Reliable and versatile synthesis of 2-aryl-substituted cinnamic acid esters

Article abstract of DOI:10.1055/s-2006-942404

2-Aryl-substituted phosphono acetates can be readily synthesized by a four-step sequence from the respective arenes. Succeeding Horner-Wadsworth- Emmons olefinations provide stereoselectively the 2-aryl cinnamic acid esters even when sensitive moieties are involved. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942404

PAPER
2103
Reliable and Versatile Synthesis of 2-Aryl-Substituted Cinnamic Acid Esters
Reliable and
V
ersa
l
tile Sy
e
2
n
-Aryl-Substitute
d
C
I
innamic
a
A
cid
E
ste
n
r
s
ni, Siegfried R. Waldvogel*
Rheinische Friedrich-Wilhelms-Universität Bonn, Kekulé-Institut für Organische Chemie und Biochemie, Gerhard-Domagk-Straße 1,
53121 Bonn, Germany
Fax +49(228)739608; E-mail: waldvogel@uni-bonn.de
Received 9 March 2006
Dedicated to Prof. Dr. Dieter Hoppe on the occasion of his 65th birthday
1 for the corresponding phosphono acetates, the procedure
Abstract: 2-Aryl-substituted phosphono acetates can be readily
involves a Friedel–Crafts acylation11 of 1 to the phenyl
synthesized by a four-step sequence from the respective arenes.
glyoxalic acid esters, which are subsequently reduced
Succeeding Horner–Wadsworth–Emmons olefinations provide ste-
with sodium borohydride.12 The resulting mandelic acid
reoselectively the 2-aryl cinnamic acid esters even when sensitive
moieties are involved.
derivatives 3 are converted to the respective bromides,13
which are superb substrates for the Arbuzov reaction.14
Key words: olefination, phosphorylation, acylation, Arbuzov reac-
tion, Horner–Wadsworth–Emmons reaction
Although this sequence involves several steps, it can be
easily performed in large scale and allows a quick access
to the corresponding phosphono acetates (Scheme 1).
2-Aryl-substituted cinnamic acid derivatives are common
structural features for potent inhibitors acting as antimi-
totic agents1 or as selective endothelin A receptor antago-
nists.2–4 Furthermore, they serve as important
intermediates for the construction of phenanthrene-con-
taining alkaloidal natural products, like (–)-thylophorine.5
The traditional pathway for the synthesis of 2-aryl cin-
namic acid derivatives exploits the Perkin reaction, which
involves the direct condensation of aryl acetic acid with
the corresponding benzaldehyde derivative. However, the
Perkin condensation reaction proceeds under acidic con-
ditions at elevated temperatures.6,7 Furthermore, the alde-
hyde component should be not too electron-rich. If
phenolic hydroxy moieties are present, they are acetylated
during the transformation and lead to an increased reactiv-
ity. In addition, the acidic reaction conditions result usu-
ally in an olefinic mixture of both stereoisomers.
Consequently, the Perkin reaction has found limited appli-
cations for the construction of 2-aryl cinnamic acid deriv-
atives and is not particularly useful when acid-sensitive
substrates are employed.
CO2Et
PO(OEt)2
ArH
Ar
1
5
Ar
CO2Et
HWE
Ar1
7
Scheme 1
All aims to exploit a shorter reaction sequence starting
with phenylacetic derivatives failed since the functional-
ization in the a-position did not work or was accompanied
by several side-reactions.
Some of the products mentioned in Scheme 2 are rarely
described in literature with modest characterizations.
Therefore, a full set of modern spectroscopic data is giv-
en. The Friedel–Crafts acylation was performed in most
examples as a clean transformation. If the arene was too
electron-rich then some decomposition occurred (Table 1,
entry 3). Reaction of anisole or benzodioxane gave com-
plete conversion with an isomeric ratio of about 4:1 in fa-
vor of the desired product. Purification was done by
column chromatography (2e) or crystallization (2g). A to-
tal chemoselectivity in the reduction of the a-keto func-
tion was obtained when sodium borohydride was applied
at low temperature in ethanol. This spot-to-spot transfor-
mation resulted in crude ethyl mandelate derivatives of
good quality. If necessary, chromatographic purification
could be easily performed. Similarly, the installation of
the a-bromo substituent was achieved without any prob-
lems. The subsequent Arbuzov reaction also turned out to
be a very smooth conversion. Removal of excess of trieth-
We developed a novel and stereoselective pathway to (E)-
2-aryl cinnamic esters, exploiting the Horner–Wads-
worth–Emmons (HWE) olefination reaction.8 This partic-
ular transformation requires the corresponding aryl-
derived phosphono acetates, which are very sparingly de-
scribed in literature; few protocols for the 2-phenyl trieth-
yl phosphono acetate are reported. For phosphono
lactones a phosphate–phosphonate rearrangement was ap-
plied,9 whereas in some cases the corresponding iodo are-
nes can be converted by copper catalysis.10
Thus, a general and facile strategy for the preparation of a
variety of aryl-substituted phosphono acetates was estab-
lished. Starting with the corresponding benzene moieties
SYNTHESIS 2006, No. 13, pp 2103–2112
x
x.
x
x
.
2
0
0
6
Advanced online publication: 08.06.2006
DOI: 10.1055/s-2006-942404; Art ID: C00806SS
© Georg Thieme Verlag Stuttgart · New York

2104
A. Ianni, S. R. Waldvogel
PAPER
yl phosphite in vacuo offered reasonably pure substituted
phosphono mandelates. Therefore, crude phosphonates 5
can be directly employed in further synthesis. Analytical-
ly pure compounds were obtained by chromatographic
purification as almost colorless viscous compounds.
CO2Et
O
ClCOCO2Et
ArH
Ar
Ar
AlCl3, CH2Cl2, 0 °C
1
2
CO2Et
Employing classical conditions for the HWE olefination
with sodium hydride in toluene at various temperatures
gave modest results with different substrates. In general,
elevated reaction temperatures led to high yields but also
to significant loss in selectivity. The best E/Z ratios did
not exceed 4:1 and are in most cases lower. Application
of other bases consisting of alkoxides resulted in a com-
plete loss of selectivity. Switching to more polar solvents
like tetrahydrofuran or N,N-dimethylformamide gave al-
most no desired product. Significant amelioration was
achieved when the phosphonates 5 were treated with
DBU–LiCl in acetonitrile (Scheme 3). Although the
transformation requires about one week at ambient condi-
tions, it is superior in yield and product quality. The E-iso-
mer is formed highly stereoselectively with an E/Z ratio
of 7:1. In most cases only traces of the Z-isomer were de-
tected by 1H NMR of the crude olefin. Elevated reaction
temperature rendered tremendously lower yield as well as
less selectivity.
NaBH4
OH
2
EtOH, –30 °C
3
CO2Et
PBr3
Ar
Ar
Br
3
CH2Cl2, 0 °C
4
CO2Et
P(OEt)3
reflux
PO(OEt)2
4
5
Scheme 2
tions reveal that the 2-aryl substituent exhibits a
perpendicular orientation to the cinnamic acid moiety.
Higher temperatures will promote the formation of a sig-
nificant amount of the Z-isomer.15
The high E-selectivity at ambient conditions is consistent
with the theoretical studies on the preferred conforma-
tions of 2-aryl substituted cinnamic acids. The calcula-
Table 1 Conversion of 1 to Phosphonates 5
Entry
1
1
Ar
Yield (%)
Yield (%)
Yield (%)
Yield (%)
a
a
1a
-
-
70 (4a)
96 (5a)
2
3
1b
1c
98 (2b)
77 (2c)
77 (3b)
95 (3c)
89 (4b)
95 (4c)
80 (5b)
99 (5c)
MeO
MeO
MeO
MeO
OMe
4
1d
98 (2d)
76 (3d)
89 (4d)
91 (5d)
OMe
OMe
5
1e
79 (2e)
98 (3e)
92 (4e)
94 (5e)
MeO
6
7
1f
99 (2f)
81 (2g)
91 (3f)
98 (3g)
70 (4f)
98 (4g)
91 (5f)
97 (5g)
O
O
1g
O
O
a Commercially available.
Synthesis 2006, No. 13, 2103–2112 © Thieme Stuttgart · New York

PAPER
Reliable and Versatile Synthesis of 2-Aryl-Substituted Cinnamic Acid Esters
2105
CO2Et
sive stereoselectivity and excellent yields. Moreover,
employing these phosphonates 5 as reagents allows the in-
stallation of sensitive moieties and is therefore superior to
the Perkin condensation.
