Total synthesis of α-asarone

Full text of DOI:10.1080/00304948.2012.715061

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Organic Preparations and Procedures
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Total Synthesis of α-Asarone
Elvia V. Cabrera a , Kelly P. Marrugo a , José G. Ortega a , Ajoy K.
Banerjee b & Jennifer L. Sanchez b
a Department of Chemistry, Faculty of Sciences , University of Zulia ,
Maracaibo , Venezuela
b Chemistry Center , Venezuelan Institute of Scientific Research
(IVIC) , Caracas , Venezuela
Published online: 24 Sep 2012.
To cite this article: Elvia V. Cabrera , Kelly P. Marrugo , José G. Ortega , Ajoy K. Banerjee & Jennifer
L. Sanchez (2012) Total Synthesis of α-Asarone, Organic Preparations and Procedures International:
The New Journal for Organic Synthesis, 44:5, 455-459, DOI: 10.1080/00304948.2012.715061
To link to this article: http://dx.doi.org/10.1080/00304948.2012.715061
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Organic Preparations and Procedures International, 44:455–459, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2012.715061
OPPI BRIEFS
Total Synthesis of α-Asarone
Elvia V. Cabrera,1 Kelly P. Marrugo,1 Jose´ G. Ortega,1
Ajoy K. Banerjee,2 and Jennifer L. Sanchez2
1Department of Chemistry, Faculty of Sciences, University of Zulia,
Maracaibo, Venezuela
2Chemistry Center, Venezuelan Institute of Scientific Research (IVIC),
Caracas, Venezuela
α-Asarone (6), a substance of potent hypolipidemic activity1 is mainly found in wild ginger
(Asarum europaeumL-Aristolochiceae)2 and guatteria (Guatteria gaumeri-Annonacea),3
the plant growing in Southwestern Mexico. In addition, α-asarone is known to have se-
dating, neuroleptic, spasmolytic, antiulcerogenic and antiatherogenic activity.4 The potent
biological activities coupled with its low availability from natural source have given the ori-
gin of a plethora of publications5,6 dealing with the studies directed towards the synthesis of
α-asarone. However α-asarone (trans-isomer, 6), obtained in the most published methods6,7
is contaminated with undesired toxic β-asarone (cis-isomer, 7) whose separation by column
chromatography is difficult due to the similarities in Rf values of the two isomers. Therefore
isomerization method was sought for the conversion of β-asarone to α-asarone. The Pd(II)
catalysed [(MeCN)2 PdCl2] isomerization of a mixture of α- and β-asarone, attempted by
Xu and collaborators,8 improved the yield of α-asarone (71%) but also produced two dimers
of α-asarone. However, the cost of the catalyst does not recommend the use of this method
for large scale preparations. Moreover traces of palladium are difficult to remove from the
product. Although the iodine-catalyzed isomerization of a mixture of α- and β-asarone has
been reported6 to yield α-asarone in high yield (81%) and high purity, β-asarone, a dimer
and a trimer were present (less than 0.5%). The knowledge gained from a study of these
approaches6 encouraged us to develop a concise and convenient route which would only
afford α-asarone.
We selected a suitable starting material whose transformation to α-asarone could be
realized without using the Wittig,6,8 Friedel-Crafts9 and Grignard10 reactions respectively
and thus the formation of β-asarone (7) as well the process of isomerization could be
avoided. The synthetic route is outlined in Scheme 1. Reduction of commercially available
Received March 9, 2012
Address correspondence to Ajoy K. Banerjee, Centro de Quimica, Venezuelan Institute of
Scientific Research (IVIC), Aptd-21827, Caracas-1020A, Venezuela. E-mail: aabanerje@gmail.com
455

456
Banerjee et al.
Br
3
1
Me
2
Me
1
Me
iii
ii
i
O
OH
OH
MeO
MeO
MeO
OMe
OMe
OMe
3
(95%)
1
2
(95%)
Br
Br
OMe
3
2
OMe
1
1'
1
2
Me
Me
Me
iv
v
2'
O
Me
MeO
1'
MeO
MeO
MeO
4'
SO2
OMe
OMe
OMe
OMe
6'
7
4
5
6
(97%)
(90%)
(84%)
Reagents and conditions: (i) NaBH4, EtOH, rt, 30 min; (ii) NH4Br, H2O2, AcOH, rt, 4 h; (iii)
PhSO2Cl, Pyridine, rt, 24 h; (iv) NaH, DMF (anhyd), rt, 24 h; (v) Cu(I)Br, MeONa, DMF,
reflux, 18 h.
