A short and facile synthesis of 2-(1Z)-(3-hydroxy-3,7-dimethylocta-1,6- dienyl)-1,4-benzenediol and 1-(3′-methoxypropanoyl)-2,4,5- trimethoxybenzene isolated from Cordia alliodora

Article abstract of DOI:10.1080/14786410903201624

A novel synthesis of 2-(1Z)-(3-hydroxy-3,7-dimethylocta-1,6-dienyl)-1,4- benzenediol and 1-(3′-methoxypropanoyl)-2,4,5-trimethoxybenzene has been carried out by making use of an easily available starting material, acceleration by MW irradiation and the use of water as a green solvent in the key steps.

Full text of DOI:10.1080/14786410903201624

Natural Product Research
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
A short and facile synthesis of 2-(1Z)-(3-
hydroxy-3,7-dimethylocta-1,6-dienyl)-1,4-
benzenediol and 1-(3′-methoxypropanoyl)-2,4,5-
trimethoxybenzene isolated from Cordia alliodora
Sukhbir Kaur , Vasundhara Singh , Gulshan Kumar , G.L. Kad & Jasvinder
Singh
To cite this article: Sukhbir Kaur , Vasundhara Singh , Gulshan Kumar , G.L. Kad & Jasvinder
Singh (2010) A short and facile synthesis of 2-(1Z)-(3-hydroxy-3,7-dimethylocta-1,6-dienyl)-1,4-
benzenediol and 1-(3′-methoxypropanoyl)-2,4,5-trimethoxybenzene isolated from Cordia
alliodora , Natural Product Research, 24:5, 440-447, DOI: 10.1080/14786410903201624
To link to this article: http://dx.doi.org/10.1080/14786410903201624
Published online: 17 Mar 2010.
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Date: 05 November 2015, At: 13:47

Natural Product Research
Vol. 24, No. 5, 20 March 2010, 440–447
A short and facile synthesis of 2-(1Z)-(3-hydroxy-3,7-dimethylocta-
1,6-dienyl)-1,4-benzenediol and 1-(30-methoxypropanoyl)-
2,4,5-trimethoxybenzene isolated from Cordia alliodora
b
a
Sukhbir Kaura, Vasundhara Singhb , Gulshan Kumar , G.L. Kad and
*
Jasvinder Singha
aDepartment of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University,
Chandigarh 160014, India; Department of Applied Sciences, Panjab Engineering College
(Deemed University) Chandigarh 160012, India
b
(Received 30 January 2009; final version received 23 July 2009)
A novel synthesis of 2-(1Z)-(3-hydroxy-3,7-dimethylocta-1,6-dienyl)-1,4-
benzenediol and 1-(30-methoxypropanoyl)-2,4,5-trimethoxybenzene has
been carried out by making use of an easily available starting material,
acceleration by MW irradiation and the use of water as a green solvent in
the key steps.
Keywords: microwave irradiation; aqueous media; aldol reaction; Heck
reaction; prenylated hydroquinone
1. Introduction
A variety of biologically active prenylated hydroquinones have been extracted from
plant extracts (Danelutte, Lago, Young, & Kato, 2003; Yamaguchi, Lago, Tanizaki,
Mascio, & Kato, 2006). A prenylated hydroquinone, 2-(1Z)-(3-hydroxy-3,7-
dimethylocta-1,6-dienyl)-1,4-benzenediol (4), and 1-(30-methoxypropanoyl)-2,4,5-
trimethoxybenzene (7) have been isolated from the root bark of Cordia alliodora,
(Aknin, Dayan, Rudi, Kashman, & Gaydon, 1999; Ioset, Marston, Gupta, &
Hostettmann, 2000), also known as Cerdana alliodora Ruiz and Pavon. It is a tall tree
frequently encountered in Central America, South America and the Caribbean.
In Panama, C. alliodora is the most widespread species. A decoction of the leaves is
used as a tonic for pulmonary diseases in traditional Mexican medicine, and is
applied on bruises and swelling in Salvador. An ointment made of the plant seeds is
employed to treat skin diseases. Compound 4 also showed antifungal properties
against the pythogenic mould Cladosporium cucumerinum. The title compound 7 is
reported to have antifungal and larvicidal activities against the phytopathogenic
mould C. cucumerinum and the larvae of yellow fever transmitting mosquito, Aedes
aegypti, respectively.
One of the main goals of organic synthesis has been the search for new
compounds that exhibit novel physical, chemical and biological properties as well as
*Corresponding author. Email: vasun7@yahoo.co.in
ISSN 1478–6419 print/ISSN 1029–2349 online
ß 2010 Taylor & Francis
DOI: 10.1080/14786410903201624
http://www.informaworld.com

