Facile synthesis of symmetrical 3,3-diarylacrylates by a Heck-Matsuda reaction: An expedient route to biologically active indanones

Article abstract of DOI:10.1016/j.tetlet.2011.05.039

A simple and straightforward synthesis of symmetrical 3,3-diarylacrylates based on a Heck-Matsuda reaction of arenediazonium salts bearing electron-donating groups with methylacrylates is described. The reaction employs Pd(OAc)₂ as catalyst and goes to completion within 1 h affording the corresponding unsaturated diaryl esters in good to high yields. This method permitted the expeditious and efficient synthesis of the anticancer 3-arylindanone 5 in two operative steps in 43% overall yield.

Full text of DOI:10.1016/j.tetlet.2011.05.039

Tetrahedron Letters 52 (2011) 3861–3864
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of symmetrical 3,3-diarylacrylates by a Heck-Matsuda
reaction: an expedient route to biologically active indanones
Jason G. Taylor a, Rodrigo da Silva Ribeiro b, Carlos Roque D. Correia b,
⇑
a Departamento de Química, ICEB, Universidade Federal de Ouro Preto, Campus Morro do Cruzeiro, CEP. 35400-000, Ouro Preto, Minas Gerais, Brazil
b Instituto de Química, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, CEP. 13084-971, Campinas, São Paulo, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and straightforward synthesis of symmetrical 3,3-diarylacrylates based on a Heck-Matsuda
reaction of arenediazonium salts bearing electron-donating groups with methylacrylates is described.
The reaction employs Pd(OAc)2 as catalyst and goes to completion within 1 h affording the corresponding
unsaturated diaryl esters in good to high yields. This method permitted the expeditious and efficient syn-
thesis of the anticancer 3-arylindanone 5 in two operative steps in 43% overall yield.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 12 April 2011
Revised 6 May 2011
Accepted 9 May 2011
Available online 19 May 2011
Keywords:
Arenediazonium tetrafluoroborates
Heck-Matsuda
Arylation
3,3-Diarylacrylates
Palladium
Indanones
1. Introduction
groups, a conspicuous structural motif in many bioactive com-
pounds (see Fig. 1). The Heck-Matsuda (HM) reaction involves the
Diaryl substituted carbon centers where both aryl units are
identical is a ubiquitous structural motif. For example, this moiety
can be found in numerous natural products, such as the Pepero-
min’s,1a Verimol-F,1b Kadangustin-J,1c Henricine-B,1d Metaseol,1e
Daphneresinol,1f and Tatarinoid-C1g (Fig. 1).
b,b-Diarylacrylates are useful building blocks in organic synthe-
sis as well.2 They can be used for the synthesis of a wide variety of
compounds of high value as they can be readily converted into en-
als or allylic alcohols. Symmetrical b,b-diarylacrylates bearing elec-
tron withdrawing groups can be easily prepared from the
corresponding benzophenone and phosphonium ylide in high yiel-
d.3a,3b However, when the requisite ketone is substituted with elec-
tron donating groups, the carbonyl is rendered less electrophilic.
Typical olefination reactions, such as the Horner–Wadsworth–
Emmons (HWE) reactions are then considerably slower, usually
requiring strong bases and refluxing conditions to provide synthet-
ically useful yields (Scheme 1).3b
Pd-catalysed coupling of arenediazonium salts to olefins and has
been known for some time to proceed smoothly with alkyl acrylates
affording the corresponding cinnamate esters in high yields.4,5
Alkyl acrylates were evaluated as substrates for the HM reaction
in Matsuda’s earliest report,6 and more recently the cinnamate es-
ter products were investigated as substrates for arylation by our
group in the synthesis of unsymmetrical b,b-diarlyacrylates.7 The
arylation of alkyl acrylates is frequently carried out using an excess
O
O
HO
OH
OH
HO
MeO
HO
OMe
OH
R
R
HO
R = 3,4,5-OMe: Peperomin-C
R = 3-OCH2O-4: Peperomin-D
Metaseol
Daphneresinol
Therefore, milder and straightforward methods that are comple-
mentary to the HWE reaction for the preparation of symmetrical
b,b-diarylacrylates are highly desirable. Such methodologies would
be particularly attractive for the synthesis of b,b-diarylacrylates
carrying aromatic rings containing several electron-donating
X
OH
R
R
R
R
R
R
R = 4-OMe: Verimol-F
R = 2,4,5-OMe: Tatarinoid-C
R = 3,4-OMe and X = OH: Kadangustin-J
R = 3-OMe, 4-OH and X = OAc: Henricine-B
⇑
Corresponding author. Fax: +55 19 37883023.
E-mail address: roque@iqm.unicamp.br (C.R.D. Correia).
Figure 1. Natural products bearing symmetrical diaryl substituted carbon centers.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.039

