Nájera oxime-derived palladacycles catalyze intermolecular Heck reaction with Morita-Baylis-Hillman adducts. An improved and highly efficient synthesis of α-benzyl-β-ketoesters

Article abstract of DOI:10.1016/j.tet.2009.06.084

An improved and highly efficient synthesis of several α-benzyl-β-ketoesters from Morita-Baylis-Hillman adducts is described. These adducts were used as substrates for an intermolecular Heck reaction catalyzed by a Na?jera oxime-derived palladacycles. These efficient catalytic conditions probed to be very selective providing only the corresponding functionalized β-ketoesters in high yield with no decarboxylation product. It seems that the method herein described is one of the most efficient for the synthesis of α-benzyl-β-ketoesters.

Full text of DOI:10.1016/j.tet.2009.06.084

Tetrahedron 65 (2009) 7712–7717
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
´
Najera oxime-derived palladacycles catalyze intermolecular Heck reaction
with Morita–Baylis–Hillman adducts. An improved and highly efficient
synthesis of a-benzyl-b-ketoesters
*
Bruno R.V. Ferreira, Rodrigo V. Pirovani, Luis G. Souza-Filho, Fernando Coelho
Laboratory of Synthesis of Natural Products and Drugs, Institute of Chemistry, PO Box 6154, University of Campinas, UNICAMP, 13084-971, Campinas, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 May 2009
Received in revised form 15 June 2009
Accepted 19 June 2009
Available online 25 June 2009
An improved and highly efficient synthesis of several a-benzyl-b-ketoesters from Morita–Baylis–Hillman
adducts is described. These adducts were used as substrates for an intermolecular Heck reaction catalyzed by
´
a Najera oxime-derived palladacycles. These efficient catalytic conditions probed to be very selective pro-
viding only the corresponding functionalized -ketoesters in high yield with no decarboxylation product. It
seems thatthe methodherein described isone of the mostefficientfor the synthesis of -benzyl- -ketoesters.
Ó 2009 Elsevier Ltd. All rights reserved.
b
a
b
The authors dedicate this paper in memo-
rium of the recently deceased Prof. Octa´vio
Antunes for his outstanding contributions to
brazilian palladium chemistry
Keywords:
C–C bond formation
Heck reaction
Morita–Baylis–Hillman reaction
Palladacycles
1. Introduction
Cl
Cl
OH
H
3C
The C–C
s bond is the backbone of organic molecules. Hence, the
formation of new C–C bonds is one of the most important trans-
formations in life. In organic chemistry, countless efforts have
therefore been made to develop new, clean, and easy-to-handle
methods to form such unique and crucial bonds.1 Among the most
efficient methods currently available, coupling reactions mediated
by a transition-metal catalyst have been the most attractive. Their
popularity resides in their mild conditions and applications to
a great diversity of functional groups, usually unprotected.
The Heck reaction plays a important role among C–C bond for-
mation methods catalyzed by transition metals.2 Its high synthetic
usefulness has stimulated a search for improved catalysts and ex-
perimental conditions. At present, Heck reactions can be performed
efficiently using an infinitesimal amount of catalyst in the presence
of moisture at room or moderate temperatures.
Pd Cl
N
Pd Cl
N
HO
HO
2
2
1
2
´
Figure 1. Oxime-derived palladacycles developed by Najera.
The palladacycles 1 and 2 are thermally robust, and insensitive
to both oxygen and moisture. They have been shown to function as
efficient phosphine-free Heck precatalysts. In most cases, these
palladacycles are a kind of palladium(0)-repository. Apparently,
they form a nanoparticulate palladium under the reaction condi-
tions, thus increasing their efficiency.5
Acrylates are interesting substrates for the preparation of a va-
riety of functionalized cinnamates or 1,3-dicarbonyl compounds via
Heck reaction (Scheme 1).6,7
Palladacycles have recently attracted great attention as efficient
Heck catalysts,3 eliminating the need of phosphine addition. Ex-
An efficient method to produce such acrylates is the Morita–
Baylis–Hillman (MBH) reaction.8 Highly functionalized acrylates
obtained via MBH reactions have already been used as substrates
for Heck reactions.9 However, MBH adducts are allylic alcohols,
a structural moiety that usually forms a mixture of products when
used as substrate for a Heck reaction, compromising both yield and
amples of palladacycles used as Heck catalysts are the oxime-de-
4
´
rived palladacycles developed by Najera (Fig. 1).
* Corresponding author. Tel.: þ55 19 3521 3085; fax: þ55 19 3521 3023.
E-mail address: coelho@iqm.unicamp.br (F. Coelho).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.084

B.R.V. Ferreira et al. / Tetrahedron 65 (2009) 7712–7717
7713
O
O
Table 1
- HaPdX
Preparation of Morita–Baylis–Hillman adducts
R
O
OH
O
OH
Ha
O
MBH adducts
OH
Heck
Ar
R
O
R
O
α-benzyl-β-ketoesters (3)
O
PdX
Ar
DABCO
O
Hb
Hb
OH
O
ultrasound
R= alkyl or aryl
R
OR1
R
H
R
O
MBH adduct
- HbPdX
CO2R1
R = aryl or alkyl
R1 = Me or Et
Ar
aldehydes
1-12
β-aryl-MBH
adducts (4)
13-24
Scheme 1. Heck reaction using MBH adducts.
Entry
MBH adducts
(%)a
1
2
3
4
5
6
7
8
13, R¼Phenyl; R1¼OCH3
14, R¼Phenyl; R1¼OEt
91
71
81
76
96
90
65
70
91
94
80
85
selectivity.10a–c Thus, this reaction normally produces the coupling
products in moderate yields, resulting in the need for critical ex-
perimental protocols (high temperatures, long reaction times,
special solvents).
