Palladium-catalyzed carbonylative cyclization of Baylis-Hillman adducts. An efficient approach for the stereoselective synthesis of 3-alkenyl phthalides

Article abstract of DOI:10.1016/j.tet.2006.02.045

A palladium-mediated carbonylative cyclization reaction of Baylis-Hillman adducts is disclosed. This simple, efficient and straightforward sequence leads to the formation of an array of 3-alkenylphthalides with different substitution patterns on the aromatic ring, with good chemical yields and selectivities.

Full text of DOI:10.1016/j.tet.2006.02.045

Tetrahedron 62 (2006) 4563–4572
Palladium-catalyzed carbonylative cyclization of Baylis–Hillman
adducts. An efficient approach for the stereoselective synthesis
of 3-alkenyl phthalides
a
a
b
Fernando Coelho,a, Demetrius Veronese, Cesar H. Pavam, Vanderlei I. de Paula
*
and Regina Buffonb,
*
aLaboratory of Synthesis of Natural Products and Drugs, IQ/DQO, PO Box 6154, 13084-971 Campinas, SP, Brazil
bIQ/DQI, UNICAMP, PO Box 6154, 13084-971 Campinas, SP, Brazil
Received 9 December 2005; revised 10 February 2006; accepted 15 February 2006
Available online 10 March 2006
Abstract—A palladium-mediated carbonylative cyclization reaction of Baylis–Hillman adducts is disclosed. This simple, efficient and
straightforward sequence leads to the formation of an array of 3-alkenylphthalides with different substitution patterns on the aromatic ring,
with good chemical yields and selectivities.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
compounds and show a broad spectrum of biological
effects.7
Natural products play a pivotal role in modern drug
discovery. Among the class of oxygen heterocycles,
benzoannulated lactones (phthalides or 3H-isobenzofuran-
1-one) are commonly found in many naturally occurring
substances,1–6 as well as some of their synthetically related
Particularly, the 3-alkylated phthalides are present in some
natural products such as vermistatin (1),8 (K)-hidrastine (2)
and fuscinarin (3),9,10 alcyopterosin E (4),11 isoochracinic
(5) and herbaric (6) acids (Fig. 1).7,12 Phthalides, such as the
O
OCH3
H3CO
O
O
O
H3CO
O
O
O
O
O
O
OCH3
O
HO
OH
H3C N
Fuscinarin (3)
(-)-Hidrastine or Narcotine (2)
Vermistatin (1)
OH
O
O
O
O
R
ONO2
(-)-Alcyopterosin E (4)
CO2H
R= H, Isoochracinic acid (5)
R= OH, Herbaric acid (6)
Figure 1. Some naturally occuring 3-substituted phthalides, which exhibited relevant biological activity.
Keywords: Baylis–Hillman adducts; Phthalides; Cyclization; Palladium.
*
Corresponding authors. Tel.: C55 19 3788 3085; fax: C55 19 3788 3023 (F.C.); Tel.: C55 19 3788-3090; fax: C55 19 3788-3023 (R.B.);
e-mail addresses: coelho@iqm.unicamp.br; buffon@iqm.unicamp.br
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.045

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F. Coelho et al. / Tetrahedron 62 (2006) 4563–4572
aforementioned, possess a wide range of biological activity.
(K)-Hidrastine (2) is active at the human opioid receptor
known as CCR5, while fuscinarin (3) interferes with HIV
entry into cells. Vermistatin (1) and alcyopterosin E (4) are
both cytotoxic.
alternative to prepare the required phthalides. An oxidative
addition of a Pd catalyst to the C–Br bond followed by a CO
insertion would give an acyl–palladium intermediate
(Scheme 1). The secondary hydroxyl group of the Baylis–
Hillman adduct could then effect a nucleophilic addition on
the acyl–palladium complex to give a free lactone
(phthalide), as depicted in Scheme 1.
Besides its biological activities, phthalides are versatile
starting materials for the synthesis of a variety of structures,
including key intermediates in the synthesis of functiona-
lized naphtalenes and anthracenes, which in turn are used as
synthons for tricyclic and tetracyclic linear aromatic natural
products.13–18
R
CH3
R
O
O
R1
R1
Due to its biological and synthetic importance, several
methods have been developed for the synthesis of
phthalides.19–22 Classical methods for their preparation are
based on the chloromethylation of benzoic acids, which
unfortunately often result in low yields and are not suitable
for the regioselective preparation of substituted phtha-
lides.23–25 To circumvent these difficulties, useful
approaches based on the reduction of phthalic anhydrides
or the oxidation of diols have been developed, however, the
regioselectivity of the products obtained from these
methods are frequently problematic.26–28 Strategies based
on the solid phase-synthesis have already been used as
alternative for the preparation of this important class of
compounds.29
O
O
R= EWG or EDG
3-isopropenyl
phthalides
3-alkenyl
phthalides
CO2CH3
OH
CO2CH3
OH
PdX
R1
R1
Br
O
Baylis-Hillman
adduct
More recently, palladium-catalyzed carbonylation
reactions30 of several halogenated substrates have been
reported as a convenient route for the synthesis of phthalides
Scheme 1. Retrosynthetic proposition for the synthesis of phthalides from
Baylis–Hillman adducts mediated by palladium.
