A convenient and effective synthesis of 3-(3,5-dimethoxyphenyl)propanal

Article abstract of DOI:10.1081/SCC-120004271

A convenient and effective synthesis of 3-(3,5-dimethoxyphenyl) propanal, an important intermediate in the synthesis of various biologically active compounds is described.

Full text of DOI:10.1081/SCC-120004271

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A CONVENIENT AND EFFECTIVE SYNTHESIS OF 3-(3,5-
DIMETHOXYPHENYL)PROPANAL
a
a
a
Spyros P. Nikas , Ganesh A. Thakur & Alexandros Makriyannis
a
Department of Pharmaceutical Sciences , Department of Molecular and Cell Biology ,
Institute of Materials Science , University of Connecticut , Storrs, CT, 06269, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Spyros P. Nikas , Ganesh A. Thakur & Alexandros Makriyannis (2002) A CONVENIENT AND EFFECTIVE
SYNTHESIS OF 3-(3,5-DIMETHOXYPHENYL)PROPANAL, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:11, 1751-1756, DOI: 10.1081/SCC-120004271
To link to this article: http://dx.doi.org/10.1081/SCC-120004271
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SYNTHETIC COMMUNICATIONS, 32(11), 1751–1756(2002)
A CONVENIENT AND
EFFECTIVE SYNTHESIS OF
-(3,5-DIMETHOXYPHENYL)PROPANAL
3
Spyros P. Nikas, Ganesh A. Thakur,
and Alexandros Makriyannis*
Departments of Pharmaceutical Sciences
and of Molecular and Cell Biology and
Institute of Materials Science,
University of Connecticut, Storrs, CT 06269, USA
ABSTRACT
A convenient and effective synthesis of 3-(3,5-dimethoxy-
phenyl) propanal, an important intermediate in the synthesis
of various biologically active compounds is described.
3
-(3,5-Dimethoxyphenyl)propanal 5 is an important intermediate for
[
1]
the synthesis of various isomeric tetrahydrocannabinols and other related
cannabinoids or cannabinoid-like compounds, for the stereoselective syn-
[
thesis of 1-aryl-4a-methyloctahydrophenanthrenes and for the introduction
2]
2
13
of stable isotopes (e.g. H, C) in different positions of the above compounds.
However, at present there are only two methods reported for its
[
preparation. The first method involves esterification of trans-cinnamic
2]
[3]
[
acid followed by LAH reduction to give 3-(3,5-dimethoxyphenyl)-1-
2]
propanol 4, which is subsequently oxidized under Swern conditions to
*
Corresponding author. E-mail: makriyan@uconnvm.uconn.edu
751
1
Copyright & 2002 by Marcel Dekker, Inc.
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752
NIKAS, THAKUR, AND MAKRIYANNIS
Scheme 1. Sequence of reactions for synthesis of aldehyde 5.
give 5. Reported yields are 60% for the combined reduction and oxidation
[
4]
steps and 57% overall yield. The second method involves Perkin conden-
sation of commercially available 3,5-dimethoxybenzaldehyde with acetic
anhydride at high temperature to give dimethoxycinnamic acid in 72%
yield. This is followed by LAH reduction using a Soxhlet apparatus to the
corresponding alcohol 4, which was then subjected to Swern oxidation with
a reported, overall yield of 53%. Our interest in the synthesis of several
functionalized cannabinoids required availability of aldehyde 5 on a larger
scale. However, in our hands the first method led to inconsistent yields that
were generally significantly lower than those reported. In addition, the dis-
advantages associated with second method such as low overall yield,
requirement of high temperature, and long reaction time prompted us to
develop a convenient method for the large scale synthesis of this useful
intermediate. The present communication describes synthesis of compound
5
from 3,5-dimethoxybenzaldehyde in an overall 90% yield (Scheme 1).
RESULTS AND DISCUSSION
Treatment of 3,5-dimethoxybenzaldehyde with commercially available
(
carbethoxymethylene)triphenylphosphorane in dry THF afforded an iso-
meric mixture of ethyl 3,5-dimethoxycinnamate favoring the trans isomer
cis : trans ¼ 3 : 97) in a quantitative yield. These isomers could be separated
by flash column chromatography, thus also affording a convenient route for
(