Scheme 1
3,4-dimethoxyphenylacetone (1) with sodium borohydride produced the known alcohol 2
in 95% yield.11 Bromination12 of 2 with ammonium bromide and hydrogen peroxide (32%)
in acetic acid yielded bromide 3 in 95% yield. Considerable difficulty was encountered
in finding the proper conditions to effect the direct conversion of 3 to 5. Although this
transformation appeared straight forward, in practice none of an extensive list of typical
dehydrating reagents (p-toluenesulfonic acid in toluene at reflux, sulfuric acid and SiO2
in toluene at room temperature, thionyl chloride and pyridine, anhydrous sodium acetate
and acetic anhydride at reflux temperature) were successful. Finally the dehydration of
benezenesulfonyl derivative 4 effected with sodium hydride in dimethylformamide (DMF)
at room temperature furnished the desired product 5 in 84% yield.
The benzenesulfonyl derivative 4 was obtained in 90% yield by stirring the alcohol
3 in pyridine with benzenesulfonyl chloride (PhSO2Cl) at room temperature. Dehydration
of 2 followed by bromination to obtain 5 was not attempted to avoid the possibility of the
bromination of the double bond. With the synthesis of the compound 5, we were ready to
address the repeated attempts using published methods7,13 met with limited success. Finally
following the method of Aalten and coworkers14 with minor modifications, compound 5
was heated with a saturated solution of sodium methoxide, DMF and copper(I) bromide
to afford α-asarone 6 in 97% yield which was homogeneous on TLC in different system.
Its mp. was identical with that of the published report.10 The 1H NMR and 13C NMR data
agreed with the reported data15 of α-asarone indicating α-configuration of the resulting
asarone. No trace of the oily β-asarone (7) was detected.
In conclusion, a concise approach to the synthesis of α-asarone as the sole product in
high overall yield (66%) has been developed. The unwanted toxic β-asarone (7) detected
in most of the published papers was not formed.5,8
Experimental Section
Unless otherwise stated all meting points are uncorrected and were determined on an Elec-
trothermal melting point apparatus. Infrared (IR) spectra were recorded on a Nicolet-Fourier

Total Synthesis of α-Asarone
457
(FT) Instrument and NMR (1H and 13C) spectra were determined on a Brucker AM-300
spectrometer in CDCl3. Chemical shifts (δ) are expressed in ppm. The form of signals is
expressed as s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet. Mass
spectra (MS) were determined on a Dupont 21-492B. Column chromatography was carried
on silica gel 60 (Merck). Thin layer chromatography (TLC) plates were coated with silica
gel and the spots were visualized using ultraviolet light. All organic extracts were dried
over anhydrous MgSO4 and solvents were evaporated in vacuo. Elemental analyses were
performed on a Carlo-Erba 1108 Elemental Analyser.
1-(3,4-Dimethoxyphenyl)propan-2-ol (2)
To a solution of ketone 1 (2.01 g, 10.30 mmol) in EtOH (14 ml) was added a solution
of sodium borohydride (510 mg, 13.50 mmol) in EtOH (15 ml) and stirred for 30 min at
room temperature. The solvent was partially evaporated and the residue was extracted with
CH2Cl2. The organic extract was washed with a diluted solution of HCl (35 ml, 10%),
brine (40 ml), dried and evaporated. The resulting oil was chromatographed (hexane:Et2O
1:1) to obtain the alcohol 2 (1.92 g, 95%), Rf 0.19 (hexane:Et2O 1:1), mp 42–44◦C (from
hexane) (lit.9 43–44◦C); IR (cm−1): 3399 (OH); MS (m/z): 179 (M+1-H2O)+; 1H NMR: δ
6.78 (d, 1H, J = 8.58 Hz) (ArH at C-5), 6.71 (m, 2H) (ArH at C-2 and C-6), 4.00-3.90
(m, 1H) (H at C-2), 3.84 (s, 3H, OMe), 3.82 (s, 3H, OMe), 2.70 (dd, 1H, J = 4.68 Hz and
J = 13.57 Hz) (H at C-1), 2.57 (dd, 1H, J = 8.07 Hz and J = 13.57 Hz) (H at C-1), 1.68
(br s, 1H, OH), 1.20 (d, 3H, J = 6 Hz) (H at C-3); 13C NMR: δ 149.00 (ArC-3), 147.76
(ArC-4), 131.07 (ArC-1), 121.29 (ArC-6), 112.67 (ArC-2), 111.48 (ArC-5), 68.79 (C-2),
55.89 (OMe), 55.81(OMe), (45.30 (C-1), 22.67 (C-3).
