Acid-catalyzed reactions of aromatic aldehydes with ethyl diazoacetate: An investigation on the synthesis of 3-hydroxy-2-arylacrylic acid ethyl esters

Article abstract of DOI:10.1021/jo0489418

Several commercial Lewis acids, including those of the Bronsted type, specifically HBF₄·OEt₂, are able to catalyze the reaction between aromatic aldehydes and ethyl diazoacetate to produce 3-hydroxy-2-arylacrylic acid ethyl esters and 3-oxo-3-arylpropanoic acid ethyl esters. Reactions catalyzed by the iron Lewis acid [(η⁵-C ₅H₅)Fe⁺(CO)₂(THF)]BF ₄^- (i.e., 1) have the best yields and greatest ratio of 3-hydroxy-2-arylacrylic acid ethyl ester. The product distribution of 1 is not affected in the presence of Proton Sponge, but is dependent on temperature and the nature of the substrate aldehyde, whereas the activity of HBF ₄-OEt₂ is affected by the presence of Proton Sponge and is reactive at temperatures as low as -78 °C. Consequently, both 1 and HBF₄·OEt₂ are valuable catalysts in producing important 3-hydroxy-2-arylacrylic acid ethyl esters as precursors to biologically active compounds.

Full text of DOI:10.1021/jo0489418

Acid -Ca ta lyzed Rea ction s of Ar om a tic Ald eh yd es w ith Eth yl
Dia zoa ceta te: An In vestiga tion on th e Syn th esis of
3-Hyd r oxy-2-a r yla cr ylic Acid Eth yl Ester s
Matthew E. Dudley, Md. Monzur Morshed, Courtney L. Brennan, M. Shahidul Islam,
M. Syarhabil Ahmad, Mary-Rose Atuu, Bryan Branstetter, and M. Mahmun Hossain*
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211
mahmun@uwm.edu
Received J une 22, 2004
Several commercial Lewis acids, including those of the Brønsted type, specifically HBF4‚OEt2, are
able to catalyze the reaction between aromatic aldehydes and ethyl diazoacetate to produce
3-hydroxy-2-arylacrylic acid ethyl esters and 3-oxo-3-arylpropanoic acid ethyl esters. Reactions
-
catalyzed by the iron Lewis acid [(η5-C5H5)Fe+(CO)2(THF)]BF4 (i.e., 1) have the best yields and
greatest ratio of 3-hydroxy-2-arylacrylic acid ethyl ester. The product distribution of 1 is not affected
in the presence of Proton Sponge, but is dependent on temperature and the nature of the substrate
aldehyde, whereas the activity of HBF4‚OEt2 is affected by the presence of Proton Sponge and is
reactive at temperatures as low as -78 °C. Consequently, both 1 and HBF4‚OEt2 are valuable
catalysts in producing important 3-hydroxy-2-arylacrylic acid ethyl esters as precursors to
biologically active compounds.
In tr od u ction
Our group has found that the cyclopentadienyl dicar-
bonyl iron Lewis acid, [(η5-C5H5)Fe+(CO)2(THF)]BF4-, 1,
catalyzes a variety of reactions including cyclopropana-
tion,1 aziridination,2 and Diels-Alder reactions.3 Recently
we reported the synthesis of 3-hydroxy-2-arylacrylic acid
ethyl esters (3-hydroxyacrylates) along with 3-oxo-3-
arylpropanoic acid ethyl esters (â-keto esters) from
aromatic aldehydes and ethyl diazoacetate (EDA) cata-
lyzed by 1 (eq 1).4 This method has been used in a three-
step synthesis of the naproxen precursor 2-(6-methoxy-
2-naphthyl)propenoic acid and other related compounds.5
Very recently, Kanemasa and co-workers also reported
the synthesis of 3-hydroxyacrylates and â-keto esters
from aromatic aldehydes and EDA using ZnCl2 in the
presence of chlorotrimethylsilane.6 Research by Roskamp
focused on the reaction of aryl aldehydes and EDA
catalyzed by commercial Lewis acids (LA) such as SnCl2,
BF3, GeCl2, ZnCl2, ZnBr2, AlCl3, and SnCl4.7 The only
product reported was â-keto ester produced in moderate
to good yields (eq 2). When aromatic aldehydes were used,
yields were considerably lower.
To determine if our iron Lewis acid (1) is unique, we
decided to revisit those commercial Lewis acid catalysts
to see if 3-hydroxyacrylates were indeed produced but
overlooked. As part of our ongoing research, commercial
Lewis acid, Brønsted acid, and substituent effect studies
were utilized in the determination of what affects and
controls the formation of 3-hydroxyacrylates and are
reported herein. Our group is currently interested in
3-hydroxyacrylates because they have potential for fur-
ther downstream synthesis of important biologically
active compounds.
(1) (a) Seitz W. J .; Hossain, M. M. Tetrahedron Lett. 1994, 35, 7561.
(b) Seitz, W. J .; Saha, A. K.; Hossain, M. M. Organometallics 1993,
12, 2604. (c) Seitz, W. J .; Saha, A. K.; Casper, D.; Hossain, M. M.
Tetrahedron Lett. 1992, 33, 7755.
Resu lts a n d Discu ssion
(2) Mayer, M. F.; Hossain, M. M. J . Org. Chem. 1998, 63, 6839.
(3) Saha, A. K.; Hossain, M. M. Tetrahedron Lett. 1993, 34, 3833.
(4) Mahmood, S. J .; Hossain, M. M. J . Org. Chem. 1998, 63, 3333.
(5) Hossain, M. M. Synthesis of 2-Aryl Propenoic Acid Esters for
the Production of Nonsteroidal Antiinflammatory Drugs, U.S. Patent
6,683,205 B2, J anuary 27, 2004.
(6) Kanemasa, S.; Kanai, T.; Araki, T.; Wada, E. Tetrahedron Lett.
1999, 40, 5055.
(7) Holmquist, C. R.; Roskamp, E. J . J . Org. Chem. 1989, 54, 3258.
Lew is Acid Ca ta lysis. The Lewis acids chosen for
study were some of those reported by Roskamp.7 In each
reaction the aldehyde was added to a flask charged with
15-25 mL of CH2Cl2. The appropriate amount of catalyst
(0.1 equiv) was added to the aldehyde (1.0 equiv) and the
mixture was stirred. The EDA was diluted in approxi-
10.1021/jo0489418 CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/30/2004
J . Org. Chem. 2004, 69, 7599-7608
7599

Dudley et al.
TABLE 1. Isola ted Yield s of 3-Hyd r oxya cr yla te a n d
â-Keto Ester fr om Rea ction s of EDA w ith Ben za ld eh yd e
Ca ta lyzed by Lew is Acid sa
3-hydroxyacrylates, whereas electron-withdrawing groups
favor the â-keto ester. To ascertain if this is true with
other catalysts, several reactions were performed with
electron-rich and electron-poor aldehydes catalyzed by
commercial Lewis acids (SnCl2, 1, and HBF4‚OEt2, Table
3). To compare the results, all reactions were carried out
at room temperature under the same conditions.
In the case of SnCl2, the nature of the substituent has
no effect on product distribution, the main product was
â-keto ester. No formation of 3-hydroxyacrylate was
observed with electron-rich or electron-poor aldehyde.
The yields of â-keto esters were low with electron-rich
groups (entry 3, Table 3) and high with electron-poor
substituents such as the p-nitro group (entry 2, Table
3). However, with HBF4‚OEt2 product distribution de-
pends on the nature of the substituents and is similar to
that of 1,4 i.e., more 3-hydroxyacrylate with electron-rich
aldehyde (entry 6, Table 3) and less 3-hydroxyacrylate
with electron-poor aldehyde (entry 5, Table 3). After
evaluating the results thus far, it was determined that
the highest yields and ratios of 3-hydroxyacrylates were
obtained in reactions catalyzed by 1 and also by HBF4‚
OEt2.
3-hydroxy-
â-keto
entry
Lewis acid
acrylate (2),b %
ester (3),b %
1
2
3
4
5
6
7
8
SnCl2
SnCl2‚2H2O
ZnCl2
AlCl3
BF3‚OEt2
SnCl4
1
15
8
62
59
7
3
9
21
18
42
58
18
24
21
25
HBF4‚OEt2
1
a
1 equiv of benzaldehyde was reacted with 1.2 equiv of EDA
(which was added dropwise over 7 h) in the presence of 0.1 equiv
of catalyst. The reaction was then stirred for an additional 14 h
b
at room temperature. Isolated yield.
