Palladium-catalyzed arylation of enoates with iodobenzene: Stereoselective synthesis of trisubstituted olefins

Article abstract of DOI:10.5935/0103-5053.20130067

The Heck reaction between E- and Z-enoates and iodobenzene was studied in the presence of Pd(OAc)₂. The stereochemistry in resulting adducts was dependent on the enoate geometry (stereospecific reaction). Best yields were obtained from Z-isomer

Full text of DOI:10.5935/0103-5053.20130067

http://dx.doi.org/10.5935/0103-5053.20130067
J. Braz. Chem. Soc., Vol. 24, No. 3, 500-506, 2013.
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Article
A
Palladium-Catalyzed Arylation of Enoates with Iodobenzene:
Stereoselective Synthesis of Trisubstituted Olefins
Talita de A. Fernandes,a,b Boniek G. Vaz,c,d Alcides J. M. da Silva,a
Pierre M. Esteves,b Marcos N. Eberlin,*,c and Paulo R. R. Costa*,a
aLaboratório de Química Bioorgânica (LQB), Núcleo de Pesquisas de Produtos Naturais,
Centro de Ciências da Saúde, Bloco H, Ilha da Cidade Universitária,
Universidade Federal do Rio de Janeiro, 21941-590 Rio de Janeiro-RJ, Brazil
bInterlab, Instituto de Química, Universidade Federal do Rio de Janeiro,
21945-470 Rio de Janeiro-RJ, Brazil
cLaboratório ThoMSon de Espectrometria de Massas, Instituto de Química,
Universidade Estadual de Campinas, 13083-970 Campinas-SP, Brazil
dInstituto de Química, Universidade Federal de Goiás, Campus Samambaia,
CP 131, CEP 74001-970, Goiânia, GO, Brazil
A reação de Heck entre enoatos de configuração Z e E e o iodobenzeno foi estudada na
presença de Pd(OAc)2. A estereoquímica nos adutos formados foi dependente da geometria do
enoato (reação estereoespecífica). Os melhores rendimentos foram obtidos a partir de enoatos Z,
em acetona, utilizando Ag2CO3 como base. Os principais intermediários catiônicos de paládio
possivelmente envolvidos no ciclo catalítico puderam ser interceptados e caracterizados por
espectrometria de massas com ionização electrospray (ESI-MS).A estereosseletividade observada
pôde ser racionalizada através do mecanismo clássico da reação de Heck.
The Heck reaction between E- and Z-enoates and iodobenzene was studied in the presence
of Pd(OAc)2. The stereochemistry in resulting adducts was dependent on the enoate geometry
(stereospecific reaction). Best yields were obtained from Z-isomers in acetone using Ag2CO3 as
base. The main cationic palladium intermediates possibly involved in the catalytic cycle could
be intercepted and characterized by electrospray ionization mass spectrometry (ESI-MS). The
stereoselectivity observed was rationalized through the classic mechanism of the Heck reaction.
Keywords: Heck reaction, enoates, palladium catalysis, mass spectrometry
Introduction
Intramolecular Heck reactionallows the preparation of
heterocycles and molecules bearing tertiary and quaternary
centers, via carbopalladation of 1,2-disubstituted and
trisubstituted double bonds.6 In contrast, we found scattered
examples involving the intermolecular Heck reaction
of conjugate double bond bearing substituents at the
b-position, such as crotonates and cinnamates.7
Stereoselective synthesis of 1,2 disubstituted olefins
is a well established process and these products can be
synthesized viaWittig-type reactions,8 using organometallics9
and more recently by metathesis.10 In contrast, stereocontrol
in construction of trisubstituted olefins remains a challenge.11
In this article we report stereoselective arylation of a
series of enoates with iodobenzene. These reactions were
studied under classical Heck conditions,3 in which the
Heck and collaborators described in 1968 the
preparation of methyl cinnamate by the reaction of
phenylmercuric chloride with methyl acrylate in the
presence of stoichiometric amounts of PdCl2/LiCl.1
Mizoroki, et al. in 19712 and Heck and Nolley in 19723
reported the arylation of styrene by iodobenzene in the
presence of catalytic amounts of palladium salts. Since
then, the scope of the Heck reaction has been extensively
expanded and new sources of organopalladium species as
well as new types of olefins have been incorporated into
the set of starting materials suitable for this reaction.4,5
*e-mail: eberlin@iqm.unicamp.br, prrcosta2011@gmail.com

Vol. 24, No. 3, 2013
Fernandes et al.
