Microwave- and ultrasound-assisted semisynthesis of natural methoxylated propiophenones from isomeric mixture of phenylpropenes in minutes

Article abstract of DOI:10.1139/v05-185

A rapid and practical semisynthesis of natural methoxylated propiophenones (3a-3f) is realized by reacting stereo- and regio-isomeric mixture of phenylpropenes (1a-1f) with a catalytic amount of palladium chloride - sodium formate in formic acid, methanol, and water (2:1:2) into single product phenylpropanes (2a-2f) followed by its oxidation with 2,3-dichloro-5,6- dicyanobenzoquinone (DDQ) in wet dioxane, containing a few drops of formic acid. Conventional, ultrasound, and microwave heating were compared through these studies.

Full text of DOI:10.1139/v05-185

1826
Microwave- and ultrasound-assisted
semisynthesis of natural methoxylated
propiophenones from isomeric mixture of
phenylpropenes in minutes1
Bhupendra P. Joshi, Anuj Sharma, and Arun K. Sinha
Abstract: A rapid and practical semisynthesis of natural methoxylated propiophenones (3a–3f) is realized by reacting
stereo- and regio-isomeric mixture of phenylpropenes (1a–1f) with a catalytic amount of palladium chloride – sodium
formate in formic acid, methanol, and water (2:1:2) into single product phenylpropanes (2a–2f) followed by its oxida-
tion with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in wet dioxane, containing a few drops of formic acid. Conven-
tional, ultrasound, and microwave heating were compared through these studies.
Key words: focused microwave, ultrasound, phenylpropene, propiophenone, DDQ.
Résumé : On a mis au point une semi-synthèse rapide et pratique des propiophénones méthoxylées naturelles (3a–3f)
en faisant réagir des mélanges stéréo- et régio-isomères de phénylpropènes (1a–1f) avec une quantité catalytique de
chlorure de palladium – formiate de sodium dans l’acide formique, le méthanol et l’eau (2 : 1 : 2) qui conduisent à
des phénylpropanes isolés sous la forme de produits uniques (2a–2f) qui ont été isolés par du 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ) dans du dioxane humide contenant quelques gouttes d’acide formique. Dans toutes les
études mentionnées ci-dessus, on a comparé les méthodes de chauffage traditionnelle, aux ultrasons et aux micro-ondes.
Mots clés : micro-onde focalisée, ultrason, phénylpropène, propiophénone, DDQ.
[Traduit par la Rédaction] Joshi et al. 1832
Introduction
Propionylation of a methoxylated aromatic ring, however,
suffers from some degree of demethoxylation (11) with
Lewis acids such as aluminium chloride (12). The methods
in category (b) include the reaction of substituted benzalde-
hydes (13–15), benzonitrile (16), or benzoic acids (17, 18)
with cyanohydrin – vinyl ether (13), chlorotrimethylsilane–
KCN (14), Grignard (15), isobutylmagnesium bromide (16),
thionyl chloride – Cd(C2H5)2 (17), or propionic acid –
iron(II) salt (18), respectively. Overall, all of the synthetic
methods in categories (a) and (b) are limited by expensive
starting material, maintenance of anhydrous conditions, and
environmentally hostile reagents (19).
In this regard, the methods in category (c) hold a better
semisynthetic approach (20, 21) than categories (a) and
(b) because the former utilizes an already existing C6–C3
unit in the form of substituted phenylpropenes for the forma-
tion of methoxylated propiophenones. Hence, only slight
modifications in the structure are desired, which may not re-
quire harsh conditions if a suitable choice of substrate and
reagent is made.
Methoxylated propiophenones (1) are isolated from a
large number of medicinally important plants and possess a
wide range of biological (2–5) activities such as choleretic
(2), antiplatelet activating factor (anti-PAF) (3), antifungal
(4), and hypolipidemic (5) activities. In addition, methoxy-
lated propiophenones are utilized as intermediates for the
production of various bioactive molecules (6) and are also
used as modifiers in flavour and perfumery formulations (7).
