Consecutive palladium-catalyzed Hiyama-Heck reactions in aqueous media under ligand-free conditions

Article abstract of DOI:10.1039/b707583a

Symmetric and asymmetric (E)-1,2-diarylethenes are synthesized from aryl bromides by consecutive one-pot Hiyama-Heck reactions carried out in water and under air; the only additives required are sodium hydroxide, palladium acetate and poly(ethylene glycol), and the products are isolable in many cases by simple filtration of the water solution. The Royal Society of Chemistry.

Full text of DOI:10.1039/b707583a

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Consecutive palladium-catalyzed Hiyama–Heck reactions in aqueous
media under ligand-free conditions{
a
Alvaro Gordillo, Ernesto de Jesu´s* and Carmen Lo´pez-Mardomingo
b
a
´
Received (in Cambridge, UK) 21st May 2007, Accepted 3rd July 2007
First published as an Advance Article on the web 25th July 2007
DOI: 10.1039/b707583a
synthesis of vinylarenes (3) therefore requires close control of the
relative kinetics of the Hiyama and Heck reactions in order to
minimize the formation of (E)-1,2-diarylethenes (4) and other
Heck by-products (Scheme 1b). At the same time, the development
of procedures that allow good kinetic control makes the sequential
combination of the Hiyama and Heck reactions to afford
asymmetrically substituted olefins (5) in a one-pot reaction more
feasible (Scheme 1c). Although palladium-mediated coupling
reactions are widely used for the synthesis of functionalized (E)-
stilbenes and other (E)-1,2-diarylethenes,12 the preparation of
asymmetric compounds usually starts from previously isolated
vinylarenes.13 To the best of our knowledge, only two reports have
appeared in the literature describing one-pot syntheses of
asymmetric (E)-1,2-diarylethenes directly from aryl halides, both
of which involve aromatic iodides, high catalyst loadings, and
phosphine ligands or fluoride additives.14,15 Herein, we describe
remarkable yields and selectivities in the synthesis of vinylarenes
and symmetric and asymmetric (E)-1,2-diarylethenes in water with
modest Pd loadings and under ligand-free conditions.
Symmetric and asymmetric (E)-1,2-diarylethenes are synthe-
sized from aryl bromides by consecutive one-pot Hiyama–Heck
reactions carried out in water and under air; the only additives
required are sodium hydroxide, palladium acetate and poly-
(ethylene glycol), and the products are isolable in many cases by
simple filtration of the water solution.
It is widely recognized that water offers practical advantages in
several organic reactions involving soluble or non-soluble sub-
strates.1 Palladium-catalyzed carbon–carbon couplings, which are
some of the most common transition-metal-catalyzed processes,2
are more and more often being performed in aqueous or biphasic
media.3 The Hiyama arylation of haloarenes,4 for example, has
recently been described in water using a variety of Pd precatalysts
and, usually, arylsiloxanes activated with sodium or potassium
hydroxide (Scheme 1a).5–7 The most interesting results from these
investigations suggested that bromides might react efficiently with
arylsiloxanes at high temperatures in the presence of relatively low
concentrations of palladium salts and in the absence of phosphanes
or other expensive or toxic ligands (ligand-free conditions8).6,7
Herein, we show that this attractive and unique combination of
accessible and stable organosiloxanes, aqueous media, low Pd
loadings, and aerobic and fluoride- and ligand-free conditions are
also valid for sequential reactions that afford more complex
products in a one-pot synthesis.