501
neutral mechanism is favored and the results are compared
with those obtained in conditions favoring the cationic
mechanism (in the presence of Ag2CO3 or using water as
solvent).4,12 A mechanistic rationalization was proposed
based on electrospray ionization mass spectrometry
(ESI-MS) monitoring.
the yields of Heck reaction between Z-1 and 2 decreased
in water. Cinnamate E-3 was obtained in 48% yield from
Z-1 (entry 6), while E-1 furnished Z-3 in only 18% yield
(entry 7). These reactions were stereospecific and only one
geometric isomer was observed in crude spectra.
O
O
I
O
Results and Discussion
O
Pd(OAc)2
PPh3
CO2Et
+
Ph
CO2Et
Base
Solvent
In contrast to acrylates, which under classical Heck
conditions (neutral mechanism) are known to react
with iodobenzene (2) leading to cinnamates in good
yields,3,13 enoate Z-1 furnished only traces of adduct
E-3 in the presence of Pd(OAc)2, PPh3, Et3N and DMF
(Dimethylformamide) at 70 ºC for 40 h (Scheme 1,
Table 1, entry 1). Yield of E-3 did not increase when Z-1
and 2 were allowed to react under reflux in this solvent,
leading to extensive isomerization from Z-1 to E-1 (data
not showed). Enoate E-1 was completely recovered when
allowed to react under these conditions (entry 2). Due to
these disappointing results, we decided to try reaction
conditions that would favor the cationic mechanism, using
silver salts as bases. Indeed, the yield of E-3 obtained from
Z-1 increased to 71% in the presence of Ag2CO3, PPh3 and
acetone (entry 3) and higher yield (79%) was obtained
in the absence of PPh3 (entry 4). Reaction times could
not be reduced without decrease in yields. An excess of
enoate is necessary but it can be recovered in the reaction
purification. Enoate E-1 was much less reactive than
Z-1 under these same conditions, leading to adduct Z-3
in moderate yield (entry 5). This difference in chemical
reactivity between Z-1 and E-1 suggest that the transition
state for the carbopalladation step of Z-1 is sterically less
hindered. Since it has been accepted that Heck reactions in
water also proceed through a cationic mechanism,4,12 these
reactions were also studied in water using Pd(OAc)2 and
Et3N. In contrast with Heck-lactonization reactions with
enoate Z-1, which proceeds quite well in aqueous medium,12
Z-1
2
E-3
O
O
I
O
O
Pd(OAc)2
PPh3
Base
Solvent
CO2Et
+
Ph
CO2Et
E-1
2
Z-3
Scheme 1. Palladium catalyzed reaction between iodobenzene 2 and
olefins Z-1 and E-1.
To further evaluate the scope of this Heck reaction, a
few other enoates were selected to react with 2 (Scheme 2,
Table 2). Methyl maleate (Z-4) led to adduct E-8 in 63%
yield whereas its isomer Z-8 was obtained from E-4 in
35% yield (Scheme 2, Table 2, entries 1 and 2). Kondolff
co-workers7 described a mixture of stereoisomers in which
the geometry of preferential product was independent on
the starting material geometry in the reaction of these
olefins with iodobenzene using a tedicyp-palladium
complex in DMF.7 Methyl maleate (Z-4) produced the
corresponding adduct in worse yields than Z-1 but in
better yields than its isomer E-4. Only traces of the
corresponding geometric isomers were observed in the
purified products (they not appeared in crude mixtures).