Various methods are reported for the preparation of pro-
piophenones (C6–C3). These methods fundamentally fall un-
der three categories: (a) combination of a C6 unit with a C3
unit, (b) combination of a C6–C1 unit with a C2 unit, and
(c) semisynthetic route from an already existing C6–C3 unit.
The methods in category (a) include reactions of substituted
benzene with phenyllithium – lithium propionate (8) and
Zn-Cu–Pd(PPh3)4–CO (9). Similarly, Friedel–Crafts propi-
onylation (6) of an aromatic ring with a Lewis acid (10) also
falls under this category and remains a well-exploited method.
Received 17 June 2005. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 22 December 2005.
B.P. Joshi, A. Sharma, and A.K. Sinha.2 Natural Plant Products Division, Institute of Himalayan Bioresource Technology,
Palampur, HP 176061, India.
1IHBT communication No. 0307.
2Corresponding author (e-mail: aksinha08@rediffmail.com).
Can. J. Chem. 83: 1826–1832 (2005)
doi: 10.1139/V05-185
© 2005 NRC Canada

Joshi et al.
1827
Scheme 1.
O
OH
2'
Pd(OAc)2
P(o-Tol)3
O
O
1
3
O
O
2
O
2
H
6'
/
Br
S
K2CO3
B
90%
75%
1
2
N
.
f
e
r
3b
Bromohydrin
O
O
O
PdCl
2 /CuClO2
O
O
O
1b
+
O
66%
18%
O
3b
Scheme 2.
R2
R2
R2
O
R3
R4
R
R3
R4
PdCl2/HCOONa (cat.)3
DDQ/wet dioxane
HCOOH (cat.)
MW
HCOOH/MeOH/H2O
R6
MW
R4
R6
R6
R5
R5
Phenylpropane
R5
Propiophenone
cis, trans & γ-Phenylpropene
(stereo- and region-isomeric mixture)
3
2
1
(a) R2=R4=R5=OMe; R3=R6=H (b) R3=R4=OCH2O; R2=R5=R6=H (c) R3=R4=R5=OMe; R2=R6=H
(d) R3=R4=OMe; R2=R5=R6=H (e) R4=OMe; R2=R3=R5=R6=H (f) R3=OMe; R4=OH; R2=R5=R6=H
Phenylpropenes are readily available natural phenylpro-
panoids (22)3 whose structures and economical prices make
them excellent precursors for the semisynthesis of a large
number of products (23, 24) including propiophenones.
Some methoxylated propiophenones (20, 21) (3a and 3b)
have already been synthesized from phenylpropenes utilizing
either N-bromosuccinimide – H2O – palladium acetate or
PdCl2–CuCl–O2 (Scheme 1). However, the extension of
these semisynthetic methods for a large-scale preparation of
propiophenones is not viable due to a longer reaction time
(20), the maintenance of anhydrous conditions, and the use
of expensive reagents (21). In addition, phenylpropenes are
usually available from natural sources as an isomeric (22)
mixture, and their purification into a pure single isomer is
tedious (25). Consequently, chemical modification of any
isomer of phenylpropenes results in the formation of side
products owing to the presence of its other two isomers
(23).4
Against this backdrop, we report microwave- (26) and ul-
trasound-assisted (27) rapid and practical semisynthesis of
methoxylated propiophenones (3a–3f) where toxic (28) cis-
phenylpropenes with their stereo- and regio-isomeric mix-
tures (1a–1f) were first hydrogenated into a single product
phenylpropane (2a–2f). This method thus eliminated the
possibility of the formation of side products arising from the
isomeric nature of phenylpropenes. These phenylpropanes
(2a–2f) were then oxidized to provide bioactive propi-
ophenones (3a–3f) (Scheme 2). The above microwave- and
ultrasound-assisted reactions were also conducted under
conventional conditions to compare all three methods viz.
microwave, ultrasound, and conventional methods to estab-
lish the superiority of the microwave-assisted reactions.
Experimental
Melting points were determined with a Metler FP80
micromelting point apparatus and are uncorrected. Column
chromatography was performed on silica gel (60–120 mesh
size). 1H (300 MHz) and 13C (75.4 MHz) NMR spectra were
recorded in CDCl3 on a Bruker Avance-300 spectrometer. A
CEM Discover® focused microwave (2450 MHz, 300 W)
and a Sonics ultrasonicator (20 kHz, 750 W) were used for
all the given reactions. GC and HR-ES-MS were determined
using Shimadzu-2010 and Micromass Q-TOF Ultima spec-
trometers, respectively.