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J. G. Taylor et al. / Tetrahedron Letters 52 (2011) 3861–3864
Table 2
EtO2C
O
NaH
Evaluation arenediazonium tetrafluoroborates
(EtO)2P(O)CH2COOEt
DME-dry, N2,
OMe
MeO
MeO
OMe
reflux, 24h
CO2Me
R
Pd(OAc)2 (7 mol%)
N2BF4
90% Yield
CO2Me
+
R
Scheme 1. Synthesis of 3,3-diarylacrylate by a HWE reaction.
R
MeOH, reflux, 1h
2.5 equiv
R2O2C
R1
Entry
1
R
Product
Yield/%
95
N2BF4
CO2Me
R1
>2.0 equiv
CO2R2
[Pd]
+
R1
4-OMe
MeO
OMe
OMe
Scheme 2. Synthesis of 3,3-diarylacrylate by a HM reaction.
1a
CO2Me
of the olefin. Therefore, we reasoned that by simply inverting the
stoichiometry of the reactants, symmetrical b,b-diarylacrylates
would be provided in a one step procedure in somewhat smoother
conditions (Scheme 2).
Herein, we describe a method of synthesising symmetrical b,b-
diarylacrylates in a one pot procedure from methyl acrylates and
arenediazonium tetrafluoroborates. The utility of this protocol is
further exemplified by the its application towards the synthesis
of a highly active antineoplastic 3-aryl indanone compound 5.
2
3
2-OMe
90
85
MeO
1b
CO2Me
MeO
MeO
OMe
OMe
3,4-(OMe)2
1c
CO2Me
2. Results and discussion
MeO
MeO
OMe
4
5
3,4,5-(OMe)3
53
95
OMe
OMe
1d
CO2Me
Our previous results involving the arylation of methyl cinna-
mate indicated that a base was not necessary for the attainment
of high yields, so we initiated an optimization study that basically
evaluated the Pd source (Table 1).
Using methyl acrylate and 2.5 equiv of 4-methoxyarenediazoni-
um tetrafluoroborate as a model reaction, we found that 7 mol%
catalytic loading of Pd(OAc)2 in MeOH were the optimum condi-
tions (entry 2). Although heterogeneous Pd(OAc)2 supported on
charcoal was equally as effective, its use was abandoned due to
diminished reactivity upon reuse. Interestingly, Pd2dba3 as catalyst
gave only the monoarylated product in 72% yield (entry 4).
Next, we turned our attention to evaluating the substrate scope
with respect to the aryl donor (Table 2).8
Generally, yields were modest to excellent for alkoxy and phen-
oxy substituted arenediazonium salts (entries 1–9) and only rea-
sonable for the most highly substituted arenediazonium
tetrafluoroborate evaluated (entries 4 and 6). Where yields are
only modest (entries 4 and 6), the main side product was the
monoarylated compound. Somewhat surprisingly, repeat reactions
using more equivalents of arenediazonium salt did not improve the
yields. Diarylation with the 4-hydroxy arenediazonium
tetrafluoroborates provided only the monoarylated Heck adduct
in a modest isolated yield of 33% (entry 10).
OMe
OMe
2,4-(OMe)2
MeO
MeO
1e
CO2Me
OMe
N2BF4
O
O
O
O
O
6
7
8
58
75
74
O
1f
CO2Me
O
N2BF4
O
O
O
O
O
1g
CO2Me
Cl
Cl
OMe
3-Cl, 4-OMe
MeO
1h
CO2Me
9
4-OPh
4-OH
86
33
Table 1
Optimization studies
PhO
HO
OPh
1i
CO2Me
CO2Me
10a
[Pd],
CO2Me
MeO
N2BF4
1j
MeOH, reflux, 1h
MeO
OMe
Yield/%
a
Reaction ran at room temperature for 15 min.
Entry
[Pd]/(mol %)
1
2
3
4
Pd(OAc)2 (10)
Pd(OAc)2 (7)
Pd(OAc)2 (5)
Pd2dba3 (5)
Pd(OAc)2/C (5)
Pd(OAc)2/C (5)
96
95
77
—
90
23
The effect of an alkyl substituent at the alpha carbon of the
acrylate was explored and unexpectedly gave rise to a 1:1 mixture
of isomers 2a and 2b as determined by GC–MS (Scheme 3). This
was further confirmed by reduction of the mixture under hydrogen
over Pd/C affording one single compound 2c. Interestingly,
although double bond isomerisation for the initially formed
5
6a
a
First re-use of the heterogeneous catalyst.