Adduct 9 was obtained from 5 in 40% yield in the
presence of Ag2CO3 but only 14% yield was obtained in
water (entries 3 and 4). Methyl crotonate (6) and methyl
cinnamate (7) led to the corresponding adducts 10 and 11,
respectively, in poor yields (entries 5, 6 and 7).14
Table 1. Yields and major conditions for the reactions shown in Scheme 1
Entry
1b
2b
3c
4c
5c
6d
7d
Olefin
Z-1
Base
Et3N
PPh3
Solvent
DMF
Product
%3a
20 mol%
20 mol%
20 mol%
absence
20 mol%
absence
absence
E-3
Traces
E-1
Z-1
Et3N
DMF
no reaction
Ag2CO3
Ag2CO3
Ag2CO3
Et3N
Acetone
Acetone
Acetone
H2O
E-3
E-3
Z-3
E-3
Z-3
71
79
44
48
18
Z-1
E-1
Z-1
E-1
Et3N
H2O
Reaction mixtures were heated for 40 h in the presence of 10 mol% of Pd(OAc)2, 20 mol% PPh3 and 3 equiv of base. aIsolated yields; bReactions in DMF
were heated to 70 oC; cReactions in acetone were heated to 70 ºC (bath temperature); dReactions in water were heated to 80 ºC in the absence of PPh3.

502
Palladium-Catalyzed Arylation of Enoates with Iodobenzene
J. Braz. Chem. Soc.
I
Pd(OAc)2
Ph
CO2Me
+
CO2Me
MeO2C
PPh3, Base
Solvent
MeO2C
Ph
2
Z-4
E-8
I
CO2R'
Pd(OAc)2
+
CO2R'
R
PPh3, Base
Solvent
R
2
E-4: R = CO2Me, R' = Me
5: R = i-Bu, R' = Et
6: R = Me, R' = Me
7: R = Ph, R' = Me
Z-8: R = CO2Me, R' = Me
9: R = i-Bu, R' = Et
10: R = Me, R' = Me
11: R = Ph, R' = Me
Scheme 2. Palladium catalyzed reaction between iodobenzene 2 and olefins 4 to 7.
Table 2. Yields and conditions for the reactions shown in Scheme 2
a
Entry
Olefin
Base
Ag2CO3
Ag2CO3
Ag2CO3
Et3N
PPh3
Solvent
Acetone
Acetone
Acetone
H2O
Product
%
1
Z-4
E-4
5
20 mol%
20 mol%
20 mol%
absence
20 mol%
20 mol%
absence
E-8
Z-8
9
63
35
40
14
26
33
19
2
3
4b,c
5
5
9
6
Ag2CO3
Ag2CO3
Et3N
Acetone
Acetone
H2O
10
11
11
6
7
7a
7
Reaction mixtures were heated to 70 ºC for 40 h in the presence of 10 mol% of Pd(OAc)2, 20 mol% PPh3 and 3 equiv of base. aIsolated yields; bReactions
in water were heated to 80 ºC; cPdCl2 used as catalyst.
The configuration at the double bond in 3 was
established by nOe experiments (Figure 1). Irradiation
at the olefinic hydrogen of E-3 (in red) led to enhanced
signals for one of the methyl group at the dioxolane ring
and hydrogen at chiral center (Figure 1a). Similarly,
irradiation at this methyl group (in red, Figure 1b) led to
enhanced signals for the other geminal methyl group, one
hydrogen at the dioxolane ring, olefinic hydrogen and
hydrogen attached at the chiral center. As expected, for
NOE experiments with Z-3 no interference was observed
in olefinic proton after irradiation at methyl groups at the
dioxolane ring (Figure 1c and 1d). Configuration of Z-8 and
E-8 were established by comparison with literature data.15
Products 9, 10 and 11 are also described.16
DFT (Density Functional Theory) calculations at
M06-2X/6-311++G(d,p) level were carried out to confirm
the NOE interpretation. Geometries of Z-3 and E-3 were
fully optimized at this level and characterized as minimum
Figure 1. Stereochemistry assignments by NOE experiments; (a) adduct
on the potential energy surface by the absence of imaginary
frequencies after vibrational analysis. Figure 2 shows the
optimized geometries showing some selected distances.All
calculations were made with the Gaussian 09 package.17
The intermolecular distances shown confirm the assignment
made by the nOe experiments.
