Continuous-Flow Pd-Catalyzed Carbonylation of Aryl Chlorides with Carbon Monoxide at Elevated Temperature and Pressure

Article abstract of DOI:10.1002/cctc.201801974

The development of a continuous-flow protocol for a palladium-catalyzed methoxycarbonylation of (hetero)aryl chlorides using carbon monoxide gas and methanol is described. (Hetero)aryl chlorides are the least expensive of the aryl halides, but are underutilized in carbonylation reactions due to their very poor reactivity. The described protocol exploits intensified conditions at elevated temperature and pressure, which are readily accessed within a continuous-flow environment, to provide moderate to excellent product yields (11 examples) in a short 16 min residence time. The continuous-flow protocol enables the safe and potentially scalable carbonylation of aryl chlorides using CO gas.

Full text of DOI:10.1002/cctc.201801974

Accepted Article
Title: Continuous-flow Pd-catalyzed Carbonylation of Aryl Chlorides
with Carbon Monoxide at Elevated Temperature and Pressure
Authors: Alejandro Mata, Christopher H Hone, Bernhard Gutmann, Luc
Moens, and C. Oliver Kappe
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Link to VoR: http://dx.doi.org/10.1002/cctc.201801974
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10.1002/cctc.201801974
ChemCatChem
COMMUNICATION
Continuous-flow Pd-catalyzed Carbonylation of Aryl Chlorides
with Carbon Monoxide at Elevated Temperature and Pressure
Alejandro Mata,[a,b] Christopher A. Hone,[a,b] Bernhard Gutmann,[a,b] Luc Moens[c] and C. Oliver
Kappe*[a,b]
The development of a continuous-flow protocol for a palladium-
catalyzed methoxycarbonylation of (hetero)aryl chlorides using
carbon monoxide gas and methanol is described. (Hetero)aryl
chlorides are the least expensive of the aryl halides, but are
underutilized in carbonylation reactions due to their very poor
reactivity. The described protocol exploits intensified conditions at
elevated temperature and pressure, which are readily accessed within
a continuous-flow environment, to provide moderate to excellent
product yields (11 examples) in a short 16 min residence time. The
continuous-flow protocol enables the safe and potentially scalable
carbonylation of aryl chlorides using CO gas.
catalyst and ligand loadings, and long reaction times are generally
necessary.[9] More recently, protocols which use milder conditions
have been established, but these generally require more
specialized catalyst systems and extended reaction times are still
required.[10]
O
O
Cl
Ar
R
CO
CO
R
ArB(OH)2
R
R
R
R
O
O
CO
CO
Pd cat.
ROH
RSnBu3
OR
CO
CO
R
Palladium-catalyzed carbonylation of aryl halides and vinyl
halides using carbon monoxide was discovered by Schoenberg
and Heck more than 40 years ago.[1] CO is an inexpensive, atom
efficient and synthetically valuable C1 building block for organic
chemistry, and it is readily available in large quantities from the
bulk chemical industry.[2] The carbonyl group is a key component
in aldehydes, ketones, carboxylic acids and their derivatives.
Thus, carbonylation reactions using CO have found widespread
application in the chemical industry over recent years.[3-6]
Since the pioneering research by Schoenberg and Heck,
researchers have mostly focused on developing carbonylation
protocols for aryl bromides and iodides using a wide range of
phosphine ligands.[3,4] Aryl chlorides are the least expensive when
compared to other aryl halides.[7] Despite their low cost, aryl
chlorides have received far less prominence for Pd-catalyzed
carbonylation reactions.[4] Aryl chlorides are relatively inert due to
the high stability of the carbon–chlorine bond. The oxidative
addition of the aryl chloride to Pd(0) is generally accepted to be
the rate limiting step in the catalytic cycle.[8] The utilization of aryl
chlorides in carbonylation reactions potentially gives access to a
wide range of useful products at low cost (Scheme 1). The
procedures reported for the carbonylation of aryl chlorides
typically use elevated temperature and pressure, require high
H
2O
RNH2
O
H2
CO
O
OH
NHR
O
R
R
H
R
Scheme 1. Possible carbonylation reactions of (hetero)aryl chlorides using CO.