Representative experimental for conversion of stereo-
and regio-isomeric mixtures of phenylpropenes (1a–1f)
into phenylpropane (2a–2f)
A homogeneous mixture containing PdCl2 (0.01 g) and
sodium formate (0.01 g) was prepared by completely mixing
both in a mortar. To this powdered mixture, the isomeric
3 A large number of methoxylated phenylpropenes are found in high concentration (22) up to 90% in many essential oil-bearing plants, but
generally exist as an isomeric mixture of three isomers namely trans (α), cis (β), and γ-isomers whose purification into a pure single isomer
is tedious by column chromatography (25). On the other side, cis-phenylpropenes (e.g., cis-2,4,5-trimethoxyphenylpropene) are proven car-
cinogenic and toxic (26), which overall restrict the market potential of an essential oil rich in cis isomer, therefore, utilization of a stereo-
and regio-isomeric mixture of phenylpropene (1a–1f) is an added benefit for phenylpropenes towards the formation of useful products in-
cluding propiophenones (3a–3f).
4 For example, the oxidation of cis- and (or) trans-phenylpropenes provides phenylaldehyde; however, contamination of γ-phenylpropene will
lead to phenylacetaldehyde (23).
© 2005 NRC Canada

1828
Can. J. Chem. Vol. 83, 2005
Table 1. Comparative analysis among microwave, ultrasound, and conventional reactions for the
formation of phenylpropanes (2a–2f) and propiophenones (3a–3f) from phenylpropenes (1a–1f).
Conventionalc
Timee
Ultrasonicb
Microwavea
Time
Time
Yield
Substrated
Yield
(%)
Yield
(%)
S. No.
1
Product
(min)
(min)
(min)
10
(%)
OMe
OMe
OMe
84
94
300
60
79
2a
2a
MeO
MeO
OMe
1a
1b
O
O
O
O
10
81
84
86
82
89
300
300
60
76
2
3
MeO
MeO
MeO
MeO
10
10
10
93
94
92
60
60
60
78
77
79
2c
1c
OMe
OMe
OMe
OMe
300
300
2d
1d
MeO
MeO
4
5
2e
2f
MeO
HO
1e
1f
MeO
HO
10
16
89
64
96
69
60
84
59
300
6
7
OMe
OMe
OMe
OMeO
20
20
480
480
MeO
2a
MeO
3a
3b
OMe
OMe
O
O
O
O
O
16
16
70
65
73
71
64
58
8
9
2b
2c
2d
O
MeO
MeO
MeO
MeO
20
20
480
OMe
OMe
3c
OMe
O
16
78
81
66
70
58
47
480
480
MeO
MeO
HO
10
11
3d
3e
MeO
MeO
OMe
O
16
16
20
61
53
2e
2f
O
3f
HO
12
OMe
OMe
56
480
20
aCEM monomode synthesizer at temp. 110–120 °C, power 150–250 W.
bSonics with pulse length 9 s, 75% duty, pause after every 10 min.
cAt reflux temp.
dDotted lines over the phenylpropenes represent an isomeric mixture of cis, trans, and allyl isomers.
eThe mentioned reaction period required for maximum yield.
mixture of substituted phenylpropene 1a–1f (2.9 mmol) and
an 8–10 mL reagent mixture of HCOOH–MeOH–H2O
(2:1:2) was added. The mixture was then either irradiated
using a focused monomode microwave system (in a round
bottom flask fitted with a reflux condenser at 110–120 °C,
power 150–250 W) for 10 min, or ultrasonicated (power 560
W) for 60 min, or refluxed for 300 min using the conven-
tional method. After completion of the reaction, the catalyst5
was removed by filtration and the filtrate was evaporated.
