A continuous-flow approach to palladium-catalyzed alkoxycarbonylation reactions

Article abstract of DOI:10.1021/op200037n

Using a continuous-flow approach, it is possible to perform alkoxycarbonylation reactions of aryl iodides. Optimized reactor design allows for adequate mixing of gaseous and liquid reagents. Reactions are performed at rates of around 3 mL/min and at concentrations of 1 M, allowing for significant volumes to be processed per unit time. Palladium acetate (0.5 mol %) is used as the catalyst without the need for an additional ligand.

Full text of DOI:10.1021/op200037n

TECHNICAL NOTE
pubs.acs.org/OPRD
A Continuous-Flow Approach to Palladium-Catalyzed
Alkoxycarbonylation Reactions
Christopher B. Kelly, Christopher (Xiang) Lee, Michael A. Mercadante, and Nicholas E. Leadbeater*
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06269, United States
ABSTRACT: Using a continuous-flow approach, it is possible to perform alkoxycarbonylation reactions of aryl iodides. Optimized
reactor design allows for adequate mixing of gaseous and liquid reagents. Reactions are performed at rates of around 3 mL/min and
at concentrations of 1 M, allowing for significant volumes to be processed per unit time. Palladium acetate (0.5 mol %) is used as the
catalyst without the need for an additional ligand.
’ INTRODUCTION
Palladium-mediated carbonylation chemistry is an important
tool in the synthetic chemist’s portfolio.1,2 Using aryl halides as
starting materials, carboxylic acids and esters can be prepared by
using water or alcohols as nucleophiles, respectively. In our
laboratory we have developed methodologies for performing
these transformations within 30 min using microwave heating.3,4
The chemistry can be scaled up quite effectively in sealed batch
mode.5,6 However, two issues that arise are that, first, a significant
quantity of toxic carbon monoxide has to be loaded into the
reaction vessel and, second, under some conditions, the palla-
dium catalyst can be deactivated over time by carbon monoxide.
To overcome these drawbacks, we developed a methodology that
only requires a near stoichiometric quantity of carbon mon-
oxide.7 Recently, we have turned our attention to a continuous-
Figure 1. Optimized setup for reactions involving reactive gases as
reagents.
flow approach using a dual-phase gasꢀliquid flow to effect
alkoxycarbonylation of aryl iodides using conventional heating
as an alternative to batch microwave heating.
area between the gas/liquid interface was an important factor to
consider. Our optimized experimental setup is shown in Figure 1.
The development of flow approaches to synthetic organic
transformations is a topic of considerable interest in current
literature.8,9 The use of reactive gases as reagents has received
We introduced the gas through a back-pressure regulator and at
an angle of 90° to the liquid flow. The gas/liquid flow then
attention. Hydrogenation reactions can be performed using the
now ubiquitous H-cube system.10,11 Gases such as oxygen,12
entered the heated zone. By using a PTFE coil mounted on an
fluorine,13 and dimethylsulfide14 have also been used in flow. The
aluminium mandrel, we were able to observe the bubbles, noting
the size and spacing between them as they passed through the
use of carbon monoxide in flow chemistry is not unprecedented.
Aminocarbonylation reactions have received particular attention15
reactor coil. Our desired bubble size was between 0.5 and 1.0 mm
as has the radical carbonylation of alkyl halides.16 However, a
in cross section, the bubbles being separated by slugs of reaction
mixture of between 1.0 and 2.0 mm.
Our next step was to find suitable conditions for the alkox-
theme running through much of the literature reporting the
application of gases in flow mode is the use of microscale
ycarbonylation reaction, the results being shown in Table 1. As a
equipment. Our interest lay in performing chemistry on the
starting point we turned to the conditions developed for our
mesoscale, allowing us to process larger quantities of material per
batch approach using microwave heating, namely using palla-
unit time. We therefore embarked on a study with the objective
dium acetate as catalyst, DBU (1,8-diazobicyclo[5.4.0]undec-7-
ene) as base and performing the reaction in the requisite alcohol
as solvent at 120 °C for 20 min. Using 4-iodotoluene (1 mmol) as
our aryl halide starting material, ethanol as the nucleophile and
solvent (10 mL), DBU (1.1 equiv) as base and 1 mol %
of developing an approach for alkoxycarbonylation in flow mode.
This required designing apparatus, optimizing reaction condi-
tions, and substrate screening. Our results are presented here.
Pd(OAc)2 as catalyst we passed the reagents through the unit
’ RESULTS AND DISCUSSION
Our first objective was to modify our commercially available
flow reactor so that we could reliably and reproducibly introduce
an input of gas. In order to ensure effective reaction, the contact
Received: February 11, 2011
Published: April 13, 2011
r
2011 American Chemical Society
717
dx.doi.org/10.1021/op200037n Org. Process Res. Dev. 2011, 15, 717–720
|