Natural Product Research
441
synthesis of molecules of nature. The use of clean technology tools is adding a new
dimension towards greening the synthesis of natural products. Water is a very
attractive solvent as a reaction medium (Matsushita, Kamata, Yamaguchi, &
Mizuno, 2005). It is safe, harmless, non-flammable, non-toxic and extremely eco-
friendly. Ionic liquids may be viewed as an alternative to volatile organic solvents,
representing a new class of non-molecular ionic solvents (Holbrey & Seddon, 1999;
Wasserchied & Keim, 2000; Welton, 1999). Ionic liquids have been extensively
studied in the past few years as media for organic synthesis and catalysis in particular
(Dupont, de Souza, & Suarez, 2002; Song, 2004).
Microwave heating has been used to accelerate organic chemical transformations.
The many advantages of this enabling technology, such as reduced reaction times,
increased product yields and enhanced product purities (De La Hoz, Diaz-Ortiz, &
Moreno, 2005; Hayes, 2002, 2004; Kappe, 2004; Kappe & Sandler, 2005; Kingston &
Haswell, 1997; Loupy, 2002; Perreux & Loupy, 2001; Strauss, 2002) have not only
been exploited for organic synthesis in the context of medicinal chemistry/drug
discovery (Kappe & Dallinger, 2006; Larhed & Hallberg, 2001; Shipe, Wolkenberg,
& Lindsley, 2005; Wathey, Tierney, Lidstrom, & Westman, 2002), but have also
penetrated fields such as polymer synthesis (Bogdal, Penczek, Pielichowski, &
Prociak, 2003; Wiesbrock, Hoogenboom, & Schubert, 2004), material sciences
(Barlow & Marder, 2003; Zhu, Wang, Qi, & Hu, 2004), nanotechnology (Tsuji,
Hashimoto, Nishizawa, Kubokawa, & Tsuji, 2005) and biochemical processes
(Orrling, Nilsson, Gullberg, & Larhed, 2004). We report the synthesis of two
bioactive natural products, 2-(1Z)-(3-hydroxy-3,7-dimethylocta-1,6-dienyl)-1,4-ben-
zenediol (4) and 1-(30-methoxypropanoyl)-2,4,5-trimethoxybenzene (7), by making
use of clean technologies, such as microwave irradiation, aqueous media and ionic
liquids.
2. Discussion
The literature does not record any synthesis of 2-(1Z)-(3-hydroxy-3,7-dimethylocta-
1,6-dienyl)-1,4-benzenediol (4). Keeping in mind the medicinal value of the
compound, its synthesis has been undertaken. Aldol condensation in aqueous
media and a Grignard reaction in the presence of CeCl3 have been employed as key
steps in the novel synthesis of the title compound 4. A diagrammatic representation
of the different steps used in this multi-step synthesis is shown in Scheme 1.
Aldol condensation (Kad, Singh, & Kaur, 1999) of 2,5-dimethoxybenzaldehyde
with 6-methylhept-5-en-2-one using aq. NaOH under MW was carried out to yield
a transparent liquid (2) in 84% yield. MeMgI in THF, upon Grignard reaction
(Imamoto, Takiyama, Wakamura, Hatajima, & Kamiya, 1989) in the presence of
CeCl3 with 2-(1Z)-(7-methyl-3-oxoocta-1,6-dienyl)-1,4-dimethoxybenzene gave a 1,2-
addition product (3) in 87% yield. CeCl3 was used to get exclusively the 1,2 addition
product instead of the 1,4 addition in the Grignard reaction.
Deprotection (Demuynck, Clercq, & Vandewalle, 1979) of (3) using BBr3 in
DCM at ꢀ78ꢁC furnished the title compound 4 as a yellow viscous liquid in 85%
yield. The spectral data of this title compound matched well with that reported in the
literature (Aknin et al., 1999; Ioset et al., 2000). The title compound 4 has been
obtained in 62.1% overall yield.

