Solvent-free, open-vessel microwave-promoted Heck couplings: From the mmol to the mol scale

Article abstract of DOI:10.1055/s-2006-951512

The rapid, microwave-promoted Heck coupling of aryl iodides in open reaction vessels is presented and scale-up of the reactions to the mol scale demonstrated. Reactions are performed using 0.1 mol% palladium acetate as the catalyst, sodium carbonate and tributylamine as bases and tetrabutylammonium bromide as an additive. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951512

LETTER
2953
Solvent-Free, Open-Vessel Microwave-Promoted Heck Couplings: From the
mmol to the mol Scale
a
a
b
b
S
N
olvent-Free,
O
pe
i
n-Vesse
c
l
Microw
a
h
ve-Promoted
o
H
eckCoupl
l
ings as E. Leadbeater,* Victoria A. Williams, Thomas M. Barnard, Michael J. Collins Jr.
a
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269-3060, USA
Fax +1(860)4862981; E-mail: nicholas.leadbeater@uconn.edu
b
CEM Microwave Technology, 3100 Smith Farm Road, Matthews, NC 28104, USA
Received 10 May 2006
process solids, highly viscous liquids or heterogeneous re-
action mixtures. Also, adaptation of conditions from sim-
ple small-scale reactions to the continuous flow cell could
Abstract: The rapid, microwave-promoted Heck coupling of aryl
iodides in open reaction vessels is presented and scale-up of the re-
actions to the mol scale demonstrated. Reactions are performed us-
ing 0.1 mol% palladium acetate as the catalyst, sodium carbonate end up being time consuming; reoptimization of reaction
and tributylamine as bases and tetrabutylammonium bromide as an conditions often being required. The other option is to use
additive.
a batch-type process. This could either involve using one
Key words: palladium, Heck reaction, catalysis, solvent-free, mi- large vessel28–30 or parallel batch reactors. The latter has
crowave
recently been applied successfully by Kappe and co-
workers to the scale-up of reactions such as the Biginelli
dihydropyrimidine synthesis, the Diels–Alder cycloaddi-
tion as well as a Heck coupling. The Heck chemistry was
performed using four sealed reaction vessels, each con-
taining 20 mmol of substrate. More recently, Alcázar and
co-workers have used a similar parallel scale-up method-
ology to perform alkylation reactions.32 In both reports,
translation of reaction conditions developed on commer-
3
1
The palladium-catalyzed C–C coupling between aryl ha-
lides or vinyl halides and activated alkenes in the presence
of a base is well known now as the Heck reaction. There
have been a number of recent reviews of the scope and
1
,2
3
–7
versatility of the reaction. Its popularity started to grow
in the mid 1980’s when synthetic chemists found that they
were able to control the reaction and use it to make disub- cially available single-mode to a multimode reactor for
stituted olefins. More recently, the intramolecular Heck the scale-up proved not to be a problem.
reaction has also been well-established as a powerful syn-
In our laboratories, we have investigated the scale-up of
microwave-promoted Suzuki and Heck reactions in water
as a solvent. One approach we have taken is to use an au-
tomated stop-flow apparatus, this bringing together some
8
,9
thetic tool. It can be used for the construction of com-
plex polycyclic ring systems in the context of natural
product synthesis.1
0
Microwave heating is an area of increasing interest in both of the advantages of a batch reactor with those of a contin-
academic and industrial laboratories because it can en- uous flow reactor. This allowed us to scale the reactions
3
3
hance the rate of reactions and in many cases improve from the 1-mmol level to batches of 10 mmol. However,
1
1–13
product yields.
tool in Heck coupling reactions with considerable suc-
cess.
Microwave heating has been used as a we were keen to develop a procedure for the preparation
of multigram quantities of product in one run. To do this,
we decided to move away from sealed tubes and instead
investigate the possibility of using an open vessel since,
when working on a large scale, atmospheric pressure
conditions offer significant safety and operational advan-
tages.