The only exception was described some years ago by Basavaiah
and Muthukumaran, in which the combination of Pd(OAc)2/
NaHCO3/n-Bu4NBr (‘Jeffery protocol’) was employed.9a,10d–f Despite
the good yields, there is a long time of reflux, a high amount of
palladium is used, and a small methodological scope, only having
tested three different aryl bromides. Some years ago, we tried to
use Pd(OAc)2, alone or associated, to perform a Heck reaction with
MBH adducts. These experimental conditions work nicely with
some model acrylates, however failed when MBH adducts were
used as substrates.11
15, R¼4-OMe-Ph; R1¼OEt
16, R¼4-tButyl-Ph; R1¼OEt
17, 4-NO2-Ph; R1¼OEt
18, R¼4-ClPh; R1¼OEt
19, R¼Piperonyl; R1¼OEt
20, R¼Piperonyl; R1¼OCH3
21, R¼3,5-di-Fluoro-Phenyl; R1¼OMe
22, R¼3,5-di-Fluoro-Phenyl; R1¼OEt
23, R¼3-Pyridinyl; R1¼OCH3
24, R¼CH2CH3; R1¼OEt
9
10
11
12
a
Yields refer to isolated and purified products (by silica gel column
chromatography).
4
´
concentration. Based on the results previously disclosed by Najera,
a concentration of 0.001 mol % of 1 was employed initially. How-
ever, no coupling product was observed after several hours.
The second experiment (now using 0.01 mol % of catalyst) was
monitored each 15 min, however we observed no significant con-
version after 3 h time. After that, all experiments were performed
for 15 h and monitored by C.G. chromatography. Every three hours,
an aliquot was collected, treated, and analysed by HP-5 column
chromatography. To our delight we were able to observe only
a modest conversion of 22% after 3 h, which increased to 64% after
7 h. No higher conversion percentage was observed ever after 15 h.
We next investigated the impact of the catalyst concentration. The
results of this study are summarized in Table 2.
An experimental protocol to prepare a-substituted cinnamates
such as 4 (Scheme 1), in moderate to good yields, has been recently
described by Kim et al.9h Some years ago, we described the syn-
thesis of 3 using MBH adducts as substrates of a Heck reaction with
diazonium salts in moderate yields (Scheme 1).9f
a
-Benzyl-b-ketoesters such as 3 (Scheme 1) are important
substrates for synthetic transformations, such as asymmetric dy-
namic resolution, asymmetric biotransformations, and the syn-
thesis of heterocyclic compounds and natural products.12
The preparation of this type of compound requires the use of
a special base, anhydrous conditions and low temperatures. Then,
the use of a Heck reaction should be a very attractive alternative for
their syntheses.
The increase in the catalyst concentration led to a direct increase
in conversion resulting in a shortened net reaction time (compare
entries 2, 5 and 6). The best experimental conditions were in which
In a researchprogramdirected toward the asymmetricresolution
of b-ketoesters, weneeded to selectively prepare a setof a-benzyl-b-
ketoesters. We therefore decided to search for conditions yielding
optimal intermolecular Heck reactions using MBH adducts.
Herein we report a protocol leading to a simple, direct, selective,
and fast synthesis of 3 and derivatives. It is based on an in-
termolecular Heck reaction of MBH adducts with aryl halides me-
Table 2
Evaluation of the concentration of Na´jera catalyst (1) for the intermolecular Heck
reaction with MBH adducts
O
O
OH
O
Nájera
catalyst
OEt
OEt
´
diated by Najera oxime-derived palladacycles. These palladacycles
DMF, 110 °C
PhI, Et3
could contribute toward increasing the efficiency of an in-
termolecular Heck reaction with a particularly troublesome sub-
strates such as Morita–Baylis–Hillman adducts.
N
MBH adduct (13)
Intermolecular Heck
product (25)
2. Results and discussion
Entry
Reaction conditionsa
Catalyst (mol %)
Conversion (%)b,c
3h
7h
15h
We start our investigation by preparing a set of different MBH
adducts using a methodpreviouslydescribed byourresearchgroup.13
Thus, aldehydes (1–12) were treated with an excess of methyl or
ethyl acrylate in the presence of DABCO. The mixture was placed in
an ultrasound bath to give the corresponding adducts in good to
excellent yields (Table 1).
1
2
3
4
5
6
7
8
9
0.001
0.01
0.025
0.05
0.1
0.25
0.5
0.75
1.0
0
0
0
22
32
46
54
92
>98
85
76
64
62
60
62
d
d
d
d
d
d
d
90
d
d
d
d
´
Having the adducts on hand, we began to evaluate the Najera
catalysts. Initially, we choose to work with catalyst 1 (Fig. 1), since it
is the most adequate for reactions performed in organic solvents.
The intermolecular Heck reaction between the adduct obtained
from benzaldehyde and phenyl iodide was used as a model to test
for reaction feasibility as well as determine the best catalyst
a
All reactions were performed in DMF at 110 ꢀC, using triethylamine as base.
Conversions were determined by GC chromatography using a HP-5 column.
No alteration was detected in conversion when a longer warming period was
b
c
used (24 h).

7714
B.R.V. Ferreira et al. / Tetrahedron 65 (2009) 7712–7717
0.5 mol % of catalyst 1 was employed (see entry 7), in a solution of
DMF warmed at 110 ꢀC, in the presence of triethylamine for 3 h.