TABLE 2. P er cen t Con ver sion to 3-Hyd r oxya cr yla te
fr om th e Rea ction of Ben za ld eh yd e a n d EDA Ca ta lyzed
by 1, HBF 4‚OEt2, or Na BF 4 in th e P r esen ce/Absen ce of
P r oton Sp on gea
catalyst
(0.1 equiv)
equiv of
Proton Sponge
3-hydroxy-
entry
acrylate (2),b %
1
2
3
4
1
1
0.01
0.1
0.1
0
60
50
5
Role of Su bstr a te. Following this preliminary study,
a comparison of the catalytic activity of 1 and HBF4‚OEt2
was performed with a variety of carbonyl substrates. The
results of these reactions are summarized in Table 4.
Evaluation of acid-sensitive aromatic aldehydes such as
furfuraldehyde (entries 1 and 2, Table 4) produced
interesting results. At 0 °C, 1 gave only 3-hydroxyacrylate
in 70% yield, whereas HBF4‚OEt2 at 0 °C (entry 1, Table
4) gave a mixture of decomposed side products that
HBF4‚OEt2
NaBF4
0
a
The catalyst was dissolved in the appropriate solvent and then
benzaldehyde and Proton Sponge were added. Equivalents are
relative to benzaldehyde. The EDA was added dropwise and stirred
as before. The reactions were performed at room temperature.
1
bAnalyzed by H NMR, % conversion based on benzaldehyde to 2.
1
appeared polymeric in nature by H NMR. Due to the
mately 4 mL of CH2Cl2 and added dropwise over 6-7 h
by using a syringe pump. All reactions were run at the
temperatures indicated (Tables 1-5).
mild nature of 1, it is useful for substrates that are
sensitive to protic acids such as furfuraldehyde. Analysis
of aromatic ketones such as acetophenone and trifluoro-
acetophenone (entries 5-8, Table 4) showed that only
acetophenone reacted with HBF4‚OEt2, while no reaction
was observed in the presence of 1, whereas trifluoro-
acetophenone was unreactive regardless of the catalyst
used (entries 7 and 8, Table 4). Trifluoroacetophenone’s
inability to react may be explained by the powerful
electron-withdrawing effect of the trifluoromethyl group
on the neighboring carbonyl carbon, thus preventing
activation of the ketone. The reaction of salicylaldehyde
(entries 10 and 11, Table 4) and o-aminobenzaldehyde
(entries 12 and 13, Table 4) produced only small amounts
(10-20%) of product, namely benzofuran-3-carboxylic
acid ethyl ester and 3-ethoxycarbonyl indole in the
presence of HBF4‚OEt2. These products are formed from
3-hydroxyacrylates by acid-catalyzed cyclization (Scheme
1). These aldehydes were deemed essentially unreactive
in the presence of 1. A potential explanation for this
result is due to deactivation of the catalyst since both
aldehydes contain an electron donor (e.g., -OH or -NH2)
in the ortho position, which can compete at the reactive
site for the aldehyde’s carbonyl oxygen and consequently
inhibit the Lewis acidity of 1.
All of the catalysts investigated gave a mixture of
3-hydroxyacrylate and â-keto ester in different ratios.
Some catalysts gave good overall yields and others gave
low yields (Table 1). The most interesting results with
respect to yield and ratio of products were those reactions
catalyzed by SnCl2, HBF4‚OEt2, and 1. For example, the
main product observed from SnCl2 and SnCl2‚2H2O is the
â-keto ester (entries 1 and 2, Table 1). In comparison, 1
gave mainly 3-hydroxyacrylate.4 Surprisingly, it was
observed that HBF4‚OEt2 also catalyzes the reaction
between aromatic aldehydes and EDA to provide 3-hy-
droxyacrylates in good yields versus the corresponding
â-keto esters.
The idea of using the HBF4‚OEt2 acid as a catalyst
came from the fact that HBF4‚OEt2 is used in the
synthesis of 1.4 Acid impurities from HBF4‚OEt2 could
be a possible source of catalytic activity. To establish that
1, and not HBF4‚OEt2 impurities, was truly the catalyst
in the reaction of aromatic aldehydes with EDA, the
reaction was performed in the presence of Proton Sponge,
1,8-bis(dimethylamino)naphthalene. The activity of 1 was
not inhibited by the addition of Proton Sponge (Table 2).
In the case with HBF4‚OEt2, the reaction was almost
completely inhibited by the addition of Proton Sponge and
only the aldehyde starting material was recovered.
Su bstitu en t Effects. We had reported4 earlier that
substituents on the aromatic aldehyde play an important
role in product distribution when reactions are catalyzed
by 1. Electron-donating groups favor the formation of
Entries 14-29 (Table 4) show various substituted
benzaldehyde derivatives at different temperatures. Ac-
tually, in terms of EWG/EDG substituent effects, the
product distributions of 3-hydroxyacrylates and â-keto
esters catalyzed by either HBF4‚OEt2 or 1 are similar at
0 °C.
7600 J . Org. Chem., Vol. 69, No. 22, 2004

Synthesis of 3-Hydroxy-2-arylacrylic Acid Ethyl Esters
TABLE 3. Yield s of 3-Hyd r oxya cr yla tes a n d â-Keto Ester s fr om th e Rea ction s of p-Meth oxy- a n d p-Nitr oben za ld eh yd e
w ith EDA Ca ta lyzed by Sn Cl2, HBF 4‚OEt2, a n d 1a
a
1 equiv of aldehyde was reacted with 1.2 equiv of EDA (which was added dropwise over 7 h) in the presence of 0.1 equiv of the
catalyst. The reaction was then stirred for an additional 14 h at room temperature. Results from Table 1. c Isolated yield.
b
Interestingly, it is possible to perform the reaction at
-78 °C in the presence of HBF4‚OEt2. At this tempera-
ture the yield of the 3-hydroxyacrylate is significantly
improved (entries 9, 15, 20, and 30, Table 4). In some
cases, the only product isolated from the reaction was
the desired 3-hydroxyacrylate, whereas 1 is ineffective
as a catalyst at this temperature (entries 4 and 17, Table
4) due to slow dissociation of the THF ligand from 1.4
To investigate why acids such as sulfuric acid and
HBF4‚OEt2 are reactive, EDA degradation experiments
were performed in the NMR tube. In a 1.0-equiv sample
of EDA in the presence of 0.5 equiv of sulfuric acid at
temperatures below 0 °C, the methine 1H proton of EDA
(broad singlet, 4.74 ppm) is still present, in addition to
an intermediate having 2H singlet protons as observed
1
by H NMR (4.78 ppm) and 13C NMR (67.2 ppm). The
13C DEPT, edited HSQC, and HMBC spectra of this
mixture confirmed that both of these proton singlets are
bound on the methine carbon of the intermediate, sug-
gesting a diazonium salt similar to the protonated
intermediate 25 as represented in Scheme 2. Interest-
ingly, at temperatures above 0 °C, rapid loss of nitrogen
and subsequent coordination of the dianion of sulfuric
acid is observed producing the final compound, 2,2′-
[sulfonylbis(oxy)]bisacetic acid diethyl ester, (CH3CH2-
OCOCH2O)2SO2 (27). This NMR study revealed that
rapid decomposition of EDA by sulfuric acid occurs at
room temperature and consequently neutralizes the
acidity of sulfuric acid. This neutralization of the acid
catalyst explains why limited formation of 3-hydroxy-
Br øn sted Acid Ca ta lysis. Following the observation
that H+ (Brønsted acidity of HBF4‚OEt2) may specifically
catalyze the formation of 3-hydroxyacrylates from aro-
matic aldehydes and EDA, an investigation into the
activity of several commercial Brønsted acids was per-
formed to verify the potential source of catalytic activity
of HBF4‚OEt2. A number of Brønsted acids with varying
acid strengths were investigated. Results are sum-
marized in Table 5.
It became apparent that yield was dependent on the
following order: BF4 > HSO4 > NO3 > ClO4 > Cl-
and CH3COO-. Those Brønsted acids with nonnucleo-
philic anions gave the best results, for example, sulfuric
acid (entry 9, Table 4) and HBF4‚OEt2 (Table 3), whereas
acids with nucleophilic anions such as Cl-, AcO-, and
NO3- gave only a trace or small amount of product since
they readily quench EDA according to Scheme 2.8,9,10,11
-
-
-
-
(8) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.
(9) Holmberg, B. Chem. Ber. 1908, 41, 1343.
(10) Curtius, T. J . Prakt. Chem. 1889, 39, 128.
(11) Curtius, T.; Schwan. J . Prakt. Chem. 1895, 51, 358.
J . Org. Chem, Vol. 69, No. 22, 2004 7601

Dudley et al.
