Concise access to primin, miconidin and related natural resorcinols

Article abstract of DOI:10.1016/j.tet.2017.07.029

An efficient and short synthetic procedures affording the biologically active natural products primin, miconidin, olivetol, grevillol, and cardol (adipostatin A) in high yields are reported. The two strategies involve Sonogashira and Suzuki cross-couplings as the crucial steps for the installation of the alkyl side-chains. Syntheses start from cheap, commercially available 1-bromo-3,5-dimethoxybenezene to obtain 1,3-dimethoxy-5-(alk-1-yn-1-yl)benzene as the key intermediate. This intermediate can be easily and economically oxidized to provide primin in excellent overall yield while avoiding undesired side products by the virtue of its symmetry. The demethylation of the key intermediate affords natural resorcinols olivetol, grevillol, and cardol, respectively. The reduction of primin provides its hydroquinone derivative miconidin.

Full text of DOI:10.1016/j.tet.2017.07.029

Accepted Manuscript
Concise access to primin, miconidin and related natural resorcinols
Miroslav Sisa, Marcela Dvorakova, Tomas Vanek
PII:
S0040-4020(17)30764-0
10.1016/j.tet.2017.07.029
TET 28861
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 January 2017
Revised Date: 29 June 2017
Accepted Date: 14 July 2017
Please cite this article as: Sisa M, Dvorakova M, Vanek T, Concise access to primin, miconidin and
related natural resorcinols, Tetrahedron (2017), doi: 10.1016/j.tet.2017.07.029.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Concise access to primin, miconidin and
related natural resorcinols
Miroslav Sisaa , Marcela Dvorakovaa and Tomas Vaneka,
Leave this area blank for abstract info.
a Laboratory of Plant Biotechnologies
Institute of Experimental Botany, The Czech Academy of Sciences v.v.i.
Rozvojová 263, 165 02 Prague 6 - Lysolaje, Czech Republic
E-mails: sisa.miroslav@gmail.com, dvorakova@ueb.cas.cz, vanek@ueb.cas.cz

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Concise access to primin, miconidin and related natural resorcinols
Miroslav Sisaa, Marcela Dvorakovaa and Tomas Vaneka,
a Laboratory of Plant Biotechnologies
Institute of Experimental Botany, Czech Academy of Sciences v.v.i.
Rozvojová 263, 165 02 Prague 6 - Lysolaje, Czech Republic
E-mails: sisa.miroslav@gmail.com, dvorakova@ueb.cas.cz, vanek@ueb.cas.cz
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and short synthetic procedures affording the biologically active natural products
primin, miconidin, olivetol, grevillol, and cardol (adipostatin A) in high yields are reported. The
two strategies involve Sonogashira and Suzuki cross-couplings as the crucial steps for the
installation of the alkyl side-chains. Syntheses start from cheap, commercially available 1-
bromo-3,5-dimethoxybenezene to obtain 1,3-dimethoxy-5-(alk-1-yn-1-yl)benzene as the key
intermediate. This intermediate can be easily and economically oxidized to provide primin in
excellent overall yield while avoiding undesired side products by the virtue of its symmetry. The
demethylation of the key intermediate affords natural resorcinols olivetol, grevillol, and cardol,
respectively. The reduction of primin provides its hydroquinone derivative miconidin.
Available online
Keywords:
primin
qionones
resorcinols
cross-coupling
natural products
2009 Elsevier Ltd. All rights reserved
.
———
Corresponding author. Tel.: +420-225-106-832; e-mail: vanek@ueb.cas.cz

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
Even though several syntheses of primin have been reported,
these suffer from poor yields and/or expensive starting materials.
For instance, Watanabe et al.13 reported primin six-step synthesis
with 56% overall yield starting from 5-iodovanillin and
employing Suzuki-Miyaura cross-coupling reaction as the key
step. A three-step synthesis starting from o-vanillin and using
Grignard reaction for the installation of the aliphatic side chain
was described by Gunatilaka et al.3 Despite being short it yielded
primin in only 8% overall yield. Grignard reaction was also
employed by Bhattacharya et al.16 in a long, nine-step procedure
starting from o-vanillin and resulting in 34% overall yield. On
the other hand, an interesting four-step strategy starting from
guaiacol was designed by Jacob et al.15 They applied Claisen
rearrangement for the crucial alkylation step providing primin in
43% overall yield. All these strategies, however, succumb to an
uneconomical final oxidation step due to the utilization of large
excess of expensive Fremy’s salt or of oxygen/salcomine
catalytic system.
