A mild and convenient procedure for the conversion of toxic β-asarone into rare phenylpropanoids: 2,4,5-Trimethoxycinnamaldehyde and γ-asarone

Article abstract of DOI:10.1021/np010559s

Oxidation of β-asarone (2) with DDQ gave trans-2,4,5- trimethoxycinnamaldehyde (3), which on treatment with p-toluenesulfonyl hydrazine provided corresponding α,β-unsaturated hydrazone derivative (4). Reduction of 4 with sodium borohydride in acetic acid afforded γ-asarone (1) in 43% yield.

Full text of DOI:10.1021/np010559s

764
J . Nat. Prod. 2002, 65, 764-765
A Mild a n d Con ven ien t P r oced u r e for th e Con ver sion of Toxic â-Asa r on e in to
Ra r e P h en ylp r op a n oid s: 2,4,5-Tr im eth oxycin n a m a ld eh yd e a n d γ-Asa r on e†
Arun K. Sinha,* Ruchi Acharya, and Bhupendra P. J oshi
Natural Plant Products Division, Institute of Himalayan Bioresource Technology, Palampur (H.P.)-176061, India
Received November 7, 2001
Oxidation of â-asarone (2) with DDQ gave trans-2,4,5-trimethoxycinnamaldehyde (3), which on treatment
with p-toluenesulfonyl hydrazine provided corresponding R,â-unsaturated hydrazone derivative (4).
Reduction of 4 with sodium borohydride in acetic acid afforded γ-asarone (1) in 43% yield.
In nature asarones1 exist in three isomeric forms,
Sch em e 1
namely, R-, â-, and γ-asarone (trans-2,4,5-trimethoxy-1-
propenylbenzene, cis-2,4,5-trimethoxy-1-propenylbenzene,
and 1-allyl-2,4,5-trimethoxybenzene, respectively). γ-Asa-
rone (1) is a rare phenylpropanoid2 first isolated from
Caesulia axillaries3 and later detected as a biologically
active4 constituent of various essential oil bearing plants.5
However, no simple method is available for separation and
isolation of asarones (R, â, and γ) in single isomeric form
due to their similar physical properties. Separation of less
abundant 1 via column chromatography of asarones-rich
essential oil is particularly difficult. A few methods for the
synthesis of 1 are found in the literature,2,6 but protocols
either involve multiple steps starting from dimethoxy-
phenol6a,c with overall poor yield or require careful handling
of sodium perchlorate during electrolysis of methyl
eugenol.2,6b Herein we report a simple synthesis of 1 from
toxic â-asarone7 (2) via formation of a key intermediate,
2,4,5-trimethoxycinnamaldehyde (3), as outlined in Scheme
1; compound 3 is itself a rare phenylpropanoid found in
traces in C. axillaries8 and Alpinia flabella.9
tosylhydrazone derivative (4) in 79% yield. To obtain the
product 1, the reduction and double-bond migration17 of
tosylhydrazone derivative 4 proceeded smoothly and in
good yield (43%) with acetic acid-sodium borohydride, but
yields were lower using sodium cyanoborohydride-sul-
folane. The Rf value (0.39 in 4% ethyl acetate in hexane)
of 1 was exactly the same as that for 2; however, spectral
data of 1 were found consistent with those in the litera-
ture.1,6c Finally, we conclude that the synthesis of 3 and 1
from 2 is convenient and efficient in comparison to re-
ported2,6,8 methods.