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TECHNICAL NOTE
Table 1. Optimization of conditions for the alkoxycarbony-
lation reaction
Table 2. Alkoxycarbonylation of aryl halidesa
entry
reaction conditionsa,b
conv (%)c
1
2
3
4
5
6
7
8
9
1 mmol, 1 mol % Pd, 10 mL EtOH, 0.3 mL/min
1 mmol, 1 mol % Pd, 10 mL EtOH, 0.4 mL/min
1 mmol, 1 mol % Pd, 10 mL EtOH, 1 mL/min
1 mmol, 1 mol % Pd, 20 mL EtOH, 0.6 mL/min
1 mmol, 1 mol % Pd, 2 mL EtOH, 1.2 mL/min
1 mmol, 1 mol % Pd, 2 mL EtOH, 1.2 mL/min
10 mmol, 0.5 mol % Pd, 10 mL EtOH, 1.2 mL/min
10 mmol, 0.1 mol % Pd, 10 mL EtOH, 1.2 mL/min
10 mmol, 0.1 mol % Pd, 5 mL EtOH, 1.2 mL/min
50
68
56
20
75
88d, 94e
91
15
75
a Reactions were performed at 120 °C using a CO pressure of ∼180 psi
and 1.1 equiv of DBU. b For clarity, changes in reaction conditions from
c
1
entry 1 are noted in bold. Determined using H NMR spectroscopy.
d After two passes through the heated zone. e After three passes through
the heated zone.
at 0.3 mL/min. Accounting for the added effect of the gas flow,
this gave a residence time in the heated zone of approximately
20 min. We obtained a 50% conversion to the desired ethyl ester
product (Table 1, entry 1).
Increasing the flow rate to 0.4 mL/min had a beneficial effect
on the outcome, the conversion rising to 68% (Table 1, entry 2).
However, at flow rates greater than this, the conversion dropped
(Table 1, entry 3). Reducing the concentration of the reaction
mixture had a deleterious effect (Table 1, entry 4) but increasing
the concentration 5-fold while also increasing the flow rate
improved the product conversion significantly (75%; Table 1,
entry 5). We took the product mixture from this run and
resubmitted it to the reaction conditions (with no additional
catalyst or base). After a second pass the conversion reached 88%
and, after a third pass, 94% (Table 1, entry 6). We did try using a
slower rate and a single pass, but in order to maintain steady
bubble flow, we found that there was a threshold rate that we
could not go below. Therefore, multiple passes through the
reactor proved to be a more reliable approach.
a Reactions were performed on the 10 mmol scale at 1 M concentration,
0.5 mol % Pd(OAc)2 as catalyst, 1.1 equiv of DBU as base, a gas flow at
∼180 psi, and a reagent flow rate of 1.2 mL/min, corresponding to a
total flow rate of 3.3 mL/min and a residence time in the heated zone
(120 °C) of approximately 4 min. b Determined using 1H NMR
spectroscopy c Isolated yield. d Data for the first and a second pass
through the heated zone.
While leading to a high product conversion, passing the
reaction mixture through the heated zone three times is labor-
ious. We decided to scale up the reaction and determine whether
a one-pass strategy was feasible. Working on a significantly larger
scale (10 mmol) and at a higher concentration (1 M) and
reducing the catalyst loading to 0.5 mol % we were pleased to
find that a 91% conversion to product could be obtained after
only one pass through the heated zone. During a few of the runs,
small quantities of palladium black appeared as tiny particles in
the reactor coil. This particulate matter did not interfere with the
flow under these conditions, nor did it lead to any immediate
clogging of the back-pressure regulator at the exit of the heated
zone. At higher concentrations or catalyst loadings we saw the
formation of larger quantities of palladium black, and blockage
of the back-pressure regulator ultimately occurred. As a result,
product conversions were compromised (Table 1, entries 8
and 9, respectively). Thus, our optimal conditions were 1 M
concentration, 0.5 mol % Pd(OAc)2 as catalyst, 1.1 equiv of DBU
as base, a gas flow at ∼180 psi, and a reagent flow rate of 1.2 mL/
min, corresponding to a total flow rate of 3.3 mL/min and a
residence time in the heated zone (120 °C) of approximately 4 min.
With the optimized conditions in hand, we screened a range of
aryl iodides to probe the substrate scope of the methodology.
The results are shown in Table 2. A range of aryl iodides can be
converted to the ethyl esters including ortho-substituted exam-
ples (Table 2, entries 6 and 7). A representative heteroaromatic
substrate, 3-iodopyridine, gave a good yield of the desired ester
(Table 2, entry 9). Both 1-propanol and 2-propanol can be used
as the alcohol for the reaction (Table 2, entries 10 and 11). With
some less reactive substrates, a second pass through the heated
zone was required in order to obtain higher, more acceptable
product conversions (Table 2, entries 6, 7, 8, and 11). In the case
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TECHNICAL NOTE
of 4-iodoaceophenone, solubility issues meant that the reaction
had to be performed at a concentration of 0.5 M, and this resulted
in only a moderate conversion to the ester product (Table 2,
entry 5). Overall, product conversions are on par with those