Recently, a one-step synthesis by Nasiri et al.17 was reported,
albeit starting from already expensive 2-methoxybenzo-1,4-
quinone. In this strategy, the alkyl chain was introduced by the
reaction with analogous alkyl acid or alkyl boronic acid catalyzed
by silver nitrate or persulphate. However, this reaction affords
maximum 50% yield and, due to poor regioselectivity, a mixture
of isomers in ~3:1 ratio with the iso-primin isomer being favored.
Plants are a vast source of biologically active compounds.
However, these compounds are often of complex structure
rendering them challenging to synthesize. Even those compounds
with simple-looking structures are often scarcely available by
common organic chemistry methods. This is also the case for
plant quinone primin (1) and its reduced form miconidin (2) and
their related plant resorcinols, olivetol (3), grevillol (4), and
cardol (5, adipostatin A, Fig. 1). Despite their structural
simplicity and attractive biological activity, they are either not
commercially available or their price on the market is as high as
$US 100/10 mg.1 It is caused by their time-consuming and costly
isolation from plant material and the lack of appropriately
efficient and high-yielding synthesis from accessible compounds.
Primin (1), and its reduced form miconidin (2), are found in a
variety of plants, predominantly in Primula genus.2 Their various
biological activities have been studied. For example, primin (1)
exhibited anti-proliferative activity against M109 murine cancer
cells (IC50 = 10 µg/mL) and A2780 human ovarian cancer cell
line (IC50 = 2.9 µg/mL)3 as well as anti-bacterial activity against
Stapchylococus aureus (IC50 = 8 µg/mL).4 Even though it also
acts as a skin sensitizer causing allergic reaction called primrose
dermatitis,2 it has definitely high potential in medicinal chemistry
due to its unique 1,4-benzoquinone structural core able to
manipulate redox processes.
In case of 5-alkylated natural resorcinols, various rather long
and inefficient syntheses may be found throughout the literature.
From these, the methods of Alonso et al.18 and Wu et al.19 are the
most efficient. Alonso et al.18 reported five-step synthesis of
these resorcinols employing the catalytic reaction of 3,5-
dimethoxybenzyl trimethylsilyl ether with suitable aldehyde as
the crucial step. In this case, the overall yield was approximately
24%. Shorter and more elegant synthesis was published by Wu et
al.19 who used Wittig reaction as the key reaction in three-step
synthesis affording the resorcinols in mediocre 67% overall
yield.
2. Results and discussion
Figure 1. Structures of primin, miconidin, olivetol, grevillol
and cardol. (adipostatin A).
Herein, three elegant and high-yielding (77-87 %) strategies to
provide primin and related compounds are reported, with each
preparation offering unique benefits (Scheme 1).
In our laboratory, in the search for new anti-inflammatory
agents, primin (1) and its derivatives were examined for their
Firstly, the “Sonogashira route” started from cheap,
commercially available 1-bromo-3,5-dimethoxybenezene (6) and
employed Sonogahira cross-coupling for the aromatic alkylation.
Various catalysts and conditions were examined in order to
obtain the best possible yield. These conditions are summarized
in Table 1. Due to the same Rf of the starting material and the
product, even when different solvent elution systems were
employed, the conversion of the reaction had to be monitored by
NMR analysis. Therefore, complete conversion of the starting
material is vital to avoid isolation difficulties of the product.
inhibitory
activity
against
inflammatory
enzymes,
cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and 5-
lipooxygenase (5-LOX).5 Primin was comparably active to
reference substances in COX-2 and 5-LOX assays thus exhibiting
desired dual COX-2/5-LOX inhibitory activity.5 High 5-LOX
inhibitory activity was also reported for miconidin acetate, the
hydroquinone derivative of primin.6 For miconidin itself (2), an
anti-plasmoidal activity was reported7 and it was also found to
act as insect-detergent.8
Natural resorcinols are compounds structurally related to
primin. Olivetol (3) is found mainly in lichens9 and some
insects.10 Olivetol (3), through its derivative, olivetolic acid,
serves as a biosynthetic precursor of cannabinoids, thus can be
useful key intermediate in the synthesis of their derivatives.
Grevillol (4) and cardol (5) are plant secondary metabolites
exhibiting 5-LOX and COX inhibitory activity,11 as well as
cytotoxic activity against selected human cancer cell lines.12
Furthermore, these 5-alkylated resorcinols are also structurally
similar to another group of biologically active compounds,
stilbenoids.