Under this simple and relatively easy protocol the intermolecular
Heck products were obtained very clean with very good yields and
selectivity, after purification by silica gel column chromatography.
1,3-Dicarbonyl compounds are prone to decarboxylate under
warming, however when the methyl esters were used, only a tiny
amount of decarboxylation product was detected. Replacing the
methyl ester for the corresponding ethyl ester led to the desired
Heck product with no decarboxylation product detected (Table 2).
We also observed that shorter reaction times avoid decarboxylation
sideproducts, allowing the use of both methylorethylesters equally.
The concentration of 0.5 mol % was then used as a standard
concentration for the next steps. Different MBH adducts were
submitted to coupling reactions with phenyl iodide, bromide and
aryl iodides (Table 3).
Although those types of b-ketoesters could be prepared by di-
rect benzylation of 1,3-dicarbonyl compounds, the strategy de-
scribed herein is a valuable alternative for the preparation of these
compounds. It does not require special experimental conditions
(non-nucleophilic bases, special enolates, low temperature), and
avoids mixtures of products normally obtained when different es-
ters are used in a classical Claisen reaction.14 This is also the first
report describing the use of palladacycles to perform an in-
termolecular Heck reaction with MBH adducts. Further studies are
ongoing in our laboratory aiming at extending the scope of this
reaction. We intend to develop intramolecular versions that will be
disclosed in due time.
3. Experimental
3.1. General methods
The following procedures are representative for all the Baylis-
Hillman adducts and a-benzyl-b-ketoesters prepared in this work.
Table 3
Heck reaction between MBH adducts and aryl halides catalyzed by Na´jera pallada-
cycle 1
All the reagents were purchased from specialized suppliers with
analytical purity and were utilized without previous purification,
unless noted. The 1H and 13C spectra were recorded on a Bruker at
250 MHz and 62.5 MHz, respectively, or on an Inova instrument at
500 MHz and 125 MHz, respectively. The mass spectra were
recorded using a Micromass (Manchester, UK) QT of instrument of
ESI-QT of configuration with 5000 mass resolution and 50 ppm
mass accuracy in the TOF mass analyzer. IR were obtained with
a Nicolet model Impact 410. Only the spectral data of the unknown
Morita–Baylis–Hillman adducts are enclosed.
Entry
MBH adduct
Reaction conditionsa
ArX
Yieldb,c (%)
Base
1
2
3
4
5
6
7
8
13
13
14
14
15
16
17
18
19
20
20
21
22
22
23
24
PhI
Et3N
Et3N
Et3N
K2CO3
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
K2CO3
Et3N
Et3N
25, 81
26, 30
27, 85
27, 83
28, 95
29, 78
30, 85
31, 81
32, 85
33, 84
34, 87
35, 89
36, 79
36, 82
37, 70
38, 87
4-NO2-PhI
PhI
d
PhBr
PhI
PhI
PhI
PhI
PhI
9
3.2. General experimental protocol for the preparation of the
Morita–Baylis–Hillman adducts
10
11
12
13
14
15
16
4-MeO-PhI
4-HO-PhIe
PhI
PhI
PhBr
PhI
A mixture of aldehyde (1–2 mmol,1–12), methyl or ethyl acrylate
(20 equiv, used as reagent and solvent), and DABCO (0.65 equiv) was
sonicated (180 W, 25 kHz) for a certain period of time (5–96 h). The
ultrasound bath temperature was constantly monitored and kept at
30–40 ꢀC during the reaction, through ice addition or by using a re-
frigerated circulator. After the reaction time, the mixture was evap-
orated under reduced pressure in order to remove the excess
of acrylate. The residue was diluted with dichlorometane or ethyl
acetate (30 mL). The organic solution was washed with 10% aqueous
HCl (2ꢁ10 mL), saturated NaHCO3 (20 mL), brine (20 mL), and dried
over Na2SO4. After filtration and solvent removal, the residue was
filtered through a pad of gel of silica to afford the corresponding
Morita-Baylis-Hillman adducts (13–24) in good to excellent yield.
d
PhI
a
Reactions were carried out in DMF at 110 ꢀC for 3 h.
Yields refer to isolated and purified products.
In some cases, besides the Heck coupling product a tiny amount (2–4%) of
b
c
starting material was detected, however without consequences for the yield.
d
In this particular case TBAB should be used as additive and the reaction was
performed at 130 ꢀC.
e
In this case was used 2.8 equiv of Et3N.
In every case, the yields were higher than those described pre-
viously using diazonium salts.9f The reaction time and yields are
also better than some described using Pd(OAc)2.8a–e,g,i
The reaction works quite well with all MBH adducts tested,
regardless of the nature of aromatic substituents. The only ex-
ception occurred when 4-nitro-iodophenol was used (entry 2,
Table 3). In this particular case a low yield was observed, although
no optimization has been performed Nevertheless, the reaction
worked well even for heterocyclic aromatic rings (see entry 15).
The reactions are very clean and can be easily purified by usual
chromatographic methods. We also achieved a high degree of se-
lectivity with no mixture of products detected. This result was
remarkable considering that our substrates were highly function-
alized allylic alcohols.
