Microwave-assisted minutes synthesis of bioactive phenylbutanoids occurring in Zingiber cassumunar

Article abstract of DOI:10.1007/s10600-005-0154-3

Microwave-assisted condensation of benzaldehyde (3a,b) with acetone in aqueous sodium hydroxide adsorbed on basic alumina provides phenylbutenone (4a-4b) in 68-71% yield within 4 min, which upon further reduction with sodium borohydride and basic alumina gives phenylbutenol (5a,b) in 91-94% yield within 2 min. Dehydration of 5 with anhydrous copper (II) sulfate gives phenylbutadiene (1a,b), a metabolite of Zingiber cassumunar, within 3 min in 42-48% yield, respectively. All the steps involve environmental friendly solvents and reagents, mild reaction conditions, and overall formation of product 1a,b from 3a,b in 34-38% yield within 9 min under microwave irradiation. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10600-005-0154-3

Chemistry of Natural Compounds, Vol. 41, No. 4, 2005
MICROWAVE-ASSISTED MINUTES SYNTHESIS OF BIOACTIVE
PHENYLBUTANOIDS OCCURRING IN Zingiber cassumunar
B. P. Joshi, N. P. Singh, A. Sharma,
and A. K. Sinha
UDC 547.53
Microwave-assistedcondensationof benzaldehyde (3a,b)withacetoneinaqueoussodiumhydroxide adsorbed
on basic alumina provides phenylbutenone (4a–4b) in 68–71% yield within 4 min, which upon further
reduction with sodium borohydride and basic alumina gives phenylbutenol (5a,b) in 91–94% yield within 2
min. Dehydration of 5 with anhydrous copper (II) sulfate gives phenylbutadiene (1a,b), a metabolite of
Zingiber cassumunar
, within 3 min in 42–48%yield, respectively. Allthe steps involve environmental friendly
solvents and reagents, mild reaction conditions, and overall formation of product 1a,b from 3a,b in 34–38%
yield within 9 min under microwave irradiation.
Key words: microwave, phenylbutanoids, phenylbutadiene, Zingiber cassumunar.
A large number of methoxylated phenylbutanoids have been isolated form plants sources [1] that exhibit promising
biological activities [2], including modifiers in flavor and perfumeryformulations [3]. Moreover, these phenylbutanoids are also
employed as simple starting materials for synthesis ofvarious organic compounds, including natural products [4]. E-4-(2′,4′,5′-
trimethoxyphenyl)buta-1,3-diene (1a) and (E)-4-(3′,4′-dimethoxyphenyl)but-1-ene (1b), metabolites of
Zingiber cassumunar
[5], are two such important phenylbutenes, which are known to possess numerous pharmacological activities such as anti-
inflammatory [6], antioxidant [7], insecticidal [8], and, most importantly, hypolipidemic [9] activities. However, both 1a and
1b are isolated together in minute amounts and their separation from each other is reported to be difficult even by preparative
TLC [5]. There are a few methods reported for the synthesis of these all important 1a and 1b which include multistep synthesis
employing the Grignard[4]reaction, Friedel-Crafts[10]reaction, Wittig [5] reaction, and aldol condensation [11] etc. However,
maintenance of anhydrous conditions, use of expensive and highly acidic catalyst, and prolonged reaction times affects the
viability of all these methods. Furthermore, use of a large amount of solvents in conventional methods is neither economically
nor environmentally benign. Microwave induced Organic Reaction Enhancement [12] (MORE chemistry) has created a lot of
interest in the organic chemistrydue toless solvent consumption, higher yields, moreselectivity, mildreaction conditions, easier
work-up, and rapid synthesis as compared to conventional heating. Furthermore, “dry media” synthesis using inorganic solid
supports coupled with microwave irradiation have attracted significant interest worldwide, and many such microwave-assisted
synthesis with solid mineral supports [13] such as alumina, silica gel, and clays have been reported with higher selectivity, yield,
and purityas compared tothe traditional methods. We, in thisregard, report a microwave-mediated simple and efficient protocol
for the synthesis of natural bioactive phenylbutanoids 1a and 1b in three steps as outlined in Scheme 1.