From the optimalization study it was determined that the best
conversion was achieved when bis(triphenylphosphine)-
palladium(II) chloride was used as a catalyst (entry 1, Table 1).
Precise temperature control was found to be essential (compare
entry 1 and 2, Table 1). The product, 1,3-dimethoxy-5-(pent-1-
yn-1-yl)benzene (7) was thus obtained in excellent yield (97%).
Subsequent hydrogenation of the triple bond with palladium on
carbon at 5 bars hydrogen pressure gave the desired product 8 in
almost quantitative yield. The employment of normal
atmospheric pressure for the reduction resulted in much longer
reaction time (days). The obtained crucial intermediate 1,3-

3
dimethoxy-5-pentylbenzene (8) with the requisite regiosymmetry
installed longer alkyl chains gave rise to grevillol (4), and
cardol (5), respectively, in excellent overall yields (Scheme 2).
ACCEPTED MANUSCRIPT
was oxidized using inexpensive chromium(VI) oxide yielding
primin (1) in 91% yield. This mentioned symmetry forestalls the
formation of undesirable mixture of isomers. The immense
advantage of this strategy is the excellent overall yield (87%) and
the utilization of cheap starting material and reagents.
Table 1. Optimization of Sonogoshira cross-coupling to compound 7.
entry catalyst
solvent
T(°C)/t(h) yield(%)
1
Pd(PPh3)Cl2
CH2Cl2/Et3N
r.t./16 then 97
65/2
MeO
Br
1 eq
MeO
2
3
4
5
6
7
Pd(PPh3)Cl2
CH2Cl2/Et3N
65/16
52[a]
71[a]
82[a]
10[a]
15[a]
trace[a]
, 5% Pd(PPh3)2Cl2, 10% CuI
CH2Cl2, Et3N, 65°C, overnight
97%
Pd(PhCN)2Cl2P(tBu)3 1,4-dioxane/NHiPr2 r.t./16
OMe
OMe
7
6
Pd(PhCN)2Cl2P(tBu)3 DMSO/ NHiPr2
r.t./16
80/16
110/40
80/16
"Sonogashira"
route
HO
"Suzuki"
route
B
Pd2(dba)3
Pd2(dba)3
Pd(PPh3)4
Et3N
1.5 eq
OH
10% Pd(10%)/C
MeOH, r.t., overnight
5% PdCl2[(PPh2)2Fc], 3 eq K3PO4
toluene, 110°C, overnight
95%
Et3N/toluene
Et3N
99%
"olivetol"
route
HO
MeO
2.2 eq MeI, 2.5 eq K2CO3
Conditions: pentyne: 1 (to 1.5 eq), catalyst: 0.05 eq, CuI: 0.1 eq.
aYield determined by 1H NMR.
DMF, rt, 3-5h
85%
2.2 eq BBr3
OH
OMe
3
8
CH2Cl2, -15°C, 1.5h
92%
olivetol
1 eq CrO3
AcOH-H2O (1:1)
rt, 3-5h
Table 2. Optimization of Suzuki cross-coupling to compound 8.
91%
entry catalyst
base
solvent
toluene
T(°C)/t(h) yield(%)
OH
OH
O
O
MeO
MeO
PdCl2[(PPh2)2Fc[a]]
K3PO4
110/16
95
1 eq Na2S2O4
1
2
Et2O/H2O (5%)
79%
Pd(PPh3)Cl2
Pd(10%)/C
K2CO3 1,4-dioxane/ 80/1
H2O
trace
2
1
miconidin
primin
3
K2CO3 H2O
80/16
0
Scheme 1. Syntheses of primin, miconidin and olivetol.
Secondly, primin may also be obtained via “Suzuki route”
using Suzuki cross-coupling for the aromatic alkylation. The
synthesis started again from compound 6 enabling incorporation
of the pentyl side chain fragment in only one-step. Nevertheless,
such incorporation was surprisingly more problematic and just
one set of conditions afforded the product in excellent yield. The
optimalization conditions are summarized in Table 2. Thus, the
Conditions: boronate: 1.5 eq, catalyst: 0.05 eq, base: 3 eq.
aFc = ferrocene.