3.3. General experimental protocol for the synthesis of
a-benzyl-b-keto esters
A 10-mL round-bottom flask was charged with 4-iodophenol
(81.4 mg, 0.37 mmol), Morita–Baylis–Hillman adduct 8 (127 mg,
0.54 mmol), triethylamine (0.2 mL, 1.51 mmol), palladacycle
(2.2 mg, 0.0027 mmol, 0.5 mol % Pd) and DMF (2-3 mL). The mix-
ture was stirred at 110 ꢀC in air and the reaction progress was an-
alyzed by TLC. The crude reaction mixture was extracted with water
and EtOAc (3ꢁ15 mL). The organic phase was dried over Na2SO4,
evaporated and the resulting crude product was purified by silica
gel flash chromatography (hexane/EtOAc) to give the correspond-
1
In summary, a very efficient strategy to synthesize highly
functionalized
b
-ketoesters from MBH adducts has been estab-
ing a-benzyl-b-keto ester.
lished. The selectivity observed is high with no detected side
products. Currently, it seems to be the most efficient phosphine-
free Heck reaction using MBH adducts, and may be used to afford
a myriad of useful intermediates for organic synthesis. This protocol
is more efficient than the Jeffery protocol, since the amount of
catalyst and the reaction time are lower.
3.4. General protocol for the Heck coupling with aryl bromide
A 10-mL, round-bottom flask was charged with aryl bromide
(40mL, 0.38 mmol), Morita–Baylis–Hillman adducts 22 (77.3 mg,
0.32 mmol),
potassium carbonate (62 mg, 0.45 mmol),

B.R.V. Ferreira et al. / Tetrahedron 65 (2009) 7712–7717
7715
tetrabutylamonium bromide (21 mg, 0.064 mmol, 20 mol %), pal-
(62.5 MHz, CDCl3):
d
166.2; 164.9 (d, J¼12.6 Hz, C–F aromatic);
ladacycle 1 (1.3 mg, 0.0016 mmol, 0.5 mol % Pd) and DMF (2–3 mL).
The mixture was stirred at 130 ꢀC in air and the reaction progress
was analyzed by TLC. The reaction mixture was diluted in ethyl
acetate (30 mL) and washed with distilled water (4ꢁ10 mL). The
organic phase was dried over Na2SO4 and evaporated. The crude
residue was purified by preparative thin layer chromatography to
161.0 (d, J¼12.6 Hz, C–F aromatic); 145.5 (t, J¼8.5 Hz); 140.9; 109.4
(d, J¼25.5 Hz); 109.3 (d, J¼7.8 Hz); 103.2 (t, J¼25.4 Hz); 72.5 (t,
J¼2.1 Hz); 52.1; 46.3; IR (film): 3396, 1719, 1625, 1598, 1459, 1441,
1313, 1270, 1196, 1154, 1057, 991 cmꢂ1. HRMS (ESI, m/z) Calcd for
C11H10F2O3 228.0598. Found: 251.0408 [Mþ þNa (23)].
ꢃ
give the corresponding
a
-benzyl-
b-keto ester (36).
3.5.7. Ethyl 2-[(3,5-difluorophenyl)(hydroxy)methyl]prop-2-
enoate (22)
3.5. Characterization data
Colorless viscous oil. 94% yield; 1H NMR (250 MHz, CDCl3):
d
6.91 (dd, J¼1.8 Hz and J¼8.3 Hz, 2H); 6.69 (tt, J¼2.3 Hz and 8.9 Hz,
3.5.1. Ethyl 2-[hydroxy(phenyl)methyl]prop-2-enoate (14)
1H); 6.35 (s, 1H); 5.87 (t, J¼1.0 Hz, 1H); 5.47 (d, J¼5.6 Hz, 1H); 4.15
(q, J¼7.1 Hz, 2H); 3.97 (d, J¼5.8 Hz, 1H); 2.47 (sl, 1H); 1.24 (t,
Pale yellow viscous oil. 71% yield; 1H NMR (250 MHz, CDCl3):
d
7.40–7.24 (m, 5H); 6.34 (t, J¼1.0 Hz,1H); 5.81 (t, J¼1.2 Hz,1H); 5.56
J¼7.1 Hz, 3H); 13C NMR (62.5 MHz, CDCl3):
d 166.3; 164.9 (d,
(d, J¼3.5 Hz,1H); 4.18 (q, J¼7.1 Hz, 2H); 3.08 (d, J¼5.0 Hz,1H); 1.24 (t,
J¼12.7 Hz, C–F aromatic); 160.9 (J¼12.5 Hz, C–F aromatic); 146.2 (t,
J¼8.6 Hz); 141.7; 126.3; 109.4 (d, J¼25.3 Hz); 109.3 (d, 8.1 Hz); 102.9
(t, J¼25.3 Hz); 71.7 (t, J¼2.3 Hz); 52.0; 46.5; IR (film, lmax): 3453,
1710, 1625, 1598, 1462, 1372, 1312, 1119, 855 cmꢂ1. HRMS (ESI, m/z)
J¼7.1 Hz, 3H). 13C NMR (62.5 MHz, CDCl3):
d 167.7; 140.8; 140.4;
128.9; 128.2; 128.0; 127.0; 75.3; 60.5; 14.0. IR (film, lmax): 3451,1715,
1628, 1493, 1453, 1370, 1271, 1175, 1149, 1079, 765 cmꢂ1. HRMS (ESI,
m/z) Calcd for C12H14O3 206.2378. Found: 229.0891 [Mþ þNa (23)].
Calcd for C12H12F2O3 242.0755. Found: 265.2178 [Mþ þNa (23)].