Ar1CHO
Ar
PO(OEt)2
+
5
6
All reagents were used in analytical grades. Solvents were purified
if necessary by standard methods. Column chromatography was
performed on silica gel (particle size 63–200 mm, Merck, Darms-
tadt, Germany) using mixtures of cyclohexane and ethyl acetate as
eluents. TLC was done on silica gel 60 F254 on glass (Merck, Darm-
stadt, Germany). 1H and 13C NMR spectra were recorded on a Bruk-
er DPX 300 or on a DPX 400 spectrometer. Chemical shifts (d) are
reported in ppm relative to tetramethylsilane as internal standard or
traces of chloroform or DMSO-d5 in the corresponding deuterated
solvents. 31P NMR spectra were recorded at 25 °C on a Bruker AC
200 spectrometer by external calibration relative to 85% H3PO4.
Mass spectra were obtained on a MAT8200 spectrometer (Finni-
gan-MAT, Bremen, Germany) employing EI technique. Mass spec-
tra (e.g. HRMS) were obtained on a MAT8200, MAT95XL
(Finnigan, Bremen, Germany), or MS50 (Kratos, Manchester, UK)
spectrometer employing EI technique and on a Quattro LC instru-
ment (Waters-Micromass).
Ar
CO2Et
DBU, LiCl
MeCN, r.t.
Ar1
7
Scheme 3
The HWE olefination using the phosphonates 5 gives ac-
cess to a reliable and modular approach to 2-aryl substitut-
ed cinnamic acid esters with a wide scope. Especially
electron-rich products are made in synthetically attractive
yields. All HWE olefinations were carried out until the
phosphono mandelate component 5 was consumed. Sur-
prisingly, very electron-rich aldehydes gave better results
than the more electrophilic congeners (Table 2, entries 2
vs. 3).
Friedel–Crafts Acylation Reaction (2); General Procedure
In a three-necked round-bottomed flask mounted with a cooler sys-
tem under inert conditions, AlCl3 (11.29 g, 84.9 mmol) was sus-
pended in CH2Cl2 (60 mL) at 0 °C. To this mixture ethyl oxalate
chloride (9.5 mL, 84.9 mmol) was added dropwise in about 10–15
min. After 10 min the stirred suspension became a pale yellow so-
lution. At 0 °C arene 1 (47.0 mmol) was added dropwise in about 10
min. Then the solution was stirred at r.t. for 1 h. To this reaction
mixture the threefold volume of H2O was carefully added. Extrac-
tion was performed with EtOAc (5 × 30 mL). The organic layers
were collected and washed with sat. NaCl solution (2 × 100 mL),
dried over Na2SO4 and concentrated in vacuo. The crude product
was purified by filtration employing a silica pad and a EtOAc–cy-
In most cases quantitative conversion was obtained. When
the sensitive 5-iodo veratryl aldehyde (6e) was reacted
some unidentified side-products were formed, which di-
minished the yield (Table 2, entry 5). Free phenolic
groups are deprotonated under these reaction conditions
and inhibit the olefination process. A partial deblocking of
the phenolic groups takes place under these prolonged re-
action conditions. The conversion of silylated vanillin 6g
provided the olefin only in poor yield. As by-products
10% of the unsilylated product was isolated and about
40% of the deprotected starting material. The established clohexane mixture (40:60) as eluent.
method is also applicable to heterocyclic aldehydes
Reduction of 2 to 3; General Procedure
In a round-bottomed flask under inert conditions, 2 (11.2 mmol)
(Table 1, entries 4, 9, 10, 11 and 14).
The reliability of the olefination reaction seems to be in-
dependent of the electronic nature of the carbonyl compo-
nent. Electron-rich aldehydes allow almost quantitative
conversion (Table 2, entries 4, 6, 10 and 12–14). Lower
yields are due to the limited stability of the corresponding
aldehyde under these conditions (Table 2, entry 11). De-
spite the cross-conjugation in the obtained cinnamic acid
derivatives, electron-poor aldehydes also led to superb
yields (Table 2, entry 9).
was suspended in EtOH (20 mL) at –30 °C. To this mixture NaBH4
(0.21 g, 5.6 mmol) was added in three small portions. After 15 min
the conversion was controlled by GC. When the reaction was com-
plete the reaction mixture was quenched with 10% HCl until evolu-
tion of gas stopped. For work-up the mixture was diluted with H2O
(ca. 50 mL). Extraction was performed with EtOAc (5 × 20 mL).
The organic layers were washed with sat. NaCl solution (2 × 30 mL)
and dried over MgSO4. Compounds 3 were obtained as clean color-
less oils and were used without further purification.
Bromination Reaction (4); General Procedure
Most olefinations were performed with phosphonate 5b
since veratryl systems are omnipresent in natural prod-
ucts.16 The double bond formation by HWE is also per-
formed in excellent yields when ortho-substituents on the
2-aryl moiety are present. Since perpendicular arrange-
ment of 2-aryl substituent and cinnamic ester is anticipat-
ed, no steric influence will result (Table 2, entries 12–14).
In a round-bottomed flask under inert conditions, 3 (10.3 mmol)
was dissolved in CH2Cl2 (20 mL) at 0 °C. To this solution and at this
temperature PBr3 (0.65 mL, 6.9 mmol) was added. The solution was
stirred for 1 h and then quenched with distilled H2O (20 mL). The
work-up was carried out by extracting the mixture with EtOAc (5 ×
30 mL). The organic layers were washed with sat. NaCl solution (2
× 30 mL), dried over MgSO4 and concentrated in high vacuum. The
a-brominated products 4 were isolated as colorless oils which were
pure and suitable for the next conversion. To maintain the quality of
4 for several months a storage at 4 °C is highly recommended.
In conclusion, triethyl 2-aryl phosphono acetates are eas-
ily accessible by a four-step sequence from the corre-
sponding arenes. With these phosphonates 5 a modular
approach to highly substituted cinnamic acid esters was
realized. The HWE olefination reaction provides the de-
sired (E)-cinnamic acid derivatives in most cases in exclu-
Arbuzov Reaction (5); General Procedure
In a round-bottomed flask under inert conditions, 4 (8.6 mmol) was
heated to reflux with triethylphosphite (1.65 mL, 9.5 mmol) for 2 h.
After the reaction was brought to ambient temperature H2O (20 mL)
Synthesis 2006, No. 13, 2103–2112 © Thieme Stuttgart · New York

PAPER
Reliable and Versatile Synthesis of 2-Aryl-Substituted Cinnamic Acid Esters
2106
Table 2 Horner–Wadsworth–Emmons Olefination of Phosphonates 5
Entry
1
Ar (Phosphonate)
Ar1 (Aldehyde)
Yield (%)
MeO
MeO
5a
6a
46 (7a)
2
3
5b
5b
6b
6c
94 (7b)
64 (7c)
MeO
MeO
MeO
MeO
MeO
MeO
OMe
4
5
5b
5b
6d
6e
99 (7d)
50 (7e)
O
O
MeO
MeO
MeO
MeO
MeO
MeO
MeO
I
6
7
5b
5b
6f
96 (7f)
17 (7g)
OMe
MeO
6g
MeO
MeO
MeO
TIPSO
OMe
8
9
5b
5b
5b
5b
6h
6i
47 (7h)
96 (7i)
88 (7j)
58 (7k)
Br
MeO
MeO
N
MeO
MeO
10
11
6l
S
MeO
MeO
6m
N
MeO
12
13
14
5c
5c
5c
6b
6c
6d
94 (7l)
OMe
OMe
OMe
MeO
MeO
MeO
MeO
MeO
MeO
MeO
96 (7m)
90 (7n)
OMe
O
O
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2107
A. Ianni, S. R. Waldvogel
PAPER
was added. The work-up was performed by extracting the mixture
with EtOAc (5 × 40 mL). The organic layers were washed with sat.
NaCl solution (2 × 20 mL), dried over Na2SO4 and concentrated in
vacuo. The crude product was purified by a short-path distillation
removing the excess of reagent. Compound 5 was obtained as pale
yellow oils. Short column chromatography using a EtOAc–cyclo-
hexane mixture (40:60) as eluent, resulted in analytically pure and
colorless oils.
HRMS: m/z [M]+ calcd for C12H16O5: 240.0998; found: 240.1003.