R1
MeO
Br
1 eq
MeO
R1
, 5% Pd(PPh3)2Cl2, 10% CuI
best
catalyst
was
found
to
be
[1,1′-
CH2Cl2, Et3N, 65°C, overnight
OMe
OMe
bis(diphenylphosphino)ferrocene]-dichloropalladium (entry 1,
Table 2), affording compound 8 in a remarkable 95% yield as
determined by 1H NMR. The overall yield of primin obtained by
this strategy was 86%. Even though this route is shorter than the
previous one and gives excellent overall yield, it has to be taken
into account that more expensive reagent (pentylboronic acid) is
utilized here for the alkylation step.
, R1 = C11H23 (70%)
9
9,10
6
, R1 = C13H27 (96%)
10
10% Pd(10%)/C
MeOH, r.t., overnight
99%
R1
MeO
R1
Finally, primin intermediate 8 may be also obtained in one-
step reaction via "Olivetol route" by simple methylation of
olivetol (3) in 85% yield. The benefit of this method stems from
the already-installed pentyl side chain, while its major
disadvantage is the price of olivetol (3). Still, the employment of
this method may be desirable when possible contamination by
palladium is a downstream concern. The overall yield of primin
obtained by this strategy was 77%.
HO
2.2 eq BBr3
CH2Cl2, -15°C, 1.5h
OMe
OH
4,5
, R1 = C13H27 (82%) = grevillol
11,12
11, R1 = C13H27 (99%)
12, R1 = C15H31 (99%)
4
, R1 = C15H31 (86%) = cardol (adipostatin A)
5
Scheme 2. Syntheses of grevillol and cardol (adipostatin A).
The above mentioned procedures for the synthesis of primin
may be extented for the synthesis of miconidin (2) and naturally
occuring resorcinols, olivetol (3), grevillol (4) and cardol (5).
Miconidin (2) was obtained from primin by its reduction with
sodium dithionite in 79% yield. Olivetol (3) may be attained by
simple demetylation of the key intermediate 8. Analogously, the
demethylation of the corresponding intermediates 11 and 12 with
3. Conclusions
In summary, three new, efficient and concise syntheses of
primin (1) with excellent overall yields (77-87%) are reported
herein. These synthetic strategies are economic, starting from
cheap 1-bromo-3,5-dimethoxybenezene (6) and utilizing

4
Tetrahedron
inexpensive reagents. Especially, the oxidation of the key
Compound 7 (red-brown oil), Rf (19:1 petrolether:ethyl acetate)
ACCEPTED MANUSCRIPT
intermediate 8 was elegantly achieved using cheap oxidizing
agent chromium(VI) oxide while avoiding undesired side
products. All herein reported strategies are suitable to be used as
general methods to provide primin (1) on a large scale.
0.28: IR (KBr) νmax: 682, 831, 845, 1056, 1158, 1195, 1206,
1420, 1456, 1588, 1597, 2934, 2961 cm-1. H NMR (400 MHz,
1
CDCl3): δ 6.56 (d, J = 2.3 Hz, 2H), 6.40 (t, J = 2.3 Hz, 1H), 3.77
(s, 6H), 2.38 (t, J = 7.1 Hz, 2H), 1.68-1.58 (m, 2H), 1.05 (t, J =
7.4 Hz, 3H). 13C NMR (400 MHz, CDCl3): δ 160.6, 152.2, 109.5,
101.2, 90.1, 80.8, 55.5, 22.3, 21.5, 13.7. HRMS(ESI) m/z: calcd
for C13H17O2 (M+H)+: 205.1229. Found: 205.1230.
In addition, these strategies were herein successfully
employed for the synthesis of miconidin and naturally occuring
resorcinols in excellent yields. On the top of that, the
methodology of these strategies makes them also suitable for the
synthesis of related cannabinoids and stilbenoids.
Compound 9 (brown oil), Rf (19:1 petrolether:ethyl acetate) 0.25:
1H NMR (400 MHz, CDCl3): product: δ 6.55 (d, J = 2.2 Hz, 2H),
6.40 (t, J = 2.2 Hz, 1H), 3.77 (s, 6H), 2.39 (t, J = 7.2 Hz, 2H),
1.64-1.55 (m, 2H), 1.48-1.38 (m, 2H), 1.36-1.17 (m, 18H), 0.87
(t, J = 6.9 Hz, 3H); substrate: 6.66 (d, J = 2.1 Hz, 2H), 6.38 (d, J
= 2.2 Hz, 2H), 3.77 (s, 6H) – overlapped with product. 13C NMR
(400 MHz, CDCl3): δ 160.4, 125.4, 109.3, 101.0, 90.2, 80.5,
55.4, 31.9, 29.7, 29.6, 29.5, 29.4, 29.2, 29.0, 28.7, 22.68, 19.4,
14.1. HRMS(ESI) m/z: calcd for C21H33O2 (M+H)+: 317.2475.
Found: 317.2475.