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3
-(3,5-DIMETHOXYPHENYL)PROPANAL
1753
the preparation of synthetically very useful but expensive trans-3,5-
dimethoxycinnamic acid or its ester. Attempted direct reduction of a mix-
[
2]
ture of cinnamates using LAH gave the required alcohol in only 55% yield
with other by-products. A more effective modification involved, first, cata-
lytic hydrogenation of 2 to give ethyl 3-(3,5-dimethoxyphenyl)propionate 3
in quantitative yields, followed by further reduction using LAH to give
alcohol 4 in 97% isolated yield. The yields for both steps were consistent
even when the reaction was carried out on 100 g scale. The crude product,
1
which was more than 98% pure (by H-NMR), was subjected to oxidation
without further purification. The potential difficulties associated with the
[1,2]
Swern oxidation
when used in large scale synthesis, namely the require-
ment of strictly anhydrous conditions and lower temperatures, led us to the
use of pyridinium chlorocromate as oxidant. This afforded the required
aldehyde in 79% isolated yield. However, the use of Dess-Martin
[5]
Periodinane at room temperature in wet dichloromethane led to 5 in
excellent yield (93% after column chromatography) in just 1 h. The reaction
was clean and was easily scaled up.
Dess-Martin Periodinane was prepared on a large scale by the
[5]
reported procedure and has a number of advantages such as good to
excellent yields obtained, non-requirement of dry conditions and low tem-
peratures. Moreover no toxic by products are formed when DMP is used as
[6]
an oxidant.
In summary, we have developed a convenient route for the large scale
synthesis of 3-(3,5-dimethoxyphenyl)-propanal that offers several advan-
tages over the earlier reported methods leading to higher overall yields
while requiring simple reaction conditions and shorter reaction times.
EXPERIMENTAL
Melting points were determined on a micro-melting point apparatus
1
and are uncorrected. H-NMR spectra were recorded on a Bruker AC-E200
instrument, and chemical shifts are in ꢀ (ppm) relative to internal TMS. All
anhydrous solvents were obtained commercially and were used without
further drying or purification.
Preparation of Ethyl 3,5-Dimethoxycinnamate (2)
To a stirred solution of (carbethoxymethylene) triphenylphosphorane
ꢀ
(
314 g, 903 mmol) in anhydrous THF (2.5 l) at 0 C under an argon
atmosphere was added a solution of 3,5-dimethoxybenzaldehyde (100 g,

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754
NIKAS, THAKUR, AND MAKRIYANNIS
602 mmol) in anhydrous THF (500 ml) over a period of 30 min. Following
the addition, the reaction was warmed to room temperature, stirred for an
additional 2 h and was then quenched by addition of saturated ammonium
chloride. The reaction mixture was diluted with diethyl ether, the organic
layer was separated, washed with brine, dried over MgSO , and evaporated
4
under reduced pressure to give an oil. The product was purified through a
short column of silica gel using 17% Et O: petroleum ether as eluent to give
2
compound 2 in quantitative yield (142 g) as a mixture of cis and trans isomer
in 3 : 97 ratio, respectively.
1
Cis-isomer: colorless viscous oil, H-NMR (200MHz, CDCl ): 1.25
3
(
(
(
t, J ¼ 7.0 Hz, 3H), 3.79 (s, 6H), 4.17 (q, J ¼ 7.0 Hz, 2H), 5.93
d, J ¼ 12.7 Hz, 1H), 6.45 (t, J ¼ 2.2 Hz, 1H), 6.78 (d, J ¼ 2.2 Hz, 2H), 6.84
d, J ¼ 12.7 Hz, 1H).
ꢀ
[3]
ꢀ
Trans-isomer: white crystalline solid, m.p. 45–46 C, (lit. 45–46 C)
1
H-NMR (200 MHz, CDCl ): 1.34 (t, J ¼ 7.0 Hz, 3H), 3.81 (s, 6H), 4.27
3
(
(
q, J ¼ 7.0 Hz, 2H), 6.40 (d, J ¼ 16.0 Hz, 1H), 6.49 (t, J ¼ 2.2 Hz, 1H), 6.67
d, J ¼ 2.2 Hz, 2H), 7.60 (d, J ¼ 16.0 Hz, 1H).
Preparation of Ethyl 3-(3,5-Dimethoxyphenyl)propionate (3)
To a solution of ethyl 3,5-dimethoxycinnamate (100 g, 424 mmol) in
ethyl acetate (2.1 l) was added 10% Pd/C (17.0 g) and the resulting suspen-
sion was stirred vigorously under a hydrogen atmosphere for 4 h at room
temperature. The catalyst was removed by filtration through celite and the
filtrate was evaporated under reduced pressure to afford pure ester 3 as oil in
ꢀ
[7]
ꢀ
a quantitative yield (100.5 g). B.p. 96–101 C (0.6mm) (lit. 125–130 C at
.0 mm).
3
1
H-NMR (200 MHz, CDCl ): 1.25 (t, J ¼ 7.0 Hz, 3H), 2.60 (t,
3
J ¼ 7.7 Hz, 2H), 2.90 (t, J ¼ 7.7 Hz, 2H), 3.78 (s, 6H), 4.12 (q, J ¼ 7.0 Hz,
2
H), 6.31 (t, J ¼ 2.1 Hz, 1H), 6.36 (d, J ¼ 2.1 Hz, 2H).
Preparation of 3-(3,5-Dimethoxyphenyl)-1-propanol (4)
To a stirred suspension of LAH (18.7 g, 491 mmol) in anhydrous THF
ꢀ
(
900 ml) at 0 C under argon atmosphere was added a solution of ethyl 3,5-
dimethoxyphenyl propionate (90 g, 378 mmol) in anhydrous THF (250 ml)
over a period of 10 min. The reaction mixture was stirred vigorously for
2
4
.5 h at the same temperature and then quenched by adding NaF (20.6g,
91 mmol) followed by dropwise addition of 10% aqueous NaOH and
water. The reaction mixture was then warmed to room temperature, diluted