Anal. Calcd. for C11H16O3: C, 67.32; H, 8.22. Found: C, 67.53; H, 8.36.
1-(2-Bromo-4,5-dimethoxyphenyl)propan-2-ol (3)
To a solution of the alcohol 2 (508 mg, 2.59 mmol) in glacial acetic acid (9.3 ml) was
added ammonium bromide (410 mg, 5.13 mmol) and dropwise hydrogen peroxide (2 ml,
5 mmol) of 35% and the contents were allowed to stirred at room temperature for 4 h. The
progress of the reaction was monitored by thin layer chromatography (TLC). The resulting
yellow solution was treated with a saturated solution (10 ml) of NaHCO3 and extracted
with Et2O. The organic extracts were washed with brine, dried and evaporated to give the
bromide 3 (677 mg, 95%) as white solid, Rf 0.17 (hexane:Et2O 1:1), mp 82–83◦C (from
ether); IR (cm−1): 3412 (OH); MS (m/z): 257 (M+ -H2O), 178 (M+1-H2O-Br); 1H NMR:
δ 7.01 (s, 1H) 6.74 (s, 1H) (ArH-3, ArH-6), 4.13-4.03 (m, 1H, H-2), 3.83 (s, 6H) (4-OMe,
6-OMe), 2.87 (dd, 1H, J = 4.62, J = 13.66 Hz) (H at C-1), 2.72 (dd, 1H, J = 8.13, J =
13.66 Hz) (H at C-1), 1.25 (d, 3H, J = 6 Hz) (H at C-3); 13C NMR: δ 148.36 (ArC-3,
ArC-4), 130.07 (ArC-1), 115.82 (ArC-2), 114.62 (ArC-6), 114.32 (ArC-5), 67.78 (C-2),
56.17 (OMe), 56.10 (OMe), 45.20 (C- 1), 22.93 (C-3).
Anal. Calcd for C11H15BrO3: C, 48.01; H, 5.45. Found: C, 48.24; H, 5.61.
Benzenesulfonic Acid 2-(2-Bromo-4,5-dimethoxyphenyl-1-methylethyl Ester (4)
To a solution of the bromide 3 (545 mg, 1.98 mmol) in dry pyridine (20 ml) was added
dropwise benzenesulfonyl chloride 957 mg (5.47 mmol) and stirred for 20 h at room

458
Banerjee et al.
temperature. The reaction mixture was treated with ice-water and extracted with Et2O
(100 ml). The ether extracts were washed successively with a diluted solution of HCl
(20 ml, 5%), a solution of NaHCO3 (25 ml, 5%), brine, dried and evaporated. The resulting
solid on chromatographic purification (hexane:Et2O 8:2) furnished the sulphonyl derivative
4 (740 mg, 90%), Rf 0.33 (hexane:Et2O 1:1), mp 75–76◦C (from ether); IR (cm−1): 1342,
1168; MS (m/z): 259 (M+1 -C6H5O3S); 1H NMR: δ 7.63 (dd, 2H, J = 1.25 Hz, J = 8.28 Hz)
(H at C-2ꢀ and H at C-6ꢀ), 7.49 (dt, 1H, J = 1.15 Hz, J = 7.50 Hz) (H at C-4ꢀ), 7.35 (t, 2H,
J = 7.83 Hz) (H at C-3ꢀ and H at C-5ꢀ), 6.76 (s, 1H, ArH-5), 6.51 (s, 1H, ArH-2), 4.81-4.87
(m, 1H, H-2), 3.80 (s, 3H, OMe), 3.73 (s, 3H, OMe), 2.88 (dd, 1H, J = 4.95 Hz, J =
14.28 Hz) (H at C-1), 2.84 (dd, 1H, J = 8.25 Hz, 14.25 Hz, H-1), 1.43 (d, 3H, J = 6 Hz) (H
at C-3); 13C NMR: δ 148.46 (ArC-4),148.09 (ArC-3), 136.84 (C-1ꢀ), 133.07 (C-4ꢀ), 128.81
(C-2ꢀ and C-6ꢀ), 127.79 (ArC-1), 127.44 (C-3ꢀ and C-5ꢀ), 115.41 (ArC-2), 114.42 (ArC-5),
114.29 (ArC-6), 79.80 (C-2), 56.07 (OMe), 55.95 (OMe), 42.46 (C-1), 21.29 (C-3).