Bromo 3,4-Dimethoxyphenylacetic Acid Ethyl Ester (4b)20
Yield: 1.81 g (6.0 mmol; 89%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H, CH3), 3.87
(s, 3 H, OCH3), 3.90 (s, 3 H, CH3), 4.24 (dq, J = 7.1, 10.8 Hz, 2 H,
CH2), 5.32 (s, 1 H, CHBr), 6.80 (d, J = 8.3 Hz, 1 H, arom.), 7.06 (dd,
J = 2.1, 8.3 Hz, 1 H, arom.), 7.15 (d, J = 2.1 Hz, 1 H, arom.).
13C NMR (101 MHz, CDCl3): d = 14.0, 47.2, 56.0, 56.0, 62.4, 110.9,
HWE Reaction (6); General Procedure
111.8, 121.4, 128.1, 149.3, 150.0, 168.4.
In a round-bottomed flask under inert conditions, LiCl (3.56 g, 84.1
mmol) was suspended in MeCN (100 mL) and was stirred together
with 5 (28.0 mmol) and DBU (12.5 mL, 83.4 mmol) for 10 min at
r.t. Then 6 (53.6 mmol) was added and the mixture was stirred for
about one week. Then the reaction was stirred for 10 min with an aq
solution of citric acid (50 mL, 10%), followed by extraction with
EtOAc (5 × 20 mL) The organic layer was washed with sat. NaCl
solution (3 × 15 mL), dried over MgSO4 and concentrated under re-
duced pressure. By a short-path distillation the crude product was
liberated from excess of starting material, which was recovered.
Subsequently, column chromatography using a mixture of EtOAc–
cyclohexane (20:80) yielded olefin 7.
MS (EI, 70 eV): m/z (%) = 302, 344 (8) [M]+·, 231, 229 (8) [M –
C3H5O2]+, 224 (28) [M – Br + H]+·, 223 (100) [M – Br]+·, 151 (48)
[M – Br – C3H5O2]+.
HRMS: m/z [M]+ calcd for C12H15BrO4: 302.0154; found:
302.0158.
(Diethoxyphosphoryl)-3,4-dimethoxyphenylacetic Acid
Ethyl Ester (5b)
Yield: 4.37 g (12.1 mmol; 99%); slightly yellow crystals.
1H NMR (400 MHz, CDCl3): d = 1.20 (t, J = 7.1 Hz, 3 H, CH3), 1.26
(t, J = 7.1 Hz, 6 H, 2 × CH3), 3.85 (s, 3 H, OCH3), 3.88 (s, 3 H,
OCH3), 3.94–4.26 (m, 7 H, CH, 3 × CH2), 6.81 (d, J = 8.3 Hz, 1 H,
arom.), 6.98 (dt, J = 2.4, 8.3 Hz, 1 H, arom.), 7.15 (t, J = 2.1 Hz, 1
H, arom.).
13C NMR (101 MHz, CDCl3): d = 13.8, 16.0, 16.1, 49.9, 55.3, 55.4,
61.1, 62.3, 62.5, 111.3, 113.47, 122.0, 123.4, 148.1, 148.4, 167.4.
31P NMR (162 MHz, DMSO-d6): d = 20.1.
Bromophenylacetic Acid Ethyl Ester (4a)17
Yield: 19.62 g (80.7 mmol; 71%); colorless liquid.
(Diethoxyphosphoryl)phenylacetic Acid Ethyl Ester (5a)10
Yield: 6.81 g (22.7 mmol; 96%); colorless liquid.
1H NMR (300 MHz, CDCl3): d = 1.14 (t, J = 7.1 Hz, 3 H, CH3), 1.17
(t, J = 7.1 Hz, 3 H, CH3), 1.18 (t, 3 H, CH3), 4.05 (m, 7 H, CH, 3 ×
CH2), 7.23 (m, 3 H, arom.), 7.44 (m, 2 H, arom.).
13C NMR (75 MHz, CDCl3): d = 13.8, 15.9, 16.0, 52.0, 61.5, 62.8,
63.1, 127.7, 128.2, 129.4, 130.7, 167.3.
MS (EI, 70 eV): m/z (%) = 360 (100) [M]+·, 287 (20) [M –
C3H5O2]+, 223 (40) [M – C4H10O3P]+, 151 (40) [M – C3H5BrO2]+·.
HRMS: m/z [M]+ calcd for C16H25O7P: 360.1338; found: 360.1339.
31P NMR (162 MHz, DMSO-d6): d = 20.3.
MS (EI, 70 eV): m/z (%) = 300 (24) [M]+·, 255 (8) [M – C2H3O]+,
227 (12) [M – C3H5O2]+, 164 (20) [M – C3H4O2]+, 118 (100)
[C7H6O]+·, 91 (40) [C7H7]+.
2,3,4-Trimethoxyphenylglyoxylic Acid Ethyl Ester (2c)
Yield: 10.49 g (39.2 mmol; 63%); colorless oil.
1H NMR (300 MHz, CDCl3): d = 1.29 (t, J = 7.2 Hz, 3 H, CH3), 3.75
(s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 4.28 (q,
J = 7.2 Hz, 2 H, OCH2), 6.69 (d, J = 8.9 Hz, 1 H, arom.), 7.57 (d,
J = 8.9 Hz, 1 H, arom.).
HRMS: m/z [M]+ calcd for C14H21O5P: 300.2873; found: 300.1125.
3,4-Dimethoxyphenylglyoxylic Acid Ethyl Ester (2b)18
Yield: 10.98 g (46.1 mmol; 98%); colorless crystalline powder.
1H NMR (400 MHz, CDCl3): d = 1.40 (t, J = 7.1 Hz, 3 H, CH3), 3.92
(s, 3 H, OCH3), 3.95 (s, 3 H, OCH3), 4.42 (q, J = 7.1 Hz, 2 H, CH2),
6.91 (d, J = 8.5 Hz, 1 H, arom.), 7.55 (d, J = 2.0 Hz, 1 H, arom.),
7.62 (dd, J = 2.0, 8.4 Hz, 1 H, arom.).
13C NMR (75 MHz, CDCl3): d = 14.1, 56.3, 60.7, 61.6, 61.7, 107.8,
120.1, 126.1, 141.3, 155.3, 160.0, 15.7, 185.5.
MS (EI, 70 eV): m/z (%) = 268 (8) [M]+·, 195 (100) [M – C3H5O2]+·,
168 (8) [M – C4H5O3]+·, 152 (8) [M – C5H5O4]+.
HRMS: m/z [M]+ calcd for C13H16O6: 268.095; found: 268.095.
13C NMR (102 MHz, CDCl3): d = 14.1, 56.0, 56.2, 62.1, 110.3,
Ethyl 2,3,4-Trimethoxymandelate (3c)
Yield: 16.02 g (59.3 mmol; 95%); slightly yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.21 (t, J = 7.1 Hz, 3 H, CH3), 3.84
(s, 6 H, 2 × OCH3), 3.90 (s, 3 H, OCH3), 4.22 (dq, J = 7.1, 13.2 Hz,
2 H, OCH2), 5.19 (s, 1 H, CHOH), 6.64 (d, J = 8.6 Hz, 1 H, arom.),
6.95 (d, J = 8.6 Hz, 1 H, arom.).
110.8, 125.6, 126.2, 149.4, 155.0, 164.1, 184.9.
MS (EI, 70 eV): m/z (%) = 238 (12) [M]+·, 165 (100) [M –
C3H5O2]+, 166 (10) [M – C3H4O2]+, 151 (4) [M – C4H8O2]+·, 137 (4)
[M – C4H5O3]+·, 122 (4) [M – C5H9O3]+, 74 (8) [C3H6O2]+.
HRMS: m/z [M]+ calcd for C12H14O5: 238.0841; found: 238.0843.
13C NMR (101 MHz, CDCl3): d = 14.1, 56.0, 60.7, 61.2, 61.9, 69.8,
Ethyl 3,4-Dimethoxymandelate (3b)19
Yield: 1.60 g (6.7 mmol; 79%); slightly yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.23 (t, J = 7.1 Hz, 3 H, CH3), 3.36
(s, 1 H, OH), 3.87 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 4.22 (dq,
J = 7.1, 13.2 Hz, 2 H, OCH2), 5.09 (s, 1 H, CHOH), 6.84 (d, J = 8.0
Hz, 1 H, arom.), 6.93 (dd, J = 1.9 Hz, 1 H, arom.), 6.96 (dd, J = 1.6,
8.0 Hz, 1 H, arom.).
107.2, 123.6, 125.0, 142.2, 151.8, 154.3, 174.0.
MS (EI, 70 eV): m/z (%) = 270 (8) [M]+·, 197 (100) [M – C3H5O2]+·,
182 (14) [M – C4H8O2]+, 168 (12) [C9H12O3]+.