32
using either CO gas31 or Mo(CO)6 as carbonylation
From our point of view, the impressive list of biological
effects associated with phthalides (also for 3-alkenylphtha-
lides)40 promptly justify the development of alternative
strategies for the preparation of these compounds.
source. The use of supercritical CO2 as solvent has also been
successfully combined with palladium-mediated carbonyla-
tions to prepare phthalides.33
The Baylis–Hillman (BH) reaction is a useful and general s
C–C bond-forming reaction, providing a straightforward
single-step synthetic method to form densely functionalized
precursors (a-methylene-b-hydroxy derivatives).34,35 The
versatility of these multifunctionalized compounds have
made these adducts valuable synthetic intermediates36 and
has also stimulated their utilization as substrates for
chemical transformations mediated by palladium, especially
for Heck reactions.37,38
A palladium-mediated carbonylation of an o-brominated
Baylis–Hillman adduct could tolerate different substituents
on the aromatic ring as well as different types of acrylates.
Besides, o-brominated substituted aldehydes could be
prepared using directed ortho metallation reactions, through
the trapping of the aryl–lithium intermediates with
bromine.41 As far as we know, Baylis–Hillman adducts
has never been used before as substrates for a palladium-
catalyzed carbonylation reaction42 having as aim the
preparation of 3-alkenyl phthalides.
Owing to its highly synthetic versatility, Baylis–Hillman
adducts are also employed as substrates for the preparation
of phthalides. Kim et al.39 described the utilization of
Baylis–Hillman adducts generated from 2-carboxyaldehyde
as substrates for the synthesis of phthalides. Despite its
elegance, the method has some drawbacks with respect to
the preparation of phthalides having different substituents
on the aromatic ring. The scope of the method was
demonstrated only by varying the acrylates used in the
Baylis–Hillman reaction.
In this communication, we describe an efficient and direct
approach for the preparation of phthalides based on a
palladium-mediated cyclocarbonylation reaction of Baylis–
Hillman adducts.
2. Results and discussions
We started our work by preparing the Baylis–Hillman
adducts, using a method we recently developed.43 The
results are summarized in Table 1. Most aldehydes we used
are commercially available, although aldehyde 10 had to be
prepared from the corresponding carboxylic acid, according
to a method described by Brown et al.44
In an ongoing research program based on the biological
evaluation of 3-alkenylphthalides as antiproliferative
agents, we needed to prepare some particular derivatives
of this class of compounds. In a preliminary approach, we
were interested in exploring a palladium-catalyzed carbo-
nylative cyclization of Baylis–Hillman adducts as an

F. Coelho et al. / Tetrahedron 62 (2006) 4563–4572
4565
Table 1. Results for the preparation of Baylis–Hillman adducts
of dicyclohexylmethylamine (Cy2NMe), at 70–90 8C under
CO (2 atm) pressure. To our delight, the reactions worked
quite nicely to provide the expected 3-alkenylphthalides
(22–32) as the sole detectable products in few hours. The
results are summarized in Table 2.
OH
O
acrylate
R
Ar
Ar
H
sonication
r.t., DABCO
Baylis-Hillman
adduct
Analysis of the data shown in Table 2 revealed that the
carbonylation cyclization procedure works well with
different Baylis–Hillman adducts. In most cases, the
phthalides were obtained with good to excellent yields.
The presence of electron-withdrawing (see entries 8 and 9)
or electron-donating groups (see entry 5) has no influence on
the rate and efficiency of the procedure. Baylis–Hillman
adducts prepared from heteroaromatic aldehydes work
equally well as substrates for this palladium-mediated
carbonylative process (entries 6 and 7), although the
yield is lower when a sulfur-containing Baylis–Hillman
adduct was used (see entry 10). Moreover, we observed
some restrictions with respect to the acrylates. Cyanide
derivatives might deactivate palladium(0) in the catalytic
cycle,46 which perhaps could explain the moderate yield
achieved in the preparation of the corresponding phthalide
(entry 4).
Ar= o-brominated
aromatic substituent
Aldehyde
Producta
Time Yield
(h)b
(%)c
CHO
Br
OH
R
7
Br
18
17
96
7
89
92
85
93
12, RZCO2Me
13, RZCO2Et
14, RZCO2n-Bu
15, RZCN
CHO
Br
OH
O
O
CO2CH3
O
O
96
76
8
Br
16
CHO
Cl
OH
Cl
In most cases, the only afforded product was that in which
the double bond was totally conjugated (tetrasubstituted
alkene). Probably a palladium–hydride intermediate is
responsible for double bond isomerization, leading to the
formation of the most stable alkene. The only exception was
observed when Baylis–Hillman adduct 18, prepared from
the reaction between ethyl acrylate and 2-chloro-3-
quinolinecarboxyaldehyde, was employed as substrate. In
this particular case, we observed the formation of
3-isopropenyl phthalide (29), which could be considered
as a Baylis–Hillman adduct in which the conformation was
partially restricted, in 60% yield.
R
R
N
9
N
1
15
%99
97
17, RZCO2Me
18, RZCO2Et
OH
O2N
CHO
Br
O2N
10d
Br
19, RZCO2Me
20, RZCO2Et
Br
2
3
92
91
Br
CHO
18
98
CO2CH3
S
The formation of this unusual product is particularly
interesting, because it constitutes evidence that the
formation of the 3-alkenylphthalides (with a tetrasubstituted
double bond) may go through this intermediate, with an
in situ palladium-catalyzed double bond isomerization step
being responsible for the formation of the enol–lactones, as
expected (see Scheme 2). The presence of large substituents
would hamper re-coordination of the palladium species,
preventing the isomerization step and thus favoring the
formation of phthalide 29.