Anal. Calcd for C17 H19BrO5S: C, 49.15; H, 4.57. Found: C, 49.43; H, 4.76.
1-Bromo-4,5-dimethoxy-2-propenylbenzene (5)
To a suspension of sodium hydride (60% dispersion in mineral oil) (338 mg, 14 mmol) in
dry DMF (6 ml) was added a solution of sulfonyl derivative 4 (604 mg, 1.46 mmol) in dry
DMF (4 ml) under nitrogen. The reaction mixture was stirred for 24 h at room temperature,
diluted with cold water and extracted with CHCl3. The organic extract was washed with a
diluted solution of HCl (20 ml, 5%), saturated solution of NaHCO3, distilled water, dried
and evaporated. The resulting product was chromatographed (hexane:Et2O 9:1) to obtain
the olefine 5 (316 mg, 84%), Rf 0.36 (hexane:Et2O 9:1), mp 43–44◦C (from hexane); IR
1
(cm−1): 3088, 3034, 3000, 1650, 1600; MS (m/z): 257 (M+), 178 (M+1 -Br); H NMR:
δ 6.96 (s, 1H, ArH-6), 6.95 (s,1H, ArH-3), 6.62 (dq, 1H, J = 1.70 Hz, J = 15.63 Hz)
(H at C-1), 6.06 (dq, 1H, J = 6.65 Hz, J = 15.56 Hz) (H at C-2), 3.86 (s, 3H, OMe),
3.84 (s, 3H, OMe), 1.89 (dd, 3H, J = 1.70, J = 6.65 Hz) (H at C-3); 13C NMR: δ 148.74
(ArC-4), 148.58 (ArC-5), 129.99 (ArC-1), 129.63 (C-1), 126.88 (C-2), 115.40 (ArC-6),
113.33 (C-2), 109.15 (ArC-3), 56.16 (OMe), 56.01 (OMe), 18.49 (C-3).
Anal. Calcd for C11H13BrO2: C, 51.36; H, 5.05. Found: C, 51.57; H, 5.17.
(E)-1-(2,4,5-Trimethoxyphenyl)-1-propene (α-Asarone) (6)
To a saturated solution of sodium methoxide, prepared by dissolving sodium (700 mg)
and dry methanol (4 ml), was added dry DMF (2 ml) and heated under reflux followed
by the addition of copper(I) bromide (114 mg, 0.79 mmol). Heating was continued for
an additional 30 min and to the suspension was added dropwise a solution of the olefin
5 (202 mg, 0.78 mmol) in dry DMF (4 ml). The resulting mixture was heated under
reflux for 18 h. The reaction was cooled, filtered, diluted with water and extracted with
CHCl3.The organic extract was washed with a saturated solution of NaHCO3, brine, dried
and evaporated to afford an oil which was chromatographed (hexane:Et2O 9:1) to obtain
α-asarone 6 (158 mg, 97%), Rf 0.21 (hexane:Et2O 9:1), as crystalline white solid, mp
43–44◦C (from exane) (lit.5,13 44–45◦C); IR(cm−1): 3036, 2997 and 1609; MS (m/z): 209
(M+1), 178 (M+1 –OMe); δ 6.92 (s, 1H) (H at C-6), 6.63 (dq, 1H, J = 1.7 Hz and

Total Synthesis of α-Asarone
459
J = 15.9 Hz) (H at 1ꢀ), 6.46 (s, 1H) (H at C-3), 6.08 (dq, 1H, J = 6.6 Hz and J = 15.8 Hz)
(H at C-2ꢀ), 3.86 (s, 1H), 3.84 (s, 1H), 3.80 (s, 3H) (OMe at C-2, C-4 and C-5), 1.87 (dd,
3H, J = 1.74 Hz and J = 6.63 Hz) (H at C-3ꢀ); 13C NMR: δ 150.69 (C-2), 148.78 (C-4),
143.43 (C-5), 125.07 (C-2ꢀ), 124.35 (C-1ꢀ), 119.11 (C-1), 109.92 (C-6), 98.09 (C-3), 56.74
(OMe), 56.51 (OMe), 56.13 (C-2), 18.76 (C-3ꢀ).
Anal. Calcd for C12 H16 O3: C, 69.21; H, 7.74. Found: C, 69.33; H, 7.82.
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