HRMS: m/z [M]+ calcd for C13H18O6: 270.1103; found: 270.1101.
Bromo 2,3,4-Trimethoxyphenylacetic Acid Ethyl Ester (4c)
Yield: 17.38 g (59.2 mmol; 95%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 1.28 (t, J = 7.1 Hz, 3 H, CH3), 3.86
(s, 6 H, 2 × OCH3), 3.97 (s, 3 H, OCH3), 4.24 (dq, J = 7.1, 10.6 Hz,
13C NMR (101 MHz, CDCl3): d = 14.1, 55.9, 56.0, 62.2, 72.7, 109.6,
111.1, 119.2, 131.0, 149.2, 149.2, 173.8.
MS (EI, 70 eV): m/z (%) = 240 (24) [M]+·, 168 (12) [M – C3H4O2]+,
167 (100) [M – C3H5O2]+, 151 (8) [M – C3H5O3]+·.
Synthesis 2006, No. 13, 2103–2112 © Thieme Stuttgart · New York

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Reliable and Versatile Synthesis of 2-Aryl-Substituted Cinnamic Acid Esters
2108
2 H, OCH2), 5.80 (s, 1 H, CHBr), 6.69 (d, J = 8.8 Hz, 1 H, arom.),
7.34 (d, J = 8.8 Hz, 1 H, arom.).
13C NMR (75 MHz, CDCl3): d = 14.0, 41.8, 56.0, 60.8, 61.2, 62.4,
107.7, 122.6, 124.5, 141.9, 151.3, 154.7, 168.4.
1H NMR (400 MHz, DMSO-d6): d = 1.07 (t, J = 7.0 Hz, 3 H, CH3),
1.18 (t, J = 7.3 Hz, 3 H, CH3), 1.21 (d, J = 7.3 Hz, 3 H, CH3), 3.70
(s, 3 H, OCH3), 3.74 (s, 3 H, OCH3), 3.90 (dq, J = 7.2, 14.4 Hz, 2 H,
OCH2), 4.02 (q, J = 7.1 Hz, 2 H, OCH2), 4.12 (dq, J = 3.3, 7.1 Hz,
2 H, OCH2), 4.75 (d, J = 24.1 Hz, 1 H, CH), 6.88 (ddd, J = 1.8, 3.0,
9.0 Hz, 1 H, arom.), 6.96 (d, J = 9.0 Hz, 1 H, arom.), 7.22 (t, J = 2.7
Hz, 1 H, arom.).
MS (EI, 70 eV): m/z (%) = 332, 334 (4) [M]+·, 254 (40) [M –
C3H4O2]+·, 253 (100) [M – C3H5O2]+, 181 (40) [M – C3H4BrO2]+.
HRMS: m/z [M]+ calcd for C13H17BrO6: 332.0259; found:
332.0242.
13C NMR (101 MHz, DMSO-d6): d = 13.8, 15.9, 16.1, 42.5, 55.3,
56.3, 61.3, 62.4, 62.6, 112.0, 113.3, 116.6, 120.0, 150.5, 152.6,
167.1.
31P NMR (162 MHz, DMSO-d6): d = 20.0.
MS (EI, 70 eV): m/z (%) = 360 (72) [M]+·, 314 (64) [M – C3H5O2]+·,
224 (100) [M – C4H10O4]+·, 151 (84) [M – C3H5O2]+, 137 (24) [M –
C8H16O5P]+.
(Diethoxyphosphoryl)-2,3,4-trimethoxyphenylacetic Acid
Ethyl Ester (5c)
Yield: 4.88 g (12.5 mmol; 99%); colorless oil.
1H NMR (300 MHz, DMSO-d6): d = 1.08 (t, J = 7.0 Hz, 3 H, CH3),
1.21 (t, J = 7.0 Hz, 3 H, CH3), 1.18 (t, J = 7.1 Hz, 3 H, CH3), 3.74
(s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.89 (dq,
J = 7.1, 14.1 Hz, 2 H, OCH2), 4.03 (dq, J = 7.5, 14.8 Hz, 2 H,
OCH2), 4.12 (dq, J = 6.9, 14.0 Hz, 2 H, OCH2), 4.63 (d, J = 24.0 Hz,
1 H, CH), 6.85 (d, J = 8.9 Hz, 1 H, arom.) 7.35 (dd, J = 2.4, 8.9 Hz,
1 H, arom.).
13C NMR (75 MHz, DMSO-d6): d = 13.8, 15.9, 16.1, 42.7, 55.7,
60.2, 61.0, 61.2, 62.4, 62.5, 107.7, 116.6, 124.7, 141.3, 151.0,
153.1, 167.3.
HRMS: m/z [M]+ calcd for C16H25O7P: 360.1338; found: 360.1334.
4-Methoxyphenylglyoxylic Acid Ethyl Ester (2e)23
Yield: 8.07 g (33.9 mmol; 93%); slightly yellow oil.
Ethyl 4-Methoxymandelate (3e)24
Yield: 0.85 g (4.0 mmol; 98%); colorless oil.
1H NMR (400 MHz, DMSO-d6): d = 1.12 (t, J = 7.1 Hz, 3 H, CH3),
3.74 (s, 3 H, OCH3), 4.06 (q, J = 7.0 Hz, 2 H, CH2), 5.05 (s, 1 H,
CHOH), 6.90 (d, J = 8.7 Hz, 2 H, arom.), 7.32 (d, J = 8.7 Hz, 2 H,
arom.).
31P NMR (162 MHz, DMSO-d6): d = 20.2.
MS (EI, 70 eV): m/z (%) = 390 (12) [M]+·, 344 (20) [M – C2H4O]+,
254 (8) [M – C2H9O5P]+, 253 (24) [M – C2H10O5P]+, 197 (20) [M –
C3H17O6P]+, 155 (100) [M – C9H16O5P]+, 127 (44) [M –
C10H16O6P]+.
13C NMR (75 MHz, DMSO-d6): d = 13.9, 55.0, 60.2, 71.9, 113.5,
127.8, 131.7, 158.8, 172.7.
MS (EI, 70 eV): m/z (%) = 210 (8) [M]+·, 137 (100) [M – C3H5O2]+,
HRMS: m/z [M]+ calcd for C17H27O8P: 390.1444; found: 390.1443.
109 (12) [M – C4H5O3]+, 94 (8) [M – C5H8O3]+·, 77 (8) [C6H5]+.
2,5-Dimethoxyphenylglyoxylic Acid Ethyl Ester (2d)21
HRMS: m/z [M]+ calcd for C11H14O4: 210.0892; found: 210.0892.
Yield: 8.55 g (35.9 mmol; 98%); yellow crystals.
Bromo 4-Methoxyphenylacetic Acid Ethyl Ester (4e)25
Yield: 0.90 g (3.3 mmol; 92%); light yellow oil.
1H NMR (300 MHz, DMSO-d6): d = 1.30 (t, J = 7.1 Hz, 3 H, CH3),
3.77 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 4.33 (q, J = 7.1 Hz, 2 H,
OCH2), 7.21 (d, J = 9.1 Hz, 1 H, arom.), 7.24 (d, J = 3.2 Hz, 1 H,
arom.), 7.32 (dd, J = 3.2, 9.0 Hz, 1 H, arom.).
13C NMR (75 MHz, DMSO-d6): d = 14.3, 56.1, 57.2, 62.1, 112.5,
115.4, 122.6, 124.6, 154.0, 155.2, 165.2, 186.5.
MS (EI, 70 eV): m/z (%) = 238 (16) [M]+·, 165 (100) [M –
C3H5O2]+·, 150 (4) [M – C4H8O2]+, 122 (4) [M – C4H5O3]+, 107 (4)
[M – C5H8O3]+·.
(Diethoxyphosphoryl)-4-methoxyphenylacetic Acid Ethyl Ester
(5e)
Yield: 0.58 g (1.8 mmol; 94%); colorless oil.
1H NMR (400 MHz, DMSO-d6): d = 1.07 (t, J = 7.1 Hz, 3 H, CH3),
1.19 (t, J = 7.1 Hz, 3 H, CH3), 1.20 (t, J = 7.0 Hz, 3 H, CH3), 3.74
(s, 3 H, OCH3), 3.89 (dq, J = 7.1, 13.0 Hz, 2 H, OCH2), 4.02 (dq,
J = 7.0, 14.1 Hz, 2 H, OCH2), 4.12 (dq, J = 7.1, 10.5 Hz, 2 H,
OCH2), 4.51 (d, J = 23.8 Hz, 1 H, CHOH), 6.91 (d, J = 8.7 Hz, 2 H,
arom.), 7.43 (d, J = 8.8 Hz, 2 H, arom.).