1
4,15
Microwave heating has also been used for oxida-
tive Heck couplings. Considerable attention has been
focused on the use of microwave heating in conjunction
with water or ionic liquids
tion but other media, such as fluorous solvents, can also be
1
6
1
7
18,19
as solvents for the reac-
2
0
used.
The microwave-promoted Heck reaction has been per-
formed using open-vessel conditions before. Varma and
co-workers have used palladium chloride and a tetra-
phenylphosphonium bromide intercalated clay as a
catalyst mixture for the reaction, using DMF as a solvent
While many reactions have been performed on the small
scale using microwave heating, relatively few have been
further developed into larger-scale syntheses. This clearly
needs to be addressed if the technology is going to impact
3
4
2
1,22
process chemistry.
There are two possible scale-up and heating the reaction for 1–36 hours. Ritter and co-
options. The first is to use a continuous flow microwave workers have used the Heck reaction in their microwave-
35
cell, this technology being used successfully for a number promoted synthesis of organic polymers. They perform
2
3–27
of different reactions.
flow microwave apparatus are that it can be difficult to solvents such as dioxane.
The drawbacks of a continuous their reactions on a 1-mmol scale at reflux in organic
We wanted to perform the open-vessel Heck reaction
solvent-free since this could have further operational
advantages as well as being a topic that has received
considerable attention in conjunction with conventional
SYNLETT 2006, No. 18, pp 2953–2958
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951512; Art ID: S10806ST
0
3
.1
1
.2
0
0
6
©
Georg Thieme Verlag Stuttgart · New York

2
954
N. E. Leadbeater et al.
LETTER
Table 1 Optimization of Conditions for the Heck Reaction
O
O
MW, Pd(OAc)2
COMe
+
OMe base, TBAB
OMe
Br
MeOC
Entry
Reaction conditionsa,b
1 mol% Pd(OAc) , 3.7 equiv Na CO , 1 equiv TBAB, 120 °C, 20 min
Yield (%)
1
2
3
4
5
6
43
87
0
2
2
3
1 mol% Pd(OAc) , 3.7 equiv Na CO , 1 equiv TBAB, 1 equiv NBu , 120 °C, 20 min
2
2
3
3
1 mol% Pd(OAc) , 3.7 equiv Na CO , no TBAB, 1 equiv NBu , 120 °C, 20 min
2
2
3
3
0.1 mol% Pd(OAc) , 3.7 equiv Na CO , 1 equiv TBAB, 1 equiv NBu , 120 °C, 20 min
85
86
81
78
2
2
3
3
0.1 mol% Pd(OAc) , 2 equiv Na CO , 1 equiv TBAB, 1 equiv NBu , 120 °C, 20 min
2
2
3
3
0.1 mol% Pd(OAc) , 2 equiv Na CO , 1 equiv TBAB, 1 equiv NBu , 120 °C, 10 min
2
2
3
3
7
0.1 mol% Pd(OAc) , 2 equiv Na CO , 1 equiv TBAB, 1 equiv NBu , 150 °C, total reaction time 90 s
2 2 3 3
a
Reactions were run in a 50 mL round-bottomed flask with a reflux condenser attached. The reaction mixture was stirred throughout the mi-
crowave heating.
For clarity, changes in reaction conditions from entry 1 are noted in bold.
b
heating.36–42 Our starting point was to use reaction con- action time of 90 seconds had elapsed. There is a slight
ditions similar to those developed for the conventional sacrifice in product yield; the yield under these conditions
solvent-free Heck coupling; namely using ligandless being 78% (Table 1, entry 7).
palladium sources as catalysts, a suitable base and tetra-
butylammonium bromide (TBAB) as an additive. As sub-
strates for the reaction, we used 4-bromoacetophenone as
We decided to screen a range of aryl halide substrates in
the Heck coupling with methyl- and n-butyl acrylate using
our 90 seconds reaction time conditions (Table 1, entry 7).
