A Practical synthesis of a-asarone via iodine-catalyzed isomerization of αβ-asarone

Full text of DOI:10.1080/00304940902802099

This article was downloaded by: [University of Saskatchewan Library]
On: 13 January 2015, At: 10:30
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/uopp20
A Practical Synthesis of α-Asarone via
Iodine-catalyzed Isomerization of α/β-
Asarone
Guangyu Xu a , Chang Liu a , Wei Zhang b & Gaolei Zuo a
a College of Chemistry and Chemical Engineering , Hunan Normal
University , Changsha, PR, China
b College of Medicine , Hunan Normal University , Changsha, PR,
China
Published online: 22 Apr 2009.
To cite this article: Guangyu Xu , Chang Liu , Wei Zhang & Gaolei Zuo (2009) A Practical
Synthesis of α-Asarone via Iodine-catalyzed Isomerization of α/β-Asarone, Organic Preparations
and Procedures International: The New Journal for Organic Synthesis, 41:2, 152-155, DOI:
10.1080/00304940902802099
To link to this article: http://dx.doi.org/10.1080/00304940902802099
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

152
Xu et al.
5. M. Lebedev and M. Erman, Tetrahedron Lett., 43, 1397 (2002).
6. F. Rahm, A. Fischer and C. Moberg, Eur. J. Org. Chem., 4205 (2003).
7. M. Falorni, L. Lardicci and G. Giacomelli, J. Org. Chem., 54, 2383 (1989).
8. E. Cesaroti, H. Kagan, R. Goddard and D. Kruger, J. Organometall. Chem., 162, 279 (1978).
9. H. Adolfsson, K. Nordstrom, K. Warnmark and C. Mobert, Tetrahedron Asymm., 7, 1967 (1996).
10. A. Fischli and P. Muller, Helv. Chim. Acta, 63, 1619 (1980).
11. M. Yamashita, Y. Soeda, N. Suzuki, M. Yamada, K. Tsuenkawa, T. Oshikawa and S. Inokawa,
Bull. Chem. Soc. Jpn, 56, 1871 (1983).
Organic Preparations and Procedures International, 41:152–155, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940902802099
A Practical Synthesis of α-Asarone via
Iodine-catalyzed Isomerization of α/β-Asarone
Guangyu Xu,1 Chang Liu,1 Wei Zhang,2 and Gaolei Zuo1
1College of Chemistry and Chemical Engineering, Hunan Normal University,
Changsha, P. R. China
2College of Medicine, Hunan Normal University, Changsha, P. R. China
α-Asarone (1), isolated from the Guatteria guameri plant growing in southeast Mexico,
is reported to be an anti-platelet and hypolipidemic agent.1,2 In addition, it is known to
have sedating, neuroleptic, spasmolytic, anti-ulcerogenic and anti-atherogenic activity.3,4
Due to its low availability from natural sources, several synthetic approaches have been
developed for α-asarone (trans-isomer, 1), which involve Grignard, Wittig, Aldol-Grob,
Friedel-Crafts reactions.5–9 However, in the above methods, some of the unwanted toxic
β-asarone (cis-isomer, 2) was always formed, along with the desired α-asarone, which is
difficult to separate by column chromatography due to similarities in Rf values. β-Asarone
can be converted to α-asarone by fusion with KOH in good yield.10 However, this reaction
requires an excess amount of KOH (37 equiv.) and high temperature (200–220◦C). Selenium
dioxide, which can effectively convert β-asarone to α-asarone,10 is not a good choice due to
its toxicity. A recently developed palladium (II) catalyzed isomerization of cis-arylalkenes
can also be applied to the preparation of α-asarone,11,12 however, industrial applications of
this reaction on synthesis of α-asarone are challenging because the catalyst is expensive,
Submitted August 29, 2008.
Address correspondence to Guangyu Xu, Hunan Normal University, College of Chemistry and
Chemical Engineering, Changsha 410081, P. R. China. E-mail: gyxu@hunnu.edu.cn