E-3, (b) adduct E-3, (c) adduct Z-3, (d) adduct Z-3.
ionization mass spectrometry (ESI-MS) monitoring and
its tandem version (ESI-MS/MS).18 This technique has
become a major tool for mechanistic studies in organic
and inorganic chemistry owing to its outstanding ability to
“fish” ionic or ionized intermediates directly from reaction
solutions into the gas phase with high sensitivity, speed,
It was also performed an investigation of the mechanism
of enoate arylations via direct infusion electrospray

Vol. 24, No. 3, 2013
Fernandes et al.
503
Figure 2. Optimized geometries of the E and Z forms of the adduct 3.
and gentleness. The mechanism of Heck reactions has also
been the subject of extensive investigation via ESI-MS.12,19
Samples of the reaction solution were diluted in MeCN
before recording the MS data.
As expected, cationic palladium species could be
intercepted in Heck reaction between Z-1 and 2 in
presence or absence of phosphines. Figure 3 shows some
intermediates formed in oxidative addition and migratory
insertion steps. The structures of these cationic species
were confirmed by the characteristic Pd multi-isotopic
pattern (only the m/z of the most abundant isotopologue
ion is mentioned) and by ESI-MS/MS (supplementary
information).
(Scheme 3). The cationic phenyl palladium 12 is firstly
formed, reacting subsequently with Z-1 via a regio and
syn-stereoselective carbopalladation, to form the key
cationic intermediate 13. Syn-elimination of HPd+ from
13 (conformer C2) leads stereoselectively to adduct E-3
(Scheme 3a).4,5 Similarly, Z-3 is formed when E-1 is used
as the olefin (Scheme 3b).
Conclusions
This study has shown that Z-enoates are better substrates
for the Heck reaction than E-enoates, which are more
sterically hindered. The use of such enoates allowed
the stereospecific synthesis of isomeric b-substituted
cinnamates. These present results are in contrast with those
previously reported for Heck reactions of cinnamates with
Based on the ESI-MS data and in the observed
stereoselectivity, it was rationalized a mechanism for the
Heck reaction between 1 and 2 in the presence of Ag2CO3
(a) Oxidative addition intermediates:
MeCN
MeCN
Ph3P
Ph3P
Pd
Pd
MeCN Pd
MeCN
Pd
MeCN
MeCN
Ph3P
m/z 486
m/z 306
(b) Migratory insertion intermediates:
m/z 265
m/z 707
O
O
O
O
O
O
O
O
O
O
O
O
PPh3
PPh3
Pd
Pd
Pd
NCMe
PPh3
m/z 645
m/z 424
m/z 907
Figure 3. Some detected intermediates on ESI(+)-MS of the reaction solution of Z-1 and 2; (a) oxidative addition intermediates, (b) migratory insertion
intermediates.

504
Palladium-Catalyzed Arylation of Enoates with Iodobenzene
J. Braz. Chem. Soc.
O
O
(a)
I
CO2Et
Pd
Pd
CO2Et
Z-1
Pd[0]
R
Ag2CO3
H
H
2
12
13 (C1)
AgI
+
EtOH
O
HPd
+
O
CO2Et
base
R
H
Pd
H
Ph
CO2Et
Pd[0]
E-3
13 (C2)
(b)
Pd
O
+
Pd
H
O
R
R
H
H
CO2Et
CO2Et
Pd
H
CO2Et
12
14(C2)
E-1
14 (C1)
+
O
EtOH
HPd
+
O
CO2Et
base
Pd[0]
Ph
Z-3
Scheme 3. Proposed mechanism for the Heck reaction between enoates Z-1 (a) and E-1 (b) with 2 in the presence of Ag2CO3.
