Electrochemically assisted heck reactions

Article abstract of DOI:10.1021/ol0519487

(Chemical Equation Presented) During efforts to develop chip-based Heck reaction chemistry, it was discovered that normal solution-phase Heck reactions can be dramatically accelerated using electrochemistry. The acceleration makes room temperature Heck reactions proceed at synthetically useful rates in the absence of added ligand. Presumably, the current passed through the reaction maintains a high level of active catalyst.

Full text of DOI:10.1021/ol0519487

ORGANIC
LETTERS
2
005
Vol. 7, No. 24
381-5383
Electrochemically Assisted Heck
Reactions
5
Jun Tian and Kevin D. Moeller*
Department of Chemistry, Washington UniVersity, St. Louis, Missouri 63130
moeller@wustl.edu
Received August 12, 2005
ABSTRACT
During efforts to develop chip-based Heck reaction chemistry, it was discovered that normal solution-phase Heck reactions can be dramatically
accelerated using electrochemistry. The acceleration makes room temperature Heck reactions proceed at synthetically useful rates in the
absence of added ligand. Presumably, the current passed through the reaction maintains a high level of active catalyst.
Recently, we reported the development of a site-selective
Heck reaction on an electrochemically addressable, semi-
conducting chip. In this work, pre-selected electrodes on
2
treated with Pd(OAc) in a 9:1 DMF/water solution contain-
6
ing triethylamine and tetrabutylammonium bromide. The
reaction did not proceed at all when the DMF solvent was
exchanged for acetonitrile. The reaction proceeded in 3 and
12 h, respectively, when a cathode was inserted into the
1
2
the chip were used to reduce Pd(OAc) and generate the
required Pd(0) catalyst. The Pd(0) catalyst was then confined
to the region of the chip surrounding the selected electrode
by adding allyl methyl carbonate to the reaction. The allyl
methyl carbonate scavenged the Pd(0) catalyst by converting
it into an inactive π-allylpalladium(II) species. As with any
such reaction, optimization of spatial selectivity on the chips
benefited from reaction conditions that showed only a
minimal amount of background reaction in the absence of
an active electrode. For the Heck reaction, this was ac-
complished by running the reactions at room temperature in
2
reaction, and the Pd(OAc) reduced electrochemically. This
observation made it clear that site-selective, chip-based Heck
reactions were possible. It also suggested that preparative-
scale, room-temperature Heck reactions might benefit from
the passage of current. A similar observation was made by
Mangold and J u¨ ttner in their work utilizing polypyrrole/
7
palladium composite modified cathodes. Using this hetero-
geneous catalyst and “electrochemically-driven” conditions,
the authors found that the Heck coupling of iodobenzene to
styrene could be accomplished at room temperature without
additives. However, the yield of stilbene product obtained
2
3
4
5
the absence of phosphine, thiourea, or carbene ligands.
For example, a reaction between methyl 4-iodobenzoate and
-pyrenemethyl acrylate took 18 h to reach completion when
-
5
was very low (5 × 10 M product for a reaction using 0.1
M substrate). Our work in connection with chip-based
reactions indicated that this would not be the case for Heck
reactions involving a homogeneous catalyst. We report here
conditions for electrochemically assisted Heck reactions that
not only significantly accelerate the room-temperature Heck
1
(
1) Tian, J.; Maurer, K.; Tesfu, E.; Moeller, K. D. J. Am. Chem. Soc.
005, 127, 1392.
2) For room-temperature Heck reactions in the presence of phosphine
2
(
ligands, see: (a) DeVasher, R. B.; Moore, L. R.; Shaughnessy, K. H. J.
Org. Chem. 2004, 69, 7919. (b) Stambuli, J. P.; Stauffer, S. R.; Shaughnessy,
K. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 2677. (c) Littke, A. F.;
Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. (d) Hiroshige, M.; Huaske,
J. R.; Zhou, P. Tetrahedron Lett. 1995, 36, 4567. (e) Jeffery, T. Tetrahedron
Lett. 1994, 35, 3051.