442
S. Kaur et al.
OMe
OMe
OMe
OMe
OMe
OH
O
CHO
a
b
OMe
1
2
3
OH
OH
c
OH
4
Scheme 1. Reagents and conditions: (a) aq. NaOH, MW, 7-methyl-5-hepten-2-one,
(b) MeMgI, CeCl3, THF, (c) BBr3, DCM, 78ꢁC.
OCH3
O
OCH3
OCH3
O
I
b
OCH3
OCH3
a
H3CO
H3CO
H3CO
OCH3
7
OCH3
5
OCH3
6
O
OMe
Scheme 2. Reagents and conditions: (a)
(b) ZnCl2, Mg, H2O.
Pd(OAc)2 (1 mol%), NaOAc, (bmim)Br,
Several synthesis methods of the title compound 7 have been reported in the
literature (Aguilar, Benavides, & Tamariz, 2004; Sinha, Joshi, Sharma, Kumar, &
Kaul, 2003; Sinha, Sharma, & Kumar, 2006; Vanisree, Kavitha, & Subbaraja, 2002).
We herein report a simple, inexpensive and short synthesis of 1-(30-methoxy-
propanoyl)-2,4,5-trimethoxybenzene from readily available starting materials using
the Heck reaction of the unactivated ring and an appropriate alkene as the key steps.
The reaction sequence employed is as shown in Scheme 2.
The Heck reaction (Bianco, Claudia, & Marcella, 2004; Xu, Chen, & Xiao, 2000)
of 1-iodo-2,4,5-trimethoxybenzene (5) using Pd(OAc)2 as catalyst and (bmim)Br as
solvent, with methyl acrylate, led to the formation of methyl 2,4,5-trimethoxy
cinnamate (6). The Mg/ZnCl2-mediated selective reduction (Anil, Gopal, &
Chandra, 2005) of C¼C in aqueous media led to the formation of the final
1
compound 7 in 55.4% overall yield. Its H NMR, 13C NMR and IR spectra were
found to be in agreement to that reported for the original compound (Aknin et al.,
1999; Ioset et al., 2000).
To conclude, a short synthesis of two biologically active products, 2-(1Z)-(3-
hydroxy-3,7-dimethylocta-1,6-dienyl)-1,4-benzenediol (4) and 1-(30-methoxypropa-
noyl)-2,4,5-trimethoxybenzene (7), isolated from the root bark of C. alliodora, have
been carried out using easily available starting materials, and in good overall yields.

Natural Product Research
443
The synthesis has been carried out using green methodologies, such as aqueous
media, ionic liquids and microwave irradiations.
3. Experimental
Melting points were determined with a Sunbim melting point apparatus. IR spectra
were recorded on a Perkin-Elmer model 1430 spectrometer. 1H NMR and 13C NMR
spectra were recorded using Joel 300 MHz spectrometer. Chemical shifts are reported
in parts per million with tetramethylsilane as the internal standard. Microwave-
induced reactions were carried out in a domestic microwave (MG-396W A,
2450 MHz, 800 W).
3.1. 2-(1Z)-(7-methyl-3-oxoocta-1,6-dienyl)-1,4-dimethoxybenzene (2)
A mixture of 2,5-dimethoxybenzaldehyde (1.9 mmol), 6-methylhept-5-en-2-one
(11.7 mmol) and 10% aq. NaOH (3.25 mL) was taken in a 50 mL conical flask and
was irradiated in a microwave oven at 150 W for 10 min. Then the reaction mixture
was extracted with diethyl ether (3 ꢂ 10 mL). The combined extract was washed with
water and dried to get a colourless liquid (2) in 84% yield, after purification on silica
gel column chromatography using 3% ethyl acetate in n-hexane as eluant.
IR (CDCl3)/ꢀmax cmꢀ1: 3032, 1680, 1660, 1240. 1H NMR (300 MHz, CDCl3)
ꢁ: 7.34 (d, 1H, J ¼ 7.2 Hz, Ar–CH¼CH–), 6.69–6.96 (m, 3H, Ar–H), 6.50 (d, 1H,
J ¼ 7.2 Hz, Ar–CH¼CH–), 5.08 (m, 1H, (CH3)2C¼CH–), 3.87 (s, 3H, –OCH3), 3.72
(s, 3H, –OCH3), 2.62 (t, 2H, J ¼ 7.2, –CO–CH2), 2.28 (m, 2H, –CH2CH¼C(CH3)2),
1.64 (s, 6H, –CH¼C(CH3)2). 13C NMR (300 MHz, CDCl3) ꢁ: 198.2, 153.7, 152.7,
136.9, 132.0, 129.0, 125.4, 123.6, 55.9, 55.4, 40.3, 25.9, 23.0, 21.6.
3.2. 2-(1Z)-(3-hydroxy-3,7-dimethylocta-1,6-dienyl)-1,4-dimethoxybenzene (3)
CeCl3 ꢃ 7H2O (2.0 mmol) was quickly and finely ground to powder in a mortar and
placed in a 30 mL two necked flask. The flask was immersed in an oil bath and
heated gradually to 135–140ꢁC with evacuation. After maintaining the CeCl3 at a
constant temperature for 1 h, a magnetic bead was placed in the flask and CeCl3 was
completely dried in vacuum with stirring at the same temperature for an additional
1 h. While the flask was still hot, nitrogen gas was introduced, the flask was then
cooled in an ice bath and THF (6 mL) was added at once with vigorous stirring. The
ice bath was removed and the suspension was stirred overnight at room temperature
under nitrogen. The flask was then immersed in an ice bath and MeMgI (2.0 mmol)
was added. After stirring for 1.5 h at 0ꢁC, the compound 2-(1Z)-(7-methyl-3-
oxoocta-1,6-dienyl)-1,4-dimethoxybenzene (1.3 mmol) was added, and stirring was
continued for an additional 2 h. Then the reaction mixture was treated with 10%
aqueous CH3COOH (12 mL). The product was extracted with diethyl ether
(3 ꢂ 10 mL) and the combined extract was washed with water (1 ꢂ 5 mL), aq.
NaHCO3 solution, brine, and then dried with Na2SO4. The solvent was evaporated
to furnish product (3) in 87% yield after purification on silica gel column
chromatography using 10% ethyl acetate in n-hexane as eluant.