haloarenes, in which the stereochemistry in the adducts is
defined by isomerisation of products via thermodynamic
control.4 The results are also in contrast with those
previously reported for Heck reactions of maleates and
fumarates with iodobenzene, in which a mixture of
isomeric products was formed.7 Although it was used a
limited number of variations, further studies with a large
set olefins and iodoarens must be accomplished to confirm
the suitability of this stereoselective methodology as an
important tool to synthesize trisubstituted olefins.
10 µL min−1. ESI and the mass spectrometer was operated
in the positive ion mode. Main conditions were capillary
voltage, 3500 eV; cone voltage, 35 eV; source temperature,
100 oC; desolvation temperature, 100 oC. The cationic species
were subjected to collision-induced dissociation (CID) with
argon by using collision energies ranging from 5 to 45 eV.
Cinnamates 3, 8, 9, 10 and 11; General procedure in
organic solvents
A mixture of iodobenzene (2, 102 mg, 0.5 mmol),
enoate (Z-1, 300 mg, 1.5 mmol), Pd(OAc)2 (11.2 mg,
0.05 mmol), PPh3 (26.2 mg, 0.1 mmol), Ag2CO3 (414 mg,
1.5 mmol) and acetone (15 mL) was stirred at 70 ºC for
40 h under inert atmosphere. It was cooled, filtered through
diatomaceous earth, extracted with ethyl acetate. The
organic phase was washed with brine, dried over Na2SO4
and filtered. The solvent was removed in vacuum and the
residual mass was purified by column chromatography
(hexane/EtOAc, 97:3 v/v) to give E-3 (98 mg, 71%).
Experimental
General procedure of ESI-MS and ESI-MS/MS
All experiments were performed on a hybrid quadrupole
time-of-flight mass spectrometer (Q-TOF, Waters). For
typical electrospray ionization (ESI) conditions, the Teflon-
sealed microsyringe was put in a pump that delivered
the reagent solution into the ESI source at a flow rate of

Vol. 24, No. 3, 2013
Fernandes et al.
505
Cinnamates 3, 8, 9, 10 and 11; General procedure in water
Dimethyl 2-phenylmaleate (Z-8)15
A mixture of Pd(OAc)2 (11.2 mg, 0.05 mmol), enoate
(Z-1, 300 mg, 1.5 mmol), iodobenzene (2, 102 mg,
0.5 mmol) and Et3N (0.208 mL, 1.5 mmol) in H2O (10 mL)
was stirred at 80 ºC for 40 h under N2 atmosphere. The
mixture was allowed to cool, H2O (10 mL) was added
and it was extracted with EtOAc. The organic phase
was washed with brine, dried over Na2SO4 and filtered
through diatomaceous earth. The solvent was removed
in vacuum and the residual mass was purified by column
chromatography (hexane/EtOAc, 97:3 v/v) to give E-3
(66 mg, 48%).
Compound Z-8 was obtained as a pale yellow oil after
purification by flash chromatography (EtOAc/hex 5:95 v/v).
1H NMR (400 MHz, CDCl3) d 7.50-7.46 (2H, m), 7.44-7.36
(3H, m), 6.32 (1H, s), 3.95 (3H, s), 3.79 (3H, s). 13C NMR
(126 MHz, CDCl3) d 168.3, 165.4, 149.0, 133.1, 130.6,
129.0, 126.7, 126.7, 117.1, 117.0, 52.7, 52.7, 52.1, 52.0.