TABLE 4. Resu lts fr om th e Rea ction s of Va r iou s Ar om a tic Ca r bon yl Com p ou n d s w ith EDA Ca ta lyzed by Ir on Lew is
a
Acid 1 or HBF 4‚OEt2
a
1 equiv of substrate was reacted with 1.2 equiv of EDA (which was added dropwise over 6 to 7 h) in the presence of 0.1 equiv of
b
catalyst and stirred for an additional 14 h at that temperature unless otherwise stated. Yields based upon starting aldehyde or ketone.
c 3 equiv of EDA were used. The reaction was allowed to stir for an additional 2-4 days. e Only product isolated was benzofuran-3-
d
carboxylic acid ethyl ester (11). f The only product isolated was 3-ethoxycarbonyl indole (12).
7602 J . Org. Chem., Vol. 69, No. 22, 2004

Synthesis of 3-Hydroxy-2-arylacrylic Acid Ethyl Esters
SCHEME 1
SCHEME 2
TABLE 5. Resu lts fr om th e Rea ction s of Ben za ld eh yd e
w ith EDA Ca ta lyzed by 0.1 equ iv of Br øn sted Acid s
temp,
°C
3-hydroxy-
â-keto
entry
Brønsted acid
acrylate (2),a
%
ester (3),a %
1
2
3
4
5
6
8
9
CH3COOH
HCl (dry)
rt
rt
0
rt
0
0
rt
0
0b
0b
traceb,c
traceb
traceb
18
traceb
HCl (12 M)
HNO3 (15.8 M)
HNO3 (15.8 M)
HClO4 (9.2 M)
H2SO4
0b
0b
0
F IGURE 1. (Z)-, (E)-O-protonated and benzoxonium carbocat-
ions of benzaldehyde.
10
0
6b
0b
0
larly, if BF3 was the catalyst (from the decomposition of
HBF4‚OEt2), then results for HBF4‚OEt2 and BF3‚OEt2
should be the same, but they are not (Table 1). Ulti-
mately, H+ was identified as the catalyst, after a reaction
with a 1:1 ratio of HBF4‚OEt2 and Proton Sponge showed
no activity and only starting materials were observed by
1H NMR (Table 2). This result is plausible because H+
can easily coordinate to the aldehyde carbonyl forming
H2SO4
26
10
H2SO4
-78
33
7
a
b
Isolated yield unless otherwise stated. From the analysis of
reaction mixture by proton NMR. c Ethylchloroacetate was isolated
from this reaction.
acrylate (entry 8, Table 5) occurs in reactions at room
temperature, whereas at 0 °C or below, the slow neu-
tralization of sulfuric acid during dropwise addition of
EDA permits activation of benzaldehyde by the sulfuric
acid to form 3-hydroxyacrylates (entries 9 and 10, Table
5). This phenomenon observed with sulfuric acid is even
more true for HBF4‚OEt2.
-
an oxonium ion with BF4 as the counterion. This may
-
further be explained by the idea that BF4 is not as
nucleophilic as Cl- or CH3COO- and thus the resultant
O-protonated benzaldehyde carbocation would be stabi-
-
lized and not destroyed by the BF4 anion (Figure 1).
To investigate the presence of the carbocation of
O-protonated benzaldehyde, an acid titration study was
performed at -100 °C (Figure 2), using NMR. 13C NMR
studies were carried out with various concentrations of
HBF4‚OEt2 (1, 2.5, and 6.5 equiv) in the presence of
substrate benzaldehyde and CD2Cl2. Upon increasing
concentration of HBF4‚OEt2 in the 13C coupled spectrum,
the coupling constants for both the (E)- and (Z)-confor-
mations of O-protonated benzaldehyde carbocations in-
crease with increasing acid concentration. Proton ex-
change is rapid between (E)- and (Z)-conformations.
Assignment of the (E)-conformation at 202.7 ppm (J CH
)196.18 Hz) and the (Z)-conformation at 204.1 ppm (J CH
)185.86 Hz) with use of 6.5 equiv of HBF4‚OEt2 is in
agreement with previous work by Olah et al. with
superacid media.12 Furthermore, another carbocation
species is present in the mixture at 206.2 ppm (J CH
)189.3 Hz) that does not undergo rapid exchange; we
believe this absorption belongs to the benzoxonium
carbocation. In summary, the presence of these cationic
species of benzaldehyde provides an essential require-
In the presence of 0.1 equiv of HBF4‚OEt2 with 1 equiv
of EDA at or below 0 °C, the 1H methine proton of EDA
(4.74 ppm) shows practically no decomposition and
consequently neutralization of HBF4‚OEt2 is prevented.
1
This result is borne out by H NMR because HBF4‚OEt2
exhibits a broad acid peak at 10.3 ppm even in the
presence of EDA. This NMR study confirms that 0.1
equiv of HBF4‚OEt2 is almost completely available to
activate the benzaldehyde in the presence of EDA and is
not as susceptible to neutralization as sulfuric acid. This
is a unique characteristic of HBF4‚OEt2 in comparison
to the other Brønsted acids investigated and is the reason
for its effectiveness as a catalyst in 3-hydroxyacrylate
synthesis (Table 3, entry 4 and Table 4, entry 9).
Interestingly, a small amount of ethyl fluoroacetate forms
with higher concentrations of acid (1 equiv).
After our investigation of commercially available Brøn-
sted and Lewis acids (Tables 1 and 5), it became apparent
-
that catalysts containing the BF4 anion (i.e., 1 and
HBF4‚OEt2) gave the best results. Investigation of the
-
BF4 anion and its derivatives provided a rational ap-
proach in finding the potential source of catalytic activity.
No reaction was observed with NaBF4 thus eliminating
the BF4 anion as a potential catalyst (Table 2). Simi-
(12) Olah, G. A.; Reddy, V. P.; Rasul, G.; Prakash, G. K. S. J . Am.
Chem. Soc. 1999, 121, 9994.
-
J . Org. Chem, Vol. 69, No. 22, 2004 7603

Dudley et al.
energy rotamer, which favors aryl migration. Rotamer
A, the lowest energy rotamer, contains the least number
of bulky interactions. Thus the groups that come into
eclipse with each other upon migration and subsequently
form 3-hydroxyacrylate are minimized with rotamer A,
where the aryl group is anti to the leaving N2 group.
â-Keto ester formation can be explained by hydride
migration from the next higher energy rotamer D. The
four remaining rotamers are not reasonable at low
temperature because there is a large steric interaction
when the bulky catalyst and ester group are next to one
another.
In the case of a less bulky catalyst such as HBF4‚OEt2,
rotamer A is still the lower energy rotamer thus favoring
the formation of 3-hydroxyacrylate. At lower temperature
with HBF4‚OEt2, a significant increase in yield of 3-hy-
droxyacrylate is observed. In some cases, no formation
of â-keto ester (entries 9, 15, 20, and 30, Table 4) is
observed, suggesting rotamer A predominates over other
rotamers at this temperature. This result implies that
thermodynamic control can influence the selectivity (3-
hydroxyacrylate vs â-keto ester) of HBF4‚OEt2.
F IGURE 2. 13C NMR decoupled spectra of benzaldehyde at
various concentrations of HBF4‚OEt2 at (-100 °C).
Moreover, it is also possible with 1 or HBF4‚OEt2 that
aryl migration is favorable over hydride (Figure 3,
rotamers B and D) or oxo migration (rotamers C and F)
due to its ability to stabilize an intermediate carbocation
by the formation of phenonium ion (Figure 3, G). The
stabilized phenonium ion is a result of rotamers A and
E. Rotamer A being the most stable of the rotamer
configurations provides an explanation for 3-hydroxy-
acrylate formation at low temperatures. Furthermore,
this stabilized phenonium ion provides a reason why
more 3-hydroxyacrylate formation is observed with elec-
tron-donating groups (EDG), since electron-donating
groups can enhance the stability of the resultant phe-
nonium ion thus favoring selective formation of 3-hy-
droxyacrylate. Likewise, electron-withdrawing groups
(EWG) destabilize the phenonium ion resulting in de-
creased formation of 3-hydroxyacrylate.
Con clu sion
In summary, our results from these studies indicate
that both HBF4‚OEt2 and 1 are efficient catalysts for the
formation of 3-hydroxyacrylates from aromatic aldehydes
and EDA. In the case of acids such as HBF4‚OEt2, the
catalyst appears to be H+, whereas 1 exhibits Lewis
acidity at the iron center and is not dependent on H+. In
both cases, the reaction requires activation of the aro-
matic aldehyde followed ultimately by loss of N2 and
subsequent rearrangement (either phenyl or hydride
migration) to the products 3-hydroxyacrylate or â-keto
ester, respectively. The nonnucleophilic behavior of the
catalyst anion (BF4-) plays two roles: (1) in preventing
deactivation of the aldehyde toward the addition of the
relatively weak nucleophilic methine carbanion of EDA
and (2) in preventing degradation (i.e., loss of N2) of EDA
prior to nucleophilic addition to aldehyde. Furthermore,
selective phenyl migration is enhanced in the presence
of electron-rich aldehydes, i.e., those with EDG substit-
uents. The outcome of the reaction yield (3-hydroxyacry-
late or â-keto ester) is dependent on temperature, which
is readily explained by the stability of various rotamer
configurations resulting from nucleophilic addition of
EDA to the aromatic aldehyde.