As an endeavor towards synthesis of rare bioactive molecules [14] employing microwave irradiation, we initially
decided to synthesize 1a, taking 2,4,5-trimethoxybenzaldehyde (3a) as the starting compound, which itself was obtained from
microwave-assisted oxidation ofabundantlyavailabletoxicβ-asarone[15]ofAcoruscalamus. In thefirst step, 3a was condensed
with acetone in aqueous NaOH solution under microwave irradiation at 900 w for 2–3 min; however, phenylbutenone (4a) was
obtained in a mere 42% yield only and the rest remained the unreacted 3a. There was no increase in the yield of the product
on further irradiation of the reaction mixture. During the reaction, we realized that there was tremendous evaporation ofacetone
going on inside the reactor, which might have adversely affected the yield of 4a. Consequently, the reaction mixture was
Natural Plant Products Division, Institute of Himalayan Bioresource Technology, Palampur (H.P.), 176061, India, fax
91 1894 230433, e-mail: aksinha08@rediffmail.com. Published in Khimiya Prirodnykh Soedinenii, No. 4, pp. 300-302, July-
August, 2005. Original article submitted February 10, 2005.
0009-3130/05/4104-0370 ©2005 Springer Science+Business Media, Inc.
370

irradiated at varying low power levels (306 W to 540 W) which, though it checked evaporation of acetone to a large extent, was
insufficient for the progress of the reaction. All this prompted us to perform the above reactions in the solid phase, which we
believed would hold back acetone efficiently and check its evaporation.
R
1
R
1
O
R
1
CHO
NaIO /OsO (cat.)
CH COCH /aq NaOH
NaBH /MeOH
4
4
4
3
3
M.W., ref. 15
M.W., 4 min
M. W., 3 min
R
2
R
2
R
2
R
3
R
3
R
3
4a, b
2a, b
3a, b
R
R
R
OH
1
1
CuSO
4
M.W., 2 min
R
2
R
2
R
3
3
5a, b
1a, b
a: R = R = R = OMe; b: R = H, R = R = OMe
1
2
3
1
2
3
Hence, we performed another condensation reaction wherein 3a is reacted with acetone/aq. NaOHunder phase transfer
conditions using cetyltrimethylammonium chloride in conjugation with basic alumina as a solid support [13, 16]. Interestingly,
the above reaction under microwave irradiation at 630 w for 4 min enhanced the yield of pure ketone 4a up to 68% yield.
However, the same reaction under stirring for 5 h at room temperature provided 4a in 44% yield only, which emphatically
manifests the advantage of microwave irradiation. In the next step, ketone4a upon treatment with sodium borohydride adsorbed
on basic alumina gave 4-(2′,4′,5′-trimethoxyphenyl)but-3-en-2-ol (5a) as a light yellow solid in 91% yield under microwave
irradiation for 2 min while the same reaction under conventional conditions required 7 h to provide 5a in 88% yield. The final
step involving acid-catalyzed dehydration of alcohol 5a remained crucial as a variety of reported dehydrating agents [17] such
as phosphoryl chloride/pyridine, p-toluenesulfonic acid, thionyl chloride/triethylamine, triphenylphosphine, oxalic acid, and
dilute H2SO4 are impregnated with drawbacks such as maintenance ofanhydrous conditions or poor yield due topolymerization
of highly conjugated product (5a). Recently, dehydration of alkanol derivatives with anhydrous copper (II) sulfate [18] is
reported as a clean and better yielding process, which encouraged us to investigate this dehydrating agent in our case under
microwave irradiation. As a result, dehydration of 5a with anhydrous copper (II) sulfate was performed under microwave
irradiation, which provided 1a in 42% yield within 3 min with some side products, and the yield did not improve either on
increasing the reaction time or the amount of the reagent. Inspite of the moderate yield of the dehydrated product (1a) in the
above case, the method appeared meritorious in that no strong acidic catalyst (i.e., copper (II) sulfate) is required in contrast
to the reported [11] methods which required strong acids as harsh as H2SO4 and obtained yields in the range of 20%. Moreover,
mere filtration was all that was required for work up of the reaction in our case, which is crucial from the industrial point of
view. Having achieved success with 1a, the same methodology was extended for the synthesis of another bioactive
phenylbutanoid 1b utilizing commercially available 3b as the starting compound, and the product 1b was obtained in overall
38% yield and the whole process is completed within 9 min. This is a remarkable improvement in the yield and reaction time
as there are reports of formation of 1b from 3b following the same synthetic route as ours under conventional conditions in a
mere 10% yield in hours.