4. Experimental
General Remarks: All reactions requiring anhydrous or inert
conditions were carried out under a positive atmosphere of argon
in oven-dried glassware. Solutions or liquids were introduced in
round bottom flasks using oven dried syringes through rubber
septa. All reactions were stirred magnetically using Teflon-
coated stirring bars. If needed, reactions were warmed up using
electrically-heated silicon oil bath, and the stated tem-perature
corresponds to the temperature of the bath. Organic solutions
obtained after aqueous work-up were dried over MgSO4. The
removal of solvents was accomplished under reduced pressure
using a rotary evaporator. Chemicals were purchased from
Sigma-Aldrich Chemical Company. Technical grade solvents for
extractions and chromatography were purchased from Penta
Chemicals s.r.o., Czech Republic. Solvents used in reactions
were distilled from appropriate drying agents and stored under
argon over activated Linde 4Å molecular sieves. Column and
flash chromatography was carried out using Merck Silica (60-200
µm). Analytical TLC was performed with Merck Silica gel 60
F254 plates. Visualisation was accomplished by UV-light (254
nm) and staining with a vanillin solution, followed by heating. IR
Compound 10 (orange oil), Rf (19:1 petrolether:ethyl acetate)
0.24: IR (KBr) νmax: 682, 831, 848, 1066, 1156, 1195, 1206,
1419, 1457, 1589, 1598, 2853, 2925, 2962 cm-1. H NMR (400
1
MHz, CDCl3): δ 6.55 (d, J = 2.3 Hz, 2H), 6.40 (q, J = 2.3 Hz,
1H), 3.77 (s, 6H), 2.39 (t, J = 7.1 Hz, 2H), 1.64-1.54 (m, 2H),
1.48-1.39 (m, 2H), 1.34-1.20 (m, 24H), 0.88 (t, J = 6.8 Hz, 3H).
13C NMR (400 MHz, CDCl3): δ 160.1, 125.2 109.0, 100.7, 89.9,
80.2, 55.0, 31.6, 29.4, 29.4, 29.3, 29.3, 29.2, 29.0, 28.9, 28.6,
28.4, 22.4, 19.1, 13.8. HRMS(ESI) m/z: calcd for C23H37O2
(M+H)+: 235.2788. Found: 35.2788.
1,3-Dimethoxy-5-pentylbenzene (8):
a) "Sonogashira route": From compound 7. 400 mg (1.96
mmol, 1 eq) of 1,3-dimethoxy-5-(pent-1-yn-1-yl)benzene was
dissolved in 20 mL of methanol, palladium (10% on carbon, 42
mg, 0.02 eq) was added and the reaction mixture was
hydrogenated under pressure of 5 bars overnight. The mixture
was filtered through a pack of celite and silica gel using ethyl
acetate eluent and then concentrated in vacuo using rotary
evaporator to afford yellow oil. The crude product was dry
loaded onto silica gel and purified by column chromatography
(19:1 petrolether:ethyl acetate) to afford 405 mg (99%) of
product as a transparent colorless oil.
1
spectra were recorded on Nicolet 6700 FT-IR spectrometer. H,
13C and 2D (H-COSY, HMQC) NMR spectra were all recorded
on Bruker Avance III™ HD 400 MHz. Trimethylsilane (0 ppm,
1H NMR) and CDCl3 (77 ppm, 13C NMR) were used as internal
references. The chemical shifts (δ) are reported in ppm (parts per
millions) and the coupling constants (J values) are recorded in Hz
(Hertz). Mass spectra were recorded on a LTQ Orbitrap XL
spectrometer.