F IGURE 3. Newman projections (i.e., rotamers A through F)
of possible transition states and a phenonium ion transition
state (G) resulting from aryl migration.
ment for activation of benzaldehyde prior to attack by
EDA to form product in the reaction mixture.
Rota m er s a n d Regioselectivity. In each case where
a metal-halogen type catalyst was used (SnCl2, AlCl3)
significantly more â-keto ester than 3-hydroxyacrylate
forms. Work by Kanemasa using the metal-halogen type
catalyst SnCl4 provides an explanation. Kanemasa’s
suggested chelation transition state orients the migrating
hydride (from the aldehyde) and leaving nitrogen (from
EDA) anti to one another.6 This transition state reduces
the steric interactions and facilitates â-keto ester forma-
tion.
The catalysts, other than those of the metal-halogen
type, bind to the aldehyde first and then the nucleophilic
methine carbanion of EDA can attack either the re- or
si-face of the aldehyde. Thus six Newman projections can
be drawn (Figure 3). The effectiveness of 1, which is a
bulky catalyst, must originate from its ability to direct
the activated aldehyde and EDA to form the lowest
7604 J . Org. Chem., Vol. 69, No. 22, 2004

Synthesis of 3-Hydroxy-2-arylacrylic Acid Ethyl Esters
mL (1.49 mmol) of benzaldehyde, and 0.2 mL (1.78 mmol) of
EDA at room temperature. In addition, 9% of 3-oxo-3-phenyl-
propanoic acid ethyl ester (3)14 was isolated.
In conclusion, we feel the selectivity of both 1 and
HBF4‚OEt2 have potential as selective catalysts for future
work on downstream synthesis of biologically important
compounds from 3-hydroxyacrylates.
BF 3‚OE t 2-ca t a lyzed r ea ct ion bet w een ben za ld eh yd e
a n d E DA: 3-Hydroxy-2-phenylacrylic acid ethyl ester (2)13
was isolated in 21% yield from 0.014 g (0.099 mmol) of BF3‚
OEt2, 0.10 mL (0.99 mmol) of benzaldehyde, and 0.18 mL (1.49
mmol) of EDA at room temperature. In addition, 18% of 3-oxo-
3-phenylpropanoic acid ethyl ester (3)14 was isolated.
Sn Cl4-ca ta lyzed r ea ction betw een ben za ld eh yd e a n d
EDA: 3-Hydroxy-2-phenylacrylic acid ethyl ester (2)13 was
isolated in 18% yield from 0.018 g (0.149 mmol) of SnCl4, 0.15
mL (1.49 mmol) of benzaldehyde, and 0.2 mL (1.78 mmol) of
EDA at room temperature. In addition, 24% of 3-oxo-3-
phenylpropanoic acid ethyl ester (3)14 was isolated.
HBF 4‚OEt2-ca ta lyzed r ea ction betw een ben za ld eh yd e
a n d E DA: 3-Hydroxy-2-phenylacrylic acid ethyl ester (2)13
was isolated in 42% yield from 0.068 mL (0.497 mmol) of HBF4‚
OEt2, 0.50 mL (4.97 mmol) of benzaldehyde, and 0.66 mL (5.96
mmol) of EDA at room temperature. In addition, 21% of 3-oxo-
3-phenylpropanoic acid ethyl ester (3)14 was isolated.
At -78 °C, 74% of 3-hydroxy-2-phenylacrylic acid ethyl ester
(2)13 was isolated from 0.068 mL (0.497 mmol) of HBF4‚OEt2,
0.50 mL (4.97 mmol) of benzaldehyde, and 0.66 mL (5.96
mmol) of EDA.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. The chemical shifts (δ) are
expressed in ppm relative to tetramethylsilane, and CDCl3 was
used as the solvent. All organometallic operations were
performed under a dry nitrogen atmosphere with standard
Schlenk techniques. All of the glass flasks were flamed under
vacuum and filled with nitrogen prior to use. Column chro-
matography was performed with silica gel (40-140 mesh).
HPLC grade CH2Cl2 was distilled under N2 from P2O5. HPLC
grade pentane was distilled from sodium under an inert
atmosphere immediately prior to use. Reagent grade Et2O and
tetrahydrofuran were freshly distilled under a N2 atmosphere
from sodium benzophenone ketyl. Benzaldehyde, p-tolualde-
hyde, and p-anisaldehyde were purified by extraction with
NaHCO3 solution, washed with water, dried over Na2SO4, and
distilled under vacuum. p-Nitrobenzaldehyde and p-chlorobenz-
aldehyde were purified by recrystallization from ethanol and
dried under vacuum for several days. Ethyl diazoacetate (EDA)
was obtained from Aldrich Chemical Co.
Ir on Lew is a cid -ca ta lyzed r ea ction betw een ben za l-
d eh yd e a n d EDA: 3-Hydroxy-2-phenylacrylic acid ethyl ester
(2)13 was isolated in 58% yield from 0.206 g (0.58 mmol) of the
iron Lewis acid, 0.7 g (5.8266 mmol) of benzaldehyde, and
0.735 g (6.99 mmol) of EDA at room temperature. In addition,
25% of 3-oxo-3-phenylpropanoic acid ethyl ester (3)14 was
isolated.
Sn Cl2-ca ta lyzed r ea ction betw een p-n itr oben za ld e-
h yd e a n d EDA: 3-Oxo-3-(4-nitrophenyl)propanoic acid ethyl
ester (5)4 was isolated in 80% yield from 0.024 g (0.124 mmol)
of SnCl2, 0.185 g (1.24 mmol) of p-nitrobenzaldehyde, and 0.17
mL (1.24 mmol) of EDA at room temperature. 1H NMR (CDCl3,
300 MHz): δ 8.3 (m, 4H), 4.3 (q, 2H), 4.0 (s, 2H), 1.3 (t, 3H).
Sn Cl2-ca ta lyzed r ea ction betw een p-m eth oxyben za l-
d eh yd e a n d EDA: 3-Oxo-3-(4-methoxyphenyl)propanoic acid
ethyl ester (6)4 was isolated in 30% yield from 0.024 g (0.125
mmol) of SnCl2, 0.15 mL (1.25 mmol) of p-methoxybenzalde-
hyde, and 0.17 mL (1.25 mmol) of EDA at room temperature.
1H NMR (CDCl3, 300 MHz): δ 7.2 (m, 4H), 4.3 (q, 2H), 3.8 (s,
2H), 3.6 (s, 3H), 1.3 (t, 3H).
HBF 4‚OEt2-ca ta lyzed r ea ction betw een p-n itr oben za l-
d eh yd e a n d EDA: 3-Hydroxy-2-(4-nitrophenyl)acrylic acid
ethyl ester (4)4 was isolated in 27% yield from 0.017 mL (0.124
mmol) of HBF4‚OEt2, 0.0185 g (1.24 mmol) of p-nitrobenzal-
dehyde, and 0.17 mL (1.24 mmol) of EDA at room temperature.
1H NMR (CDCl3, 300 MHz): δ 12.4 (d, 1H), 8.2 (d, 2H), 7.5 (d,
2H), 7.4 (d, 1H). In addition, 54% of 3-oxo-3-(4-nitrophenyl)-
propanoic acid ethyl ester (5)4 was isolated.
At 0 °C, 35% of 3-hydroxy-2-(4-nitrophenyl)acrylic acid ethyl
ester (4)4 and 53% of 3-oxo-3-(4-nitrophenyl)propanoic acid
ethyl ester (5)4 were isolated from 0.017 mL (0.124 mmol) of
HBF4‚OEt2, 0.0185 g (1.24 mmol) of p-nitrobenzaldehyde, and
0.17 mL (1.24 mmol) of EDA.
Ca ta lytic Rea ction : Gen er a l P r oced u r e. For each ex-
periment, 1.5-5.0 mmol of the aldehyde was dissolved in 15-
25 mL of freshly distilled dichloromethane under nitrogen. A
0.1-equiv sample of the appropriate catalyst was added and
then the reaction mixture was stirred. Ethyl diazoacetate (1.2
equiv; EDA) was diluted in 4 mL of freshly distilled dichlo-
romethane and drawn into a gas-tight syringe. The diluted
EDA was then added to the aldehyde over a period of 6-7 h
with the help of a syringe pump. The reaction mixture was
allowed to stir for an additional 16-24 h. Each reaction was
quenched by adding THF, to remove any products that might
be bound to catalyst. The reaction mixture was filtered through
a silica plug and the solvent removed by rotary evaporation.