In conclusion, this microwave-assisted three-step synthesis of 1a,b starting from 3a,b is completed within 9 min
involving environmental friendly solvents and mild reaction conditions, which makes this method an attractive alternative to
the reported classical methods. In addition, using this method, we can greatly increase the yield of products and reduce the
reaction cost as generally encountered in reported [4, 5, 10, 11] protocols.
EXPERIMENTAL
Melting points were determined with a Mettler FP80 micromelting point apparatus and areuncorrected. 1H (300 MHz)
and 13C (75.4 MHz) NMR spectra were recorded in CDCl3 on a Bruker Avance-300 spectrometer. A Kenstar domestic
microwave oven (2450 MHz, 900 Watts) was used for all the reactions.
371

General Method for Microwave-Assisted Synthesis of Phenylbutenone (4a,b). A mixture of benzaldehyde (3a or
3b) (0.02 mol), acetone (20 mL), and 10% NaOH (30 mL), cetyltrimethylammonium chloride (0.1–0.15 g), and basic alumina
(2 gm) was taken in a 100 mL Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well, placed inside
a microwave oven, and irradiated for 4 min with an interval of 2–3 sec after every 40 sec of irradiation. The reaction mixture
was poured into ice cold water, acidified with 5% HCl, and extracted with dichloromethane (3 × 10 mL). The organic layer was
washed with water and dried over anhydrous Na2SO4. The obtained yellow viscous liquid on evaporation was chromatographed
on a silica gel column using hexane–ethyl acetate mixture with an increasing proportion of ethyl acetate up to 40% to afford
4-(2′,4′,5′-trimethoxyphenyl)but-3-en-2-one (4a) or 4-(3′,4′-dimethoxyphenyl)but-3-en-2-one (4b) as a pure compound.
Compound 4a: 68%, mp 106–108°C.
1H NMR (CDCl3, δ, J/Hz): 7.88 (1H, d, J = 15.0, H-4), 7.06 (1H, s, H-6′), 6.52 (1H, s, H-3′), 6.63 (1H, d, J = 15.0,
H-3), 3.96 (3H, s, 2′-OCH3), 3.91 (3H, s, 4′-OCH3), 3.88 (3H, s, 5′-OCH3), 2.40 (3H, s, H-1).
13C NMR (CDCl3, δ): 199.5, 154.3, 152.9, 143.8, 138.8, 125.7, 115.7, 110.5, 97.1, 56.8, 56.7, 56.4, 27.3.
Compound 4b: 71%, mp 83–84°C.
1H NMR (CDCl3, δ, J/Hz): 7.14 (1H, d, J = 16.1, H-4), 6.77 (2H, m, H-2′ and H-5′), 6.53 (1H, d, J = 8.1, H-6′), 6.28
(1H, d, J = 16.1, H-3), 3.54 (3H, s, OCH3), 3.50 (3H, s, OCH3), 2.01 (3H, s, H-1).
13C NMR (CDCl3, δ): 197.8, 151.1, 149.1, 143.2, 127.1, 124.9, 122.8, 111.0, 109.3, 55.6, 27.0.
General Methodfor Microwave-AssistedSynthesisofPhenylbutenol (5a,b). Ketone(4a or 4b) (0.004 mol), sodium
borohydride (0.005 mol), and basic alumina (1 gm) in methanol (3 mL) were suspended in a 100 ml Erlenmeyer flask and the
mixture was irradiated under microwave for 2 min until disappearance of the starting material based upon TLC analysis. The
mixture was cooled and washed with dichloromethane (3 × 10 mL) and filtered. The organic layer was washed with water and
dried over anhydrous Na2SO4. The residue obtained on evaporation of the filtrate was chromatographed on a neutral alumina
column using hexane-ethyl acetate mixture with an increasing proportion of ethyl acetate up to 60% to afford 4-(2′,4′,5′-
trimethoxyphenyl)but-3-en-2-ol (5a) or 4-(3′,4′-dimethoxyphenyl)but-3-en-2-ol (5b) as a pure compound.
Compound 5a: 91%, mp 64–65°C.