the halide component and methyl acrylate as the olefin in
The results are shown in Table 2. In the coupling with me-
a 1:2 stoichiometric ratio. We performed screenings on a
thyl acrylate, aryl iodides (Table 2 entries 1–6) couple
5
-mmol scale. Initially, 1 mol% Pd(OAc) was used as the
2
better than bromides (Table 2 entries 7–11) using this
methodology. This is not unexpected in the light of litera-
ture to date. In couplings with representative aryl iodides,
comparable or slightly better yields are obtained with n-
butyl acrylate and methyl acrylate (Table 2, entries 12–
4
3
catalyst and sodium carbonate (3.7 equiv) as base. A
monomode microwave apparatus was used. The reaction
mixture was heated to 120 °C using a microwave power of
1
50 W, this taking around 45 seconds, and held at this
temperature for 20 minutes giving a 43% yield of the de-
sired product (Table 1, entry 1). We decided to add an or-
ganic amine to the reaction mixture since this is known to
have beneficial effects on the Heck coupling since it po-
tentially can act as a base, a ligand for the palladium cata-
lyst and a sequestrating agent for the HBr generated in the
reaction. Keeping all other parameters the same, addition
of tributylamine to the reaction mixture resulted in a sig-
nificant increase in product yield (Table 1, entry 2). A
gray colloidal palladium species was clearly observable at
the end of the reaction. No product was obtained if the re-
action is run in the absence of TBAB (Table 1, entry 3).
The catalyst loading could be reduced to 0.1 mol% with
no effect on product yield (Table 1, entry 4). The quantity
1
4). Reduction of the stoichiometric ratio of aryl iodide to
butyl acrylate from 1:2 to 1:1 has a deleterious effect on
the product yield; the yield dropping in the coupling with
4
1
-iodoanisole from 90% to 81% (Table 2, entries 12 and
5).
Table 2 Heck Coupling of Aryl Halidesa
O
O
X
MW, 90 s
R'
R'
+
0
.1 mol% Pd(OAc)2,
2
equiv Na2CO3,
R
R
1
equiv Bu3N,
equiv TBAB
1
of sodium carbonate could be reduced to 2 equivalents Entry Aryl halide
with no effect on product yield (Table 1, entry 5) The time
for which the reaction is held at 120 °C could be reduced
Alkene
Product yield (%)
74
1
OMe
CO Me
2
to 10 minutes with no significant effect on product yield
I
(
Table 1, entry 6). The time could be dramatically reduced
2
MeO
CO Me
91
2
if the reaction was run at 150 °C. At this temperature, the
reaction reaches completion within a total reaction time of
I
9
0 seconds. The mixture was heated to 150 °C using a mi-
crowave power of 150 W, this taking approximately 1
minute, and then held at this temperature until a total re-
Synlett 2006, No. 18, 2953–2958 © Thieme Stuttgart · New York

LETTER
Solvent-Free, Open-Vessel Microwave-Promoted Heck Couplings
2955
Table 2 Heck Coupling of Aryl Halidesa (continued)
Our next objective was to scale-up the reaction from 5
mmol to 1 mol. Our results are shown in Table 3. We de-
cided to do this in increments using the coupling of iodo-
benzene and butyl acrylate as our test reaction. Moving
from 5 mmol to 10 mmol required moving from a 50-mL
to a 100-mL reaction vessel. This could still be accommo-
dated in the monomode microwave apparatus and, using
identical reaction conditions, a 97% yield of the desired
product was obtained (Table 3, entry 1).
O
O
X
MW, 90 s
R'
R'
+
0
.1 mol% Pd(OAc)2,
2
equiv Na2CO3,
R
R
1
equiv Bu3N,
equiv TBAB
1
Entry
3
Aryl halide
Alkene
Product yield (%)
77
Me
CO Me
2
To scale-up the chemistry further, we needed to move
from a monomode to a multimode microwave apparatus.