b) "Suzuki route": From compound 6, Table 2, entry 1. 100 mg
of 1-bromo-3,5-dimethoxybenzene (0.46 mmol, 1 eq) was
dissolved in 5 mL of toluene, and to this mixture was added 293
mg of potassium phosphate (1.38 mmol, 3 eq), 80 mg of
pentylboronic acid (0.69 mmol, 1.5 eq), and 17 mg of [1,1′-
1,3-Dimethoxy-5-(alk-1-yn-1-yl)benzene (7, 9, 10): general
method:
To
a
flask
charged
with
bis(triphenylphosphine)palladium(II) chloride (81.0 mg, 115
µmol, 0.05 eq) and copper(I) iodide (43.9 mg, 0.23 mmol, 0.10
eq) was added 6 mL of triethylamine. To the resulting bright
yellow suspension was added a solution of the corresponding
alkyne (3.46 mmol, 1.5 eq) and 1-bromo-3,5-dimethoxybenezene
(500 mg, 2.30 mmol, 1.0 eq) in 6 mL of dichloromethane in one
portion. The flask was rinsed with 1 mL of triethylamine and
added to the reaction mixture. Solvents were degassed by deep-
freezing method. The reaction vessel was stirred under argon
atmosphere at rt overnight and then 2 h at 65 °C. The reaction
was monitored by NMR. When the conversion was completed,
the mixture was filtered through a pack of celite and silica gel
using ethyl acetate as eluent and then concentrated in vacuo using
rotary evaporator to afford brown oil. The crude product was dry
loaded onto silica gel and purified by column chromatography
(19:1 petrolether:ethyl acetate) to afford compound 7 in 97%
yield, compound 9 in 60% yield (estimated by NMR), and
compound 10 in 96% yield.
bis(diphenylphosphino)ferrocene]-dichloropalladium
(0.23
mmol, 0.05 eq). Solvent was degassed by deep-freezing method.
The reaction mixture was stirred under argon at 110 °C
overnight. The mixture was filtered through a pack of celite and
silica gel using ethyl acetate as eluent and then concentrated in
vacuo using rotary evaporator to afford yellow oil. The crude
product was dry loaded onto silica gel and purified by column
chromatography (19:1 petrolether:ethyl acetate) to afford 91 mg
(95%) of product as a transparent colorless oil with identical
analytical data obtained by "Sonogahira route".
c) "Olivetol route": From olivetol (3). A mixture of olivetol (3)
(100 mg, 0.555 mmol, 1 eq), methyl iodide (173 mg, 1.22 mmol,
2.2 eq) and potassium carbonate (192 mg, 1.39 mmol, 2.5 eq) in
anhydrous dimethylformamide was stirred for 3-5 h at rt under an
argon atmosphere. The reaction mixture was diluted with water
and extracted with ethyl acetate. The organic phase was washed
with water, brine, dried (MgSO4), and concentrated in vacuo
using rotary evaporator. The residue was purified by flash

5
column chromatography on silica gel (19:1 petrolether:ethyl
acetate) to afford 98 mg (85%) of product as a transparent
colorless oil with identical analytical data obtained by
"Sonogashira route". Rf (19:1 petrolether:ethyl acetate) 0.35. IR
(KBr) νmax: 684, 828, 848, 1060, 1150, 1206, 1428, 1463, 1596,
crude material was loaded on short silica gel column and eluted
ACCEPTED MANUSCRIPT
with petrolether:ethyl acetate (9:1) to afford 40.0 mg (79%) of
product 2 as a white-grey crystalline material.
Compound 2 (white-grey crystals), Rf (9:1 petrolether:ethyl
acetate) 0.28: M.p.: 96-98 °C. IR (KBr) νmax: 1071, 1146, 1197,
1219, 1445, 1477, 1497, 1608, 1627, 2855, 2925, 2957, 3429 cm-
1607, 2857, 2931, 2956 cm-1. H NMR (400 MHz, CDCl3): δ
1
6.35 (d, J = 2.3 Hz, 2H), 6.30 (t, J = 2.3 Hz, 1H), 3.78 (s, 6H),
2.55 (t, J = 7.7 Hz, 2H), 1.66-1.55 (m, 2H), 1.38-1.28 (m, 4H),
0.90 (t, J = 7.0 Hz, 3H). 13C NMR (400 MHz, CDCl3): δ 160.8,
145.6, 106.6, 97.7, 55.4, 36.4, 31.7, 31.1, 22.7, 14.2.
HRMS(ESI) m/z: calcd for C13H21O2 (M+H)+: 209.1542. Found:
209.1541.
1. H NMR (400 MHz, CDCl3): δ 6.31 (d, J = 2.8 Hz, 1H), 6.21
1
(d, J = 2.7 Hz, 1H), 5.23 (s, 1H), 4.36 (s, 1H), 3.84 (s, 3H), 2.57
(m, J = 2.6 Hz, 2H), 1.64-1.54 (m, 2H), 1.38-1.21 (m, 4H), 0.92-
0.86 (m, 3H). 13C NMR (400 MHz, CDCl3): δ 148,3, 146.7,
137.4, 129.0, 107.9, 97.1, 56.0, 31.7, 29.7, 29.4, 22.6, 14.1.