(5) For Heck reactions accelerated using ultrasound, see: (a) Ambulgekar,
G. V.; Bhanage, B. M.; Samant, S. D. Tetrahedron Lett. 2005, 46, 2483.
(b) Deshmukh, R. R.; Rajagopal, R.; Srinivasan, K. V. Chem. Commun.
2001, 33, 1544.
(6) A prior room-temperature Heck reaction using Pd(OAc)2 and related
conditions showed similar results: Jeffery, T. Tetrahedron Lett. 1985, 26,
2667.
(
3) For a room-temperature Heck reaction using a thiourea-based ligand,
see: Dai, M.; Liang, B.; Wang, C.; Chen, J.; Yang, Z. Org. Lett. 2004, 6,
21.
4) For a room-temperature Heck reaction using a carbene-type ligand,
see: Andrus, M. B.; Song, C.; Zhang, J. Org. Lett. 2002, 4, 2079.
2
(
(7) Mangold, K.-M.; Meik, F.; J u¨ ttner, K. Synth. Met. 2004, 144, 221.
1
0.1021/ol0519487 CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/27/2005

reactions in the absence of added ligands but also lead to
excellent yields of product.
behavior suggests that the rate acceleration is not simply due
to a very efficient initial reduction of Pd(II) to the active
Pd(0) catalyst. Instead, it appears that the current passed
continually maintains a higher level of active catalyst than
found in the absence of current. At this time, the exact role
of the current in the reactions is not known. However, it is
thought that the concentration of active catalyst in ligand-
free Heck reactions is reduced by the aggregation of unstable
Our study of these reactions began by examining the
generality of the electrolysis conditions developed for the
chip-based reactions. This was accomplished by coupling
iodobenzene to a series of electron-poor, electron-rich, and
conjugated olefins (Table 1). The electrolysis reactions
8
Pd(0) clusters to form catalytically inactive precipitates. One
plausible explanation for the role of the current in the
reactions is that the clusters being formed are broken up by
the oxidation of Pd(0) to Pd(II) at the anode (the reactions
Table 1. Use of Aryliodide Substrates
9
are run in an undivided cell). Rereduction of the Pd(II)
species at the cathode then effectively recycles the palladium
back into catalytically active Pd(0) species. The net result is
a steady state of active catalyst.
From a practical standpoint, the compatibility of the
reactions with the redox cycle and the presence of a steady-
state concentration of Pd(0) is very important because it
allows for the use of a simple constant current reaction setup.
In a constant current reduction, the potential of the cathode
climbs after the electrolysis substrate is consumed, a
development that can lead to the reduction of electron-poor
products and a decrease in product yield. However, in the
case of the redox cycle described above, the reaction never
runs out of Pd(II) substrate and the potential at the cathode
remains constant for the entire duration of the experiment.
Hence, there is no risk of reducing the Heck reaction product
and no need to regulate the potential at the cathode.
time electricity
yield (%)
entrya
R′
R
(h)
(F/mol)
(trans/cis)
1a
1b
2a
2b
3a
3b
4a
4b
5a
5b
6a
6b
7a
7b
8a
8b
9a
9b
H
H
H
H
H
H
H
H
H
H
H
H
CO
CO
Ph
Ph
CONH
CONH
n-C
n-C
CN
CN
OEt
OEt
2
Me
Me
16
2.5
18
4
none
1.22
none
1.33
none
1.57
none
1.47
none
1.37
none
1.06
none
1.78
none
0.91
none
1.26
85 (trans only)
89 (trans only)
84 (trans only)
87 (trans only)
81 (trans only)
84 (trans only)
74 (4.2/1)
2
2
16
3
2
8
H
H
16CO
16CO
2
Me
Me
18
3.5
16
2.5
12
2
8
2
84 (4.2/1)
80 (3.4/1)
82 (3.4/1)
70 (4.6/1)
78 (4.6/1)
CO
CO
CO
CO
CO
CO
2
2
2
2
2
2
Me CO
Me CO
2
CH
CH
2
-pyrene 18
78 (12/1)
2
2
-pyrene
4
18
2
84 (12/1)
Me CONH
Me CONH
Me Ph
2
80 (trans only)
85 (trans only)
80 (trans only)
88 (trans only)
2
The ability to run the reactions using constant current
conditions means that the experiments are compatible with
the use of a readily available 6-V lantern battery as the power
18
3
Me Ph
a
a ) no current; b ) 15 mA.