S
OH
21
11
a All reactions were carried out using an excess of acrylate (methyl, ethyl,
n-butyl and acrylonitrile) in the presence of DABCO (0.65 equiv). For the
preparation of Baylis–Hillman adducts 12, 13, 16 and 17, N-butyl-2-
methyl-imidazolium hexafluorate [(bmim)PF6] (7 mol%) was used as
co-catalyst.
b For total conversion.
c Yields refer to isolated and purified products.
d 5-Nitro-2-bromobenzaldehyde was prepared from the corresponding
carboxylic acid by reduction with borane, followed by treatment of the
intermediate trialkoxyboroxine with PCC in dichloromethane to afford the
required aldehyde in 61% overall yield.44
The configuration of the double bond was deduced from
NOE experiments. The aromatic proton adjacent to the
double bond of the phthalide was irradiated and an
increment was observed in the spectra. For the Z
configuration an increment in the absorption of the vinylic
methyl group was observed (increments ranged from
0.3 to 0.45%).39 Otherwise, for the E configurations
increments in the absorption of the alkyl residue of the
ester group were observed (increments ranged form
0.3–0.4%) (Fig. 2).
After that, our work aimed at finding or developing a set of
reaction conditions that would use the Baylis–Hillman
adducts to produce the required 3-alkenylphthalides.
Recently, Littke and Fu45 described mild conditions for
the Heck reaction of aryl chlorides and bromides. Since the
initial step of the palladium-catalyzed carbonylative
cyclization process, as well as in the Heck reaction, is an
oxidative addition of the C–halogen bond to a Pd catalyst,
we started our work testing the experimental conditions
proposed by Littke and Fu.45
In most cases, the E isomer was exclusively or almost
exclusively formed. The degree of stereoselectivity might
vary depending on the Baylis–Hillman adduct employed,
and an inversion in the stereoselectivity Z/E could also be
Solutions of Baylis–Hillman adducts (12–21) in anhydrous
dioxane were treated with Pd2(dba)3/P(tBu)3 in the presence

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F. Coelho et al. / Tetrahedron 62 (2006) 4563–4572
Table 2. Palladium-catalyzed carbonylative cyclization of Baylis–Hillman adducts
b,c
%
Entry
BH adducts
Phthalidesa
Time (h)
H3CO2C
CH3
1
12
15
94
O
22 (E/Z ≥ 95:5)
23 (E/Z 88:12)
O
C2H5O2C
CH3
2
3
4
13
14
15
5b
78
15
96
O
O
n-BuO2C
CH3
68d
O
24 (E/Z ≥ 95:5)
25 (E/Z ≥ 95:5)
26 (E/Z ≥ 95:5)
O
NC
CH3
59
96
98
O
O
H3CO2C
CH3
O
O
5
16
17
15
O
O
H3C
CO2CH3
6
15
O
N
27 (E/Z 5:95)
O
H3C
CO2Et
CO2Et
+
O
O
7
18
18
82;e 22 (28); 60 (29)
N
N
O
O
28 (E/Z ≥ 5:95)
29
H3CO2C
CH3
O2N
8
19
20
16
76
O
30 (E/Z ≥ 95:5)
O
EtO2C
CH3
O2N
9
25
71
O
31 (E/Z 95:5)
O
(continued on next page)

F. Coelho et al. / Tetrahedron 62 (2006) 4563–4572
4567
Table 2 (continued)
b,c
%
Entry
BH adducts
Phthalidesa
Time (h)
O
O
10
21
72
29d
S
CH3
32 (E/Z 85:15)f
H3CO2C
a The double bond configurations were determined using NOE experiments, in which the aromatic proton adjacent to the phthalide double bond was
irradiated.39 In some cases the isomer distribution could also be observed by 1H NMR.
b All reactions were carried out in the presence of Pd2(dba)3 (1 or 2 mol%)/P(tBu3), Cy2NCH3 and CO (2 atm) at 70–90 8C.
c Yields refer to isolated and purified products.
d Yield based on the recovered starting material.
e Global yield (mixture of products).
f
We assume the stereochemistry of the majoritary product as being E or Z based on NOE experiments. We observed an increment of only 0.1% on proton
adjacent to the sulfur atom when the methylic ester was irradiated. No increment was observed when vinylic methyl was irradiated.
quality. In this particular aspect, we believe that the
disclosed approach could be used for the stereoselective
preparation of several phthalides.
EtO2C
CO2Et
Ha
PdX
Hb
- HaPdX
O
O
N
N
Due to its operational simplicity this approach could be
considered as a valuable, broadly applicable alternative for
the preparation of this class of compounds, since o-bromi-
nated Baylis–Hillman adducts are readily accessible from
the corresponding o-brominated aromatic aldehydes. This
simplicity could be seen as an advantage of our approach,
since some palladium-mediated methods reported for the
synthesis of phthalides require the preparation of elaborated
starting materials.
O
O
Possible intermediate
of the carbonylation
process
29
Pd-mediated
isomerization
CO2Et
O
O
N
Additional work describing the biological profile of these
phthalides and their synthetic utility are underway in our
laboratory and the results will be disclosed in due course.