The residue was partitioned between ethyl acetate (70 mL)
and water (15 mL), and the ethyl acetate layer was washed
with water (2 × 10 mL), NaHCO3 (10%), brine (10 mL),
dried over Na2SO4, and filtered. The filtrate was evaporated,
and the obtained residue was purified by column chromatog-
raphy (hexane – ethyl acetate, 9:1) to afford phenylpropane
2a–2f in 89%–96% yield (Table 1).
1-(2′,4′,5′-Trimethoxyphenyl)propane (2a) (23)
1
Liquid. H NMR (CDCl3) δ: 6.81 (1H, s, H-6′), 6.32
(1H, s, H-3′), 3.84, 3.82, 3.78 (each 3H, s, three -OCH3),
5 After reaction, palladium chloride was filtered and was reused for the hydrogenation reaction, and was found to be active even after three
cycles of reuse with a mere 5% loss in the activity.
© 2005 NRC Canada

Joshi et al.
1829
2.42 (2H, t, J = 7.7 Hz, H-1), 1.64 (2H, m, H-2), 0.93 (3H, t,
J= 7.2 Hz, H-3). 13C NMR (CDCl3) δ: 151.4 (C-2′), 147.4
(C-4′), 142.7 (C-5′), 122.7 (C-1′), 114.3 (C-6′), 98.0 (C-3′),
56.5, 56.2, 55.0 (2′-OCH3, 4′-OCH3, 5′-OCH3), 31.6 (C-1),
23.3 (C-2), 13.7 (C-3).
tered, and the red-coloured filtrate was evaporated and sub-
sequently chromatographed on silica gel (hexane – ethyl ac-
etate, 7:3) to provide methoxylated propiophenone 3a–3f in
56%–81% yield (Table 1).
1-(2′,4′,5′-Trimethoxyphenyl)propan-1-one (3a)
White solid; mp 108 to 109 °C (lit. value (6b) mp 108–
110 °C). 1H NMR (CDCl3) δ: 7.45 (1H, s, H-6′), 6.77
(1H, s, H-3′), 3.96, 3.93–3.89 (each 3H, s, three OCH3),
2.99 (2H, q, J = 6.9 Hz, H-2), 1.18 (3H, t, J = 6.9 Hz, H-3).
13C NMR (CDCl3) δ: 201.1 (C-1), 155.5 (C-2′), 153.9 (C-
4′), 143.3 (C-5′), 118.9 (C-1′), 112.6 (C-6′), 96.7 (C-3′),
56.1 (4′-OCH3, 5′-OCH3), 55.9 (2′-OCH3), 36.9 (C-2), 8.4
(C-3).
1-(3′,4′-Dioxymethylenephenyl)propane (2b) (29a)
1
Liquid. H NMR (CDCl3) δ: 6.79 (3H, m, H-2′, H-5′,
H-6′), 5.94 (2H, s, -OCH2O-), 2.56 (2H, t, J = 7.8 Hz, H-1),
1.66 (2H, m, H-2), 0.99 (3H, t, J = 7.3 Hz, H-3). 13C NMR
(CDCl3) δ: 147.5 (C-3′), 145.4 (C-4′), 136.5 (C-1′), 121.4
(C-6′), 108.9 (C-5′), 107.9 (C-2′), 100.6 (-OCH2O-), 37.5
(C-1), 24.8 (C-2), 13.6 (C-3).
1-(3′,4′,5′-Trimethoxyphenyl)propane (2c)
1
Liquid. H NMR (CDCl3) δ: 6.46 (2H, s, H-2′, H-6′), 3.89
1-(3′,4′-Dioxymethylenephenyl)propan-1-one (3b)
(9H, s, three -OCH3), 2.55 (2H, t, J = 7.8 Hz, H-1), 1.66
(2H, m, H-2), 0.96 (3H, t, J = 7.2 Hz, H-3). 13C NMR
(CDCl3) δ: 151.2 (C-3′, C-5′), 140.5 (C-1′), 136.8 (C-4′),
107.2 (C-2′, C-6′), 60.9 (4′-OCH3), 56.7 (3′-OCH3, 5′-
OCH3), 31.3 (C-1), 23.9 (C-2), 13.4 (C-3). HR-EI-MS (posi-
tive) m/z: 211.2826. Anal. calcd. for C12H19O3: 211.2821.