Using a 3-L round-bottomed flask, we attempted to scale
the reaction of iodobenzene and butyl acrylate from 10
mmol to 0.5 mol. The multimode microwave apparatus
was again equipped with an opening in the top through
which a glass tube could be placed, connecting the flask
in the microwave cavity with a reflux condenser located
outside the microwave apparatus. Working on a large
scale, accurate temperature measurement and control is
important. This was achieved using a fiber-optic probe in-
serted into the reaction mixture by means of a glass ther-
mowell. Since calculations suggest that the Heck reaction
is somewhat exothermic, we wanted to be cautious when
irradiating large quantities of reagents with microwaves in
I
4
Me
CO Me
84
2
I
5
6
CO Me
86
67
2
I
COMe
OMe
CO Me
2
I
7
8
9
CO Me
36
15
2
Br
44
our solvent-free protocol. We performed the reaction us-
Me
CO Me
2
6
ing an initial microwave power of 600 W. The reaction
mixture was heated to 150 °C over a 3 minutes time peri-
od but, even after the microwave irradiation was stopped,
the contents of the vessel continued to heat to 180 °C
demonstrating the exothermic nature of the reaction once
initiated. A quantitative conversion to the desired product
was obtained. We repeated the reaction on the 0.5-mol
scale but heating to 100 °C and holding at this temperature
for 10 minutes. In this case, the heating profile of the
reaction was more controllable and again a quantitative
conversion to the desired product was obtained. We then
scaled the reaction to 1 mol and performed the reaction us-
ing the same reaction conditions; namely using 600 W mi-
crowave irradiation, heating to 100 °C and holding for 10
minutes. The reaction was performed in a 5-L reaction
vessel. Although the temperature continued to rise after
microwave irradiation was stopped, the heating profile of
the reaction was controllable. A quantitative conversion
of the desired product was obtained, this corresponding to
a 96% isolated yield after work-up. The work-up proce-
dure involved dilution of the reaction mixture with ethyl
acetate (500 mL) followed by a hot filtration, washing the
solid (sodium carbonate) remaining on the filter with ethyl
acetate and then allowing the filtrate to cool. This resulted
in the precipitation of the TBAB out of solution. The
product, unreacted butyl acrylate, tributylamine and tribu-
tylamine hydroiodide remained in solution. The recovered
TBAB was very pure and could be recycled in further
reactions.
Br
Br
CO Me
2
39
44
1
1
1
1
0
1
2
3
CN
Cl
CO Me
2
Br
Br
I
CO Me
2
2
2
45
90
78
OMe
Me
CO Bu
CO Bu
I
I
1
1
4
5
CO Me
98
81
2
OMe
CO Bu
2
I
a
Reactions were run in a 50-mL round-bottomed flask with a reflux
condenser attached using 5 mmol aryl halide, 10 mmol alkene, 10
mmol Na CO , 5 mmol Bu N and 5 mmol TBAB. An initial micro-
2
3
3
wave irradiation power of 150 W was used, the temperature being
ramped from r.t. to 150 °C and held until a total reaction time of 90 s
had elapsed. The reaction mixture was stirred throughout the micro-
wave heating.
In summary, we have presented here a methodology for
fast, solvent-free, open-vessel microwave-promoted Heck
couplings of aryl iodides. We show that, with proper pre-
cautions, the reaction can readily be scaled from the mmol
to the mol level.