1
0,11
supply (Scheme 1).
Although the use of a battery does
utilized 15 mA of current, reticulated vitreous carbon (RVC)
anodes and cathodes, and an undivided cell. In each case,
passing current through the cell led to more than a 4.5-fold
increase in the rate of the Heck reaction. In the best case
Scheme 1
(entry 8a vs entry 8b), a 9-fold increase in rate was observed.
The rate acceleration was not changed by the presence of
an electron-withdrawing group on the aryliodide (entry 7-9)
or the use of a platinum cathode.
When the reaction utilized in entry 7b was performed using
a platinum cathode, the reaction proceeded in 3 h and
generated an 82% isolated yield of product. In each example
studied, the yield for the electrochemically assisted reaction
was slightly higher than the yield for the nonelectrochemical
reaction. The product stereochemistry obtained from the
reactions was the same for both electrochemical and non-
electrochemical reactions.
The increased reaction rate required passing current
through the cell for the entire duration of the experiment.
When current was passed for 1 h through a cell containing
the substrates for reaction 7b and then stopped, the Heck
reaction took 14 h to reach completion. The reaction was
lead to a lower yield of product (compare with Table 1, entry
b), the success of the reaction makes it clear that the utility
1
(
(
8) Reetz, M. R.; de Vries, J. G. Chem. Commun. 2004, 35, 1559
9) Sample Experimental Procedure. To a 25 mL three-neck flask with
a mixture of iodobenzene (2.45 g, 12.0 mmol), methyl acrylate (1.25 g,
4.4 mmol), Pd(OAc)2 (80.8 mg, 0.36 mmol), and tetrabutylammonium
1
bromide (3.86 g, 12.0 mmol) was added a solution of 9 mL of DMF, 1 mL
of water, and 1 mL of triethylamine. The resulting brown solution was
electrolyzed with constant current (15.0 mA) on reticulate vitreous carbon
(RVC) electrodes at room temperature under an argon atmosphere until
iodobenzene was consumed (3.5 h). HCl (1 M) was then added to the
reaction mixture until a pH <5 was reached. The resulting suspension was
extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were
first washed with water and brine and then poured into a short pad column
with silica gel eluting with CH2Cl2. The CH2Cl2 elute was concentrated
under reduced pressure. The residue was chromatographed on silica gel
eluting with hexane/ethyl acetate (15/1) to afford (E)-methylcinnamate (1.60
g) in 82% yield.
20% complete when the current was turned off. Clearly,
when the current was stopped the reaction returned to being
a normal room-temperature, ligand-free Heck reaction. This
5382
Org. Lett., Vol. 7, No. 24, 2005

of the method with new substrates can be readily evaluated
without the need for specialized equipment.