Products were isolated by column chromatography (2-10%
ether in pentane/hexane or 2-10% ethyl acetate in pentane/
hexane) and identified by comparing spectra to known 1H
1
NMR. H and 13C NMR and elemental analysis were applied
to characterize the new compounds.
Sn Cl2-ca ta lyzed r ea ction betw een ben za ld eh yd e a n d
EDA: 3-Hydroxy-2-phenylacrylic acid ethyl ester (2)13 was
isolated in 1% yield from 0.029 g (0.149 mmol) of SnCl2, 0.15
mL (1.49 mmol) of benzaldehyde, and 0.2 mL (1.78 mmol) of
EDA at room temperature. 1H NMR (CDCl3): δ 12.2 (d, 1H, J
) 13 Hz), 7.3 (m, 5H). In addition, 62% of 3-oxo-3-phenylpro-
panoic acid ethyl ester (3)14 was isolated. 1H NMR (CDCl3, 300
MHz): δ 7.4-8.0 (m, 5H), 4.20 (q, 2H), 3.98 (s, 2H), 1.24 (t,
3H).
Sn Cl2‚2H2O-ca ta lyzed r ea ction betw een ben za ld eh yd e
a n d E DA: 3-Hydroxy-2-phenylacrylic acid ethyl ester (2)13
was isolated in 15% yield from 0.034 g (0.149 mmol) of SnCl2‚
2H2O, 0.15 mL (1.49 mmol) of benzaldehyde, and 0.2 mL (1.78
mmol) of EDA at room temperature. In addition, 59% of 3-oxo-
3-phenylpropanoic acid ethyl ester (3)14 was isolated.
Zn Cl2-ca ta lyzed r ea ction betw een ben za ld eh yd e a n d
EDA: 3-Hydroxy-2-phenylacrylic acid ethyl ester (2)13 was
isolated in 8% yield from 0.021 g (0.149 mmol) of ZnCl2, 0.15
mL (1.49 mmol) of benzaldehyde, and 0.2 mL (1.78 mmol) of
EDA at room temperature. In addition, 7% of 3-oxo-3-phenyl-
propanoic acid ethyl ester (3)14 was isolated.
HBF 4‚OEt2-ca ta lyzed r ea ction betw een p-m eth oxy-
ben za ld eh yd e a n d EDA: 3-Hydroxy-2-(4-methoxyphenyl)-
acrylic acid ethyl ester (6)4 was isolated in 44% yield from 0.071
mL (0.125 mmol) of HBF4‚OEt2, 0.70 mL (5.14 mmol) of
p-methoxybenzaldehyde, and 1.47 mL (6.17 mmol) of EDA at
room temperature. 1H NMR (CDCl3, 300 MHz): δ 12.03 (d,
1H, J ) 12.6), 7.27 (d, 1H), 7.19 (d, 2H), 6.9 (d, 2H), 3.83 (s,
3H). In addition, 21% of 3-oxo-3-(4-methoxyphenyl)propanoic
acid ethyl ester (7)4 was isolated. 1H NMR (CDCl3, 300 MHz):
δ 7.3-6.9 (m, 4H), 4.27 (q, 2H), 3.80 (s, 2H), 3.46 (s, 3H), 1.26
(t, 3H).
AlCl3-ca ta lyzed r ea ction betw een ben za ld eh yd e a n d
EDA: 3-Hydroxy-2-phenylacrylic acid ethyl ester (2)13 was
isolated in 3% yield from 0.020 g (0.149 mmol) of AlCl3, 0.15
(13) Beccalli, E. M.; La Rosa, C.; Marchesini, A. J . Org. Chem. 1984,
49, 4287.
(14) Clay, R. J .; Collom, T. A.; Karrick, G. L.; Wemple, J . Synthesis
1993, 290.
At 0 °C, 75% of 3-hydroxy-2-(4-methoxyphenyl)acrylic acid
ethyl ester (6)4 and 15% of 3-oxo-3-(4-methoxyphenyl)propanoic
acid ethyl ester (7)4 were isolated from the reaction of 1.00
J . Org. Chem, Vol. 69, No. 22, 2004 7605

Dudley et al.
mL (8.073 mmol) of p-methoxybenzaldehyde, 0.11 mL (0.0807
mmol) of HBF4‚OEt2, and 0.94 mL (8.00 mmol) of EDA for 24
h.
acetophenone, 0.11 g (0.332 mmol) of 1, and 0.5 mL (5.0 mmol)
of EDA at room temperature. There was no reaction at 0 °C
under similar conditions, only acetophenone was recovered.
At -78 °C, 90% of 3-hydroxy-2-(4-methoxyphenyl)acrylic
acid ethyl ester (6)4 was isolated from the reaction of 1.00 mL
(8.073 mmol) of p-methoxybenzaldehyde, 0.11 mL (0.0807
mmol) of HBF4‚OEt2, and 0.94 mL (8.00 mmol) of EDA for 24
h. No 3-oxo-3-(4-methoxyphenyl)propanoic acid ethyl ester (7)4
was isolated.
Ir on Lew is a cid -ca ta lyzed r ea ction betw een p-n i-
tr oben za ld eh yd e a n d EDA: 3-Hydroxy-2-(4-nitrophenyl)-
acrylic acid ethyl ester (4)4 was isolated in 35% yield from
0.0448 g (0.133 mmol) of 1, 0.203 g (1.33 mmol) of p-
nitrobenzaldehyde, and 0.18 mL (1.33 mmol) of EDA at room
temperature. In addition, 44% of 3-oxo-3-(4-nitrophenyl)-
propanoic acid ethyl ester (5)4 was isolated.
At 0 °C, 32% of 3-hydroxy-2-(4-nitrophenyl)acrylic acid ethyl
ester (4)4 and 56% of 3-oxo-3-(4-nitrophenyl)propanoic acid
ethyl ester (5)4 were isolated from the reaction of 0.0448 g
(0.133 mmol) of 1, 0.203 g (1.33 mmol) of p-nitrobenzaldehyde,
and 0.18 mL (1.33 mmol) of EDA for 24 h.
Ir on Lew is a cid -ca ta lyzed r ea ction betw een p-m eth -
oxyben za ld eh yd e a n d EDA: 3-Hydroxy-2-(4-methoxyphen-
yl)acrylic acid ethyl ester (6)4 was isolated in 45% yield from
the reaction of 0.139 g (0.414 mmol) of 1, 0.563 g (4.14 mmol)
of p-methoxybenzaldehyde, and 1.18 mL (4.96 mmol) of EDA
at room temperature. In addition, 35% of 3-oxo-3-(4-methoxy-
phenyl)propanoic acid ethyl ester (7)4 was isolated.
At 0 °C, 60% of 3-hydroxy-2-(4-methoxyphenyl)acrylic acid
ethyl ester (6)4 and 20% of 3-oxo-3-(4-methoxyphenyl)propanoic
acid ethyl ester (7)4 were isolated from the reaction of 0.0487
g (0.145 mmol) of 1, 0.178 mL (1.45 mmol) of p-methoxybenz-
aldehyde, and 0.19 mL (1.45 mmol) of EDA.
H BF 4‚OE t 2-ca t a lyzed r ea ct ion b et w een t r iflu or o-
a cetop h en on e a n d EDA: No product was observed by 1H
NMR, when 0.2 g (1.15 mmol) of trifluoroacetophenone was
in the presence of 0.032 mL (0.23 mmol) of HBF4‚OEt2 and
0.56 mL (5.55 mmol) of EDA at 0 °C or room temperature.
Ir on Lew is a cid -ca ta lyzed r ea ction betw een tr iflu o-
1
r oa cetop h en on e a n d EDA: No product was observed by H
NMR when 0.2 g (1.15 mmol) of trifluoroacetophenone was in
the presence of 0.04 g (0.115 mmol) of 1 and 0.155 mL (1.38
mmol) of EDA at 0 °C or room temperature.
HBF 4‚OEt2-ca ta lyzed r ea ction betw een sa licyla ld e-
h yd e a n d EDA: 3-Benzofurancarboxylic acid ethyl ester
(11)17 was isolated in 20% yield from the reaction of 0.026 mL
(0.19 mmol) of HBF4‚OEt2, 0.170 mL (1.87 mmol) of salicyl-
aldehyde, and 0.306 mL (2.25 mmol) of EDA at 0 °C. 1H NMR
(CDCl3, 300 MHz): δ 8.22 (s, 1H), 8.06 (m, 1H), 7.55 (m, 1H),
7.37 (m, 2H), 3.95 (q, 4H), 1.3 (t, 3H). No 3-oxo-3-(2-hydroxy-
phenyl)propanoic acid ethyl ester18 formed in the reaction as
1
observed by H NMR.
Ir on Lew is a cid -ca ta lyzed r ea ction betw een sa licyl-
a ld eh yd e a n d EDA: There was no reaction at 0 °C under
similar conditions, only salicylaldehyde was recovered.