obtained using the analogous batch approach.
minꢀ1, and the CO gas line was opened with an approximate
170 psi pressure. The pressure was then varied slightly until a
steady bubble size and consistent flow rate were achieved
(typically, between 160 and 196 psi). Flow rates did vary slightly
but averaged around 3.3 mL minꢀ1 once optimal bubble size had
been achieved.
Once preparation of the reactor was complete, 4-iodotoluene
(2.1835 g, 10 mmol) was added, and the reagent line was placed
inside the prepared solution, reaching the bottom of the tube.
The line was secured to the test tube and the reactor pump
switched from “solvent” to “reagent”. Collection began immedi-
ately after this switch to ensure all product was collected. After
the reaction mixture had been completely charged into the
reactor, the reactor pump was turned back to “solvent”. Collec-
tion for an additional 12 min was undertaken to ensure that all
reagents had left the reactor.
’ SUMMARY
In summary, using a continuous-flow approach, it is possible to
perform alkoxycarbonylation reactions of aryl iodides. Reactions
were performed using 0.5 mol % palladium acetate as catalyst
with no additional ligand required. The methodology offers an
alternative to previous approaches in batch mode using micro-
wave heating.
’ EXPERIMENTAL SECTION
To the product mixture was added diethyl ether (50 mL)
followed by ∼80 mL of brine, and the biphasic mixture was well
mixed. The layers were separated, and the aqueous layer was re-
extracted with diethyl ether (3 ꢁ ∼80 mL each). The combined
organic layers were then mixed with an equal volume (∼300 mL)
of hexanes. This facilitated removal of ethanol from the diethyl
ether layer. After about a 10-min wait, the ethanol layer was
removed. The diethyl ether layer was then dried with MgSO4 and
filtered. The solvent was removed by rotary evaporation and the
product conversion determined by 1H NMR spectroscopy.
General Experimental. For the alcohol substrates, 200 proof
(anhydrous) ethanol was used, and commercially available
anhydrous 1-propanol and 2-propanol were used. Reactions
were run without the need for exclusion of air. CAUTION:
Working with CO gas under pressurized conditions is not
without risk in case of a failure in the PTFE coil during the
course of a reaction. Performing the chemistry in a fume cup-
board is essential, and locating a carbon monoxide detector
outside the fume cupboard but in close proximity to the flow unit
is advisible.
’ AUTHOR INFORMATION
Apparatus. Experiments were performed on a Uniqsis Flow-
Syn system, modified in-house for use with gaseous reagents. A
carbon monoxide tank was fitted with a regulator capable of
delivering pressures of up to 250 psi. This was interfaced with a
length of 1 mm id, 3 mm od PTFE tubing, this being attached to
one of the ports of the built-in T-piece on the FlowSyn system
linked to the pressure transducer and pumps. This enabled us to
monitor CO pressure directly using the FlowSyn. A second port
(opposite that used for inputting gas) was blocked using a plug.
To the remaining empty port was attached a length of 1 mm id,
1.57 mm od PTFE tubing, and this in turn attached to a second
T-piece via a back-pressure regulator (40 psi) as a bridge. The
output from one of the two FlowSyn pumps was connected to
the second T-piece at an angle of 90° (The pump is designed to
push material one way only, this preventing material going back
through the pump head.). The 14 mL PTFE coil was attached to
the third port and the third T-piece. Unlike normal use when
reagents are passed in at the bottom of the coil and exit at the top,
in this case the coil was inverted such that the reaction stream
entered the top of the coil and exited at the bottom. We found
this led to more consistent flow of bubbles of the desired size.
After exiting the heated zone, material was passed through a
second back-pressure regulator (100 psi). The liquid output from
this was collected in Erlenmeyer flasks.
General Procedure. The Ethoxycarbonylation of 4-Iodoto-
luene. A solution of anhydrous ethanol (10 mL) and DBU
(1.64 mL, 11 mmol, 1.1 equiv) was thoroughly mixed before
adding Pd(OAc)2 (12.4 mg, 0.05 mmol). The solution was again
mixed thoroughly. If particulate matter remained, the mixture
was sonicated in an ultrasound cleaning bath to facilitate
dissolution.
With this solution prepared, the Uniqsis Flowsyn reactor was
next readied. After flushing the system with anhydrous ethanol
for at least 2 min at 7.0 mL minꢀ1 or greater, the aluminium block
was heated to 120 °C. The flow rate was reduced to 1.2 mL
Corresponding Author
*Fax: þ1 860 486 2981. Telephone: þ1 860 486 5076. E-mail:
nicholas.leadbeater@uconn.edu.
’ ACKNOWLEDGMENT
Funding from the National Science Foundation (CAREER
Award CHE-0847262) and the University of Connecticut is
acknowledged.
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