Synlett 2006, No. 18, 2953–2958 © Thieme Stuttgart · New York

2
956
N. E. Leadbeater et al.
LETTER
Table 3 Scale-Up of the Heck Reactiona
O
O
I
MW, 0.1 mol% Pd(OAc)2
OBu
OBu
+
2
equiv Na2CO3, 1 equiv Bu3N,
1
equiv TBAB
Entry Reaction conditions
Conversion (%)
97
1
2
3
5-mmol scale, 50-mL vessel, monomode microwave apparatus, 150 W microwave power; temperature ramped
from r.t. to 150 °C and held until a total reaction time of 90 s had elapsed
0.5-mol scale, 3-L vessel, multimode apparatus, 600 W microwave power; temperature ramped from r.t. to 150 °C 100
over a 3 min period
0.5-mol scale, 3-L vessel, multimode apparatus, 600 W microwave power; temperature ramped from r.t. to 100 °C 100
and held for 10 min
4
1.0-mol scale, 5-L vessel, multimode apparatus, 600 W microwave power; temperature ramped from r.t. to 100 °C 100
b
and held for 10 min
96
a
Reactions were run in a round-bottomed flask with a reflux condenser attached. The reaction mixture was stirred throughout the microwave
heating.
b
Isolated yield after work-up.
Description of the Microwave Apparatus
of 90 s had elapsed. The reaction mixture was stirred continuously.
Upon completion, the reaction vessel was allowed to cool to 50 °C.
Commercially available microwave apparatus was used for the re-
actions. Monomode: small-scale open-vessel microwave reactions
were conducted using a commercially available monomode micro-
wave unit. The machine consists of a continuous focused micro-
wave power delivery system with operator selectable power output
from 0–300 W. Reactions were performed in 50-mL or 100-mL
round-bottomed flasks. The apparatus is equipped with an opening
in the top (attenuator) through which a glass tube can be placed con-
necting the flask in the microwave cavity with a reflux condenser
located outside the microwave. The temperature of the contents of
the vessel was monitored using an IR sensor located underneath the
reaction vessel. The contents of the vessel are stirred by means of a
rotating magnetic plate located below the floor of the microwave
cavity and a Teflon-coated magnetic stir bar in the vessel. Temper-
ature and power profiles were monitored using commercially avail-
able software provided by the microwave manufacturer. For the
large-scale reactions a commercially available multimode micro-
wave apparatus was used (CEM MARS Synthesis). The machine
consists of a continuous microwave power delivery system with op-
erator selectable power output from 0–1200 W. Reactions were per-
formed in either a 3-L or 5-L round-bottomed flask. The apparatus
is equipped with an opening in the top (attenuator) through which a
glass tube can be placed connecting the flask in the microwave cav-
ity with a reflux condenser located outside the microwave. The tem-
perature of the contents of the vessel was monitored using a fiber-
optic probe inserted directly into the reaction mixture by means of
a glass thermowell. The contents of the vessel were stirred by means
of a rotating magnetic plate located below the floor of the micro-
wave cavity and a Teflon-coated magnetic stir bar in the vessel.
Then, H O (10 mL) and EtOAc (10 mL) were added to the reaction
flask and the entire contents poured into a separatory funnel. After-
2
wards, H O (100 mL) and EtOAc (100 mL) were added and the or-
2
ganic material extracted and removed. After further extraction of
the aqueous layer with EtOAc, combining the organic washings and
drying them over MgSO , and EtOAc was removed on a rotary
4
evaporator leaving the crude product, which was purified by crys-
tallization and characterized by comparison of NMR data with that
in the literature.