HBF 4‚OEt2-ca ta lyzed r ea ction betw een 2-a m in oben z-
a ld eh yd e a n d EDA: Indole-3-carboxylic acid ethyl ester (12)19
was isolated in 23% yield from the reaction of 0.035 mL (0.25
mmol) of HBF4‚OEt2, 0.225 mL (2.48 mmol) of 2-aminobenz-
aldehyde, and 0.0405 mL (2.98 mmol) of EDA at 0 °C. 1H NMR
(CDCl3, 300 MHz): δ 8.66 (s, 1H, NH), 8.21 (m, 1H), 7.94 (d,
1H, J ) 3 Hz), 7.43 (m, 1H), 7.32 (m, 1H), 4.44 (q, 2H, J ) 7
Hz), 1.45 (t, 3H, J ) 7 Hz).
Ir on Lew is a cid -ca ta lyzed r ea ction betw een 2-a m i-
n oben za ld eh yd e a n d EDA: There was no reaction at 0 °C
under similar conditions, only 2-aminobenzaldehyde was
recovered.
At -78 °C, 4% of 3-hydroxy-2-(4-methoxyphenyl)acrylic acid
ethyl ester (6)4 was isolated from the reaction of 0.4 g (2.938
mmol) of p-methoxybenzaldehyde, 0.260 g (0.77 mmol) of 1,
and 0.1 mL (0.77 mmol) of EDA.
H BF 4‚OE t 2-ca t a lyzed r ea ct ion b et w een o-t olu a ld e-
h yd e a n d EDA: 3-Hydroxy-2-(2-methylphenyl)acrylic acid
ethyl ester (13)20 was isolated in 60% yield from the reaction
of 0.28 mL (2.04 mmol) of HBF4‚OEt2, 2.5 g (20.39 mmol) of
HBF 4‚OEt2-ca ta lyzed r ea ction betw een fu r fu r a ld e-
h yd e a n d EDA: 50% of 3-hydroxy-2-(2-furyl)acrylic acid ethyl
ester (8)6 was isolated from the reaction of 0.50 g (5.2 mmol)
of furfuraldehyde, 0.0457 g (0.5 mmol) of HBF4, and 0.65 mL
(6.24 mmol) of EDA at -78 °C. 1H NMR (CDCl3, 300 MHz): δ
12.3 (d, 1H), 7.8 (d, 1H), 7.3 (s, 1H), 6.4 (d, 2H), 4.4 (q, 2H),
1.3 (t, 3H). In addition, 50% of 3-oxo-3-(2-furyl)propanoic acid
1
tolualdehyde, and 2.859 g (24.468 mmol) of EDA at 0 °C. H
NMR (CDCl3, 300 MHz): δ 12.0 (d, 1H), 7.3 (m, 5H), 4.2 (q,
2H), 2.22 (s, 3), 1.24 (q, 3H). In addition, 35% of 3-oxo-3-(2-
methylphenyl)propanoic acid ethyl ester (14)21 was isolated.
1H NMR (CDCl3, 300 MHz): δ 6.9-7.5 (m, 4H), 5.70 (s,1H),
2.40 (s, 3H), 2.04 (s, 3H).
Ir on Lew is a cid -ca ta lyzed r ea ction betw een o-tolu a l-
d eh yd e a n d EDA: 3-Hydroxy-2-(2-methylphenyl)acrylic acid
ethyl ester (13)20 was isolated in 74% yield from the reaction
of 0.206 g (0.58 mmol) of 1, 0.70 g (5.83 mmol) of tolualdehyde,
and 0.735 g (6.99 mmol) of EDA at 0 °C for 24 h. In addition,
15% of 3-oxo-3-(2-methylphenyl)propanoic acid ethyl ester
(14)21 was isolated.
HBF 4‚OEt 2-ca ta lyzed r ea ction betw een p-tolu a ld e-
h yd e a n d EDA: 3-Hydroxy-2-(4-methylphenyl)acrylic acid
ethyl ester (15)4,13 was isolated 51% yield from the reaction of
0.0046 mL (0.34 mmol) of HBF4‚OEt2, 0.41 mL (3.4 mmol) of
p-tolualdehyde, and 0.50 mL (4.2 mmol) of EDA at 0 °C. 1H
1
ethyl ester (9)15 was isolated. H NMR (CDCl3, 300 MHz): δ
13.4 (s, 1H), 7.8 (s,1H), 7.6 (s, 1H). At 0 °C under similar
conditions there were unidentified decomposition products.
Ir on Lew is a cid -ca ta lyzed r ea ction betw een fu r fu r a l-
d eh yd e a n d EDA: 3-Hydroxy-2-(2-furyl)acrylic acid ethyl
ester (8)6 was isolated in 70% yield from 0.50 g (5.2 mmol) of
furfuraldehyde, 0.0457 g (0.52 mmol) of 1, and 0.65 mL (6.24
1
mmol) of EDA at 0 °C. H NMR (CDCl3, 300 MHz): δ 12.3 (d,
1H), 7.8 (d, 1H), 7.3 (s, 1H), 6.4 (d, 2H), 4.4 (q, 2H), 1.3 (t,
3H). There was no 3-oxo-3-(2-furyl)propanoic acid ethyl ester
(9).15 There was no reaction at -78 °C under similar conditions,
only furfuraldehyde was recovered.
HBF 4‚OEt2-ca ta lyzed r ea ction betw een a cetop h en on e
a n d EDA: 2-Phenylacetoacetic acid ethyl ester (10)16 was
isolated in 74% yield from the reaction of 2.0 g (0.0166 mol) of
acetophenone, 0.5 mL (3.32 mmol) of HBF4‚OEt2, and 5.0 mL
(0.05 mol) of EDA at room temperature. 1H NMR (CDCl3, 300
MHz): δ 13.14 (s, 1H), 7.1-7.4 (m, 5H), 4.7 (s, 1H), 4.25 (q, J
) 7.1 Hz), 2.20 (s, 3H), 1.87 (s, 3H), 1.29 (t, 3H, J ) 7.2 Hz),
1.20 (t, 3H, J ) 7.2). There was no reaction at 0 °C under
similar conditions, only acetophenone was recovered.
Ir on Lew is a cid -ca ta lyzed r ea ction betw een a cetop h e-
n on e a n d EDA: 2-Phenylacetoacetic acid ethyl ester (10)16
was isolated in trace amount from 0.2 g (1.66 mmol) of
(17) Henke, B. R.; Aquino, C. J .; Birkemo, L. S.; Croom, D. K.;
Dougherty, R. W., J r.; Ervin, G. N.; Grizzle, M. K.; Hirst, G. C.; J ames,
M. K.; J ohnson, M. F.; Queen, K. L.; Sherrill, R. G.; Sugg, E. E.; Suh,
E. M.; Szewczyk, J . W.; Unwalla, R. J .; Yingling, J .; Willson, T. M. J .
Med. Chem. 1997, 40, 2706.
(18) Cushman, M.; Nagarathnam, D.; Burg, D. L.; Geahlen, R. L.
J . Med. Chem. 1991, 34, 798.
(19) Kakehi, A.; Ito, S.; Funahashi, T.; Ota, Y. J . Org. Chem. 1976,
41, 1570.
(20) Hornback, J . M.; Poundstone, M. L.; Vadlamani, B.; Graham,
S. M.; Gabay, J .; Patton, S. T. J . Org. Chem., 1988, 53, 5597.
(21) (a) Sicker, D.; Mann, G. Collect. Czech. Chem. Commun. 1998,
53, 839. (b) Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. J .
Am. Chem. Soc. 2002, 124, 4952.
(15) Balaji, B. S.; Chanda, B. M. Tetrahedron 1998, 54 (43), 13237.
(16) Kagan, J .; Agdeppa, D. A., J r.; Mayers, D. A.; Singh, S. P.;
Walters, M. J .; Wintermute, R. D. J . Org. Chem. 1976, 41, 2355.
7606 J . Org. Chem., Vol. 69, No. 22, 2004

Synthesis of 3-Hydroxy-2-arylacrylic Acid Ethyl Esters
NMR (CDCl3, 300 MHz): δ 12.2 (d, 1H), 7.3 (m, 5H), 2.4 (s,
3H). In addition, 15% of 3-oxo-3-(4-methylphenyl)propanoic
acid ethyl ester (16)4,14 was isolated. 1H NMR (CDCl3, 300
MHz): δ 7.2-7.8 (m, 4H), 4.17 (q, 2H), 3.92 (s, 2H), 2.36 (s,
3H), 1.22 (t, 3H).