Although palladium-mediated carbonylative methodology
for the preparation of phthalides have already been
reported,31 as far as we know, this is the first report
describing a successful palladium-mediated carbonylative
cyclization from Baylis–Hillman adducts.
28
Scheme 2. Palladium–hydride elimination and double bond isomerization
of 29.
observed (see entry 7, Table 2). Apparently, the stereo-
selectivity observed has no direct relationship with the size
of the ester residue exhibited by the acrylate.
In summary, we disclosed herein a stereoselective,
straightforward and high yielding method to prepare
phthalides, in only one step, from Baylis–Hillman adducts.
The method tolerates different types of substituents in the
aromatic ring, as expected for a palladium-mediated
procedure. The method can be easily scaled up, since
experiments in a scale of 1 g were carried out without any
significant alterations in either chemical yield or product
3. Experimental
3.1. General
The following procedures are representative for all the
Baylis–Hillman adducts and phthalides prepared in this
work. All the reagents were purchased from specialized
suppliers with analytical purity and were utilized without
previous purification, unless noted. The dioxane was
refluxed over CaH2 under an argon atmosphere for 48 h
and distilled at ambient pressure prior to use. After, this
solvent was degasified through external ultrasound
irradiation in a water bath cleaner (81 W, 40 kHz), over
irradiated at
2.29 ppm
irradiated at
4.43 ppm
4.40 ppm
irradiated at
2.32 ppm
0%
O
0.32%
0%
CO2CH2CH3
O
0.4%
O2N
CH3
˚
activated molecular sieves 4 A and under continuous
1
positive pressure of argon during about 5 h. The H and
O
13C spectra were recorded on a Varian GEMINI BB-300 at
300 and 75.4 MHz, respectively, or on an Inova instrument
at 500 and 125 MHz, respectively. The mass spectra were
recorded using a HP model 5988A GC/MS with a High-
Resolution Autospec-Micromass/EBE. IR were obtained
with a Nicolet model Impact 410. Melting points were
O
N
O
O
28 (Z )
31 (E)
Figure 2. Exemplifying the procedure for determination of the
configuration of the tetrasubstituted double bond of phthalides.

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F. Coelho et al. / Tetrahedron 62 (2006) 4563–4572
measured in open capillary tubes using an Electrothermal
apparatus model 9100, and are uncorrected. Only the
spectral data of the unknown Baylis–Hillman adducts are
enclosed.
d 8.58 (s, 1H), 8.22 (d, JZ8.4 Hz, 1H), 8.03 (d, JZ8.4 Hz,
1H), 7.94 (ddd, JZ1.5, 8.4 Hz, 1H), 7.76 (ddd, JZ1.5,
8.4 Hz, 1H), 6.60 (s, 1H), 6.25 (s, 1H), 5.84 (s, 1H), 4.0 (s,
3H), 1.89 (broad s, exchangeable with D2O); 13C NMR
(75.4 MHz, CDCl3) d 166.8, 149.2, 147.1, 140.1, 137.0,
132.6, 130.6, 128.1, 127.8, 127.7, 127.2, 127.1, 69.2, 52.2;
HRMS (70 eV, m/z) Calcd for C14H12ClNO3 277.0506;
Found 277.0497.
3.1.1. General procedure for the preparation of the
Baylis–Hillman adducts. A mixture of the aromatic
aldehyde (1–2 mmol), an excess of acrylate (methyl, ethyl,
butyl or acrylonitrile K20 equiv, used as reagent and
solvent) and DABCO (0.65 equiv) was sonicated (1000 W,
25 kHz) for a certain period of time (for details, see Table 1
in text). The ultrasound bath temperature was constantly
monitored and kept at 30–40 8C during the reaction, through
ice addition or by using a refrigerated circulator. After the
reaction time, the mixture was evaporated under reduced
pressure in order to remove the excess of acrylate. The
residue was diluted with ethyl acetate (30 mL). The organic
solution was washed with 10% aqueous HCl (2!10 mL),
saturated NaHCO3 (20 mL), brine (20 mL), and dried over
Na2SO4 or MgSO4. After filtration and solvent removal, the
residue was filtered through a pad of gel of silica.
3.1.1.5. Ethyl 2-[(2-chloroquinolin-3-yl)(hydroxy)-
methyl]acrylate (18). Yield: 97%; eluent for chromato-
graphic purification: ethyl acetate–hexane (30/70); yellow
solid, mp 75–77 8C; IR (neat, ymax): 3378, 3064, 2978, 1711,
1
1621, 1589, 1143 cmK1; H NMR (500 MHz, CDCl3) d
8.39 (s, 1H), 8.02 (d, JZ8.5 Hz, 1H), 7.85 (d, JZ8.2 Hz,
1H), 7.73 (m, 1H), 7.57 (m, 1H), 6.40 (s, 1H), 6.05 (s, 1H),
5.63 (s, 1H), 4.24 (q, JZ7.2 Hz, 2H), 3.60 (broad s,
exchangeable with D2O, 1H), 1.29 (t, JZ7.2 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 166.4, 149.2, 147.0, 140.3,
137.0, 132.6, 130.5, 128.1, 127.8, 127.4, 127.2, 127.1, 69.3,
61.3, 14.0; HRMS (70 eV, m/z) Calcd for C15H14ClNO3
291.06622; Found 291.05665.