White solid; mp 35 to 36 °C (lit. value (30a) mp 38 to
1
39 °C). H NMR (CDCl3) δ: 7.60 (1H, d, J = 8.1 Hz, H-6′),
7.50 (1H, s, H-2′), 6.86 (1H, d, J = 8.1 Hz, H-5′), 6.34
(2H, s, -OCH2O-), 2.91 (2H, q, J = 6.9 Hz, H-2), 1.25 (3H,
t, J = 6.9 Hz, H-3). 13C NMR (CDCl3) δ: 199.1 (C-1), 151.8
(C-4′), 148.2 (C-3′), 132.1 (C-1′), 122.4 (C-6′), 110.1 (C-
2′), 109.7 (C-5′), 100.5 (-OCH2O-), 31.4 (C-2), 8.6 (C-3).
1-(3′,4′-Dimethoxyphenyl)propane (2d) (29b)
1
Liquid. H NMR (CDCl3) δ: 6.76 (3H, m, H-2′, H-5′, H-
6′), 3.82, 3.79 (each 3H, s, two OCH3), 2.50 (2H, t, J =
7.7 Hz, H-1), 1.61 (2H, m, H-2), 0.92 (3H, t, J = 7.2 Hz, H-
3). 13C NMR (CDCl3) δ: 148.8 (C-3′), 147.1 (C-4′), 135.3
(C-1′), 120.2 (C-6′), 112.7 (C-5′), 111.6 (C-2′), 55.7 (3′-
OCH3), 55.6 (4′-OCH3), 37.6 (C-1), 24.6 (C-2), 13.7 (C-3).
1-(3′,4′,5′-Trimethoxyphenyl)propan-1-one (3c)
White solid; mp 52 to 53 °C (lit. value (17) mp 51.5–
1
52.5 °C). H NMR (CDCl3) δ: 7.23 (2H, s, H-2′, H-6′), 3.90
(9H, s, three OCH3), 2.95 (2H, q, J = 7.2 Hz, H-2), 1.22
(3H, t, J = 7.2 Hz, H-3). 13C NMR (CDCl3) δ: 199.5 (C-1),
153.1 (C-3′, C-5′), 141.4 (C-4′), 137.6 (C-1′), 105.4 (C-2′,
C-6′), 60.8 (4′-OCH3), 56.3 (3′-OCH3, 5′-OCH3), 31.8 (C-
2), 8.4 (C-3).
1-(4′-Methoxyphenyl)propane (2e)
1
Liquid. H NMR (CDCl3) δ: 7.29 (2H, d, J = 8.07 Hz, H-
2′, H-6′), 7.03 (2H, d, J = 8.07 Hz, H-3′, H-5′), 3.98 (3H,
OCH3), 2.71 (2H, t, J = 7.6 Hz, H-1), 1.77 (2H, m, H-2),
1.06 (3H, t, J = 7.1 Hz, H-3). 13C NMR (CDCl3) δ: 157.9
(C-4′), 134.7 (C-1′), 129.7 (C-2′, C-6′), 114.1 (C-3′, C-5′),
55.1 (4′-OCH3), 37.2 (C-1), 24.7 (C-2), 13.8 (C-3). HR-EI-
MS (positive) m/z: 151.2298. Anal. calcd. for C10H16O:
151.2294.
1-(3′,4′-Dimethoxyphenyl)propan-1-one (3d)
White solid; mp 59 to 60 °C (lit. value (30b) mp 59 to
1
60 °C). H NMR (CDCl3) δ: 7.62 (1H, d, J = 8.0 Hz, H-6′),
7.56 (1H, s, H-2′), 6.88 (1H, d, J = 8.0 Hz, H-5′), 3.96
(6H, s, two OCH3), 2.97 (2H, q, J = 7.2 Hz, H-2), 1.23 (3H,
t, J = 7.2 Hz, H-3). 13C NMR (CDCl3) δ: 200.0 (C-1), 153.4
(C-4′), 149.3 (C-3′), 130.5 (C-1′), 122.9 (C-6′), 110.4 (C-
2′), 110.3 (C-5′), 56.5 (3′-OCH3, 4′-OCH3), 31.7 (C-2), 9.0
(C-3).