Virtually all of the procedures reported for the carbonylation of aryl
chlorides were developed using batch autoclave apparatus.[8,9]
There are challenges associated with using batch reactors that
prevent the carbonylation of aryl chlorides with CO gas to be
widely adopted in organic synthesis, particularly at large scales.[11]
Specialized equipment is necessary to handle the elevated
temperatures and pressures used. Under batch conditions, a
large inventory of highly poisonous CO needs to be loaded and
pressurized into a batch vessel to minimize mass transfer effects,
with most of the gas remaining in the reactor headspace. In
addition, the mass transfer of CO from the gas phase to the liquid
phase can result in scalability problems.
Continuous-flow technologies have attracted attention from
the scientific community, in particular from the industrial sector
due to the safety and scalability benefits when compared to
traditional batch processing.[12] The specific characteristics of
microreactors in terms of enhanced mass and heat transfer,
precise control of reaction parameters and potential scalability
enable many of the challenges associated with handling Pd-
catalyzed carbonylation reactions to be overcome. Furthermore,
the utilization of continuous processing allows the safe access to
typically “forbidden chemistry”, such as high T/p conditions,
operation within explosive regimes, and the handling of
hazardous reagents and intermediates.[12,13] Over the past decade,
many groups have developed continuous-flow protocols for
carbonylation reactions using CO gas.[14] Hence, we envisaged
that continuous flow chemistry could be applied to the
carbonylation of aryl chlorides under high T/p conditions.
[a]
Alejandro Mata, Dr. Christopher A. Hone, Dr Bernhard Gutmann and
Prof. Dr. C. Oliver Kappe
Center for Continuous Flow Synthesis and Processing (CCFLOW),
Research Center Pharmaceutical Engineering GmbH (RCPE)
Inffeldgasse 13, 8010 Graz (Austria)
Email: oliver.kappe@uni-graz.at
Homepage: http://goflow.at
[b]
[c]
Alejandro Mata, Dr. Christopher A. Hone, Dr Bernhard Gutmann and
Prof. Dr. C. Oliver Kappe
Institute of Chemistry, University of Graz, NAWI Graz,
Heinrichstrasse 28, A-8010 Graz (Austria)
Luc Moens
Janssen Research and Development, Turnhoutseweg 30, 2340
Beerse (Belgium)
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Herein, we describe the preliminary results for a Pd-
catalyzed methoxycarbonylation of aryl chlorides using CO gas in
continuous-flow mode. To our knowledge, this is the first reported
carbonylation utilizing aryl chlorides and CO using continuous
processing.[15]
A Phoenix Flow Reactor from ThalesNano, see Fig. 1, was
assembled consisting of a high pressure pump (P, Knauer), a
residence time unit (RTU) equipped with a stainless steel coil (40
mL internal volume) and an adjustable back pressure regulator
(BPR2) with a pressure maximum of 100 bar. A mass flow
controller (MFC) was used for the introduction of CO in a
controlled manner from a cylinder. A BPR (BPR1) was used as a
check valve to avoid any possibility of solvent entering the MFC.
The mixing of the gas and liquid streams was performed using a
static mixer (M). The stream exiting the reactor was cooled down
before the BPR by using a heat exchanger (HE).
stable CO flow rate.[16] The expected residence time of 16 min
was maintained which indicated all the gas was dissolved in the
liquid phase. A benefit of having all the CO dissolved in solution
is that the residence time remains constant. The undesired
dechlorinated side product 3a was formed in less than 2% yield in
all the initial optimization experiments.