Table 3. Use of Arylbromide Substrates
After establishing that the effect of the electrolysis on the
Heck reaction was general, we turned our attention to finding
the optimal catalytic conditions. In other words, do the
reactions really require 30 mol % of the catalyst? The results
of these studies are summarized in Table 2. When the amount
time
(h)
electricity
(F/mol)
yield
(%)
entrya
R′
R
Table 2. Optimizing Catalytic Activity
1
1
2
2
3
3
4
4
5
5
a
b
a
b
a
b
a
b
a
b
H
H
Ph
Ph
Ph
Ph
CONH2
CONH2
Ph
Ph
CO2Me
CO2Me
18
none
3.19
none
3.34
none
3.15
none
2.84
none
3.13
<10
62
32
74
0
58
78
80
72
75
6
18
6
20
5.5
20
5
24
CO2Et
CO2Et
CO2Et
CO2Et
NO2
NO2
NO2
NO2
X
time substrate current electricity yield
entry (mol %)
(h)
conc (M)
(mA)
(F/mol)
(%)
5.5
1
2
3
4
5
6
7
30
30
10
10
10
3
16
2.5
5
2
2
0.09
0.09
0.09
0.09
0.27
0.49
0.88
none
15
15
25
15
none
1.22
2.86
2.05
1.12
2.94
2.05
85
89
85
76
85
80
82
a
a ) no current; b ) 15 mA.
were added to either the arylbromide or the olefin substrate.
Unlike the aryliodide-derived reactions, the arylbromide-
derived reactions were not compatible with the use of
electron-rich olefin coupling partners.
Along similar lines, room-temperature Heck reactions
using aryl chloride substrates could not be successfully
completed.
In conclusion, we have found that room-temperature Heck
reactions can be enhanced without the addition of a ligand
by passing current through the reaction. The current leads
to a significant increase in reaction rate and improved yields.
It appears that the enhancement of the reactions is the result
of the electrolysis maintaining a high level of active catalyst.
The reactions can be performed using a very simple reaction
setup by taking advantage of a battery as the power supply.
Finally, it is interesting to consider what the success of these
reactions suggests about electrochemically accelerating other
4.5
3.5
15
15
a
3
a
This reaction used 1 equiv of electrolyte.
of catalyst was decreased (entry 3), the rate of the reaction
initially dropped. A 3-fold reduction in catalyst led to a 2-fold
drop in rate. The reaction rate could be restored by increasing
the current flow through the cell from 15 mA to 25 mA (entry
4
). However, the increase in current lowered the yield of
the reaction. Fortunately, the rate of the reaction could also
be restored by increasing substrate concentration (entry 5).
With this in mind, the concentration was raised further (entry
), and the reaction proVed compatible with the use of only
mol % catalyst. Optimal conditions for the reaction used
6
3
a substrate concentration equal to 0.88 M (entry 7).
1
2
organometallic reactions.
The passage of current through reactions utilizing less
reactive arylbromide substrates also led to significant im-
provements in both the rate of the reactions and the yield of
product obtained (Table 3). Since the reactivity of the
arylbromides is very low, the reactions were explored using
Acknowledgment. We thank the National Science Foun-
dation (CHE-0314057) for their generous support of this
work. We also gratefully acknowledge the Washington
University High Resolution NMR facility, partially supported
by NIH grants RR02004, RR05018, and RR07155, and the
Washington University Mass Spectrometry Resource Center,
partially supported by NIHRR00954, for their assistance.
3
0 mol % of the catalyst. With these conditions, a room-
temperature Heck reaction between bromobenzene and
styrene produced little product even after 18 h (entry 1a).
On the other hand, the electrochemically assisted reaction
afforded a 62% isolated yield of product (entry 1b). Similar
results were obtained when electron-withdrawing groups
Supporting Information Available: Sample procedures
and spectral data for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(
10) For a simple electrochemical setup using a battery as a power supply,
see: Frey, D. A.; Wu, N.; Moeller, K. D. Tetrahedron Lett. 1996, 37, 8317.
11) All “non-battery” experiments were conducted using a model 630
OL0519487
(
coulometer, a model 410 potentiostatic controller, and a model 420A power
supply purchased from The Electrosynthesis Co., Inc. This equipment is
now available from Electrolytica, Inc.
(12) For an application of electrochemistry to a tin-based allylsilane
reaction, see: Zha, A.; Hui, A.; Zhou, Y.; Miao, Q.; Wang, Z.; Zhang, H.
Org. Lett. 2005, 7, 1903.
Org. Lett., Vol. 7, No. 24, 2005
5383