Typical Procedure (1-mol Scale): The Coupling of Iodobenzene
and Butyl Acrylate
In a 5-L two-neck round-bottomed flask containing a stir bar was
placed iodobenzene (204 g, 112 mL, 1.0 mol), butyl acrylate (256
g, 288 mL, 2 mol), Na CO (210 g, 2 mol), TBAB (322 g, 1 mol),
2
3
Bu N (185 g, 238 mL, 1 mol) and Pd(OAc) (224 mg, 1.0 mmol, 0.1
3
2
mol%). The reaction vessel was placed into the microwave cavity
and the glass connector tube attached, this connecting the flask in
the microwave cavity with a reflux condenser located outside the
microwave. The reaction mixture was subjected to a maximum of
600 W microwave power in a ramp to 100 °C and then microwave
power modulated to hold at this temperature for 10 min. During this
time, the vessel contents reached 152 °C due to the exothermic na-
ture of the reaction once initiated. The reaction mixture was stirred
continuously. Upon completion, the reaction vessel was allowed to
cool to 65 °C. Then, EtOAc (500 mL) was added to the reaction
flask and the entire contents poured into a large Büchner funnel. The
solid remaining after an initial filtration was washed with EtOAc,
this separating the organic material from the Na CO . The filtrate
2
3
Typical Procedure (5-mmol Scale): The Coupling of 4-Iodoani-
sole and Methyl Acrylate
was then allowed to cool at which point the TBAB precipitated out
of solution. A second filtration to recover the solid TBAB followed
In a 50-mL round-bottomed flask containing a stir bar was placed
by washing the TBAB with Et O left product, unreacted butyl acry-
2
4
-iodoanisole (1.17 g, 5.0 mmol), methyl acrylate (861 mg, 0.90
late, Bu N and tributylamine hydroiodide in the filtrate. The filtrate
3
mL, 10 mmol), Na CO (1.06 g, 10 mmol), TBAB (1.61 g, 5 mmol),
was poured into a separatory funnel, H O (1 L) and EtOAc (1 L)
2
3
2
Bu N (925 mg, 1.19 mL, 5 mmol) and Pd(OAc) (1.20 mg, 0.005
were added and the organic material extracted and removed. After
further extraction of the aqueous layer with EtOAc, combining the
organic washings and drying them over MgSO , and Et O and
EtOAc were removed on a rotary evaporator followed by placing on
a vacuum line. This left the product, which was characterized by
comparison of NMR data with that in the literature.
3
2
mmol, 0.1 mol%). The reaction vessel was placed into the micro-
wave cavity, the attenuator locked in place and a reflux condenser
attached to the open neck of the flask. The reaction mixture was
subjected to a maximum of 150 W microwave power in a ramp to
4
2
1
50 °C and then held at this temperature until a total reaction time
Synlett 2006, No. 18, 2953–2958 © Thieme Stuttgart · New York

LETTER
Solvent-Free, Open-Vessel Microwave-Promoted Heck Couplings
2957
Acknowledgment
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The University of Connecticut is thanked for funding.
(
(
(
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(
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(
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Process Res. Dev. 2002, 6, 374. (b) Cleophax, J.; Liagre,
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(
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(14) There are numerous reports of microwave-promoted Heck
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2
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(
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(
(
(
(
2
2002, 35, 717.
(
(
(
15) For the first report, see: Larhed, M.; Hallberg, A. J. Org.
2
Chem. 1996, 61, 9582.
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1
35) For a survey of their work, see: Koopmans, C.; Iannelli, M.;
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(
(
1091.
(
(
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(
(
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(
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(
(
(
c) Vallin, K. S. A.; Emilsson, P.; Larhed, M.; Hallberg, A.
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(
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Synlett 2006, No. 18, 2953–2958 © Thieme Stuttgart · New York

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N. E. Leadbeater et al.
LETTER
carefully modulated. A power no greater than 600 W is
(
43) It is more appropriate to call the Pd(OAc) a precatalyst
2
since a colloidal palladium species is most likely the
catalytically active species.
44) (a) It is important that a suitably sized reaction vessel is used
for scale-up reactions in the absence of solvent. It is advised
that the contents should occupy no more than 10% of the
vessel volume. In addition, microwave power should be
advised. (b) At a first glance it may seem that this would be
putting in much more microwave power than in the case of
the monomode experiments. However, the relative size of
the cavity needs to be considered. Multimode microwaves
have large cavities and so power is dissipated over a large
area. Monomode equipment has a much smaller cavity and
the energy density is up to some 30–40 times higher than the
multimode apparatus.
(
Synlett 2006, No. 18, 2953–2958 © Thieme Stuttgart · New York