A Practical Synthesis of α-Asarone
153
and difficult to recycle. Moreover, traces of palladium are difficult to remove from the
product. It would, therefore, be useful to develop a reliable, mild, economical, and environ-
mentally friendly method for the conversion of β-asarone to α-asarone. We present herein
a facile synthesis of α-asarone via iodine-catalyzed isomerization of α/β-asarone mixture
(Scheme 1).
Scheme 1
+
Reagents and conditions: i. CH3CH2PPh3 Br−, dioxane, K2CO3, reflux, 24 hours; ii. 0.1% I2, EtOAc,
rt, 5 hours.
Although the iodine catalyzed isomerization of cis-stilbenes to trans-stilbenes has
been reported,13–15 to the best of our knowledge, the successful iodine catalyzed inversion
of β-asarone has not been described. We thus investigated the effect of solvent and the
amount of iodine on the isomerization of a 43:57 mixture of α- and β-asarone obtained as
previously described.12
It was found that the use of solvents such as toluene, chloroform, dioxane, ethyl acetate,
and benzene all led to good selectivity (97/3 mixture) in 1 hour or less using 2 mol% iodine
at room temperature; the best yields (79%) were obtained in toluene and ethyl acetate.
The use of 0.1 mol% of iodine in ethyl acetate at room temperature for 5 hours gave the
best results (97/3 [by GC] and 92% yield [based the total amount of the two isomers]).
The fact that the isomerization may be performed in the dark (7 hours) makes it suitable
for large scale production. The two by-products formed in the isomerization reaction were
isolated by silicon gel column chromatography using hexane/ethyl acetate (4/1) as eluent,
and identified by NMR and MS as dimer 3 and trimer 4. By-product 3 had been reported
previously.12
In summary, a simple and practical catalytic process for the preparation of pure α-
asarone has been demonstrated. The mild conditions, operational simplicity, low toxicity,
and low loading of catalyst make this process a more useful and practical alternative to the
conventional methods for the acquisition of α-asarone from abundantly available but toxic
β-asarone in nature.

154
Xu et al.
Experimental Section
All reagents and solvents were obtained from commercial suppliers and used without
further purification. Mps were determined on a Bu¨chi 510 melting point apparatus and are
uncorrected. GC was performed on an Agilent 6890N with a capillary column (0.32 mm ×
32 m) immobile with liquid SE-30 (column flow rate 1.3 mL/min, vaporizer temperature
240◦C, column temperature 170◦C, detector temperature 250◦C). The purity of product
was determined by HPLC: column, SB-C18 column, 250 mm × 4.6 mm, 5 µ; mobile
phase, 10% CH3CN in water; flow rate 1.0 mL/min; detection, 258 nm. 1H NMR and 13
C
NMR spectra were recorded in CDCl3 on a Brucker-400 NMR spectrometer. EIMS were
determined with a HP5989B mass spectrometer.
Preparation of α-Asarone
In a 10-L glass vessel, a solution of α/β -asarone mixture (1.10 kg, 5.29 mol, 97.1% purity)
in 5.5 L of ethyl acetate was added 1.34g of I2 (5.29 mmol), and the resulting solution
was stirred at room temperature for 5 hours, after which the solution was washed with 1%
Na2S2O3 solution (2 × 500 ml) to destroy the remaining iodine. The organic phase was
washed with water and concentrated to give a pale yellow oil. The residue was dissolved
in 1.5 L of hot aq. EtOH solution (7:3 EtOH-water) then cooled to 0◦C to afford 0.87
kg (81%) of 99.1% pure (HPLC) of α-asarone as a white solid, mp. 61.5–62.1◦C, lit.5
62–63◦C. β-Asarone and other impurities were present in less than 0.5%.
2,3-Dihydro-4,5,7-trimethoxy-3-(2,4,5-trimethoxyphenyl)-1-(3-(2,4,5-trimethoxy
phenyl)pentan-2-yl)-2-methyl-1H-indene (4)
White solid (from EtOH), mp. 132.0–135.2◦C, isolated by chromatography on silica gel
(4:1 hexane-ethyl acetate). 1H NMR (400MHz, CDCl3): δ 0.58 (t, 3 H, J = 9.6 Hz, CH3),
0.63 (d, 3 H, J = 9.6 Hz, CH3), 1.66 (d, 3 H, J = 8.8Hz, CH3), 1.43 (m, 1 H, CH), 1.73
(m, 2 H, CH2), 2.21 (m, 1 H, CH), 2.83 (dd, 1 H, J = 5.6, 7.2 Hz, CH), 3.20 (m, 1 H, CH),
3.44 (s, 3 H, OCH3), 3.61 (s, 3 H, OCH3), 3.73 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.79
(s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 3.88 (s, 6 H, 2 × OCH3), 4.21
(d, 1 H, J = 5.2 Hz, CH), 6.40 (s, 1 H, ArH), 6.43 (s, 1 H, ArH), 6.48 (s, 1 H, ArH), 6.55
(s, 1 H, ArH), 6.59 (s, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ 12.4, 14.9, 21.0, 26.2,
42.1, 49.3, 49.6, 53.1, 55.1, 56.0, 56.2, 56.4, 56.5, 56.5, 56.6, 56.7, 60.0, 96.5, 97.7, 97.9,
113.0, 125.2, 126.7, 127.0, 139.7, 139.9, 142.5, 142.8, 147.0, 147.5, 151.2, 151.8, 152.4,
152.8; MS (ESI): [M+Na]+ 647.3.
Anal. Calcd. for C36H48O9: C, 69.21; H, 7.74. Found: C, 69.09; H, 7.88.
Acknowledgment
We thank the National Natural Science Foundation of China (No. 20602010) and Hunan
Provincial Natural Science Foundation of China (No. 06JJ50024) for financial support.
References
1. A. Hernandez, M. Lourdes Lopez, G. Chamorro and T. Mendoza-Figueroa, Planta Med., 59, 121
(1993).