3.1.1.1. Ethyl 2-[(2-bromophenyl)(hydroxy)methyl]-
acrylate (13). Yield: 92%; for chromatographic purifica-
tion: ethyl acetate–hexane (20/80); colorless viscous oil; IR
(Film, ymax): 3473, 2987, 1720, 1630, 1466, 1430, 1266,
1135, 1025, 759 cmK1; 1H NMR (300 MHz, CDCl3) d 7.55
(m, 2H), 7.35 (m, 1H), 7.17 (m, 1H), 6.37 (s, 1H), 5.95 (s,
1H), 5.58 (s, 1H), 4.23 (q, JZ7.0 Hz, 2H), 3.13 (broad s,
1H, exchangeable with D2O), 1.28 (t, JZ7.0 Hz, 3H); 13C
NMR (75.4 MHz, CDCl3) d 166.3, 141.2, 140.3, 133.0,
129.6, 128.7, 128.0, 127.1, 123.5, 71.9, 61.5, 14.6; HRMS
(70 eV, m/z) Calcd for C12H13BrO3 285.13382; Found
285.13375.
3.1.1.6. Methyl 2-[(2-bromo-5-nitrophenyl)(hydroxy)-
methyl]acrylate (19). Yield: 92%; white solid, mp 81–
84 8C; eluent for chromatographic purification: ethyl
acetate–hexane (30/70); IR (Film, ymax): 3452, 3105,
1723, 1629, 1523, 1343 cmK1 1H NMR (300 MHz,
;
CDCl3) d 8.45 (d, JZ2.9 Hz, 1H), 8.03 (dd, JZ2.9,
8.8 Hz, 2H), 7.73 (d, JZ8.8 Hz, 1H), 6.39 (s, 1H), 5.94 (s,
1H), 5.56 (s, 1H), 3.81 (s, 3H); 13C NMR (75.4 MHz,
CDCl3) d 166.4, 147.3, 142.0, 139.5, 133.6, 129.8, 127.7,
123.7, 123.5, 71.1, 52.4; HRMS (70 eV, m/z) Calcd for
C11H9NO5Br 314.97423; Found 314.97939.
3.1.1.2. Butyl 2-[(2-bromophenyl)(hydroxy)methyl]-
acrylate (14). Yield: 85%; for chromatographic purifica-
tion: ethyl acetate–hexane (20/80); tinged yellow viscous
3.1.1.7. Ethyl 2-[(2-bromo-5-nitrophenyl)(hydroxy)-
methyl]acrylate (20). Yield: 91%; tinged yellow viscous
oil; eluent for chromatographic purification: ethyl acetate–
hexane (30/70); IR (Film, ymax): 3444, 3109, 1711, 1634,
oil; IR (Film, ymax): 3444, 2958, 1719, 1634 cmK1 1H
;
1
NMR (300 MHz, CDCl3) d 7.50 (m, 2H), 7.32 (m, 1H), 7.15
(m, 1H), 6.35 (broad s, 1H), 5.93 (broad s, 1H), 5.61 (s, 1H),
4.14 (m, 2H), 3.37 (broad s, 1H, exchangeable with D2O),
1.61 (quintet, JZ7.5 Hz, 2H), 1.31 (sextet, JZ7.5 Hz, 2H),
0.90 (t, JZ7.5 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) d
166.2, 140.8, 139.8, 132.5, 129.0, 128.1, 127.4, 126.4,
123.0, 71.2, 64.8, 30.4, 19.0, 13.6; HRMS (ESI, m/z) Calcd
for C14H17BrNaO3 [MCNa]C335.0253; Found 335.0323.
1527, 1339 cmK1; H NMR (500 MHz, CDCl3) d 8.42 (d,
JZ2.7 Hz, 1H), 8.03 (dd, JZ2.7, 8.8 Hz, 1H), 7.72 (d, JZ
8.8 Hz, 1H), 6.39 (s, 1H), 5.94 (s, 1H), 5.57 (s, 1H), 4.25 (q,
JZ7.5 Hz, 2H), 3.22 (broad s, exchangeable with D2O, 1H),
1.29 (t, JZ7.5 Hz, 3H); 13C NMR (125.4 MHz, CDCl3) d
166.4, 147.6, 142.3, 139.8, 133.7, 130.0, 127.5, 123.7,
123.6, 71.1, 61.4, 14.0; HRMS (70 eV, m/z) Calcd for
C12H12BrNO5 328.9899; Found 328.9880.
3.1.1.3. 2-[(2-Bromophenyl)(hydroxy)methyl]acrylo-
nitrile (15). Yield: 93%; eluent for chromatographic
purification: ethyl acetate–hexane (30/70); white solid, mp
48–50 8C; IR (neat, ymax): 3444, 3064, 2950, 2234, 1466,
3.1.1.8. Methyl 2-[(3-bromo-2-thienyl)(hydroxy)-
methyl]acrylate (21). Yield: 98%; eluent for chromato-
graphic purification: ethyl acetate–hexane (30/70); pale
yellow viscous oil; IR (Film, ymax): 3436, 3113, 2949, 1711,
1
1
1437 cmK1; H NMR (300 MHz, CDCl3) d 7.58 (m, 2H),
1629, 1442, 1266, 1147, 1029, 874, 714 cmK1; H NMR
7.41 (m, 1H), 7.23 (m, 1H), 6.07 (broad s, 2H), 5.74 (m, 1H);
13C NMR (75.4 MHz, CDCl3) d 138.4, 133.5, 131.9, 130.8,
128.7, 128.6, 125.0, 123.1, 117.0, 73.1; HRMS (70 eV, m/z)
Calcd for C10H8NBrO 236.97892; Found 236.97314.