1-(4′-Hydroxy-3′-methoxyphenyl)propane (2f) (29c)
1
Liquid. H NMR (CDCl3) δ: 6.80 (2H, m, H-2′, H-6′),
6.62 (1H, d, J = 8.3 Hz, H-5′), 6.01 (1H, s, -OH), 3.91
(3H, s, -OCH3), 2.48 (2H, t, J = 7.9 Hz, H-1), 1.58 (2H, m,
H-2), 0.96 (3H, t, J = 7.3 Hz, H-3). 13C NMR (CDCl3) δ:
146.5 (C-3′), 143.7 (C-4′), 134.6 (C-1′), 121.4 (C-6′), 114.4
(C-5′), 111.4 (C-2′), 55.8 (-OCH3), 37.7 (C-1), 24.9 (C-2),
13.8 (C-3).
1-(4′-Methoxyphenyl)propan-1-one (3e) (30c)
1
Liquid. H NMR (CDCl3) δ: 7.58 (2H, d, J = 8.05 Hz, H-
2′, H-6′), 6.85 (2H, d, J = 8.05 Hz, H-3′, H-5′), 3.90 (3H, s,
OCH3), 2.93 (2H, q, J = 7.2 Hz, H-2), 1.18 (3H, t, J =
7.2 Hz, H-3). 13C NMR (CDCl3) δ: 199.2 (C-1), 163.2 (C-
4′), 130.4 (C-1′), 129.9 (C-2′, C-6′), 113.5 (C-3′, C-5′),
55.3 (4′-OCH3), 31.2 (C-2), 8.2 (C-3).
General procedure for the preparation of methoxylated
propiophenones 3a–3f from the oxidation of phenylpro-
panes 2a–2f with 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ)
1-(4′-Hydroxy-3′-methoxyphenyl)propan-1-one (3f)
A
mixture of substituted phenylpropane 2a–2f
1
White solid; mp 61 to 62 °C (lit. value (2) mp 63 °C). H
(2.4 mmol), DDQ (4.8–5.24 mmol), and HCOOH (1 to 2
drops) in wet dioxane (30 mL, water–dioxane 1:9) was irra-
diated using focused microwave irradiation (in a round bot-
tom flask fitted with a reflux condenser at 110–120 °C,
power 150–250 W) for 25 min, or ultrasonicated (power 560 W)
for 20 min, or refluxed for 240 min under conventional
method. The precipitated hydroquinone (DDQH2) was fil-
NMR (CDCl3) δ: 7.58 (2H, m, H-2′, H-6′), 6.95 (1H, d, J =
8.4 Hz, H-5′), 6.08 (1H, s, Ar-OH), 3.92 (3H, s, three
OCH3), 2.96 (2H, q, J = 6.9 Hz, H-2), 1.23 (3H, t, J =
6.9 Hz, H-3). 13C NMR (CDCl3) δ: 199.7 (C-1), 151.3 (C-
3′), 147.8 (C-4′), 130.9 (C-1′), 123.7 (C-6′), 112.1 (C-5′),
111.9 (C-2′), 55.2 (OCH3), 31.7 (C-2), 8.4 (C-3).
© 2005 NRC Canada

1830
Can. J. Chem. Vol. 83, 2005
Table 2. Catalytic transfer hydrogenation of 2,4,5-trimethoxyphenylpropene (1a) into 2,4,5-trimethoxyphenylpropane (2a) using PdCl2
as catalyst.
Catalytic transfer hydrogenating agents
CEM Discover microwave
irradiationa time (min)
Yieldb
(%)
Entry
Reagents and solvents
Catalyst
1
HCOOH (excess)
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Pd/C
80
65
50
50
50
40
9
20
15
35
38
54
82
94
94
93
25
67
79
2
HCOOH (excess) – NaOH (10%)
3
HCOOH (excess) – isopropanol
4
HCOOH (excess) – ethylene glycol
5
HCOOH (excess) – methanol
6
HCOOH (excess) – MeOH – water (2:1:2)
HCOOH (excess) – MeOH – water (2:1:2) (HCOONa, cat.)