A Practical Synthesis of α-Asarone
155
2. F. Diaz, H. Munoz, F. Labarrios, G. Chamorro, M. Salazar, M. E. Morelos and J. Tamariz, Med.
Chem. Res., 3, 101 (1993).
3. M. K. Menon and P. C. Dandiya, J. Pharm. Pharmacol., 9, 170 (1967).
4. L. F. Belova, S. D. Alibekov, A. I. Baginskaya, S. Y. Sokolov, G. V. Pokrovskaya, V. A. Stikhin,
T. Trumpe and T. I. Gorodnyuk, Farmakol.-Toksikol., 48, 17 (1985); Chem. Abs. 104, 28405
(1986).
5. F. Diaz, L. Contreras, R. Flores, J. Tamariz, F. Labarrios, G. Chamorro and H. Munoz, Org. Prep.
Proced. Int., 23, 133 (1991).
6. J. Mulzer and O. Lammer, Angew. Chem. Int. Ed., 22, 628 (1983).
7. A. Sharma, B. P. Joshi and A. K. Sinha, Bull. Chem. Soc. Jpn, 77, 2231 (2004).
8. B. P. Joshi, A. Sharma and A. K. Sinha, Tetrahedron, 61, 3075 (2005).
9. Z. Wang, L. Jiang and X. Xu, Youji Huaxue, 10, 350 (1990); Chem. Abs. 114, 5926 (1991).
10. B. S. Rao and K. Subramaniam, J. Chem. Soc., 1338 (1937).
11. J. Yu, M. J. Gaunt and J. B. Spencer, J. Org. Chem., 67, 4627 (2002).
12. G. Xu, Y. Zhou, G. Zuo and Y. Jiang, Org. Prep. Proced. Int., 39, 514 (2007).
13. K. Gaukroger, J. A. Hadfield, L. A. Hepworth, N. J. Lawrence and A. T. McGown, J. Org. Chem.,
66, 8135 (2001).
14. M. A. Ali and Y. Tsuda, Chem. Pharm. Bull., 40, 2842 (1992).
15. A. R. Battersby and I. A. Greenock, J. Chem. Soc., 2592 (1961).