444
S. Kaur et al.
IR (CDCl3)/ꢀmax cmꢀ1: 3450, 3032, 1660, 1240. 1H NMR (300 MHz, CDCl3)
ꢁ: 6.69–6.53 (m, 3H, Ar–H), 6.25 (d, 1H, J ¼ 7.2 Hz, Ar–CH¼CH–), 5.21 (d, 1H,
J ¼ 7.2 Hz, Ar–CH¼CH–), 5.08 (m, 1H, (CH3)2C¼CH–), 3.72 (s, 3H, –OCH3), 3.87
(s, 3H, –OCH3), 2.18 (m, 2H, –CH2CH¼C(CH3)2), 1.81 (t, 2H, J¼ 7.4 Hz, –CH2–C(OH)),
1.36 (s, 3H, (OH)C–CH3), 1.61 (d, 6H, J ¼ 11.4 Hz, –CH2¼C(CH3)2). 13C NMR
(300 MHz, CDCl3) ꢁ: 153.2, 149.7, 134.6, 132.3, 126.9, 124.4, 116.2, 115.6, 114.2,
111.0, 72.3, 55.3, 55.1, 29.1, 25.5. Anal. Calcd for C16H22O3: C, 73.25; H, 8.45; O,
18.29. Found: C, 73.65; H, 8.39; O, 17.96.
3.3. 2-(1Z)-(3-hydroxy-3,7-dimethylocta-1,6-dienyl)-1,4-benzenediol (4)
To
a
stirred solution of 2-(1Z)-(3-hydroxy-3,7-dimethylocta-1,6-dienyl)-1,4-
dimethoxybenzene (0.08 mmol) in dried DCM (4 mL) was added a solution of
BBr3 (0.05 mL, 0.05 mmol) in 1.0 mL DCM at ꢀ78ꢁC. After 1 h the reaction mixture
was quenched with NaHCO3 and extracted with DCM (2 ꢂ 10 mL). The combined
extract was washed with water (5 mL) and dried over CaCl2. The crude product, on
column chromatography using 20% ethyl acetate in n-hexane as eluant, yielded the
title compound 4 in 85% yield.
IR (CDCl3, cmꢀ1): 3450, 3032, 2880, 1628, 1660. 1H NMR (300 MHz, CDCl3)
ꢁ: 6.64–6.48 (m, 3H, Ar–H), 6.25 (d, 1H, J ¼ 7.2 Hz, Ar–CH¼CH–), 5.41(d, 1H,
J ¼ 7.2 Hz, Ar–CH¼CH–), 5.19 (br s, 1H, –OH), 5.08 (m, 1H, (CH3)2C¼CH), 4.12
(br s, 1H, –OH), 2.09 (m, 2H, –CH2CH¼C(CH3)2), 1.81 (t, 2H, –CH2–C(OH)), 1.36
(s, 3H, (OH)C–CH3), 1.61 (s, 6H, J ¼ 11.4 Hz, –CH2¼C(CH3)2). 13C NMR
(300 MHz, CDCl3) ꢁ: 156.3, 146.6, 130.2, 129.6, 123.9, 123.0, 122.4, 115.3, 114.8,
113.7, 80.1, 41.3, 27.2, 25.3, 22.5, 16.7.
3.4. Methyl 2,4,5-trimethoxycinnamate (6)
In a 50 mL flame dried, two necked round bottom flask fitted with a septum and
reflux condenser were placed (bmim)Br (3 mL), 1-iodo-2,4,5-trimethoxybenzene
(3 mmol), anhydrous sodium acetate (3.3 mmol) and palladium acetate
(0.03 mmol). To that was added methyl acrylate (4 mmol) through the septum,
and the reaction mixture was heated and maintained at 100ꢁC in an oil bath for
24 h. The reaction mixture was then cooled and extracted with ethyl acetate
(3 ꢂ 5 mL). The combined organic extract was washed with water (2 ꢂ 2 mL),
brine and dried over anhydrous magnesium sulphate. The solvent was evaporated
on vacuum and the product was separated by column chromatography using
hexane : ethyl acetate (8.5 : 1.5) as eluant to obtain the pure product 6 in 84%
yield.
1
IR (nujol)/ꢀmax cmꢀ1: 3030, 2880, 1717, 1624, 1610. H NMR (CDCl3, 300 MHz)
ꢁ: 7.51 (d, 1H, J ¼ 9.6, Ar–CH¼CH–), 7.12 (s, 1H, Ar–H), 6.67 (s, 1H, Ar–H), 6.20
(d, 1H, J ¼ 9.6, Ar–CH¼CH–), 3.87 (s, 3H, –OCH3), 3.80 (s, 3H, –OCH3), 3.74
(s, 3H, –OCH3), 3.71 (s, 3H, –OCH3). 13C NMR (CDCl3, 300 MHz) ꢁ: 170.2, 153.3,
145.1, 139.1, 122.6, 120.4, 115.3, 111.0, 99.6, 58.5, 58.0, 57.7, 52.5.