ꢃ
ꢃ
3.5.2. Ethyl 2-[hydroxy(4-methoxyphenyl)methyl]prop-2-
3.5.8. Ethyl 3-hydroxy-2-methylidenepentanoate (24)
enoate (15)
Colorless viscous oil. 85% yield; 1H NMR (250 MHz, CDCl3):
Viscous yellow oil. 81% yield; 1H NMR (250 MHz, CDCl3):
d
7.27
d
6.23 (d, J¼1.0 Hz, 1H); 5.77 (t, J¼1.2 Hz, 1H); 4.32 (t, J¼6.6 Hz, 1H);
(d, J¼8.5 Hz, 2H); 6.86 (d, J¼8.8 Hz, 2H); 6.30 (t, J¼1.1 Hz, 1H); 5.84
(t, J¼1.3 Hz, 1H); 5.50 (sl, 1H); 4.15 (q, J¼7.1 Hz, 2H); 3.78 (s, 3H);
3.12 (sl, 1H); 1.23 (t, J¼7.1 Hz, 3H); 13C NMR (62.5 MHz, CDCl3):
4.23 (q, J¼7.1 Hz, 2H); 2.65 (sl, 1H); 1.76–1.62 (m, 2H); 1.32 (t,
J¼7.1 Hz, 3H); 0.95 (t, J¼7.4 Hz, 3H); 13C NMR (62.5 MHz, CDCl3):
d
166.6; 142.2; 124.9; 73.2; 60.8; 29.0; 14.1; 10.1; IR (film): 3447,
d
166.3; 159.0; 142.3; 133.5; 127.8; 125.2; 113.6; 72.6; 60.8; 55.1;
2976, 1714, 1629, 1464, 1373, 1274, 1176, 1159 cmꢂ1. HRMS (ESI, m/z)
Calcd for C8H14O3 158.0943. Found: 181.0912 [Mþ þNa (23)].
ꢃ
13.9; IR (film, lmax): 3465, 1714, 1611, 1512, 1465, 1396, 1370, 1251,
1034 cmꢂ1. HRMS (ESI, m/z) Calcd for C13H16O4 236.1049. Found:
259.0948 [Mþ þNa (23)].
3.5.9. Methyl 2-benzyl-3-oxo-3-phenylpropanoate (25)
ꢃ
Yellow viscous oil. 81% yield; 1H NMR (250 MHz, CDCl3):
d 7.99–
3.5.3. Ethyl 2-[(4-tert-butylphenyl)(hydroxy)methyl]prop-2-
7.93 (m, 2H); 7.59–7.40 (m, 3H); 7.25–7.17 (m, 5H); 4.66 (t,
enoate (16)
J¼7.4 Hz); 3.68 (s, 3H); 3.33 (dd, J¼2.4 Hz and 7.5 Hz); 13C NMR
Viscous yellow oil. 76% yield; 1H NMR (250 MHz, CDCl3):
d
7.32
(62.5 MHz, CDCl3): d 194.4; 169.6; 138.2; 136.0; 135.5; 128.8; 128.7;
(dd, J¼8.5 Hz and J¼18.6 Hz, 4H); 6.32 (s, 1H); 5.87 (s, 1H); 5.53 (d,
128.6; 128.5; 126.6; 55.8; 52.5; 34.8; IR (film, lmax): 3463, 1741,
J¼4.9 Hz, 1H); 4.14 (q, J¼7.3 Hz, 2H); 3.37 (d, J¼5.3 Hz, 1H); 1.32 (s,
1686, 1596, 1581, 1448, 1435 cmꢂ1. HRMS (ESI, m/z) Calcd for
9H); 1.22 (t, J¼7.1 Hz, 3H); 13C NMR (62.5 MHz, CDCl3):
d
166.3;
C17H16O3 268.1099. Found: 291.0997 [Mþ þNa (23)].
ꢃ
150.5; 142.5; 138.5; 126.4; 125.3; 125.2; 72.7; 60.8; 34.5; 31.4; 14.0;
IR (film, lmax): 3449, 2964, 1717, 1629, 1510, 1456, 1407, 1270, 1149,
1041 cmꢂ1. HRMS (ESI, m/z) Calcd for C16H22O3 262.1569. Found:
3.5.10. Methyl 2-(4-nitrobenzyl)-3-oxo-3-phenylpropanoate (26)
Pale yellow viscous oil. 30% yield; 1H NMR (250 MHz, CDCl3):
285.1483 [Mþ þNa (23)].
d
8.37 (d, J¼8.9 Hz, 1H); 8.01–7.96 (m, 2H); 7.79 (d, J¼8.9 Hz, 1H);
ꢃ
7.60 (tt, J¼1.3 Hz and J¼7.2 Hz, 1H); 7.52–7.45 (m, 2H); 7.26 (s, 1H);
3.5.4. Ethyl 2-[hydroxy(4-nitrophenyl)methyl]prop-2-enoate (17)
4.42 (q, J¼7.1 Hz, 1H); 3.69 (s, 3H); 1.51 (d, J¼7.1 Hz, 3H); 13C NMR
Orange oil. 96% yield; 1H NMR (250 MHz, CDCl3):
d
8.20 (d,
(62.5 MHz, CDCl3): d 195.8; 171.3; 135.7; 133.5; 128.8; 128.6; 128.3;
J¼8.9 Hz, 2H); 7.60 (d, J¼8.5 Hz, 2H); 6.39 (s, 1H); 5.86 (s, 1H); 5.62
124.4; 53.4; 52.5; 48.0; 29.7; 13.8; IR (film, lmax): 3444, 1736, 1678,
(s, 1H); 4.18 (q, J¼7.1 Hz, 2H); 3.43 (sl, 1H); 1.26 (t, J¼7.1 Hz, 3H); 13C
1605, 1528, 1496, 1455, 1347, 1269 cmꢂ1. HRMS (EIþ, m/z) Calcd for
C17H15NO5 313.0950. Found: 314.0983 [Mþ þH].