â-Asarone (2) is found in several plants1 including Acorus
calamus10 (family Araceae). The high percentage of toxic
2 (varying from 70 to 90% in tetraploid and hexaploid
strains11 distributed extensively in India, Pakistan, Bang-
ladesh, J apan, and China) restricts the market potential12
of calamus oil. Therefore, as a part of our continuing efforts
to generate value-added products,13 compound 2 has been
converted into rarer phenylpropanoids 3 and 1. Treatment
of 2 (cis-isomer) with DDQ14 in wet dioxane afforded 3 in
41% yield, whereas the addition of a catalytic amount of
silica gel (60-120 mesh size) improved the yield of 3 up to
62%. 1H NMR clearly indicated the formation of 3 as trans
R,â-unsaturated aldehyde in which the olefinic proton
appeared at δ 7.81 (J ) 15.8 Hz) rather than the expected
cis-isomer.15 Alternatively, the above oxidation was re-
peated starting with trans-asarone, which produced an 84%
yield of expected trans-cinnamaldehyde (3), identified by
mixed melting point and comparison of its spectral data
with an authentic sample.8,13c These results clearly indi-
cated formation of the thermodynamically more stable
trans isomeric form of cinnamaldehyde (3) whether starting
from cis- or trans-asarone; however, trans-asarone provided
higher yields. Compound 3 has been isolated, so far, from
two plants,8,9 but only in trace amounts. Treatment of a
methanolic solution of 3 with p-toluenesulfonylhydrazine16
(1.2 equiv) afforded the corresponding R,â-unsaturated
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Melting points were
determined with a Metler FP80 micromelting point apparatus
and are uncorrected. NMR spectra were recorded on a Bruker
AM-300 spectrometer in CDCl3 using TMS as an internal
standard and EIMS on a J EOL J MS-HX 300 mass spectrom-
eter, respectively. DDQ and R-asarone were purchased from
Merck and Sigma Chemical Co., respectively.
P la n t Ma ter ia l a n d Isola tion of â-Asa r on e (2). The
rhizomes of Acorus calamus were collected from Palampur
(1300 m altitude) in May-J une 1997, and the plant specimen
was compared against a voucher specimen (no.1066) in the
herbarium of the IHBT, Palampur, India. The steam distilla-
tion of rhizomes gave calamus oil (1.7% w/w), which after
column chromatography on a silica gel column with hexane/
ethyl acetate (99:1 to 90:10) provided 1 (82% w/w) as pale
yellow liquid (Rf 0.39 on silica gel TLC plate in 4% ethyl acetate
in hexane), and its spectral data agreed well with reported1,13
literature values.
P r ep a r a tion of 2,4,5-Tr im eth oxycin n a m a ld eh yd e (3)
fr om â-Asa r on e (2). A mixture of 2 (2.08 g, 0.01 mol) and
DDQ (4.54 g, 0.02 mol) in wet dioxane (40 mL) was stirred for
15 min. A catalytic amount of silica gel (0.2-0.3 g) was added
* To whom correspondence should be addressed. Tel: 91-1894-30426.
Fax: 91-1894-30433. E-mail: aksinha8@rediffmail.com.
† IHBT Communication Number 2132.
10.1021/np010559s CCC: $22.00
© 2002 American Chemical Society and American Society of Pharmacognosy
Published on Web 04/17/2002