(300 MHz, CDCl3) d 7.25 (d, JZ5.5 Hz, 1H), 6.93 (d, JZ
5.5 Hz, 1H), 6.36 (s, 1H), 5.85 (s, 1H), 5.82 (s, 1H), 3.77 (s,
3H), 3.24 (broad s, exchangeable with D2O, 1H); 13C NMR
(75.4 MHz, CDCl3) d 166.3, 139.7, 139.2, 129.9, 126.8,
125.4, 109.0, 68.4, 52.1; HRMS (ESI, m/z) Calcd for
C9H9BrNaO3S [MCNa]C298.9348; Found 298.9445.
3.1.1.4. Methyl 2-[(2-chloroquinolin-3-yl)(hydroxy)-
methyl]acrylate (17). Yield: O99%; eluent for chromato-
graphic purification: ethyl acetate–hexane (30/70); white
solid, mp 69–71 8C; IR (neat, ymax) 3209, 1715, 1491, 1331,
1298, 1147, 1060, 764 cmK1; 1H NMR (300 MHz, CDCl3)
3.1.2. General procedure for the cyclocarbonylation
reactions—synthesis of phthalides. In a dry Fisher-Porter
flask equipped with a magnetic stirrer was deposited

F. Coelho et al. / Tetrahedron 62 (2006) 4563–4572
4569
1.0 mol% (2.0 mol% for Baylis–Hillman adducts 14 and 21)
of Pd2(dba)3. The reactor was then closed and the internal
atmosphere exchanged by argon. Then, there was injected
into the flask, sequentially, under magnetic stirring and an
argon atmosphere, 1.0 mL of anhydrous and degasified 1,4-
dioxane, 1.1 equiv of Cy2NMe and 4.0 mol% (8.0 mol%
when Baylis–Hillman adducts 14 and 21) of a 0.1 mol LK1
solution of P(tBu)3 in 1,4-dioxane, previously and freshly
prepared in a dry box. This catalytic mixture was stirred for
5 min at room temperature (rt) under argon, until the purple
color changed to red-brown. In other dry flask a solution of
the Baylis–Hillman adduct (1.12 mmol) in 2.0 mL of
anhydrous and degasified 1,4-dioxane, under argon, was
prepared. This solution was then injected into the Fisher-
Porter reactor, and the reaction mixture was stirred at rt
under argon for 15 min. At this point, the color changed to a
pale yellow. Finally, the reactor was pressurized with
carbon monoxide (CO, 2 atm). The temperature was raised
to 70–90 8C with a silicon oil bath, and the mixture stirred
under these conditions for the required time. Initially, the
color of the system changed from pale yellow to orange-
brown. In the final hours of the reaction, a gray precipitate
forms, indicating the deactivation of the catalyst (Pd black
along with the salt Cy2NMeHCBrK). After, the mixture was
cooled to rt and the reactor carefully opened. The mixture
was then filtered and the residue was washed with ethyl
acetate (10 mL). The combined solutions were washed with
a 10% solution of HCl (10 mL) and with water (10 mL) and
brine (10 mL). The organic phase was separated, dried over
a pad of Na2SO4, filtered and the solvent was removed under
reduced pressure. The residue obtained was then purified
by silica gel column chromatography (elution with ethyl
acetate/hexane–10:90) to provide the corresponding
phthalide.
HRMS (70 eV, m/z) Calcd for C13H12O4 232.07356; Found
232.07346.
3.1.2.3. Butyl (2E)-2-(3-oxo-2-benzofuran-1(3H)-
ylidene)propanoate (24). Yield: 68% (based on recovered
starting material—see Table 2); tinged yellow viscous oil;
IR (neat, ymax) 2949, 2933, 2868, 1789, 1719, 1634, 1466,
1
1237, 1045 cmK1; H NMR (300 MHz, CDCl3) d 8.55 (d,
JZ8.4 Hz, 1H), 7.92 (d, JZ7.6 Hz, 1H), 7.69 (ddd, JZ1.1,
7.5 Hz, 1H), 7.59 (m, 1H), 4.29 (t, JZ7.0 Hz, 2H), 2.26 (s,
3H), 1.71 (quintet, JZ7.0 Hz, 2H), 1.45 (sextet, JZ7.0 Hz,
2H), 0.97 (t, JZ7.0 Hz, 3H); 13C NMR (75.4 MHz, CDCl3)
d 167.2, 165.8, 151.6, 136.8, 134.8, 130.9, 126.4, 126.1,
125.2, 112.9, 65.2, 30.5, 19.1, 14.8, 13.6; HRMS (ESI, m/z)
Calcd for C15H16NaO4 [MCNa]C283.0941; Found
283.1046.