ꢃ
NMR (62.5 MHz, CDCl3):
d
165.9; 148.7; 147.3; 141.1; 127.3; 127.0;
123.5; 72.7; 61.3; 14.0; IR (film, lmax): 3483, 1711, 1629, 1607, 1522,
1401, 1349, 1269, 1176, 1109 cmꢂ1. HRMS (ESI, m/z) Calcd for
3.5.11. Ethyl 2-benzyl-3-oxo-3-phenylpropanoate (27)
C12H13NO5 251.0794. Found: 274.0739 [Mþ þNa (23)].
Pale yellow viscous oil. 83% yield; 1H NMR (250 MHz, CDCl3):
ꢃ
d
8.00–7.94 (m, 2H); 7.60–7.42 (m, 3H); 7.24–7.21 (m, 5H); 4.62 (t,
3.5.5. Ethyl 2-[1,3-benzodioxol-5-yl(hydroxy)methyl]prop-2-
J¼7.3 Hz, 1H); 4.19–4.04 (m, 2H); 3.33 (d, J¼7.2 Hz, 2H); 1.11 (t,
enoate (19)
J¼7.2 Hz, 3H); 13C NMR (62.5 MHz, CDCl3):
d IR (film, lmax): 3369,
Pale yellow oil. 65% yield; 1H NMR (250 MHz, CDCl3):
d
6.81–
2959, 1734, 1687, 1598, 1582, 1496, 1449, 1368, 1270, 1231, 1152,
6.70 (m, 3H); 6.29 (s, 1H); 5.89 (s, 2H); 5.84 (s, 1H); 5.42 (s, 1H); 4.13
749 cmꢂ1. HRMS (ESI, m/z) Calcd for C18H18O3 282.1256. Found:
(q, J¼7.1 Hz, 2H); 3.36 (s, 1H); 1.22 (t, J¼7.1 Hz, 3H); 13C NMR
305.1079 [Mþ þNa (23)].
ꢃ
(62.5 MHz, CDCl3): d 166.2; 147.6; 147.1; 142.3; 135.5; 125.2; 120.3;
108.0; 107.2; 101.0; 72.6; 60.9; 14.0; IR (film, lmax): 3449, 2983,
3.5.12. Ethyl 2-benzyl-3-(4-methoxyphenyl)-3-oxopropanoate (28)
1714, 1629, 1503, 1488, 1443, 1249, 1039 cmꢂ1. HRMS (ESI, m/z)
Yellow viscous oil. 95% yield; 1H NMR (250 MHz, CDCl3):
d 7.93–
Calcd for C13H14O5 250.0841. Found: 273.0776 [Mþ þNa (23)].
7.94 (m, 2H); 7.26–7.17 (m, 4H); 6.96–6.88 (m, 2H); 4.61–4.29 (m,
ꢃ
1H); 4.19–4.03 (m, 2H); 3.85 (s, 3H); 3.31 (dd, J¼3.5 Hz and 7.6 Hz);
3.5.6. Methyl 2-[(3,5-difluorophenyl)(hydroxy)methyl]prop-2-
enoate (21)
1.12 (t, J¼7.2 Hz, 3H); 13C NMR (62.5 MHz, CDCl3):
d 192.7; 169.4;
163.8; 138.5; 131.0; 128.9; 128.4; 126.5; 113.8; 61.3; 61.2; 55.8;
55.4; 34.7; 13.8; IR (film, lmax): 3341, 1736, 1677, 1601, 1575, 1511,
1496, 1450, 1308, 1173 cmꢂ1. HRMS (ESI, m/z) Calcd for C19H20O4
Colorless viscous oil. 91% yield; 1H NMR (250 MHz, CDCl3):
d
6.96–6.87 (m, 2H); 6.72 (tt, J¼2.4 Hz and J¼8.9 Hz, 1H); 6.38 (s,
1H); 5.86 (t, J¼1.0 Hz, 1H); 3.75 (s, 3H); 2.70 (sl, 1H); 13C NMR
312.1362. Found: 335.1226 [Mþ þNa (23)].
ꢃ

7716
B.R.V. Ferreira et al. / Tetrahedron 65 (2009) 7712–7717
3.5.13. Ethyl 2-benzyl-3-(4-tert-butylphenyl)-3-oxo-
propanoate (29)
3.5.19. Methyl 2-benzyl-3-(3,5-difluorophenyl)-3-oxo-
propanoate (35)
Yellow viscous oil. 78% yield; 1H NMR (250 MHz, CDCl3):
d
7.93–
Pale yellow viscous oil. 89% yield. 1H NMR (250 MHz, CDCl3):
7.90 (m, 2H); 7.50–7.44 (m, 2H); 7.29–7.20 (m, 5H); 4.61 (t, J¼7.4 Hz,
d 7.47–7.38 (m, 2H); 7.26–7.18 (m, 5H); 7.04–6.96 (m, 1H); 4.52 (t,
1H); 4.20–4.01 (m, 2H); 3.31 (dd, J¼2.3 Hz and 7.6 Hz); 1.32 (s, 9H);
J¼7.4 Hz, 1H); 3.67 (s, 3H); 3.33 (d, J¼7.4 Hz, 2H); 13C NMR
1.12 (t, J¼7.1 Hz, 3H); 13C NMR (62.5 MHz, CDCl3):
d
193.9; 169.4;
(62.5 MHz, CDCl3):
d
192.2; 169.0; 165.0 (d, J¼11.8 Hz, C–F aro-
157.4; 138.6; 133.5; 128.9; 128.6; 128.5; 126.5; 125.7; 61.4; 56.1;
34.7; 31.0; 13.9; IR (film, lmax): 3358, 2965, 1737, 1684, 1605, 1565,
1496, 1450, 1270, 1194 cmꢂ1. HRMS (ESI, m/z) Calcd for C22H26O3
matic); 161.0; (d, J¼11.8 Hz, C–F aromatic); 139.0 (t, J¼7.6 Hz);
137.7; 128.7 (d, J¼11 Hz); 126.9; 111.6 (d, J¼26.1 Hz); 111.6 (d,
J¼7.5 Hz); 111.5 (d, J¼26.1 Hz); 108.9 (t, J¼25.4 Hz); 56.1; 52.8; 34.7;
IR (film, lmax): 3366, 1744, 1697, 1618, 1596, 1497, 1455, 1440, 1320,
1124, 988 cmꢂ1. HRMS (ESI, m/z) Calcd for C17H14F2O3 304.0911.