HRMS(ESI) m/z: calcd for C12H17O3 (M+H)+: 211.1289. Found:
211.1289.
1,3-Dimethoxy-5-alkylbenzene (11, 12): These compounds
were prepared according to the method a) for compound 8,
"Sonogashira route". Both of the compounds 11 and 12 were
obtained in 99% yield.
1,3-Dihydroxy-5-alkylbenzenes (3, 4, 5): general method:
To the solution of 1,3-dimethoxy-5-alkylbenzenes 8, 11, and 12,
respectively, in dry dichloromethane was added dropwise 2.2 eq.
of BBr3 (1M solution in dichloromethane) at -15 °C and the
reaction was stirred under argon atmosphere with temperature
rising to r.t. over 1.5 h. The mixture was quenched with water,
neutralized with NaHCO3 and extracted with dichloromethane.
The organic phase was washed with water and brine and dried
over MgSO4. After concentration in vacuo, the crude product was
purified by silica gel column chromatography with
petrolether:ethyl acetate (9:1) as an eluent. The yields were 92%
for olivetol (3), 82% for grevillol (4), and 86% for cardol
(adipostatin A, 6), respectively.
Compound 11 (orange solid), Rf (19:1 petrolether:ethyl acetate)
0.31: M.p.: 48-50 °C. IR (KBr) νmax: 696, 821, 842, 1056, 1063,
1151, 1159, 1206, 1466, 1474, 1598, 1610, 2850, 2917, 2954 cm-
1
1. H NMR (400 MHz, CDCl3): δ 6.35 (d, J = 2.3 Hz, 2H), 6.30
(t, J = 2.3 Hz, 1H), 3.78 (s, 3H), 2.57-2.51 (m, 2H), 1.65-1.56 (m,
2H), 1.36-1.19 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (400
MHz, CDCl3): δ 160.6, 145.4, 106.5, 97.5, 55.2, 36.3, 31.9, 31.3,
29.7, 29.7, 29.6, 29.5, 39.4, 22.7, 14.1. HRMS(ESI) m/z: calcd
for C21H37O2 (M+H)+: 321.2788. Found: 321.2788.
Compound 12 (yellowish solid), Rf (19:1 petrolether:ethyl
acetate) 0.30: M.p.: 46-48 °C. IR (KBr) νmax: 695, 828, 1067,
Compound 3 (yellow crystals), Rf (9:1 petrolether:ethyl acetate)
0.32: M.p.: 47-49 °C. IR (KBr) νmax: 693, 838, 998, 1149, 1478,
1601, 1627, 2859, 2930, 2958, 3416 cm-1. 1H NMR (400 MHz,
CDCl3): δ 6.26 (t, J = 2.2 Hz, 1H), 6.19(t, J = 2.2 Hz, 1H), 2.50-
2.38 (m, 2H), 1.36-1.21 (m, 4H), 0.87 (q, J = 6.6 Hz, 3H). 13C
NMR (400 MHz, CDCl3): δ 156.4, 108.1, 100.2, 35.8, 31.5, 30.7,
22.5, 14.0. HRMS(ESI) m/z: calcd for C11H17O2 (M+H)+:
181.1184. Found: 181.1184.
1
1157, 1199, 1468, 1608, 2853, 2922 cm-1. H NMR (400 MHz,
CDCl3): δ 6.35 (d, J = 2.3 Hz, 2H), 6.30 (d, J = 2.3 Hz, 1H), 3.78
(s, 6H), 2.58-2.51 (m, 2H), 1.64-1.57 (m, 2H), 1.37-1.21 (m,
24H), 0.91-0.86 (m, 3H). 13C NMR (400 MHz, CDCl3): δ 160.6,
145.4, 106.5, 97.5, 55.2, 36.3, 31.9, 31.3, 29.9, 29.7, 29.7, 29.6,
29.5, 29.4, 22.7, 14.1. HRMS(ESI) m/z: calcd for C23H41O2
(M+H)+: 349.3101. Found: 349.3102.
2-Methoxy-6-pentyl-1,4-benzoquinone - Primin (1): 1,3-
Dimethoxy-5-pentylbenzene (8) (100 mg, 0.48 mmol, 1.0 eq)
was dissolved in 4 mL of acetic acid-water mixture (1:1) and
chromium(VI) oxide (48.0 mg, 0.48 mmol, 1.0 eq) was added.