Ir on Lew is a cid -ca ta lyzed r ea ction betw een p-tolu a l-
d eh yd e a n d EDA: 3-Hydroxy-2-(4-methylphenyl)acrylic acid
ethyl ester (15)4,13 was isolated in 67% yield from the reaction
of 0.1158 g (0.34 mmol) of 1, 0.50 mL (4.1 mmol) of p-
tolualdehyde, and 0.40 mL (3.4 mmol) of EDA at 0 °C. In
addition, 19% of 3-oxo-3-(4-methylphenyl)propanoic acid ethyl
ester (16)4,14 was isolated.
Anal. Calcd for C11H10O6: C, 48.63; H, 3.71; N, 5.16. Found:
C, 48.97; H, 3.92; N, 4.71.
Ir on Lew is a cid -ca ta lyzed r ea ction betw een 2-n itr o-
5-ch lor oben za ld eh yd e a n d EDA: 3-Hydroxy-2-(2-nitro-5-
chlorophenyl)acrylic acid ethyl ester (21) was isolated in 35%
yield and 3-oxo-3-(2-nitro-5-chlorophenyl)propanoic acid ethyl
ester (22) in 20% yield from the reaction of 0.037 g (0.11 mmol)
of 1, 0.2 g (1.1 mmol) of 2-nitro-5-chlorobenzaldehyde, and
0.154 g (1.32 mmol) of EDA at 0 °C for 24 h.
HBF 4‚OEt2-ca ta lyzed r ea ction betw een 2-n itr over a -
tr a ld eh yd e a n d EDA: 3-Hydroxy-2-(2-nitro-4,5-dimethoxy-
phenyl)acrylic acid ethyl ester (24) was isolated in 76% yield
from the reaction of 0.040 mL (0.25 mmol) of HBF4‚OEt2, 0.410
g (2.0 mmol) of 2-nitroveratraldehyde, and 0.41 mL (3.72
HBF 4‚OEt2-ca ta lyzed r ea ction betw een 2,5-d im eth yl-
ben za ld eh yd e a n d EDA: 3-Hydroxy-2-(2,5-dimethylphenyl)-
acrylic acid ethyl ester (17)22 was isolated in 45% yield from
the reaction of 0.168 g (0.122 mmol) of HBF4‚OEt2, 1.5 g (12.26
mmol) of 2,5-dimethylbenzaldehyde, and 1.96 mL (16.78 mmol)
1
mmol) of EDA at -78 °C for 24 h. H NMR(CDCl3, 300 MHz):
δ 11.93 (d, 1H, J ) 13 Hz), 8.11 (d, 1H, J ) 9 Hz), 7.28 (d, 1H,
J ) 13 Hz), 6.92 (m, 1H), 6.73 (d, 1H, J ) 3 Hz), 4.16 (br q,
2H), 3.93 (s, 3H), 1.19 (t, 3H, J ) 7 Hz). 13C NMR (CDCl3,
75.5 MHz): δ 169.9, 163.0, 161.4, 142.1, 131.8, 127.4, 117.4,
112.6, 107.2, 61.1, 55.8, 13.7. Anal. Calcd for C12H13NO6: C,
53.93; H, 4.90; N, 5.24. Found: C, 53.68; H, 4.92; N, 5.02. No
â-keto ester was isolated from this reaction.
1
of EDA at 0 °C for 24 h. H NMR (CDCl3, 300 MHz): δ 12.0
(d, 1H), 7.3 (m, 5H), 4.2 (q, 2H), 2.19 (s, 3H), 2.13 (s, 3H), 1.20
(t, 3H). In addition, 35% of 3-oxo-3-(2,5-dimethylphenyl)-
propanoic acid ethyl ester (18)23 was isolated. 1H NMR (CDCl3,
300 MHz): δ 7-7.5 (m, 3H), 4.24 (q, 2H), 3.95 (s, 2H), 2.35 (s,
3H), 2.18 (s, 3H), 1.33 (t, 3H).
NMR stu d y of EDA w ith 0.1 equ iv of HBF 4‚OEt2 a n d
ben za ld eh yd e: A 1:0.1 ratio of EDA to HBF4‚OEt2 was
cautiously prepared by mixing in a 5-mm NMR tube 0.6 mL
of CDCl3, 0.0394 mL (0.312 mmol) of EDA, and 0.0043 mL
(0.031 mmol) of HBF4‚OEt2. A total of 0.0315 mL (0.0312
mmol) of benzaldehdyde was titrated in thirds and product
was observed by 1H NMR. The resultant NMR sample was
passed through 0.2 g of silica gel and the product completely
isomerized to 3-hydroxy-2-phenylacrylic acid ethyl ester (2)13
as observed by NMR.
NMR titr a tion of ben za ld eh yd e w ith HBF 4‚OEt2: The
NMR sample was prepared by mixing 0.0315 mL (0.0312
mmol) of benzaldehyde and 0.6 mL of CD2Cl2 in a 5-mm NMR
tube. The tube was then cooled in a dry ice/acetone bath and
13C decoupled and coupled NMR spectra recorded at 173K. The
sample was then titrated with 0.0428 mL (0.0312 mmol, 1.0
equiv), 0.0642 mL (0.0468 mmol, 2.5 equivs total), and 0.1284
mL (0.0936 mmol, 6.5 equiv total) of HBF4‚OEt2, respectively.
After each titration of acid, the 13C decoupled and coupled
NMR spectra were recorded at 173 K.
Ir on Lew is a cid -ca t a lyzed r ea ct ion b et w een 2,5-d i-
m eth ylben za ld eh yd e a n d EDA: 3-Hydroxy-2-(2,5-dimeth-
ylphenyl)acrylic acid ethyl ester (17)22 was isolated in 72%
yield from the reaction of 0.175 g (0.5217 mmol) of 1, 0.718 g
(5.217 mmol) of 2,5-dimethylbenzaldehyde, and 0.658 g (6.26
mmol) of EDA at 0 °C for 24 h. In addition, 20% of 3-oxo-3-
(2,5-dimethylphenyl)propanoic acid ethyl ester (18)23 was
isolated.
HBF 4‚OEt2-ca ta lyzed r ea ction betw een p-br om oben z-
a ld eh yd e a n d EDA: 3-Hydroxy-2-(4-bromophenyl)acrylic acid
ethyl ester (19)13 was isolated in 55% yield from 0.15 mL (1.60
mmol, 300 mg) of p-bromobenzaldehyde, 0.022 mL (0.16 mmol)
of HBF4‚OEt2, and 0.261 mL (1.92 mmol) of EDA at 0 °C for
1
24 h. H NMR (CDCl3, 300 MHz): δ 12.08 (d, 1H, J ) 13 Hz),
7.27 (d 1H, J ) 13 Hz), 7.18 (d, 2H, J ) 9 Hz), 6.9 (d, 2H, J )
9 Hz), 1.26 (t, 3H). In addition, 34% of 3-oxo-3-(4-bromophen-
yl)propanoic acid ethyl ester (20) was isolated. 1H NMR
(CDCl3, 300 MHz): δ 7.3-6.9 (m, 4H), 4.27 (q, 2H), 1.26 (t,
3H).
Ir on Lew is a cid -ca ta lyzed r ea ction betw een p-br o-
m oben za ld eh yd e a n d EDA: 3-Hydroxy-2-(4-bromophenyl)-
acrylic acid ethyl ester (19)13 was isolated in 62% yield from
the reaction of 0.33 g (1.78 mmol) of p-bromobenzaldehyde,
0.0334 mL (0.101 mmol) of 1, and 0.291 mL (2.14 mmol) of
EDA at 0 °C for 24 h. In addition, 17% of 3-oxo-3-(4-
bromophenyl)propanoic acid ethyl ester (20)24 was isolated.
P r oton Sp on ge Stu d y: Gen er a l P r oced u r e. The same
general procedure was followed except that Proton Sponge was
added to the reaction flask before the EDA was added.
Ir on Lew is a cid -ca ta lyzed r ea ction betw een ben za l-
d eh yd e a n d EDA w ith P r oton Sp on ge: At 0.1 equiv of
Proton Sponge, 3-hydroxy-2-phenylacrylic acid ethyl ester (2)13
was observed in 50% conversion relative to benzaldehyde
starting material by 1H NMR from the reaction of 0.0633 g
(0.188 mmol) of 1, 0.200 g (1.88 mmol) of benzaldehyde, 0.0396
g (0.188 mmol) of Proton Sponge, and 0.263 mL (2.256 mmol)
of EDA at room temperature.
At 0.01 equiv of Proton-Sponge, 3-hydroxy-2-phenylacrylic
acid ethyl ester (2)13 was observed in 60% conversion relative
to benzaldehyde starting material by 1H NMR from the
reaction of 0.0633 g (0.188 mmol) of iron Lewis acid (1), 0.200
g (1.88 mmol) of benzaldehyde, 0.004 g (0.0188 mmol) of Proton
Sponge, and 0.263 mL (2.256 mmol) of EDA at room temper-
ature.