338.1882. Found: 339.1851 [Mþ þH].
ꢃ
Found: 305.0836 [Mþ þH].
ꢃ
3.5.14. Ethyl 2-benzyl-3-(4-nitrophenyl)-3-oxopropanoate (30)
Orange viscous oil. 85% yield; 1H NMR (250 MHz, CDCl3):
d 8.27
(d, J¼9.0 Hz, 2H); 8.06 (d, J¼9.0 Hz, 2H); 7.29–7.18 (m, 5H); 4.62 (t,
3.5.20. Ethyl 2-benzyl-3-(3,5-difluorophenyl)-3-oxo-
propanoate (36)
J¼7.4 Hz, 1H); 4.12 (q, J¼6.8 Hz, 2H); 3.35 (d, J¼7.4 Hz, 2H); 1.13 (t,
J¼7.1 Hz, 3H); 13C NMR (62.5 MHz, CDCl3):
d
193.4; 168.5; 150.4;
Pale yellow viscous oil. 82% yield; 1H NMR (250 MHz, CDCl3):
140.7; 137.7; 129.5; 128.8; 128.6; 126.8; 123.8; 61.9; 56.6; 34.6;
13.9; IR (film, lmax): 3445, 1737, 1650, 1605, 1528, 1496, 1455, 1347,
1269 cmꢂ1. HRMS (ESI, m/z) Calcd for C18H17NO5 327.1107. Found:
d
7.48–7.42 (m, 2H); 7.26–7.19 (m, 5H); 7.05–6.96 (m, 1H); 4.49 (t,
J¼7.4 Hz, 1H); 4.13 (dq, 2H); 3.32 (d, J¼7.4 Hz, 2H); 1.14 (t, J¼7.1 Hz,
3H); 13C NMR (62.5 MHz, CDCl3):
d
192.2; 168.6; 164.9 (d, J¼11.7 Hz,
350.1030 [Mþ þNa (23)].
C–F aromatic); 160.9 (d, J¼11.8 Hz, C–F aromatic); 139.1 (t,
J¼7.6 Hz); 137.8; 128.9; 128.6; 126.8; 111.5 (d, J¼26.0 Hz); 111.4 (d,
J¼7.3 Hz); 108.8 (t, J¼25.4 Hz); 61.8; 56.4; 34.6; 13.9; IR (film, lmax):
3378, 1739, 1698, 1619, 1596, 1497, 1455, 1440, 1322, 1264, 1210,
1145, 1124, 988 cmꢂ1. HRMS (ESI, m/z) Calcd for C17H14F2O3
ꢃ
3.5.15. Ethyl 2-benzyl-3-(4-chlorophenyl)-3-oxopropanoate (31)
Colorless viscous oil. 81% yield; 1H NMR (250 MHz, CDCl3):
d 7.88
(d, J¼8.4 Hz, 2H); 7.41 (d, J¼8.0 Hz, 2H); 7.23 (s, 5H); 4.56 (t, J¼7.3 Hz,
304.0911. Found: 305.0836 [Mþ þH].
ꢃ
1H);4.10 (q, J¼7.1 Hz, 2H); 3.32(d, J¼7.3 Hz, 2H);1.12 (t, J¼7.1 Hz, 3H);
13C NMR (62.5 MHz, CDCl3):
d 193.3; 169.0; 140.0; 138.1; 134.5; 130.0;
129.0; 128.8; 128.5; 61.6; 56.1; 48.3; 34.6; 13.9; IR (film, lmax): 3402,
3.5.21. Methyl 2-benzyl-3-oxo-3-(pyridin-3-yl)propanoate (37)
1737, 1687, 1589, 1571, 1455, 1401, 1368, 1231, 1093 cmꢂ1. HRMS (ESI,
Yellow viscous oil. 70% yield; 1H NMR (250 MHz, CDCl3):
d 9.19–
m/z) Calcd for C18H17ClO3 316.0866. Found: 339.0726 [Mþ þNa (23)].
9.12 (m, 1H); 8.81–8.74 (m, 1H); 8.28–8.16 (m, 1H); 7.47–7.17 (m,
ꢃ
6H); 4.64 (t, J¼7.4 Hz, 1H); 3.66 (s, 3H); 3.35 (d, J¼7.8 Hz, 2H); 13C
3.5.16. Ethyl 3-(1,3-benzodioxol-5-yl)-2-benzyl-3-oxo-
propanoate (32)
NMR (62.5 MHz, CDCl3): d 193.6; 169.1; 153.7; 149.9; 137.7; 135.9;
128.8; 128.6; 126.8; 123.6; 56.0; 52.7; 34.5; IR (film, lmax): 3463,
Pale yellow viscous oil. 85% yield; 1H NMR (250 MHz, CDCl3):
1739, 1686, 1594, 1580, 1446, 1433 cmꢂ1. HRMS (ESI, m/z) Calcd for
C16H15NO3 269.1052. Found: 270.0978 [Mþ þH].