HRMS: m/z [M]+ calcd for C12H14O5: 238.2366; found: 238.0845.
Ethyl 2,5-Dimethoxymandelate (3d)22
Yield: 4.88 g (20.3 mmol; 77%); yellow oil.
13C NMR (101 MHz, DMSO-d6): d = 13.8, 15.9, 16.1, 49.5, 54.9,
61.6, 62.2, 62.4, 113.5, 123.1, 130.8, 158.7, 167.5.
31P NMR (162 MHz, DMSO-d6): d = 20.4.
MS (EI, 70 eV): m/z (%) = 331 (8) [MH]+·, 330 (32) [M]+, 257 (20)
[M – C3H5O2]+·, 193 (52) [M – C4H10O3P]+, 151 (100) [M –
C7H16O3P]+, 148 (36) [M – C6H15O4P]+, 121 (72) [M – C8H14O5P]+·.
Bromo 2,5-Dimethoxyphenylacetic Acid Ethyl Ester (4d)
Yield: 4.58 g (15.1 mmol; 89%); yellow oil.
1H NMR (400 MHz, DMSO-d6): d = 1.12 (t, J = 7.1 Hz, 3 H, CH3),
3.69 (s, 3 H, OCH3), 3.70 (s, 3 H, OCH3), 4.06 (dq, J = 3.3, 7.1 Hz,
2 H, OCH2), 5.94 (s, 1 H, CHBr), 6.93 (dd, J = 3.0, 8.6 Hz, 1 H),
6.97 (d, J = 8.9 Hz, 1 H, arom.), 7.03 (d, J = 3.0 Hz, 1 H, arom.).
HRMS: m/z [M]+· calcd for C15H23O6P: 330.1232; found: 330.1232.
Benzo[1,3]dioxol-5-ylglyoxylic Acid Ethyl Ester (2f)26
Yield: 8.103 g (36.5 mmol; 99%); dark yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.31 (t, J = 7.1 Hz, 3 H, CH3), 4.39
(q, J = 7.1 Hz, 2 H, CH2), 6.20 (s, 2 H, CH2), 7.10 (d, J = 8.2 Hz, 1
H, arom.), 7.40 (d, J = 1.7 Hz, 1 H, arom.), 7.55 (dd, J = 1.8, 8.2
Hz, 1 H, arom.).
13C NMR (101 MHz, DMSO-d6): d = 13.9, 43.5, 55.2, 56.0, 60.1,
112.2, 113.7, 115.0, 115.0, 150.3, 153.0, 172.3.
MS (EI, 70 eV): m/z (%) = 302, 304 (28) [M]+·, 224 (44) [M – Br +
H]+, 223 (100) [M – Br]+·, 151 (40) [M – C3H5BrO2]+·.
HRMS: m/z [M]+ calcd for C12H15BrO4: 302.0154; found:
302.0153.
13C NMR (101 MHz, CDCl3): d = 14.3, 62.7, 103.2, 108.0, 109.1,
126.6, 128.4, 148.9, 154.1, 164.5, 185.4.
(Diethoxyphosphoryl)-2,5-dimethoxyphenylacetic Acid
Ethyl Ester (5d)
Yield: 3.59 g (10.0 mmol; 91%); colorless oil.
Synthesis 2006, No. 13, 2103–2112 © Thieme Stuttgart · New York

2109
A. Ianni, S. R. Waldvogel
PAPER
MS (EI, 70 eV): m/z (%) = 222 (12) [M]+·, 149 (100) [M –
C3H5O2]+, 121 (12) [M – C4H5O3]+, 110 (8) [M – C5H4O3]+, 91 (4)
[C7H7]+.
MS (EI, 70 eV): m/z (%) = 238 (24) [M]+·, 165 (100) [M –
C3H5O2]+, 136 (4) [M – C4H6O3]+·.
HRMS: m/z [M]+ calcd for C12H14O5: 238.0841; found: 238.0844.
HRMS: m/z [M]+ calcd for C11H10O5: 222.0528; found: 222.0531.
Bromo-2,3-dihydrobenzo[1,4]dioxin-6-ylacetic Acid
Ethyl Ester (4g)
Yield: 3.03 g (10.1 mmol; 97%); slightly yellow oil.
Ethyl Benzo[1,3]dioxol-5-ylhydroxyacetic Acid Ethyl Ester
(3f)27
Yield: 3.72 g (16.6 mmol; 92%); slightly yellow oil.
1H NMR (300 MHz, DMSO-d6): d = 1.11 (t, J = 7.1 Hz, 3 H, CH3),
4.04 (dq, J = 7.1 Hz, 2 H, CH2), 4.91 (s, 1 H, CHBr), 4.97 (s, 4 H,
2 × CH2), 6.80 (d, J = 1.1 Hz, 1 H, arom.), 6.82 (s, 1 H, arom.), 6.86
(d, J = 1.3 Hz, 1 H, arom.).
13C NMR (75 MHz, DMSO-d6): d = 14.3, 47.3, 60.1, 64.5, 72.3,
115.7, 117.2, 119.9, 124.7, 133.1, 143.4, 173.0.
1H NMR (400 MHz, DMSO-d6): d = 1.13 (t, J = 7.1 Hz, 3 H, CH3),
4.06 (dq, J = 7.2, 15.4 Hz, 2 H, OCH2), 5.02 (d, J = 5.0 Hz, 1 H,
CHOH), 5.97 (d, J = 5.4 Hz, 1 H, arom.), 6.00 (s, 2 H, CH2), 6.87
(s, 1 H, arom.), 6.93 (s, 1 H, arom.).
13C NMR (101 MHz, DMSO-d6): d = 13.9, 60.3, 72.1, 100.9, 106.9,
107.9, 120.1, 133.6, 146.8, 147.1, 172.5.
MS (EI, 70 eV): m/z (%) = 301 (24) [M]+·, 221 (100) [M – Br]+, 176
MS (EI, 70 eV): m/z (%) = 224 (28) [M]+·, 151 (100) [M –
(12) [M – C2H5BrO]+·, 149 (68) [(CH2O)2C6H3CH]+.
C3H5O2]+, 110 (52) [M – C4H8O3]+·, 65 (40) [M – C10H10O2]+.
HRMS: m/z [M]+ calcd for C12H13BrO4: 299.9997; found:
299.9995.
HRMS: m/z [M]+ calcd for C11H12O5: 224.0685; found: 224.0685.
Benzo[1,3]dioxol-5-ylbromoacetic Acid Ethyl Ester (4f)28
Yield: 3.18 g (11.1 mmol; 70%); slightly yellow oil.
Diethoxyphosphoryl-2,3-dihydrobenzo[1,4]dioxin-6-ylacetic
Acid Ethyl Ester (5g)
Yield: 2.99 g (8.4 mmol; 97%); colorless oil.
1H NMR (300 MHz, DMSO-d6): d = 1.12 (t, J = 7.1 Hz, 3 H, CH3),
4.01 (dq, J = 7.2 Hz, 2 H, OCH2), 5.84 (s, 1 H, CHBr), 6.04 (s, 2 H,
CH2), 7.04 (s, 1 H, arom.), 7.06 (s, 1 H, arom.), 7.09 (s, 1 H, arom.).
13C NMR (75 MHz, DMSO-d6): d = 14.0, 47.1, 62.1, 100.9, 106.9,
107.9, 120.2, 133.6, 146.8, 147.1, 172.5.
MS (EI, 70 eV): m/z (%) = 286, 288 (8) [M]+·, 212 (12) [M –
C3H5O2]+, 207 (100) [M – Br]+·, 162 (20) [M – C2H5BrO]+, 135 (68)
[M – C3H5BrO2)]+·.
HRMS: m/z [M]+ calcd for C11H11BrO4: 285.9841; found:
285.9840.