The reaction mixture was stirred at 50 °C for 2-3 h. Then the
reaction mixture was diluted with water, extracted three times
with ethyl acetate and the collected organic phase was washed
with saturated bicarbonate solution, water and brine and dried
over MgSO4. After concentration in vacuo, the crude material
was loaded on silica gel column and eluted with petrolether:ethyl
acetate (7:3) to afford 91.0 mg (91%) of product 1.
Compound 4 (yellow crystals), Rf (9:1 petrolether:ethyl acetate)
0.30: M.p.: 82-84 °C. IR (KBr) νmax: 699, 823, 841, 990, 1020,
1149, 1159, 1313, 1379, 1463, 1473, 1596, 1629, 2849, 2917,
2960, 3332 cm-1. 1H NMR (400 MHz, MeOD): δ 6.12 (d, J = 2.2
Hz, 2H), 6.08 (t, J = 2.2 Hz, 1H), 2.43 (dd, J = 8.5, 6.8, 2H), 1.56
(t, J = 7.5 Hz, 2H), 1.35-1.25 (m, 20H), 0.90 (t, J = 6.8 Hz, 3H).
13C NMR (400 MHz, MeOD): δ 159.3, 146.3, 107.9, 100.9, 37.0,
33.1, 32.5, 30.9, 30.8, 30.8, 30.7, 30.7, 30.6, 30.5, 30.4, 23.7,
14.5. HRMS(ESI) m/z: calcd for C19H31O2 (M-H)+: 291.2330.
Found: 2911.2330.
Compound 5 (yellow crystals), Rf (9:1 petrolether:ethyl acetate)
0.29: M.p.: 90-92 °C. IR (KBr) νmax: 82, 995, 1155, 1468, 1600,
1626, 2851, 2921, 2955, 3430 cm-1. 1H NMR (400 MHz, MeOD):
δ 6.12 (d, J = 2.2 Hz, 2H), 6.08 (t, J = 2.2 Hz, 1H), 2.43 (dd, J =
8.5, 6.8 Hz, 2H), 1.56 (t, J = 7.5 Hz, 2H), 1.34-1.25 (m, 29H),
0.90 (t, J = 6.7 Hz, 3H). 13C NMR (400 MHz, MeOD): δ 159.7,
146.3, 107.9, 100.3 37.0, 33.1, 32.5, 30.9, 30.8, 30.7, 30.7, 30.6,
30.5, 30.4, 23.7, 14.5. HRMS(ESI) m/z: calcd for C21H35O2 (M-
H)+: 319.2643. Found: 319.3640.
Compound 1 (yellow crystals), Rf (7:3 petrolether:ethyl acetate)
0.32: M.p.: 63-65 °C. IR (KBr) νmax: 1051, 1238, 1325, 1600,
1
1651, 1681, 2930, 2958 cm-1. H NMR (400 MHz, CDCl3): δ
6.47 (dt, J = 1.4 Hz, 1H), 5.87 (d, J = 2.4 Hz, 1H), 3.81 (s, 3H),
2.45-2.39 (m, 2H), 1.54-1.45 (m, 2H), 1.37-1.27 (m, 4H), 0.91-
0.85 (m, 3H). 13C NMR (400 MHz, CDCl3): δ 187.8, 182.3,
159.0, 147.7, 133.0, 107.2, 56.4, 31.5, 28.8, 27.5, 22.5, 14.1.
HRMS(ESI) m/z: calcd for C12H17O3 (M+H)+: 209.1172. Found:
209.1173; calcd for C12H16O3Na (M+Na)+: 231.0992. Found:
231.0991.
2-Methoxy-6-pentyl-1,4-hydroquinone
-
Miconidin (2):
Acknowledgments
Primin (1) (50.0 mg, 0.24 mmol, 1.0 eq) was dissolved in 2 mL
of ether (5% H2O) mixture and sodium dithionite (50.2 mg, 0.29
mmol, 1.2 eq) was added. The reaction mixture was stirred at rt
for 1-2 h. Then the reaction mixture was diluted with water,
extracted three times with ethylacetate and the collected organic
phase was washed with saturated bicarbonate solution, water and
brine and dried over MgSO4. After concentration in vacuo, the
The authors gratefully acknowledge the financial support by
the grant LD15006 from the Ministry of Education, Youth and
Sports of the Czech Republic and networking contribution by the
COST Action CM1407 “Challenging organic syntheses inspired
by nature – from natural products to drug discovery”.

6
Tetrahedron
ACCEPTED MANUSCRIPT
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Supplementary Material
1
Supplementary information contains H and 13C NMR spectra.