Notes
J ournal of Natural Products, 2002, Vol. 65, No. 5 765
to the above mixture with constant stirring at room temper-
ature overnight. The precipitated hydroquinone (DDQH2) was
filtered and further washed with dioxane. The filtrate and
washings were concentrated to dryness, resuspended in CHCl3
(25 mL), washed with H2O (2 × 10 mL), NaHCO3 (10%, 2 ×
10 mL), and brine (2 × 10 mL), and dried over anhydrous Na2-
SO4. The residue obtained on evaporation of the solvents was
column chromatographed on silica gel containing some neutral
alumina at the top. The column was eluted with hexanes-
ethyl acetate (9:1 to 3:2). The fractions were monitored on a
TLC plate, and the desired fractions were combined and
solvent removed under vacuum to afford 3 (1.38 g) in 62% yield
as a yellow solid with Rf 0.67 (25% ethyl acetate in hexane):
mp 139 °C (lit.8 140 °C); 1H NMR (CDCl3, 300 MHz) δ 9.65
(1H, d, J ) 7.8 Hz, H-3′), 7.81 (1H, d, J ) 15.8 Hz, H-1′), 7.03
(1H, s, H-6), 6.64 (1H, dd, J ) 15.8 Hz, J ) 7.8 Hz, H-2′), 6.51
(1H, s, H-3), 3.95 (s, 3H, 2-OCH3), 3.91 (s, 3H, 4-OCH3), 3.87
(s, 3H, 5-OCH3); 13C NMR (CDCl3, 75.4 MHz) δ 194.1 (C-3′),
154.1 (C-1′), 153.2 (C-2), 147.6 (C-4), 143.3 (C-5), 126.4 (C-2′),
114.5 (C-1), 110.5 (C-6), 96.5 (C-3), 56.4 (5-OCH3), 56.2
(2-OCH3), 56.0 (4-OCH3); EIMS m/z 222 [M]+ (44), 207 (18),
191 (100), 179 (14), 171 (27), 151 (14), 147 (7), 69 (58), 58 (80).
P r ep a r a tion of 2,4,5-Tr im eth oxycin n a m yltosylh yd r a -
zon e (4). The cinnamaldehyde 3 (1.11 g, 0.005 mol) was
dissolved in boiling MeOH (40 mL), and the solution was cooled
to room temperature. p-Toluenesulfonylhydrazine (1.12 g,
0.006 mol) was added and the solution stirred at room
temperature overnight. The red viscous material obtained on
evaporation of solvents was chromatographed on a silica gel
column with hexanes-ethyl acetate (9:1 to 3:7) as the eluent.
The fractions containing 4 were pooled on the basis of TLC.
Evaporation of solvent gave yellow crystals (1.54 g) of tosyl-
hydrazone (4) in 79% yield with Rf 0.32 (25% ethyl acetate in
hexane): mp 155-168 °C; 1H NMR (CDCl3) δ 7.88 (2H, d, Ts-
H), 7.62 (1H, d, H-3′), 7.32 (2H, d, Ts-H), 7.02 (1H, d, H-1′),
6.98 (1H, s, H-6), 6.69 (1H, dd, H-2′), 6.49 (1H, s, H-3), 3.96
(3H, s, 2-OCH3), 3.93 (3H, s, 4-OCH3), 3.86 (3H, s, 5-OCH3),
and 2.43 (3H, s, Ts-CH3).
obtain 0.18 g (43%) of 1 as a viscous liquid with Rf 0.39 (4%
ethyl acetate in hexane): 1H NMR (CDCl3) at δ 6.70 (1H, s,
H-6), 6.53 (1H, s, H-3), 5.95 (1H, m, H-2′), 5.04 (2H, m, H-3′),
3.88 (3H, s, 2-OCH3) 3.83 (3H, s, 4-OCH3), 3.80 (3H, s, 5-OCH3),
and 3.32 (2H, d, J ) 6.6 Hz, H-1′); 13C NMR (CDCl3) δ 151.72
(C-2), 148.30 (C-4), 143.40 (C-5), 137.04 (C-2′), 120.42 (C-1),
115.58 (C-3′), 114.38 (C-6), 98.41 (C-3), 56.99 (4-OCH3
&
5-OCH3), 56.62 (2-OCH3), and 34.05 (C-1′); EIMS m/z 208 [M]+
(100), 193 (60), 165 (40), 134 (10), 77 (18), 69 (34). On the basis
of the above spectral data and comparing with reported
literature,1,6c the liquid was identified as 1.
Ack n ow led gm en t. We are thankful to Dr. V. K. Kaul and
Dr. J . Kotesh of the N.P.P. division of I.H.B.T., Palampur, for
all their assistance. The authors also gratefully acknowledge
the Director of I.H.B.T., Palampur, for his kind cooperation
and encouragement.
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P r ep a r a tion of γ-Asa r on e (1). A solution of tosylhydra-
zone 4 (0.78 g, 0.002 mol) in glacial acetic acid (8 mL) was
added dropwise to a precooled solution of sodium borohydride
(0.38 g, 0.01 mol) and acetic acid (3 mL) under nitrogen
atmosphere. The reaction mixture was stirred initially at 5-10
°C for 1 h and finally at 90-120 °C for 12 h. The mixture was
poured on to ice-cooled H2O and extracted with CH2Cl2 (20
mL × 3). The organic layers were combined, washed with
dilute sodium hydroxide and saturated brine, and dried over
anhydrous Na2SO4. The crude product was chromatographed
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NP010559S