3.1.2.4. (2E)-2-(3-Oxo-2-benzofuran-1(3H)-ylidene)-
propanenitrile (25). Yield: 63% (based on recovered
starting material—see Table 2); white solid, mp 142–
144 8C (lit.19 143–144 8C); IR (neat, ymax) 2953, 2917,
2847, 2214, 1805, 1646, 1466, 1207, 1127, 1041, 980, 767,
690 cmK1 1H NMR (300 MHz, CDCl3) d 8.42 (d, JZ
;
8.0 Hz, 1H), 7.99 (d, JZ7.0 Hz, 1H), 7.84 (m, 1H), 7.7 (m,
1H), 2.32 (s, 3H); 13C NMR (75.4 MHz, CDCl3) d 164.0,
155.3, 136.0, 135.4, 131.9, 125.9, 125.0, 123.6, 118.0, 88.7,
14.8; HRMS (70 eV, m/z) Calcd for C11H7NO2 185.0477;
Found 185.0440.
3.1.2.5. Methyl (2E)-2-(7-oxofuro[3,4-f][1,3]benzo-
dioxol-5(7H)-ylidene)propanoate (26). Yield: 96%;
white solid, mp 109–110 8C; IR (neat, ymax): 2987, 2920,
1769, 1712, 1479, 1307, 1283, 1277, 1091, 1033 cmK1; 1H
NMR (300 MHz, CDCl3): d 8.12 (s, 1H), 7.20 (s, 1H), 6.18
(s, 2H), 3.98 (s, 3H), 2.12 (s, 3H); 13C NMR (75.4 MHz,
CDCl3): d 167.4, 164.9, 153.8, 150.4, 133.1, 127.3, 121.3,
111.3, 106.4, 103.7, 102.9, 52.3, 14.8; HRMS (70 eV, m/z)
Calcd for C13H10O6 262.04774; Found 262.04352.
3.1.2.1. Methyl (2E)-2-(3-oxo-2-benzofuran-1(3H)-
ylidene)propanoate (22). White solid, mp 133–135 8C
(lit.39 133–136 8C); IR (neat, ymax): 2958, 2917, 2851, 1781,
1
1708, 1634, 1246, 1062, 764 cmK1; H NMR (300 MHz,
3.1.2.6. Methyl (2Z)-2-(3-oxofuro[3,4-b]quinolin-1
(3H)-ylidene)propanoate (27). IR (neat, ymax): 2933,
2855, 1785, 1719, 1617, 1454, 1372, 1241, 1196, 1119,
1057 cmK1; 1H NMR (300 MHz, CDCl3):d 9.59(s, 1H), 8.31
(d, JZ8.8 Hz, 1H), 8.03 (d, JZ8.1 Hz, 1H), 7.88 (m, 1H),
7.72 (m, 1H), 3.93 (s, 3H), 2.29 (s, 3H). 13C NMR (75.4 MHz,
CDCl3): d 166.8, 162.7, 150.4, 149.2, 143.8, 142.7, 136.3,
132.8, 131.8, 129.3, 129.0, 113.1, 52.0, 14.0; HRMS (70 eV,
m/z) Calcd for C15H11NO4 269.06881; Found 269.06656.
CDCl3): d 8.58 (d, JZ8.1 Hz, 1H), 7.95 (d, JZ8.1 Hz, 1H),
7.75 (m, 1H), 7.62 (m, 1H), 3.91 (s, 3H), 2.28 (s, 3H); 13C
NMR (75.4 MHz, CDCl3): d 167.6, 151.9, 136.8, 134.9,
131.0, 126.5, 125.4, 112.6, 70.1, 52.3, 29.7, 14.8; HRMS
(70 eV, m/z) Calcd for C12H10O4 218.05791; Found
218.05437.
3.1.2.2. Ethyl (2E)-2-(3-oxo-2-benzofuran-1(3H)-
ylidene)propanoate (23). Diastereoisomeric mixture
(E)C(Z); tinged yellow solid, mp 70–72 8C (lit.39 69–
70 8C); IR (neat, ymax): 2958, 2925, 2847, 1793, 1711, 1621,
3.1.2.7. Ethyl (2Z)-2-(3-oxofuro[3,4-b]quinolin-1(3H)-
ylidene)propanoate (28). Yield: 22%; tinged yellow solid,
mp 196–198 8C; IR (neat, ymax): 2962, 2917, 1805, 1711,
1
1470, 1237, 1045 cmK1; H NMR (300 MHz, CDCl3): d
1
1634, 1609, 1372, 1294, 1233 cmK1; H NMR (300 MHz,
8.56 (d, JZ8.2 Hz, 1H), 8.02 (d, JZ7.6 Hz, 1H, minoritary
diastereoisomer), 7.95 (d, JZ7.6 Hz, 1H, majoritary
diastereoisomer), 7.91 (d, JZ7.9 Hz, 1H, minoritary
diastereoisomer), 7.78–7.72 (m, 2H), 7.67–7.59 (m, 2H),
7.44–7.42 (m, 2H), 4.37 (q, JZ7.0 Hz, 2H), 2.39 (s, 3H,
minoritary diastereoisomer), 2.28 (s, 3H, majoritary
diastereoisomer), 1.44 (t, JZ7.0 Hz, 3H, minoritary
diastereoisomer), 1.39 (t, JZ7.0 Hz, 3H, majoritary diaster-
eoisomer); 13C NMR (75.4 MHz, CDCl3): d 143.8, 137.3,
135.3, 131.4, 130.9, 129.4, 128.8, 126.9, 126.6, 126.5,
125.9, 125.7, 125.1, 113.4, 62.0, 61.8, 30.1, 15.3, 14.6;
CDCl3) d 9.66 (s, 1H), 8.36 (d, JZ9.0 Hz, 1H), 8.08 (d, JZ
9.0 Hz, 1H), 7.89 (m, 1H), 7.74 (m, 1H), 4.40 (q, JZ7.0 Hz,
2H), 2.32 (s, 3H), 1.43 (t, JZ7.0 Hz, 3H); 13C NMR
(75.4 MHz, CDCl3) d 166.8, 163.2, 150.6, 149.7, 144.2,
136.7, 132.1, 130.7, 129.6, 129.5, 129.4, 126.2, 114.0, 61.5,
14.4, 14.3; HRMS (ESI, m/z) Calcd for C16H13NNaO4 [MC
Na]C306.0737; Found 306.0828.