1H NMR (300 MHz, DMSO-d6): d = 1.10 (t, J = 7.0 Hz, 3 H, CH3),
1.19 (t, J = 7.1 Hz, 3 H, CH3), 1.20 (t, J = 7.0 Hz, 3 H, CH3), 3.91
(dq, J = 7.1, 14.3 Hz, 2 H, CH2), 4.02 (dq, J = 7.1, 15.3 Hz, 2 H,
CH2), 4.11 (m, 2 H, CH2), 4.22 (s, 4 H, 2 × CH2), 4.46 (d, J = 23.7
Hz, 1 H, CHPO), 6.80 (d, J = 8.4 Hz, 1 H, arom.), 6.93 (dt, J = 2.1,
8.4 Hz, 1 H, arom.), 7.03 (t, J = 2.2 Hz, 1 H, arom.).
13C NMR (75 MHz, DMSO-d6): d = 13.8, 16.0, 16.1, 49.5, 61.1,
62.3, 62.5, 64.0, 64.0, 116.5, 118.3, 122.6, 123.9, 142.8, 142.9,
167.4.
31P NMR (162 MHz, DMSO-d6): d = 22.0.
Benzo[1,3]dioxol-5-yldiethoxyphosphorylacetic Acid
Ethyl Ester (5f)
MS (EI, 70 eV): m/z (%) = 358 (100) [M]+, 285 (20) [M –
C3H5O2]+·, 221 (24) [M – C4H10O3P]+·, 149 (20) [C9H9O2]+.
Yield: 3.257 g (9.5 mmol; 91%); colorless oil.
HRMS: m/z [M]+ calcd for C16H23O7P: 358.1181; found: 358.1185.
1H NMR (400 MHz, DMSO-d6): d = 1.09 (t, J = 7.0 Hz, 3 H), 1.19
(t, J = 6.9 Hz, 3 H), 1.20 (d, J = 7.0 Hz, 3 H), 3.92 (m, 2 H), 4.03
(dq, J = 7.2, 8.1 Hz, 2 H), 4.12 (dq, J = 7.1, 10.7 Hz, 2 H), 4.53 (d,
J = 23.9 Hz, 1 H), 6.01 (s, 2 H), 6.87 (d, J = 8.0 Hz, 1 H, arom.),
6.69 (t, J = 8.0 Hz, 1 H, arom.), 7.09 (s, 1 H, arom.).
13C NMR (101 MHz, DMSO-d6): d = 13.8, 16.0, 16.1, 49.8, 61.2,
62.4, 62.6, 101.0, 107.9, 109.9, 123.3, 124.7, 146.7, 146.9, 167.4.
3-(3,4-Dimethoxyphenyl)-2-phenylacrylic Acid Ethyl Ester
(7a)30
Yield: 1.20 g (3.9 mmol; 46%); slightly yellow crystals.
1H NMR (300 MHz, DMSO-d6): d = 1.20 (t, J = 7.1 Hz, 3 H, CH3),
3.30 (s, 3 H, OCH3), 3.71 (s, 3 H, OCH3), 4.17 (q, J = 7.1 Hz, 2 H,
CH2), 6.46 (s, 1 H, CH), 6.82 (s, 2 H, arom.), 7.20 (s, 1 H, arom.),
7.22 (d, J = 1.6 Hz, 1 H, arom.), 7.42 (m, 3 H, arom.), 7.74 (s, 1 H,
CH).
13C NMR (75 MHz, DMSO-d6): d = 14.1, 55.4, 55.3, 60.4, 111.1,
112.5, 124.9, 126.5, 127.5, 128.6, 129.6, 129.8, 136.3, 139.5, 139.5,
147.8, 147.8, 149.8, 166.8.
31P NMR (162 MHz, DMSO-d6): d = 21.9.
MS (EI, 70 eV): m/z (%) = 344 (8) [M]+·, 272 (8) [M – C3H5O2]+·,
208 (28) [M – C4H9O3P]+, 135 (100) [M – C7H14O5P]+.
HRMS: m/z [M]+ calcd for C15H21O7P: 344.1025; found: 344.1028.
MS (EI, 70 eV): m/z (%) = 312 (100) [M]+·, 267 (4) [M – C2H5O]+,
2,3-Dihydrobenzo[1,4]dioxin-6-ylglyoxylic Acid Ethyl Ester
(2g)29
Yield: 4.60 g (19.5 mmol; 54%); colorless crystal powder.
239 (12) [M – C3H5O2]+.
HRMS: m/z [M]+ calcd for C19H20O4: 312.1362; found: 312.1366.
2,3-Dihydrobenzo[1,4]dioxin-6-ylhydroxyacetic Acid
Ethyl Ester (3g)
Yield: 2.60 g (10.9 mmol; 98%); colorless oil.
3-(4-Methoxyphenyl)-2-(3,4-dimethoxyphenyl)acrylic Acid
Ethyl Ester (7b)
Yield: 9.01 g (26.3 mmol; 94%); slightly yellow oil.
1H NMR (400 MHz, DMSO-d6): d = 1.13 (t, J = 7.1 Hz, 3 H, CH3),
4.06 (dq, J = 7.1, 17.1 Hz, 2 H, CH2), 4.21 (s, 1 H, CHOH), 4.98 (s,
4 H, 2 × CH2), 5.91 (s, 1 H, OH), 6.81 (d, J = 8.2 Hz, 1 H, arom.),
6.85 (dd, J = 1.7, 8.4 Hz, 1 H, arom.).
13C NMR (101 MHz, DMSO-d6): d = 14.4, 60.8, 64.5, 64.5, 72.3,
115.8, 117.2, 120.0, 133.2, 143.5, 143.5, 173.1.
1H NMR (400 MHz, DMSO-d6): d = 1.21 (t, J = 7.1 Hz, 3 H, CH3),
3.66 (s, 3 H, OCH3), 3.70 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 4.17
(q, J = 7.1 Hz, 2 H, CH2), 6.69 (d, J = 8.2 Hz, 1 H, arom.), 6.78 (m,
3 H, arom.), 6.95 (d, J = 8.2 Hz, 1 H, arom.), 7.06 (d, J = 8.1 Hz, 2
H, arom.), 7.69 (s, 1 H, CH).
13C NMR (102 MHz, DMSO-d6): d = 14.1, 54.1, 55.3, 55.4, 60.4,
111.8, 113.1, 113.7, 121.7, 126.7, 128.2, 129.7, 132.0, 138.9, 148.3,
148.8, 159.9, 167.1.
Synthesis 2006, No. 13, 2103–2112 © Thieme Stuttgart · New York

PAPER
Reliable and Versatile Synthesis of 2-Aryl-Substituted Cinnamic Acid Esters
2110
MS (EI, 70 eV): m/z (%) = 342 (100) [M]+·, 297 (4) [M – C2H5O]+,
269 (8) [M – C3H5O2]+, 162 (60) [M – C10H10O3]+·, 137 (12) [M –
C12H12O3]+.
13C NMR (101 MHz, CDCl3): d = 14.3, 55.0, 55.9, 55.9, 61.1, 101.9,
108.3, 111.3, 113.1, 122.4, 128.4, 132.9, 136.5, 139.7, 148.7, 149.0,
160.2, 167.8.
HRMS: m/z [M]+ calcd for C20H22O5: 342.1467; found: 342.1466.
MS (EI, 70 eV): m/z (%) = 372 (88) [M]+·, 267 (4) [M – C2H5O]+,
239 (12) [M – C3H5O2]+.
3-(3-Methoxyphenyl)-2-(3,4-dimethoxyphenyl)acrylic Acid
Ethyl Ester (7c)
HRMS: m/z [M]+ calcd for C21H24O6: 372.1573; found: 372.1578.
Yield: 0.37 g (1.1 mmol; 64%); slightly yellow oil.
2-(3,4-Dimethoxyphenyl)-3-(3-methoxy-4-triisopropylsilanoxy-
phenyl)acrylic Acid Ethyl Ester (7g)
Yield: 0.25 g (0.5 mmol; 17%); slightly yellow oil.
1H NMR (400 MHz, DMSO-d6): d = 1.22 (t, J = 7.1 Hz, 3 H, CH3),
3.53 (s, 3 H, OCH3), 3.65 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 4.19
(q, J = 7.1 Hz, 2 H, CH2), 6.64 (d, J = 1.5 Hz, 1 H, arom.), 6.69 (dd,
J = 1.9, 8.2 Hz, 1 H, arom.), 6.74 (d, J = 8.0 Hz, 1 H, arom.), 6.77
(d, J = 1.8 Hz, 1 H, arom.), 6.82 (dd, J = 2.5, 8.3 Hz, 1 H, arom.),
6.96 (d, J = 8.2 Hz, 1 H, arom.), 7.15 (t, J = 8.0 Hz, 1 H, arom.), 7.69
(s, 1 H, CH).