Natural Product Research
3.5. 1-(30-Methoxypropanoyl)-2,4,5-trimethoxybenzene (7)
445
To the suspension of methyl 2,4,5-trimethoxycinnamate (1.8 mmol) in distilled water
(10 mL) taken in a 50 mL round bottom flask was added magnesium metal
(2.7 mmol) and zinc chloride (2.7 mmol). The reaction mixture was stirred at room
temperature for 30 min and extracted with dichloromethane (3 ꢂ 5 mL). The organic
extracts were dried over calcium chloride. Evaporation of the solvent followed by
purification through column chromatography on silica gel, with hexane : ethyl
acetate (9 : 1) gave the pure compound (7) in 66% yield.
IR (nujol)/ꢀmax cmꢀ1: 3024, 2990, 1743, 1649, 1518, 1162. 1H NMR (CDCl3,
300 MHz) ꢁ: 6.77 (s, 1H, Ar–H), 6.54 (s, 1H, Ar–H), 3.88 (s, 3H, –OCH3), 3.83
(s, 3H, –OCH3), 3.79 (s, 3H, –OCH3), 3.67 (s, 3H, –OCH3), 2.89 (t, 2H, J ¼ 7.6,
Ar–CH2–), 2.59 (t, 2H, J ¼ 7.6, –CH2–COOCH3). 13C NMR (CDCl3, 300 MHz)
ꢁ: 174.8, 150.5, 148.3, 144.4, 122.6, 114.3, 99.6, 57.6, 56.9, 51.7, 34.5, 27.3. Anal.
Calcd for C13H18O5: C, 61.41; H, 7.13; O, 31.44. Found: C, 61.54; H, 7.06; O, 31.39.
Acknowledgement
The authors are grateful to CSIR and CEFIPRA, New Delhi for providing financial
assistance.
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