3.1.2.8. Ethyl 2-(3-oxo-1,3-dihydrofuro[3,4-b]-
quinolin-1-yl)acrylate (29). Yield: 60%; white solid, mp

4570
F. Coelho et al. / Tetrahedron 62 (2006) 4563–4572
162–164 8C; IR (neat, ymax): 2982, 2921, 2847, 1772, 1711,
References and notes
1
1629, 1376, 1335, 1286, 1123 cmK1; H NMR (300 MHz,
CDCl3) d 8.38 (s, 1H), 8.34 (d, JZ8.5 Hz, 1H), 7.93 (d, JZ
8.0 Hz, 1H), 7.83 (m, 1H), 7.69 (m, 1H), 6.47 (broad s, 2H),
6.08 (broad s, 1H), 4.21 (m, 2H), 2.32 (s, 3H), 1.24 (t, JZ
7.0 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) d 167.4, 164.3,
149.7, 144.2, 136.7, 136.1, 136.0, 131.3, 130.9, 130.8, 129.2,
129.0, 128.1, 128.0, 76.5, 61.5, 14.0; HRMS (ESI, m/z) Calcd
for C16H13NNaO4 [MCNa]C306.0737; Found 306.0808.
1. van Wassenhove, F.; Dirinck, P.; Vulsteke, G.; Schamp, N.
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3.1.2.9. Methyl (2E)-2-(6-nitro-3-oxo-2-benzofuran-
1(3H)-ylidene)propanoate (30). Yield: 76%; tinged yellow
solid, mp 155–157 8C; IR (neat, ymax): 3133, 3096, 2966,
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1809, 1707, 1644, 1618, 1544, 1441 cmK1 1H NMR
;
(300 MHz, CDCl3) d 9.51 (d, JZ1.8 Hz, 1H), 8.44 (dd,
JZ1.8, 8.4 Hz, 1H), 8.09 (d, JZ8.4 Hz, 1H), 3.95 (s, 3H),
2.30 (s, 3H); 13C NMR (75.4 MHz, CDCl3) d 166.8, 163.6,
152.3, 150.3, 137.7, 130.4, 126.3, 125.9, 122.6, 115.7, 52.7,
15.0; HRMS (70 eV, m/z) Calcd for C12H9NO6 263.04298;
Found 263.04145.
3.1.2.10. Ethyl (2E)-2-(6-nitro-3-oxo-2-benzofuran-
1(3H)-ylidene)-propanoate (31). Yield: 71%; pale yellow
solid, mp 141–144 8C; IR (neat, ymax): 3133, 3101, 2962,
2921, 2843, 1809, 1711, 1642, 1540, 1343 cmK1; 1H NMR
(300 MHz, CDCl3) d 9.50 (d, JZ1.8 Hz, 1H), 8.45 (dd, JZ
1.8, 8.4 Hz, 1H), 8.11 (d, JZ8.4 Hz, 1H), 4.43 (q, JZ
6.9 Hz, 2H), 2.32, (s, 3H), 1.43 (t, JZ6.9 Hz, 3H); 13C
NMR (75.4 MHz, CDCl3) d 166.4, 163.6, 152.2, 149.9,
137.7, 130.4, 126.3, 125.8, 122.4, 116.1, 62.0, 15.1, 14.1;
HRMS (70 eV, m/z) Calcd for C13H11NO6 277.05864;
Found 277.04955.
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6(4H)-ylidene)-propanoate (32). Yield: 29% (based on
recovered starting material—see Table 2); light yellow
viscous oil; IR (neat, ymax): 3105, 2953, 2917, 2855, 1777,
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1695, 1638, 1433, 1323, 1266, 1053 cmK1 1H NMR
;
(500 MHz, CDCl3) d 7.62 (d, JZ5.19 Hz, 1H), 7.32 (d,
JZ5.19 Hz, 1H), 3.89 (s, 3H), 2.19 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 167.6, 160.6, 150.6, 149.0, 137.0,
120.8, 108.3, 52.3, 12.6; HRMS (ESI, m/z) Calcd for
C10H8NaO4S [MCNa]C247.0035; Found 247.0094.
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Acknowledgements
We thank FAPESP (04/09745-0 and 02/03461-3) and CNPq
for financial support, for a fellowship to C.H.P. (FAPESP
02/10872-0) and for research fellowships to F.C. and R.B.
(CNPq). We thank also Prof. Carol H. Collins for helpful
suggestions about English grammar and style.
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Supplementary data
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Supplementary data associated with this article can be
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