(E)-Ethyl 5-methyl-3-phenylhex-2-enoate (9)16
Compound 9 was obtained as a pale yellow oil after
purification by flash chromatography (hexane). NMR
(400 MHz, CDCl3) d 7.46-7.31 (5H, m), 6.04 (1H, s), 4.20
(2H, q, J 7.1 Hz), 3.07 (2H, d, J 7.3 Hz), 1.71-1.58 (1H,
m), 1.31 (3H, t, J 7.1 Hz), 0.87 (6H, d, J 6.7 Hz).
(S,E)-Ethyl 3-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-
phenylacrylate (E-3)
Compound E-3 was obtained as a yellow oil after
purification by flash chromatography (EtOAc/hex 3:97
v/v); IR (KBr) nmax/cm−1 1727 cm-1; 1H NMR (400 MHz,
CDCl3) d 7.40-7.31 (3H, m), 7.19-7.13 (2H, m), 6.29 (1H,
d, J 1.5 Hz), 4.83 (1H, td, J 7.4, 1.5 Hz), 4.06-3.92 (3H,
m), 3.67 (1H, dd, J 8.1, 7.6 Hz), 1.47 (3H, s), 1.43 (3H,
s), 1.06 (3H, t, J 7.1 Hz); 13C NMR (101 MHz, CDCl3)
d 165.9, 155.3, 137.0, 128.2, 128.2, 127.6, 117.0, 110.5,
78.8, 68.8, 60.0, 26.3, 25.9, 14.0. MS, m/z : 276 [M+];
HRMS (ESI) calcd for C16H20NaO4 [M + Na] 299.1259,
found: 299.1273.
(E)-Methyl 3-phenylbut-2-enoate (10)16
Compound 10 was obtained as a pale yellow oil after
purification by flash chromatography (EtOAc/hex 1:99
1
v/v). H NMR (400 MHz, CDCl3) d 7.51-7.42 (2H, m),
7.41-7.33 (3H, m), 6.14 (1H, d, J 1.3 Hz), 3.75 (3H, s),
2.58 (3H, d, J 1.3 Hz).
Methyl 3,3-diphenylacrylate (11)16
Compound 11 was obtained as a pale yellow oil after
purification by flash chromatography (EtOAc/hex 1:99 v/v).
1H NMR (400 MHz, CDCl3) d 7.42-7.27 (8H, m), 7.23-7.18
(2H, m), 6.37 (1H, s), 3.61 (3H, s).
(S,Z)-Ethyl 3-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-
phenylacrylate (Z-3)
Compound E-3 was obtained as a pale yellow oil after
purification by flash chromatography (EtOAc/hex 2:98
v/v); 1H NMR (400 MHz, CDCl3) d 7.43 – 7.28 (5H, m),
6.00 – 5.96 (1H, m), 5.95 (1H, d, J 1.2 Hz), 4.49 (1H,
t, J 8.0 Hz), 4.21 (2H, q, J 7.1 Hz), 3.83 (1H, dd, J 8.2,
6.8 Hz), 1.37 (3H, s), 1.31 (3H, t, J 7.1 Hz), 1.21 (3H,
s); 13C NMR (101 MHz, CDCl3) d 165.9, 159.2, 138.2,
128.7, 128.5, 127.8, 120.7, 110.2, 74.0, 69.7, 60.5, 25.6,
24.8, 14.4; HRMS (ESI) calcd for C16H20NaO4 [M + Na]
299.1259, found:299.1242.
Supplementary Information
Supplementary data are available free of charge at
http://jbcs.sbq.org.br as PDF file.
Acknowledgments
The authors thank CAPES, FAPERJ, FAPESP, FINEP,
CNPq and the program of Oncobiology-UFRJ for financial
support and fellowships. We thank Meryellen M. de
Oliveira for helping in some reactions.
Dimethyl 2-phenylfumarate (E-8)15
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13C NMR (101 MHz, CDCl3) d 166.8, 165.6, 144.3, 133.8,
128.8, 128.7, 128.6, 127.9, 52.9, 51.9.
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Submitted: August 1, 2012
Published online: March 19, 2013
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