An exhaustive screening of the Hiyama vinylation of 4-bromo-
acetophenone in water established that 4-vinylacetophenone
was best synthesized at 140 uC in the presence of 0.1 mol% of
palladium(II) acetate, five equivalents of NaOH, and four
equivalents of triethoxy(vinyl)silane to reduce the undesired
formation of Heck by-products 4 and 6 (Table 1, entry 1).16
Complete conversions were also achieved with lower temperatures
and Pd loadings (0.01 mol%), although the longer reaction times
required for these conditions produced a decrease in yields due to
both extensive polymerization and Heck arylation of the 4-vinyl-
acetophenone.17 The addition of poly(ethylene glycol) (PEG, Mw =
2000) greatly enhanced the selectivity for the vinyl compound
(Table 1, entry 2) even in the presence of smaller excesses of silane
(Table 1, entry 3).18,19 Substrates such as 4-bromobenzoic acid or
3-bromopyridine were converted almost quantitatively into the
vinyl compound in the absence of PEG (Table 1, entries 4 and 5),
although the presence of this additive allowed a substantial
reduction in the amount of silane required (Table 1, entry 6). The
slower kinetics of the vinylation in the case of electronically
inactivated bromoarenes such as 4-bromoanisole (Table 1, entry 8)
or 4-bromo-N,N-dimethylaniline (Table 1, entry 9) favoured the
Heck products, therefore these reactions were carried out at higher
temperatures in the presence of PEG. It should be stressed that the
addition of PEG in these reactions enhances the solubility of the
hydrophobic bromoarenes and stabilizes not only the catalyst but
alsothe vinyl compoundsagainstpolymerizationor decomposition.
(E)-1,2-Diarylethenes 4 were obtained with high selectivities
simply by varying the aforementioned conditions. This variation
The vinylation of aryl halides with silicon-based vinyl donors9 is
complicated by the fact that palladium catalysts promote the
Heck–Mizoroki10,11 coupling of aryl halides and alkenes under
conditions similar to those of the Hiyama reaction. The efficient
Scheme 1
aDepartamento de Qu´ımica Orga´nica, Universidad de Alcala´, 28871
Alcala´ de Henares (Madrid), Spain
bDepartamento de Qu´ımica Inorga´nica, Universidad de Alcala´, 28871
Alcala´ de Henares (Madrid), Spain. E-mail: ernesto.dejesus@uah.es;
Fax: (+34) 91 885 4683
{ Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data for all compounds. See DOI: 10.1039/
b707583a
4056 | Chem. Commun., 2007, 4056–4058
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Table 1 Hiyama vinylation of aryl bromides in watera
Table 3 Synthesis of asymmetric (E)-1,2-diarylethenes by consecutive
Hiyama vinylation and Heck arylation reactions in watera
PdII (mol%)/ratio
Selectivity
Yield
Entry Ar
1 : 2/additiveb
3 : (4 + 6)c (%)d
1
2
3
0.1/1 : 4/–
0.1/1 : 4/PEG
0.1/1 : 2/PEG
94 : 6
99 : 1
95 : 5
70
95
90
PdII (A/B,
mol%)
Yield
(%)b
Entry
Product
4
0.3/1 : 4/–
99 : 1
97
1
2
0.1/0.5
0.1/0.1
91
87
5
6
0.1/1 : 4/–
0.1/1 : 2/PEG
100 : 0
99 : 1
96
95
3
4
5
0.1/0.1
0.1/0.5
0.1/0.5
0.3/0.5
81
71
90
89
7
0.1/1 : 4/PEG
99 : 1
93
8
9
a
0.1/1 : 4/PEG
0.5/1 : 4/PEG
90 : 10e
91 : 9e
75
86
In
a typical experiment, 1 mmol of aryl bromide, triethoxy-
(vinyl)silane, and palladium acetate were stirred under air in 0.5 M
NaOH at 140 (entries 1–7) or 150 uC (entries 8 and 9) for 2–3 h. All
conversions of 1 were quantitative. See ESI for further details.
6
b
c
20 wt% PEG. Selectivities were determined from 1H NMR
d
e
a
spectroscopy of the crude product. Yields of isolated 3. Ratio
4 : 6 # 75 : 25.