HCOOH (excess) – MeOH – water (2:1:2) (HCOOK, cat.)
HCOOH (excess) – MeOH – water (2:1:2) (HCOONH4, cat.)
HCOOH (excess) – MeOH – water (2:1:2) (HCOONa, cat.)
HCOOH (excess) – MeOH – water (2:1:2) (HCOONa, cat.)
HCOOH (excess) – MeOH – water (2:1:2) (HCOONa, cat.)
7
8
9
9
9
10
11
12
30
15c
6c
PdCl2
PdCl2
aCEM monomode Discover synthesizer at temp. 110–120 °C, power 150–250 W.
bYields based on GC (Shimadzu).
cThe reaction was performed using a domestic microwave oven at power 300 and 900 W (entries 11 and 12, respectively) resulting in either unreacted
starting material (entry 11) or evaporation of the product (entry 12).
40 min under microwave proved to give the optimum re-
sults, and provided an 82% yield of 2a (Table 2, entry 6).
Results and discussion
In recent years, there has been a tremendous shift in the
use of microwave (26) and ultrasound (27) irradiation in or-
ganic reactions owing to the shorter reaction time, higher
yields, operational simplicity, and most importantly, the fact
that it is a more eco-friendly process compared with conven-
tional heating. As per our ongoing interest in semisynthesis
of phenylpropanoids, we decided to prepare 2,4,5-trimeth-
oxypropiophenone (3a), a hypolipidemic (5) active compound,
from abundantly available toxic (28) 2,4,5-trimethoxy-
phenylpropene (1a) through catalytic transfer hydrogenation
(31) (CTH) of 1a in the first step to form 2,4,5-trimeth-
oxyphenylpropane (2a), which would then be oxidized by
addition of the suitable oxidant in the next step to form 3a.
For catalytic transfer hydrogenation, a stereo- and regio-
isomeric mixture of phenylpropene 1a was treated with
PdCl2 in formic acid (98%) as a hydrogen transferring agent
for 80 min under focused monomode (32) microwave (CEM
Discover® synthesizer); but only 20% of product 2a formed
(Table 2, entry 1), the rest being a number of side products.
Similarly, a combination of HCOOH and NaOH (33) did not
improve the yield of the product (Table 2, entry 2). The ad-
dition of isopropanol (34) or high boiling ethylene glycol
(31a, 35) to formic acid also did not improve the yield of
product 2a (Table 2, entries 3 and 4). Later on, hydrogenat-
ing a mixture comprising PdCl2–HCOOH in methanol was
found suitable, and 2a was obtained up to 54% yield (Ta-
ble 2, entry 5). Prompted by reports on water–methanol as-
sisted yield enhancement of products (36), we decided to
utilize a combination of methanol and water as solvents in
this reaction. After a lot of experimentation, a 2:1:2 mixture
of HCOOH–MeOH–H2O in catalytic amounts of PdCl2 for
Later on, we realized that the addition of a catalytic amount
of either sodium formate, potassium formate, or ammonium
formate,6 along with this hydrogenating system, was impor-
tant in increasing the yield of the product (2a) up to 94%
with a drastic reduction in reaction time up to 9 min under
focused monomode (32) microwave (Table 2, entries 7–9).
For comparison, the same reaction performed in a domestic
microwave oven provided the product (2a) in 79% yield and
the loss in yield may be due to the easy evaporation of the
product in the domestic microwave oven (Table 2, entries 11
and 12).
In the next step, comprising oxidation of phenylpropane
2a into 3a, several common oxidizing reagents (37) such as
pyridinium chlorochromate and potassium permanganate
were tried, but none of the oxidants was found to be effec-
tive and a number of side products were obtained with little
or no product 3a. Use of excess potassium permanganate –
copper sulphate (10 mol equiv. of reactant 2a) under ultra-
sound and microwave irradiation (38) was also unfruitful.