J. G. Taylor et al. / Tetrahedron Letters 52 (2011) 3861–3864
3863
OMe
CO2Me
4 Pd(OAc)2 (7 mol%)
MeOH, reflux, 1h
1
1
CO2Me
Pd-H
CO2Me
N2BF
3
X
3
CO2Me
MeO
MeO
OMe
I
II
2.5 equiv
MeO
CO2Me
CO2Me
CO2Me
Pd-H
OMe
Pd/C
H2
MeO
MeO
OMe
MeO
OMe
2a
2b
2c
71 % Yield
83% Yield, 1 : 1 mixture of 2a and2b
Scheme 3. Arylation of methyl methacrylate.
COMe
Pd(OAc)2 (7 mol%)
N2BF4
OMe
OMe
OMe
+
COMe
N2BF4
MeO
MeO
O
1.Pd(OAc)2 (7 mol%)
MeOH, reflux, 1h
MeOH, reflux, 1h
MeO
3
OMe
OMe
50% Yield
4
CO2Me
MeO
OMe
OMe
2.5 equiv
Scheme 4. Direct diarylation of methyl vinyl ketone.
2. Pd/C, H2
MeOH, r.t, 3h
OMe
OMe
56% over 2 steps
OMe
O
cinnamate ester I under catalytic conditions is plausible, no Heck
adducts corresponding to arylation at the ‘C1 position’ of II were
observed.
A preliminary study with similar conjugated olefin substrates
such as methyl vinyl ketone was also carried out. In spite of the fact
that monoarylation can be conducted in high yields,9 it was only
possible to carry out a direct diarylation of methyl vinyl ketone
in a modest 50% yield (Scheme 4, compound 3).
These promising results with the acrylates prompted us to ex-
plore the application of this chemistry for the preparation of the
anticancer indanone compound 5.10 Not only did 5 display very
good activities for hormone dependent cancer cell lines, but it also
showed virtually no toxicity for human erythrocytes being four
times more active than the natural product Podophylotoxin. In
the literature, the target compound 5 was prepared from gallic acid
in 5 steps with an overall yield of 11% (Scheme 5).10
We envisaged that the target compound could be prepared via a
process involving a one pot Pd-catalysed HM-reduction11 proce-
dure followed by hydrolysis of the ester 4 to afford the correspond-
ing carboxylic acid. Finally, as the last step, an acid catalysed
cyclization reaction was employed to provide compound 5. Pleas-
ingly, we were able to complete the synthesis of 5 in only three
steps (two purifications steps only) in an overall yield of 43%
(Scheme 6). Furthermore, this approach is very simple, inexpensive
and amenable to multigram synthesis.
MeO
1.KOH
EtOH-H2O
2. PPA
MeO
5
OMe
MeO
OMe
77% over 2 steps
5
µ
(IC50 = 2.2 M),for MCF-7
hormone-dependent breast cancer.
No toxicity to human erythrocytes at
high concentrations of (100 g/ml, 258 M).
µ
µ
Scheme 6. Synthesis of indanone 5 via a HM reaction.
tested. This methodology provides an easy access to a biologically
active 3-aryl indanones. Further investigations towards the syn-
thesis of natural products via a Heck-Matsuda diarylation reaction
are currently underway in our laboratory.
Acknowledgements
Authors gratefully acknowledge the generous financial support
from the Brazilian funding agencies Fundação de Amparo à Pesqu-
isa do Estado de São Paulo (FAPESP), Conselho Nacional de Desen-
volvimento Científico e Tecnológico (CNPq), and Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
In summary, we have developed a convenient methodology for
the synthesis of a variety of symmetrical 3,3-diarylacrylates via a
regio-stereoselective
Heck-Matsuda
reaction.
Various
arenediazonium salts bearing electron-donating groups were
References and notes
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OH
OMe
O
HO
HO
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MeO
MeO
5-Steps
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CO2H
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Podophyllotoxin
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11% Overall Yield
Scheme 5. Synthesis of anticancer indanone from gallic acid.