Typical conditions: reaction A: 1.78 mmol of aryl bromide 1a,
3.54 mmol of triethoxy(vinyl)silane 2, and palladium acetate were
stirred under air in 10 mL of 0.5 M NaOH and 20 wt% PEG for 3 h
at 140 uC; reaction B: 1.78 mmol of aryl bromide 1b and palladium
acetate were added and the mixture stirred for 3–6 h at 140 uC (20 h,
100 uC for entry 1). All conversions were 100%. See ESI for further
essentially consisted of using a stoichiometric amount or a slight
excess of the vinylsilane (Table 2). The addition of PEG was not
generally required in these syntheses. Remarkably, a very low
b
details. Yields of isolated product.
Table 2 Synthesis of symmetric (E)-1,2-diarylethenes by consecutive
Hiyama vinylation and Heck arylation in watera
catalyst loading was enough to afford (E)-4,49-bis(acetyl)stilbene
(0.005 mol% Pd, 24 h, 120 uC, TON = 19 400; Table 2, entry 1)
quantitatively. However, higher catalyst loadings and temperatures
are required to complete the conversion of activated substrates in
shorter times (Table 2, entries 2–5) or in the case of inactivated
bromoarenes (Table 2, entries 6 and 7).
We subsequently attempted the one-pot synthesis of asymmetric
(E)-1,2-diarylethenes 5 by combining the Hiyama vinylation of
bromoarene 1a with the in situ Heck reaction of the resulting
vinylarene with a second bromoarene 1b (Table 3). Three
substrates that yielded almost quantitative conversions and
selectivities in the Hiyama vinylation were tested as bromides 1a,
namely 3-bromopyridine (Table 3, entries 1–4), 4-bromoacetophe-
none (Table 3, entry 5), and 4-bromobenzoic acid (Table 3, entry
6).{ Full conversions were always attained, irrespective of the
electron-withdrawing or -donating nature of the bromoarene,
provided that a second load of Pd catalyst was added together with
the second bromoarene 1b. The selectivities for asymmetric (E)-
stilbenes or stilbazoles (5) were notable, as can be inferred from the
high yields of isolated products (81–91%); only small amounts of
symmetric 1,2-diarylated derivatives were observed as by-products
(,5%). 4-Bromoanisole was the only substrate that afforded
significant amounts of other by-products (mainly around 7% of
the 1,1-isomer) and therefore lower yields of the asymmetric (E)-
1,2-diarylethene (71%, Table 3, entry 4).
PdII
(mol%) time/h
Reaction Selectivity Yield
(%)c
Entry Ar
4 : 6b
1
2
3d
0.005
0.3
24
3
100 : 0
100 : 0
82 : 18
97
98
80
0.5
5
4
5
0.3
0.3
3
3
100 : 0
100 : 0
96
98
6e
7e
a
1
1
22
5
77 : 23
97 : 3
70
50
In
a typical experiment, 1 mmol of aryl bromide, triethoxy-
(vinyl)silane, and palladium acetate were stirred under air in 5 mL of
0.5 M NaOH at 120–140 uC for the specified time. Conversions of 1
b
were 100%. See ESI for further details.
Selectivities were
determined from 1H NMR spectroscopy of the crude product.
Yields of isolated product 4. Addition of 40 wt% PEG was
c
d
e
necessary for complete conversion. A larger excess of vinylarene
(1 mmol) was employed in these cases.
Blackmond et al. recently pointed out that simply replacing an
organic solvent by water does not suppose an automatic
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6 E. Alacid and C. Na´jera, Adv. Synth. Catal., 2006, 348, 945–962.
7 A. Gordillo, E. de Jesu´s and C. Lo´pez-Mardomingo, Org. Lett., 2006, 8,
3517–3520.