ꢃ
d
7.57 (dq, J¼1.8 Hz and 4.5 Hz, 1H); 7.45 (dd, J¼1.8 Hz and 5.0 Hz,
1H); 6.84 (dd, J¼8.2 Hz and 10.1 Hz); 6.04 (d, J¼4.2 Hz, 2H); 4.53 (t,
J¼7.4 Hz); 4.19–4.04 (m, 2H); 3.30 (dd, 1.7 Hz and 7.5 Hz, 1H); 1.47
(d, J¼7.1 Hz, 1H); 1.16 (dt, J¼7.1 Hz and 14.3 Hz, 3H); 13C NMR
3.5.22. Ethyl 2-benzyl-3-oxopentanoate (38)
Tinged yellow viscous oil. 87% yield; 1H NMR (250 MHz, CDCl3):
(62.5 MHz, CDCl3):
d
192.3; 169.3; 152.1; 148.3; 138.4; 130.9; 128.8;
d
7.30–7.15 (m, 5H); 4.13 (q, J¼7.1 Hz, 2H); 3.79 (t, J¼7.6 Hz,1H); 3.16
128.4; 126.5; 125.1; 108.3; 107.8; 101.9; 61.4; 55.8; 48.0; 34.8; 13.9;
IR (film, lmax): 3439, 1735, 1677, 1604, 1505, 1489, 1442, 1354, 1261,
1038 cmꢂ1. HRMS (ESI, m/z) Calcd for C19H18O5 326.1154. Found:
(d, J¼7.7 Hz, 2H); 2.45 (dq, J¼7.2 Hz and 35.6 Hz); 1.20 (t, J¼7.1 Hz,
3H); 1.00 (t, J¼7.1 Hz, 3H); 13C NMR (62.5 MHz, CDCl3):
d 192.3;
169.3; 152.1; 152; 148.3; 148.2; 138.4; 130.9; 128.8; 128.4; 126.5;
349.1059 [Mþ þNa (23)].
125.1; 108.3; 107.8; 101.9; 61.4; 55.8; 48; 34.8; 13.9; IR (film, lmax):
ꢃ
3425, 3027, 1742, 1716, 1497, 1455, 1368, 1268, 1204, 750 cmꢂ1
.
3.5.17. Methyl 3-(1,3-benzodioxol-5-yl)-2-(4-methoxybenzyl)-3-
HRMS (ESI, m/z) Calcd for C14H18O3 234.1256. Found: 257.1057
[Mþ þNa (23)].
ꢃ
oxopropanoate (33)
Pale yellow oil; 84% yield; 1H NMR (250 MHz, CDCl3):
d 7.55 (dd,
J¼1.8 Hz and 6.5 Hz, 1H); 7.43 (d, J¼1.7 Hz, 1H); 7.12 (d, J¼8.8 Hz,
2H); 6.84–6.77 (m, 3H); 6.03 (s, 2H); 4.51 (t, J¼7.3 Hz, 1H); 3.80 (s,
3H); 3.64 (s, 3H); 3.25 (dd, J¼1.9 Hz and Hz, 2H); 13C NMR
Acknowledgements
Authors thank FAPESP (# 06/06347-9) for financial support. R.V.P.
and F.C. thank CPNq for fellowship, research fellowship and financial
support, respectively. BRVF thanks Unicamp-CAPES for fellowship.
(62.5 MHz, CDCl3): d 192.4; 169.8; 158.3; 152.2; 148.3; 131.0; 130.3;
129.8; 125.2; 113.9; 108.3; 107.9; 101.9; 55.9; 55.1; 52.5; 34.1; IR
(film, lmax): 3518, 2954, 1740, 1677, 1611, 1513, 1489, 1443, 1250,
1159, 1037 cmꢂ1. HRMS (ESI, m/z) Calcd for C19H18O6 342.1103.
Supplementary data
Found: 365.0737 [Mþ þNa (23)].
ꢃ
Spectra of some unknown MBH adducts and of all a-benzyl-b-
3.5.18. Methyl 3-(1,3-benzodioxol-5-yl)-2-(4-hydroxybenzyl)-3-
oxopropanoate (34)
ketoesters are supplied as supplementary material. Supplementary
data associated with this article can be found in the online version,
at doi:10.1016/j.tet.2009.06.084.
Pale yellow viscous oil. 87% yield; 1H NMR (250 MHz, CDCl3):
d
7.55 (dd, J¼1.7 Hz and 8.3 Hz, 1H), 7.42 (d, J¼1.7 Hz, 1H), 7.06 (d,
J¼8.5 Hz, 2H), 6.82 (d, J¼8.2 Hz, 1H), 6.70 (d, J¼8.5 Hz, 2H), 6.04 (s,
2H), 4.51 (t, J¼7.4 Hz,1H), 3.64 (s, 3H), 3.23 (dd, J¼7.4 Hz and 2.1 Hz,
References and notes
2H); 13C NMR (62.5 MHz, CDCl3):
d 193.1, 170.3, 154.7, 152.5, 148.4,
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.
HRMS (ESI, m/z) Calcd for C18H16O6
328.0947. Found: 351.0697 [Mþ þNa (23)].
ꢃ

B.R.V. Ferreira et al. / Tetrahedron 65 (2009) 7712–7717
7717
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