13C NMR (101 MHz, DMSO-d6): d = 14.1, 54.6, 55.4, 55.5, 60.6,
111.8, 113.2, 114.8, 115.2, 121.8, 122.9, 127.8, 129.2, 132.6, 135.6,
138.9, 148.4, 148.7, 158.7, 166.9.
1H NMR (400 MHz, DMSO-d6): d = 0.99 (d, J = 7.3 Hz, 18 H, 6 ×
CH3), 1.16 (m, 3 H, 3 × CH), 1.21 (t, J = 7.1 Hz, 3 H, CH3), 3.38 (s,
3 H, OCH3), 3.64 (s, 3 H, CH3), 3.76 (s, 3 H, OCH3), 4.17 (q, J = 7.1
Hz, 2 H, CH2), 6.59 (d, J = 1.8 Hz, 1 H, arom.), 6.68 (d, J = 8.2 Hz,
1 H, arom.), 6.71 (dd, J = 2.0, 3.2 Hz, 1 H, arom.), 6.73 (dd, J = 2.0,
3.5 Hz, 1 H, arom.), 6.75 (d, J = 1.9 Hz, 1 H, arom.), 6.97 (d, J = 8.2
Hz, 1 H, arom.), 7.67 (s, 1 H, CH).
13C NMR (101 MHz, DMSO-d6): d = 12.2, 12.2, 14.0, 17.4, 17.5,
17.7, 54.4, 55.3, 55.4, 60.3, 111.9, 113.3, 113.4, 119.4, 121.9,
124.4, 127.9, 128.2, 130.0, 139.1, 145.8, 148.3, 148.9, 166.9.
MS (EI, 70 eV): m/z (%) = 342 (10) [M]+·, 314 (24) [M – C2H4O]+·,
269 (12) [M – C2H5O]+.
HRMS: m/z [M]+ calcd for C20H22O5: 342.1467; found: 342.1474.
MS (EI, 70 eV): m/z (%) = 514 (60) [M]+·, 471 (90) [M – C2H5O]+,
456 (100) [M – C3H5O2]+, 441 (5) [M – CO2Et]+, 279 (5) [(TIP-
SO)(MeO)C6H3]+.
3-Benzo[1,3]dioxol-4-yl-2-(3,4-dimethoxyphenyl)acrylic Acid
Ethyl Ester (7d)
Yield: 4.88 g (13.7 mmol; 99%); slightly yellow oil.
HRMS: m/z [M]+ calcd for C29H42O6Si: 514.2751; found: 514.2755.
1H NMR (300 MHz, DMSO-d6): d = 1.20 (t, J = 7.0 Hz, 3 H, CH3),
3.67 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 4.16 (q, J = 7.0 Hz, 2 H,
CH2), 5.96 (s, 2 H, CH2), 6.41 (s, 1 H, arom.), 6.69 (d, J = 8.1 Hz, 1
H, arom.), 6.76 (s, 1 H, arom.), 6.83 (s, 2 H, arom.), 6.97 (d, J = 8.2
Hz, 1 H, arom.), 7.65 (s, 1 H, CH).
13C NMR (75 MHz, DMSO-d6): d = 14.1, 55.3, 55.5, 60.4, 101.3,
108.2, 108.7, 111.8, 113.1, 121.7, 126.5, 128.0, 128.3, 130.2, 138.8,
147.0, 148.1, 148.3, 148.8, 167.0.
3-(4-Bromophenyl)-2-(3,4-dimethoxyphenyl)acrylic Acid
Ethyl Ester (7h)
Yield: 1.10 g (2.8 mmol; 47%); slightly yellow oil.
1H NMR (400 MHz, DMSO-d6): d = 1.22 (t, J = 7.1 Hz, 3 H, CH3),
3.64 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 4.19 (q, J = 7.1 Hz, 2 H,
CH2), 6.66 (dd, J = 2.0, 8.2 Hz, 1 H, arom.), 6.77 (d, J = 1.9 Hz, 1
H, arom.), 6.93 (d, J = 8.3 Hz, 1 H, arom.), 7.04 (d, J = 8.5 Hz, 2 H,
arom.), 7.42 (d, J = 8.2 Hz, 2 H, arom.), 7.68 (s, 1 H, CH).
MS (EI, 70 eV): m/z (%) = 356 (100) [M]+·, 283 (12) [M – C2H5O]+,
13C NMR (101 MHz, DMSO-d6): d = 14.0, 55.3, 55.4, 60.7, 111.6,
113.1, 121.8, 122.3, 127.2, 129.8, 131.2, 131.4, 131.9, 133.2, 133.7,
137.6, 148.5, 148.6, 166.7.
151 (20) [M – C11H10O4]+.
HRMS: m/z [M]+ calcd for C20H20O6: 356.1260; found: 356.1270.
MS (EI, 70 eV): m/z (%) = 390, 392 (100) [M]+·, 317 (8) [M –
3-(3-Iodo-4,5-dimethoxyphenyl)-2-(3,4-dimethoxyphen-
yl)acrylic Acid Ethyl Ester (7e)
Yield: 0.70 g (1.4 mmol; 50%); slightly yellow viscous oil.
C3H5O2]+, 238 (4) [M – C3H5BrO2]+·.
HRMS: m/z [M]+ calcd for C19H19BrO4: 390.0467; found:
390.0471.
1H NMR (400 MHz, DMSO-d6): d = 1.22 (t, J = 7.1 Hz, 3 H, CH3),
3.46 (s, 3 H, OCH3), 3.66 (s, 3 H, OCH3), 3.68 (s, 3 H, OCH3), 3.78
(s, 3 H, OCH3), 4.18 (q, J = 7.1 Hz, 2 H, CH2), 6.70 (dd, J = 2.4, 7.7
Hz, 1 H), 6.71 (s, 1 H, arom.), 6.80 (d, J = 1.9 Hz, 1 H, arom.), 7.00
(d, J = 8.2 Hz, 1 H, arom.), 7.20 (d, J = 1.7 Hz, 1 H, arom.), 7.74 (s,
1 H, CH).
13C NMR (75 MHz, DMSO-d6): d = 14.6, 55.7, 56.1, 56.2, 60.3,
61.2, 92.8, 112.7, 113.8, 115.1, 122.3, 128.2, 132.9, 132.9, 133.2,
137.8, 149.2, 149.2, 149.5, 151.2, 167.3.
3-(2-Pyridin)-2-(3,4-dimethoxyphenyl)acrylic Acid Ethyl Ester
(7i)
Yield: 0.69 g (2.2 mmol; 96%); slightly yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.33 (t, J = 7.1 Hz, 3 H, CH3), 3.75
(s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 4.30 (dq, J = 7.1 Hz, 2 H, CH2),
6.85 (d, J = 8.3 Hz, 1 H, arom.), 6.87 (d, J = 8.1 Hz, 1 H, arom.),
7.10 (s, 1 H, arom.), 7.29 (d, J = 7.9 Hz, 1 H, arom.), 7.38 (dd, J =
1.6, 7.7 Hz, 1 H, arom.), 7.65 (dd, J = 1.8, 7.7 Hz, 1 H, arom.), 7.68
(ddd, J = 0.8, 1.6, 4.8 Hz, 1 H, arom.), 8.60 (ddd, J = 0.9, 1.8, 4.9
Hz, 1 H, arom.).
13C NMR (75 MHz, DMSO-d6): d = 13.8, 55.5, 55.5, 60.3, 109.0,
111.7, 119.1, 121.8, 122.4, 124.2, 124.5, 128.0, 136.5, 136.7, 148.8,
148.8, 153.1, 168.9.
MS (EI, 70 eV): m/z (%) = 499 (20) [MH]+, 498 (100) [M]+, 425 (4)
[M – C2H5O]+.
HRMS: m/z [M]+ calcd for C21H23IO6: 498.0539; found: 498.0536.
3-(3,5-Dimethoxyphenyl)-2-(3,4-dimethoxyphenyl)acrylic Acid
Ethyl Ester (7f)
Yield: 0.99 g (2.7 mmol; 96%); slightly yellow oil.
MS (EI, 70 eV): m/z (%) = 313 (60) [MH]+·, 312 (100) [M]+·, 267
(4) [M – C2H5O]+·, 240 (12) [M – C3H5O2]+.
1H NMR (400 MHz, CDCl3): d = 1.31 (t, J = 7.1 Hz, 3 H, CH3), 3.55
(s, 6 H, 2 × OCH3), 3.79 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 4.27
(q, J = 7.1 Hz, 2 H, CH2), 6.26 (s, 1 H, arom.), 6.27 (s, 1 H, arom.),
6.33 (d, J = 2.3 Hz, 1 H, arom.), 6.76 (d, J = 1.9 Hz, 1 H, arom.),
6.79 (dd, J = 1.9, 8.2 Hz, 1 H, arom.), 6.87 (d, J = 8.2 Hz, 1 H,
arom.), 7.70 (s, 1 H, CH).