8 M. T. Reetz and J. G. de Vries, Chem. Commun., 2004, 1559–1563;
J. G. de Vries, Dalton Trans., 2006, 421–429.
9 Selected recent reports on the Hiyama vinylation of aryl halides:
M. E. Mowery and P. DeShong, J. Org. Chem., 1999, 64, 1684–1688;
T. Jeffery, Tetrahedron Lett., 1999, 40, 1673–1676; H. M. Lee and
S. P. Nolan, Org. Lett., 2000, 2, 2053–2055; S. E. Denmark and
J. M. Kallemeyn, J. Am. Chem. Soc., 2006, 128, 15958–15959;
S. E. Denmark and C. R. Butler, Org. Lett., 2006, 8, 63–66.
10 T. Mizoroki, K. Mori and A. Ozaki, Bull. Chem. Soc. Jpn., 1971, 44,
581; R. F. Heck and J. P. Nolley, Jr., J. Org. Chem., 1972, 37,
2320–2322; I. P. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000,
100, 3009–3066; S. Bra¨se and A. de Meijere, in Metal-Catalyzed Cross-
Coupling Reactions, ed. A. de Meijere and F. Diederich, Wiley-VCH,
Weinheim, 2nd edn, 2004, ch. 5.
enhancement in the environmental or economical efficiency of a
process because the impact of the overall process, including
workup, must be considered.20 The conversions and selectivities of
the reactions described here in water compete favourably with
those reported in organic solvents, and the use of water has specific
advantages over conventional organic solvents: (a) the activation
of aryl bromides under ligand-free conditions relies on the use of
high temperatures for which a nonflammable solvent such as water
is superior on safety grounds; (b) many of the alkenes reported,
especially 1,2-diarylethenes, are solids that precipitate from the
aqueous reaction medium and can therefore be separated by
simple filtration to afford crude products that, in many cases, are
1
pure by H NMR spectroscopy.21
In conclusion, we have provided an effective method for the
sequential performance of Hiyama and Heck reactions in aqueous
media that allows the preparation of a variety of symmetrically
and asymmetrically functionalized (E)-1,2-diarylethenes in one pot
from aryl bromides and triethoxy(vinyl)silane. The only additives
required are sodium hydroxide, palladium acetate (0.1 to 0.5 mol%)
and, in some cases, poly(ethylene glycol). The reactions are carried
out in air and the products can be isolated, in many cases, by
simple filtration of the aqueous solution.
11 Recent reports on Heck reactions between aryl halides and vinylarenes
in water: C. Na´jera, J. Gil-Molto´, S. Karlstro¨m and L. R. Falvello,
Org. Lett., 2003, 5, 1451–1454; L. Botella and C. Na´jera, Tetrahedron
Lett., 2004, 45, 1833–1836; R. B. DeVasher, L. R. Moore and
K. H. Shaughnessy, J. Org. Chem., 2004, 69, 7919–7927; H. Hagiwara,
Y. Sugawara, T. Hoshi and T. Suzuki, Chem. Commun., 2005,
2942–2944; S. Ogo, Y. Takebe, K. Uehara, T. Yamazaki, H. Nakai,
Y. Watanabe and S. Fukuzumi, Organometallics, 2006, 25, 331–338;
N. S. C. R. Kumar, I. V. P. Raj and A. Sudalai, J. Mol. Catal. A:
Chem., 2007, 269, 218–224.
12 Classical non-catalytic methods such as the Wittig or Horner–
Wadsworth–Emmons reaction usually afford poor control over the
(E) or (Z) configuration of the CLC double bonds. Catalytic methods
for the synthesis of stilbenes have been recently reviewed:
K. Ferre´-Filmon, L. Delaude, A. Demonceau and A. F. Noels,
Coord. Chem. Rev., 2004, 248, 2323–2336.
This work was supported by the Ministerio de Educacio´n y
Ciencia of Spain (project CTQ2005-00795/BQU) and the
Comunidad de Madrid (project S-0505/PPQ/0328-03). A. G. is
grateful to the MEC for a FPU Fellowship.