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3
-(3,5-DIMETHOXYPHENYL)PROPANAL
1755
with ethyl acetate and stirred for an additional 30 min. The suspension was
filtered through celite and the organic layer was separated. The aqueous
phase was extracted twice with ethyl acetate and the combined organic
layer was washed with brine, dried over MgSO , and the solvent was eva-
4
porated under reduced pressure to give compound 4 as colorless oil in 97%
ꢀ
[3]
yield (71.8 g). B.p. 148–153 C at 0.6mm. (lit. 141 C at 0.4 mm).
ꢀ
1
H-NMR (200 MHz, CDCl ): 1.70 (s, OH), 1.88 (m, 2H), 2.65 (dd as t,
3
J ¼ 7.5 Hz, 2H), 3.67 (t, J ¼ 6.7 Hz, 2H), 3.78 (s, 6H), 6.30 (t, J ¼ 2.1 Hz,
1H), 6.37 (d, J ¼ 2.1 Hz, 2H).
Preparation of 3-(3,5-Dimethoxyphenyl)propanal (5)
Procedure 1: Using Dess-Martin Periodinane: To a stirred solution of
-(3,5-dimethoxyphenyl)-1-propanol (60 g, 306 mmol) in wet methylene
3
chloride (1.1 l) at 0 C was added Dess-Martin Periodinane (169 g,
ꢀ
398 mmol) and the resulting suspension was warmed to room temperature
and stirred for 1 h. The reaction was quenched by adding a mixture of
Na S O (10% in H O) and saturated NaHCO (1 : 1), diluted with methy-
2
2
3
2
3
lene chloride, and stirred vigorously for 30 min. The slurry was filtered
through celite, the organic phase separated and the aqueous phase extracted
with methylene chloride. Subsequently, the combined organic layer was
washed with saturated NaHCO , brine, and dried over anhydrous
3
MgSO . The solvent was evaporated under reduced pressure and the alde-
4
hyde was purified by flash column chromatography on silica gel using 45%
Et O: petroleum ether as eluent afforded 5 as a pale yellow viscous oil in
2
9
3% yield (55.1 g)
1
0
0
0
0
H-NMR (200 MHz, CDCl ): 2.76(m, AA BB , 2H), 2.90 (m, AA BB ,
3
2
H), 3.78 (s, 6H), 6.31 (t, J ¼ 2.1 Hz, 1H), 6.35 (d, J ¼ 2.1 Hz, 2H), 9.80
(
s, 1H).
Procedure 2: Using pyridinium chlorochromate: To a stirred suspen-
sion of pyridinium chlorochromate (13 g, 60.7 mmol) in anhydrous
methylene chloride (100 ml) under an argon atmospere was added 3-(3,5-
dimethoxyphenyl)propanal (7.0 g, 35.7 mmol) in anhydrous methylene
chloride (20 ml) with constant stirring at room temperature. After 2.5 h
anhydrous ether was added and the supernatant liquid was decanted from
black gum. The insoluble residue was washed with anhydrous ether. The
combined organic layer was passed through a short pad of silica gel and the
solvent was removed under vacuo to give crude 3-(3,5-dimethoxyphenyl)-
propanal. The crude aldehyde was purified by flash column chromatography
on silica gel using 45% Et O: petroleum ether as eluent to give compound 5
2
in 79% yield (5.47 g).

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1
756
NIKAS, THAKUR, AND MAKRIYANNIS
ACKNOWLEDGMENT
This work was supported by the National Institute of Drug Abuse
DA03801, DA07215, and DA09158) and we are thankful to Dr. Spiro
Pavlopoulos for useful suggestions.
(
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Received in the USA June 23, 2001