HRMS: m/z [MH]+· calcd for C18H19NO4: 312.1230; found:
312.1237.
3-(3-Thienyl)-2-(3,4-dimethoxyphenyl)acrylic Acid Ethyl Ester
(7j)
Yield: 0.39 g (1.2 mmol; 88%); slightly yellow oil.
Synthesis 2006, No. 13, 2103–2112 © Thieme Stuttgart · New York

2111
A. Ianni, S. R. Waldvogel
PAPER
1H NMR (400 MHz, DMSO-d6): d = 1.21 (t, J = 7.1 Hz, 3 H, CH3),
3.68 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 4.17 (q, J = 7.1 Hz, 2 H,
CH2), 6.41 (dd, J = 1.0, 5.1 Hz, 1 H, arom.), 6.72 (dd, J = 1.9, 8.2
Hz, 1 H, arom.), 6.78 (s, J = 1.9 Hz, 1 H, arom.), 6.99 (s, J = 8.2 Hz,
1 H, arom.), 7.36 (dd, J = 3.0, 5.1 Hz, 1 H, arom.), 7.59 (d, J = 2.2
Hz, 1 H, arom.), 7.80 (s, 1 H, CH).
13C NMR (101 MHz, DMSO-d6): d = 14.6, 55.8, 56.0, 61.0, 112.2,
113.5, 121.2, 122.2, 127.8, 128.8, 130.6, 131.2, 133.9, 137.1, 149.0,
149.2, 167.5.
HRMS: m/z [M]+· calcd for C21H24O6: 372.1573; found: 372.1577.
2-Benzo[1,3]dioxol-4-yl-2-(2,3,4-trimethoxyphenyl)acrylicAcid
Ethyl Ester (7n)
Yield: 2.78 g (7.2 mmol; 90%); slightly yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.27 (t, J = 7.1 Hz, 3 H, CH3), 3.76
(s, 3 H, OCH3), 3.89 (s, 6 H, 2 × OCH3), 4.24 (q, J = 7.1 Hz, 2 H,
CH2), 5.89 (s, 2 H, CH2), 6.48 (d, J = 1.7 Hz, 1 H, arom.), 6.67 (dd,
J = 1.8, 8.3 Hz, 2 H, arom.), 6.76 (d, J = 8.5 Hz, 1 H, arom.), 6.77
(dd, J = 1.5, 8.4 Hz, 1 H, arom.), 7.71 (s, 1 H, CH).
13C NMR (101 MHz, CDCl3): d = 14.3, 55.9, 60.7, 60.9, 60.9, 101.9,
107.6, 108.1, 109.2, 123.0, 125.0, 126.5, 127.4, 129.2, 139.8, 142.6,
147.5, 148.3, 151.9, 153.8, 168.1.
MS (EI, 70 eV): m/z (%) = 318 (100) [M]+·, 274 (12) [M – C2H4O]+·,
273 (8) [M – C2H5O]+, 245 (40) [M – C3H5O2]+, 151 (32) [M –
C8H8O2]+.
HRMS: m/z [M] calcd for C17H18O4S: 318.0926; found: 318.10934.
MS (EI, 70 eV): m/z (%) = 386 (60) [M]+·, 344 (80) [M – C2H2O]+·,
271 (40) [M – C6H11O2]+, 192 (4) [M – C10H10O4]+·, 167 (60) [M –
C12H11O4]+·, 166 (100) [M – C12H12O4]+·.
3-(2-N-Methylindol)-2-(3,4-dimethoxyphenyl)acrylic Acid
Ethyl Ester (7k)
Yield: 0.35 g (1.0 mmol; 58%); slightly yellow oil.
HRMS: m/z [M]+· calcd for C21H22O7: 386.1366; found: 356.1370.
1H NMR (300 MHz, DMSO-d6): d = 1.23 (t, J = 7.1 Hz, 3 H, CH3),
3.66 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 4.21
(q, J = 7.1 Hz, 2 H, CH2), 6.79 (dd, J = 2.0, 8.2 Hz, 1 H, arom.), 5.83
(s, 1 H, arom.), 6.84 (d, J = 7.1 Hz, 1 H, arom.), 6.95 (ddd, J = 0.9,
7.0, 8.3 Hz, 1 H, arom.), 7.02 (d, J = 8.3 Hz, 1 H, arom.), 7.16 (ddd,
J = 1.1, 7.0, 8.3 Hz, 1 H, arom.), 7.35 (d, J = 7.9 Hz, 1 H, arom.),
7.46 (dd, J = 0.6, 8.4 Hz, 1 H, arom.), 7.90 (s, 1 H, CH).
13C NMR (75 MHz, DMSO-d6): d = 14.1, 29.6, 55.3, 55.5, 60.6,
105.1, 110.0, 111.9, 112.8, 119.8, 120.8, 121.5, 123.0, 126.6, 127.3,
128.2, 131.6, 133.7, 137.5, 148.5, 148.8, 166.7.
Acknowledgment
The work was supported by the University of Bonn (Germany).
References
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MS (EI, 70 eV): m/z (%) = 365 (100) [M]+·, 320 (4) [M – C2H5O1]+,
292 (16) [M – C3H5O2]+.
HRMS: m/z [M]+· calcd for C22H23NO4: 365.1627; found:
365.1627.
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3-(4-Methoxyphenyl)-2-(2,3,4-trimethoxyphenyl)acrylic Acid
Ethyl Ester (7l)
Yield: 3.79 g (10.2 mmol; 94%); slightly yellow oil.
(5) Govindachari, T. R.; Viswanathan, N. Heterocycles 1978,
1H NMR (400 MHz, DMSO-d6): d = 1.19 (t, J = 7.1 Hz, 3 H, CH3),
3.64 (s, 3 H, OCH3), 3.71 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 3.82
(s, 3 H, OCH3), 4.15 (q, J = 7.1 Hz, 2 H, CH2), 6.71 (d, J = 8.5 Hz,
1 H, arom.), 6.80 (d, J = 8.5 Hz, 2 H, arom.), 6.79 (d, J = 8.5 Hz, 1
H, arom.), 7.08 (d, J = 8.8 Hz, 2 H, arom.), 7.74 (s, 1 H, CH).
13C NMR (101 MHz, DMSO-d6): d = 14.1, 55.0, 55.6, 60.1, 60.3,
60.3, 107.9, 113.8, 122.6, 124.6, 126.7, 126.8, 131.7, 139.1, 141.9,
151.2, 153.4, 159.9, 167.2.
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MS (EI, 70 eV): m/z (%) = 373 (16) [MH]+·, 372 (100) [M]+·, 284
(8) [M – C3H8O3]+·, 161 (8) [M – C13H15O4]+, 135 (100) [M –
C11H16O4]+.
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3-(3-Methoxyphenyl)-2-(2,3,4-trimethoxyphenyl)acrylic Acid
Ethyl Ester (7m)
Yield: 0.91 g (2.5 mmol; 96%); slightly yellow oil.
1H NMR (300 MHz, CDCl3): d = 1.28 (t, J = 7.1 Hz, 3 H, CH3), 3.55
(s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 3.88 (s, 3
H, OCH3), 4.26 (q, J = 7.1 Hz, 2 H, CH2), 6.62 (d, J = 2.0 Hz, 1 H,
arom.), 6.64 (d, J = 8.6 Hz, 1 H, arom.), 6.74 (s, 1 H, arom.), 6.76
(d, J = 8.0 Hz, 1 H, arom.), 6.77 (s, 1 H, arom.), 7.11 (t, J = 8.0 Hz,
1 H, arom.), 7.76 (s, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 14.3, 54.8, 56.0, 60.7, 60.8, 61.0,
107.5, 114.3, 115.6, 123.1, 123.3, 125.0, 129.1, 129.8, 136.2, 140.0,
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MS (EI, 70 eV): m/z (%) = 372 (100) [M]+·, 327 (4) [M – C2H5O]+,
269 (8) [M – C4H11O]+.
Synthesis 2006, No. 13, 2103–2112 © Thieme Stuttgart · New York

PAPER
Reliable and Versatile Synthesis of 2-Aryl-Substituted Cinnamic Acid Esters
2112
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Synthesis 2006, No. 13, 2103–2112 © Thieme Stuttgart · New York