3864
J. G. Taylor et al. / Tetrahedron Letters 52 (2011) 3861–3864
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(1H, s), 3.90 (3H, s), 3.81 (3H, s), 3.80 (6H, s), 3.78 (6H, s), 3.63 (3H, s); dC
(62.5 MHz, CDCl3): 166.5, 156.4, 153.0, 152.7, 139.5, 138.2, 136.1, 133.8, 116.2,
106.9, 106.0, 61.0, 60.9, 56.2, 56.2, 51.3; MS m/z (EI): calcd for C22H26O8
418.1628, found 418.1617. 1f obtained as a white solid (58% yield). mp 95–
96 °C; Rf = 0.35 (hexanes/EtOAc, 4:1) after visualization by vanillin; dH
(500 MHz, CDCl3): 6.81–6.84 (3H, m), 6.77 (1H, d, J 9.0), 6.69–6.71 (2H, m),
6.21 (1H, s), 6.01 (2H, s), 5.99 (2H, s), 3.64 (3H, s); dC (125 MHz, CDCl3): 166.7,
156.6, 149.2, 148.1, 147.9, 147.5, 135.5, 132.7, 123.5, 123.4, 115.5, 110.2, 108.7,
108.3, 108.1, 101.7, 101.4, 51.5; MS m/z (EI): calcd for C18H14O6 326.0790,
found 326.0775. 1g obtained as a white solid (75% yield). mp 107–108 °C;
Rf = 0.46 (hexanes/EtOAc, 1:1) after visualization by vanillin; dH (250 MHz,
CDCl3): 6.81–6.86 (4H, m), 6.67–6.71 (2H, m), 6.19 (1H, s), 4.24–4.27 (8H, m),
3.63 (3H, s); dC (62.5 MHz, CDCl3): 166.5, 156.1, 144.9, 143.7, 143.1, 142.9,
134.5, 131.9, 122.7, 121.8, 118.4, 117.6, 116.6, 114.9, 64.5, 64.4, 64.3, 51.1; MS
m/z (EI): calcd for C20H18O6 354.1103, found 354.1117.
106, 4622; For
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8. Typical procedure for the synthesis of 3,3-diarylacrylates is as follows; a test
tube (inside diameter 13 mm; length 100 mm), equipped with a magnetic bar
was charged with methyl acrylate (0.55 mmol), Pd(OAc)2, (0.038 mmol) and
analytical grade methanol (5 mL). After vigorous stirring at room temperature
for 30 s, the diazonium salt (1.38 mmol) was added in portion and the reaction
left to stir at reflux for 1 h. Upon completion, the reaction mixture was
concentrated under reduced pressure and loaded directly onto Silica gel (using
a small amount of DCM to transfer the oily residue) then chromatographed
with ethyl acetate–hexanes to give the desired Heck-adducts. 1d obtained as a
white solid (53% yield). mp 126–127 °C; Rf = 0.17 (hexanes/EtOAc, 4:1) after
visualization by vanillin; dH (250 MHz, CDCl3): 6.52 (2H, s), 6.44 (2H, s), 6.26