Similarly, under various conditions, chromium(IV) oxide
(37b, 39) also failed to convert 2a into 3a, although a
yellow-colored solid was obtained; NMR studies revealed it
to be 2-propyl-5-methoxy-1,4-benzoquinone (40). The rea-
son for the failure of all the above general oxidants (37–39)
was believed to be due to the substituent effect of methoxy
groups present at the 2, 4, and 5 positions of phenylpropane,
while oxidation of unsubstituted phenylpropane into propio-
phenones is well-reported with potassium permanganate (38c).
Later on, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)
(41) was found to be an appropriate oxidant for successfully
converting 2a into 3a. Initially, 2a was reacted with 1.25–
6 Ammonium formate itself is a well-known hydrogen-transferring agent for reduction of various functional groups (31, 32) including
carbon–carbon double bonds; however, a large excess of ammonium formate (10 equiv.) and its sublimation on the walls of the vessels
somewhat limit its use.
© 2005 NRC Canada

Joshi et al.
1831
1.5 equiv. of DDQ in the presence of various organic sol-
vents such as methanol, ethanol, THF, and dioxane. Dioxane
along with 3 to 4 mL of water (42), considered most suit-
able, provided 3a only up to 47% along with 11% of α-
asarone (23).7 An increased amount of DDQ, varying from 2 to
2.2 equiv., provided a little more improvement in the yield
(58%) of 3a, but no more improvement in the yield resulted
from a further addition of DDQ. Interestingly, the addition
of a few drops of HCOOH (98%) in this reaction mixture in-
creased the yield of propiophenone 3a up to 69% (Scheme 2)
within 16 min under focused microwave irradiation.
Conclusion
In conclusion, we have realized a microwave and ultra-
sound-assisted rapid and mild semi-synthetic approach
towards preparation of a number of natural bioactive meth-
oxylated propiophenones (3a–3f) from abundantly available
stereo- and regio-isomeric mixtures of phenylpropenes (1a–
1f) via phenylpropanes (2a–2f). Moreover, such a comparative
analysis among microwave, ultrasound, and conventional
methodologies, to the best of our belief, is disclosed for the
first time. Overall, this is an environment friendly process
with none of the steps requiring maintenance of anhydrous
conditions or hazardous chemicals. The intermediates (2a–
2f) may have general utilities in the convenient synthesis of
many other phenylpropanoids (26d, 27c).
After choosing DDQ as the reagent, we decided to carry
out both hydrogenation of 1a into 2a and oxidation of 2a
into 3a in one pot. One-pot synthesis has recently attracted
interest, providing a simple and efficient entry to compounds
by amalgamating two or more operations into a single step.
Hence, after performing hydrogenation of 1a into 2a for
10 min, DDQ was added in the same reaction pot and irradi-
ated under microwave irradiation intermittently for 20 min.
We had thought that HCOOH, besides acting as hydrogen
source, would not interfere in the DDQ-assisted oxidation of
phenylpropane 2a into propiophenone 3a in the same pot, as
the importance of an acidic (42) medium in DDQ-assisted
oxidation is well-understood. Unfortunately, the conversion
of 2a into 3a resulted in a poor yield (up to 22%). This im-
plied that oxidation could not occur completely in one pot
probably owing to the presence of PdCl2, which would keep
on reacting with formic acid to release hydrogen, thus ham-
pering the abstraction of the benzylic proton of 2a with
DDQ for the formation of 3a. Hence, we decided to remove
PdCl2 by mere filtration in the first step before the addition
of the oxidant (DDQ) in the same pot. Although product 3a
was formed in this case, the yield was still no higher than
34% and there was no further increase in the yield by either
lengthening the reaction period or changing the amount of
DDQ. This implied that the hydrogenating solvent mixture
must have interfered in the oxidation of 2a into 3a, which is
otherwise performed effectively in dioxane in the two-step
methodology. Finally, all this prompted us to change the
one-pot two-step methodology, and retain the two-step meth-
odology by performing the hydrogenation in methanol and
oxidation in a dioxane medium.
Acknowledgments
AS and BP are indebted to the Council for Scientific and
Industrial Research (CSIR), Delhi for the award of a Senior
Research Fellowship (SRF). The authors gratefully acknowl-
edge the Director of the Institute of Himalayan Bioresource
Technology, Palampur, for his kind cooperation and encour-
agement.
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