1H NMR (CDCl3, δ, J/Hz): 6.96 (1H, s, H-6′), 6.84 (1H, d, J = 15.9, H-4), 6.49 (1H, s, H-3′), 6.63 (1H, dd, J = 15.9
and 6.1, H-3), 4.47 (1H, m, H-2), 3.96 (3H, s, 2′-OCH3), 3.91 (3H, s, 4′-OCH3), 3.88 (3H, s, 5′-OCH3), 1.36 (3H, d, J = 6.1,
H-1).
13C NMR (CDCl3, δ): 151.8, 149.9, 143.8, 132.3, 124.7, 118.1, 110.2, 98.4, 69.9, 56.8, 56.5, 56.4, 22.8.
Compound 5b: 94%, liquid.
1H NMR (CDCl3, δ, J/Hz): 6.92 (1H, d, J = 1.8, H-2′), 6.89 (1H, dd, J = 8.6 and J = 1.8, H-6′), 6.79 (1H, d, J = 8.6,
H-5′), 6.47 (1H, d, J = 15.9, H-4), 6.12 (1H, dd, J = 15.9 and 6.1, H-3), 4.47 (1H, m, H-2), 3.89 (3H, s, OCH3), 3.86 (3H, s,
OCH3), 1.35 (3H, d, J = 6.1, H-1).
13C NMR (CDCl3, δ): 148.6, 147.9, 130.4, 128.3, 124.1, 121.3, 110.4, 109.5, 69.7, 55.4, 22.4.
General Method for Microwave-Assisted Synthesis of Phenylbutadiene (1a,b). Alcohol (5a or 5b) (0.002 mol) and
copper (II) sulfate (0.002 mol) in dioxane (2 mL) were suspended in a 100 ml Erlenmeyer flask and the mixture was irradiated
under microwave for 2 min in parts till disappearance ofthe starting material based upon TLC analysis. On cooling, the mixture
was washed with ethyl acetate (3 × 10 mL) and filtered. The combined organic layer was washed with water and dried over
anhydrous Na2SO4. The solvent was evaporated and the obtained liquid was chromatographed on a silica gel column using
hexane-ethyl acetate mixture with an increasing proportion of ethyl acetate up to 20% to afford a liquid which after
recrystallization from methanol-water provided 4-(2′,4′,5′-trimethoxyphenyl)but-1,3-dien (1a)or 4-(3′,4′-dimethoxyphenyl)but-
1,3-dien (1b) as a pure compound.
Compound 1a: 42%, mp 56–58°C.
1H NMR (δ, J/Hz): 7.02 (1H, s, H-6′), 6.87 (1H, d, J = 16.0, H-4), 6.69 (1H, dd, J = 16.0 and 11.0, H-3), 6.53 (1H, dt,
J = 16.0 and 11.0, H-2), 6.51 (1H, s, H-3′), 5.29 (1H, brd, J = 16.0, H-1a), 5.09 (1H, brd, J = 11.0, H-1b), 3.91 (3H, s, 2′-OCH3),
3.89 (3H, s, 4′-OCH3), 3.85 (3H, s, 5′-OCH3).
13C NMR (CDCl3, δ): 152.0, 149.9, 143.7, 138.4, 128.4, 127.5, 118.1, 116.5, 109.5, 97.9, 57.1, 56.8, 56.4.
Compound 1b: 48 %, liquid.
1H NMR (δ, J/Hz): 6.98–6.91 (3H, m, H-6′, H-5′ and H-2′), 6.87 (1H, s, H-5′), 6.71 (1H, d, J = 16.1, H-4), 6.51 (1H,
dd, J = 16.1 and 12.2, H-3), 6.43 (1H, dt, J = 16.1 and 12.2, H-2), 5.29 (1H, brd, J = 16.1, H-1a), 5.11 (1H, brd, J = 12.2, H-1b),
3.92 (3H, s, OCH3), 3.88 (3H, s, OCH3).
13C NMR (CDCl3, δ): 149.2, 148.8, 136.4, 128.5, 127.5, 125.1, 124.8,116.2, 110.9, 110.1, 55.7.
372

ACKNOWLEDGMENT
Two of us (BPJ and AS) are indebted to CSIR, Delhi for the award of the SRF. The authors gratefully acknowledge
the Director of I.H.B.T., Palampur for his kind cooperation and encouragement.
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