13 Asymmetric 1,2-diarylethenes are also prepared by titanium-catalyzed
McMurry coupling of aldehydes and ketones or by ruthenium-catalyzed
cross-metathesis of vinylarenes, but the first procedure suffers from poor
tolerance to functional groups and the second from low selectivities. See,
for example: K. Ferre´-Filmon, L. Delaude, A. Demonceau and
A. F. Noels, Eur. J. Org. Chem., 2005, 3319–3325.
14 Itami et al. used a Heck–Hiyama sequence of reactions in THF to
couple aryl iodides and 2-pyridyldimethyl(vinyl)silane using 10 mol% of
Pd(OAc)2 and tri-2-furylphosphine: K. Itami, T. Nokami, Y. Ishimura,
K. Mitsudo, T. Kamei and J.-I. Yoshida, J. Am. Chem. Soc., 2001, 123,
11577–11585.
15 Jeffery described the synthesis of (E)-3,49,5-trimethoxystilbene in 72%
yield by two sequential Heck reactions using aryl iodides, trimethyl-
(vinyl)silane and 4 mol% of Pd(dba)2: T. Jeffery and B. Ferber,
Tetrahedron Lett., 2003, 44, 193–197.
16 We started from the conditions established in our previous study on the
Hiyama arylation (ref. 7). Palladium acetate, palladium dichloride and
complexes of the latter with the soluble phosphines 1,3,5-triaza-7-
phosphaadamantane (PTA) and PPh2Ar* (Ar* = 3,4-[18-crown-6]-
phenyl) produced comparable results.
17 In contrast with our observations that short reaction times are key in the
efficient synthesis of vinyl derivatives, high yields of 4-vinylacetophenone
after 20 h of reaction at 120 uC have been reported during the course of
our work by Alacid and Na´jera using tetrabutylammonium bromide
(TBAB) as a nanoparticle stabilizer: E. Alacid and C. Na´jera, Adv.
Synth. Catal., 2006, 348, 2085–2091.
18 Poly(ethylene glycol) (PEG), pure or as a co-solvent, is an efficient
medium for palladium-catalyzed coupling reactions. S. Chandrasekhar,
Ch. Narsihmulu, S. S. Sultana and N. R. Reddy, Org. Lett., 2002, 4,
4399–4401; C. Luo, Y. Zhang and Y. Wang, J. Mol. Catal. A: Chem.,
2005, 229, 7–12.
19 PEG was a more efficient additive than TBAB in Suzuki reactions
catalyzed by palladium(II) acetate in water and ligand-free conditions.
L. Liu, Y. Zhang and Y. Wang, J. Org. Chem., 2005, 70, 6122–6125.
20 D. G. Blackmond, A. Armstrong, V. Coombe and A. Wells, Angew.
Chem., Int. Ed., 2007, 46, 3798–3800.
Notes and references
{ The synthesis of (E)-4-[2-(3-pyridyl)vinyl]acetophenone is given as
representative: in a 35 mL pressure tube, triethoxy(vinyl)silane (0.77 mL,
3.54 mmol) and a 0.5 M NaOH solution in water (10.70 mL, 5.35 mmol)
containing 20% (w/w) of PEG 2000 (2.14 g) were vigorously stirred for
5 min at room temp. 3-Bromopyridine (0.178 mL, 1.78 mmol) and
palladium acetate (0.4 mg, 1.8 mmol) were subsequently added and the
vigorous stirring was continued for 3 h at 140 uC. 4-Bromoacetophenone
(0.3615 g, 1.78 mmol) and palladium(II) acetate (0.4 mg, 1.8 mmol)
dissolved in 1 mL of a 20% (w/w) aqueous solution of PEG 2000 were
added at room temperature and the reaction warmed for 6 h at 140 uC. The
product was extracted with ethyl acetate (3 6 20 mL) and purified by flash
chromatography on silica gel with hexane–ethyl acetate 1 : 5 (Rf = 0.24).
Yield: 0.3467 g (87%).
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4058 | Chem. Commun., 2007, 4056–4058
This journal is ß The Royal Society of Chemistry 2007