0.2→ 15.2:4.8) as the mobile phase to obtain two
fractions: Fraction I: compound 21 as a yellow viscous oil (67.5 mg,4.2%);
1H NMR: 7.01 (d, J = 8.4Hz, 1H, H-5); 6.67 (d, J = 8.4Hz, 1H, H-6); 5.13
(t, J = 6.6Hz, 1H, H-2’); 5.04 (t, J = 5.6Hz, 1H, H-6’); 4.78 (s, 1H, OH);
3.41 (d, J = 6.6Hz, 2H, H-1’); 3.13 (sept. J = 6.8 Hz, 1H CH(CH3)2); 2.26
(s, 3H, CH3-Ar); 2.09-2.06 (m, 2H, H-5’); 2.04-2.02 (m, 2H, H-4’); 1.80 (s,
3H, CH3-C3’); 1.66 (s, 3H, H-8’); 1.58 (s, 3H, CH3-C7’); 1.20 (d, J = 6.8 Hz,
6H, (CH3)2CH); 13C NMR: 151.9 (C-1); 139.3 (C-4); 137.0 (C-3’); 131.7 (C-
3); 129.7 (C-7’); 125.9 (C-2); 124.0 (C-5’); 123.3 (C-6’); 122.1 (C-2’); 114.6
(C-6); 39.7 (C-4’); 29.3(CH(CH3)2); 26.5 (C-5’); 26.1(C-1’);25.7 (C-8’); 23.6
((CH3)2CH); 17.7 (CH3-C7’); 16.2 (CH3-C3’); 14.7 (CH3-Ar); IR (cm-1): 3421,
2962, 2926, 1617, 1495, 1452, 1380, 1277, 1149, 1107, 1039, 888, 811; MS
(m/z, %): M+ 285 (38%), 194 (68), 191 (13.5), 177 (100), 163 (40). Fraction II:
isomers 21/22 mixture as dark yellow viscous oil (0.102 g, 21.6%) Compound
22: 1H NMR: 6.96 (s, 1H, H-3); 6.62 (s, 1H, H-6); 5.35 (t, J = 7.0Hz, 1H, H-2’);
ACKNOWLEDGEMENTS
The authors thank to the Centro Cientifico – Tecnológico de Valparaiso
(CCTVal, Proyecto BASAL FB/08/21, int. cod. FB/30LE/10) and Dirección
General de Investigación y Postgrado (DGIP) of the Universidad Técnica
Federico Santa María (PIIC QUI-2011 for L. T., grant Nº 13.11.36, PAC
2009-2012 for M.O., PAC 2011-2012 for A.M. and PIA for M.C.) for financial
support.
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