HBF 4‚OEt2-ca ta lyzed r ea ction betw een ben za ld eh yd e
a n d EDA w ith P r oton Sp on ge: 3-Hydroxy-2-phenylacrylic
acid ethyl ester (2)13 was observed in 5% conversion relative
to benzaldehyde starting material by 1H NMR from the
reaction of 0.405 g (3.98 mmol) of benzaldehyde, 0.0566 mL
(0.398 mmol) of HBF4‚OEt2, 0.0853 g (0.398 mmol) of Proton
Sponge, and 0.560 mL (4.80 mmol) of EDA at room tempera-
ture.
HBF 4‚OEt2-ca ta lyzed r ea ction betw een 2-n itr o-5-ch lo-
r oben za ld eh yd e a n d EDA: 3-Hydroxy-2-(2-nitro-5-chlo-
rophenyl)acrylic acid ethyl ester (21) was isolated in 45% yield
from the reaction of 0.015 mL (0.11 mmol) of HBF4‚OEt2, 0.2
g (1.1 mmol) of 2-nitro-5-chlorobenzaldehyde, and 0.154 g (1.32
mmol) of EDA at 0 °C. 1H NMR (CDCl3, 300 MHz): δ 12.04
(d, 1H, J ) 13 Hz), 8.00 (d, 1H, J ) 7 Hz), 7.46 (d, 1H, J ) 5
Hz), 7.34 (d, 1H, J ) 2 Hz), 7.30 (s, 1H), 4.19 (br q, 2H, J ) 3
Hz), 1.90 (t, 3H, J ) 7 Hz). 13C NMR (CDCl3, 75.5 MHz): δ
169.4, 162.4, 147.2, 139.3, 132.0, 130.9, 129.2, 126.4, 105.8,
61.4, 14.0. High-resolution mass (m/z): obsd 271.023881 amu,
calcd 271.024750 amu. In addition, 33% of 3-oxo-3-(2-nitro-5-
1
chlorophenyl)propanoic acid ethyl ester (22) was isolated. H
NMR (CDCl3, 300 MHz): δ 8.15 (d, 1H, J ) 8.6 Hz), 7.61 (d,
1H, J ) 8.8 Hz), 7.51 (d, 1H, J ) 2.2 Hz), 4.19 (q, 2H, J ) 7.3
Hz), 3.89 (s, 2H), 1.27 (t, 3H, J ) 7.2 Hz). 13C NMR (CDCl3,
75.5 MHz): δ 193.2, 167.4, 130.7, 129.1, 126.1, 61.5, 48.8, 13.9.
(22) Gustafsson, D.; Nystrom, J .-e. PCT Int. Appl. 136, 1997.
(23) Hofer, W.; Maurer, F.; Riebel, H. J .; Schroeder, R.; Uhrhan, P.;
Homeyer, B.; Behrenz, W.; Hammann, I. Ger. Offen. 39, 1977.
(24) Emelina, E. E.; Semenova, N. A.; Ershov, B. A. Zh. Organ-
icheskoi Khim. 1974, 10, 1034.
Na BF 4-ca ta lyzed r ea ction betw een ben za ld eh yd e a n d
EDA: Only starting materials were observed by 1H NMR from
the reaction of 0.0437 g (0.40 mmol) of NaBF4, 0.405 g (3.98
J . Org. Chem, Vol. 69, No. 22, 2004 7607

Dudley et al.
mmol) of benzaldehyde, and 0.56 mL (4.80 mmol) of EDA at
room temperature with stirring.
HNO3-ca ta lyzed r ea ction betw een ben za ld eh yd e a n d
EDA: 3-Hydroxy-2-phenylacrylic acid ethyl ester (2)13 was
observed in 3.7% conversion relative to benzaldehyde starting
material by 1H NMR from the reaction of 0.405 mL (3.98 mmol)
of benzaldehyde, 0.024 mL (15.8 M, 0.40 mmol) of HNO3, and
0.56 mL (4.8 mmol) of EDA at room temperature. In addition,
0.2% of 3-oxo-3-phenylpropanoic acid ethyl ester (3)14 was
observed.
At 0 °C, 3-hydroxy-2-phenylacrylic acid ethyl ester (2)13 was
isolated in 18% yield from 0.027 mL (15.8 M, 0.42 mmol) of
HNO3, 0.43 mL (4.2 mmol) of benzaldehyde, and 0.5 mL (5.0
mmol) of EDA.
HClO4-ca ta lyzed r ea ction betw een ben za ld eh yd e a n d
EDA: 3-Hydroxy-2-phenylacrylic acid ethyl ester (2)13 was
isolated in 10% yield from 0.046 mL (9.2 M, 0.042 mmol) of
HClO4, 0.43 mL (4.2 mmol) of benzaldehyde, and 0.5 mL (5.0
mmol) of EDA at 0 °C.
H2SO4-ca ta lyzed r ea ction s betw een ben za ld eh yd e a n d
EDA: 3-Hydroxy-2-phenylacrylic acid ethyl ester (2)13 was
observed in 5.6% conversion relative to benzaldehyde starting
material by 1H NMR from the reaction of 0.405 mL (3.98 mmol)
of benzaldehyde, 0.0213 mL (0.40 mmol) of H2SO4, and 0.56
mL (4.8 mmol) of EDA at room temperature. In addition, 0.2%
of 3-oxo-3-phenylpropanoic acid ethyl ester (3)14 was observed
and 20% of 2,2′-[sulfonylbis(oxy)]bisacetic acid diethyl ester
(27) was observed and characterized. 1H NMR (CDCl3, 300
MHz): δ 4.82 (s, 4H), 4.22 (q, 4H), 1.27 (t, 6H). 13C NMR
(CDCl3, 75.5 MHz): δ 67.2, 62.2, 13.9. FAB MS [M + 1]:
271amu. Anal. Calcd for C8H14O8S: C, 35.56; H, 5.223.
Found: C, 35.44; H, 5.11.
Br øn sted Acid Stu d y: Gen er a l P r oced u r e. About 0.1
equiv of acid catalyst was transferred to a flame-dried flask
and dissolved in the appropriate solvent (if not soluble, then
enough CH2Cl2 was added to completely dissolve the catalyst).
The corresponding amount of 1.0 equiv of benzaldehyde was
added and then 1.2 equiv of EDA dissolved in a small amount
of CH2Cl2 was added over 1 h. The reaction was allowed to
stir 12-18 h. Crude product was filtered through a small
amount of silica with ether and the solvent was removed by
rotary evaporation. The ratio of 3-hydroxy-2-phenylacrylic acid
ethyl ester (2)13 to â-keto ester (3)14 was monitored by integrat-
ing OH doublet at ∼12 ppm and the CH2 â-keto ester singlet
at ∼3.8 ppm in the 1H NMR spectra.
Acetic a cid -ca ta lyzed r ea ction betw een ben za ld eh yd e
a n d EDA: 3-Hydroxy-2-phenylacrylic acid ethyl ester (2)13 was
observed in 0.4% conversion relative to benzaldehyde starting
1
material by H NMR from the reaction of 0.405 g (3.98 mmol)
of benzaldehyde, 0.023 mL (0.398 mmol) of acetic acid, and
0.56 mL (4.80 mmol) of EDA at room temperature. In addition,
0.1% of 3-oxo-3-phenylpropanoic acid ethyl ester (3)14 was
observed.
HCl (d r y)-ca ta lyzed r ea ction betw een ben za ld eh yd e
a n d E DA: 3-Hydroxy-2-phenylacrylic acid ethyl ester (2)13
was observed in 0.4% conversion relative to benzaldehyde
starting material by 1H NMR from the reaction of 0.405 mL
(3.98 mmol) of benzaldehyde, 0.015 g (0.41 mmol) of HCl dry
gas, and 0.56 mL (4.8 mmol) of EDA at room temperature. In
addition, 0.1% of 3-oxo-3-phenylpropanoic acid ethyl ester (3)14
and 10% of ethyl chloroacetate was observed.
HCl (con cen tr a ted )-ca ta lyzed r ea ction betw een ben z-
a ld eh yd e a n d EDA: No 3-hydroxy-2-phenylacrylic acid ethyl
ester (2)13 or â-keto ester were isolated from the reaction of
0.035 mL (12 M, 0.042 mmol) of HCl, 0.43 mL (4.2 mmol) of
benzaldehyde, and 0.5 mL (5.0 mmol) of EDA at 0 °C.
At 0 °C, 3-hydroxy-2-phenylacrylic acid ethyl ester (2)13 was
isolated in 26% yield from 0.024 mL (18.1 M, 0.042 mmol) of
H2SO4, 0.43 mL (4.2 mmol) of benzaldehyde, and 0.5 mL (5.0
mmol) of EDA.
J O0489418
7608 J . Org. Chem., Vol. 69, No. 22, 2004