Table 1. Initial optimization of 4-chlorobenzonitrile 1a methoxycarbonylation
under continuous-flow conditions.a
O
Pd(OAc)2
Cl
H
N
CO, Et3
O
+
MeOH/MeCN
CN
CN
CN
1a
2a
3a
P
T
p
MeOH/MeCN Cat. loading Conv. 1a Yield 2a Yield 3a
Entry
[%]b
23
23
22
62
53
88
96
[%]b
23
23
22
60
53
86
94
[%]b
Liquid
Feed
[°C]
150
150
150
170
170
180
190
[bar] solvent ratio
[mol%]
RTU
M
HE
1c
2c,d
3
20
20
20
23
23
34
43
1:0
1:0.4
1:1
5
5
-
-
MFC
BPR1
5
-
Collection
BPR2
1:1
5
<2
<1
<2
<2
4
Figure 1. Continuous-flow setup for Pd-catalyzed carbonylation using CO (for
further details, see the Supporting Information).
5
1:1
2.5
5
6e
7e
1:1
We commenced our study by using 4-chlorobenzonitrile 1a as a
model substrate to provide methyl 4-cyanobenzoate 2a as the
desired product. We initially undertook a screening campaign to
identify reaction conditions amenable to flow processing. High
temperatures and pressures were utilized from the outset due to
the very poor reactivity of aryl chlorides (Table 1). Batch
conditions for the methoxycarbonylation of aryl chlorides typically
vary between 100 to 150 °C, 4 to 40 bar, and 1 to 5 mol%
catalyst/ligand loading, with reaction times always within the
timescale of hours (5 to 24 hours).[4,8] The nucleophile is normally
added in high excess because it also functions as the solvent. We
encountered difficulties on transferring existing batch conditions
directly to flow due to the long reaction times that would be
needed to achieve reasonable conversion and yield, and from the
poor solubility of the products formed (entries 1 and 2). The
problem associated with solubility was solved through reducing
the substrate concentration and by the utilization of MeOH/MeCN
at a ratio of 1:1. Changing the concentration and solvent ratio had
no apparent influence on reaction rate (entry 3). Gratifyingly, the
product was obtained in 60% yield within 16 min residence time
on increasing the temperature to 170 °C (entry 4). A drop in
conversion and yield was observed when the catalyst loading was
decreased to 2.5 mol% (entry 5). The conversion and yield were
improved on increasing the temperature to 180 °C (entry 6). The
conversion and yield could be successfully increased to 96% and
94%, respectively, when operating the system at 190 °C and by
using 4 equivalents of triethylamine (entry 7). At higher pressures,
it was necessary to use 3 equivalents of CO to provide a more
1:1
5
a Reaction conditions: 4-chlorobenzonitrile 1a (1 mmol), dppp (10 mol%), Et3N
(2 equiv) in solvent (10 mL), liquid flow rate = 2.4 mL min−1, CO flow rate = 12
mLn min−1, tres = 16 min. b Conversion and yields were measured by HPLC-UV
area% integration at 254 nm. c 4-Chlorobenzonitrile 1a (5 mmol). d A precipitate
blocked the reactor. e Et3N (4 equiv), CO flow rate = 18 mLn min−1
.
Once the initial conditions were established, we proceeded to
investigate the parameter effects on conversion and yield further.
The screening of conditions included the evaluation of a range of
phosphine ligands (Table 2). The oxidative addition is believed to
be the rate determining step, therefore ligands which push
electron density onto Pd and stabilize Pd(0) generally perform
better in carbonylation reactions.[3-6] At high temperatures,
phosphine Pd(0) complexes are usually short-lived with the Pd(0)
agglomerating and the irreversibly forming inactive solid (Pd
black). The monodentate phosphine ligands trialed did not work
(entries 1 and 2). 1,3-Bis(diphenylphosphino)propane (dppp), one
of the least expensive bidentate ligands, provided the best results
(entry 8). 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
(Xantphos) also showed promising results (entries 6 and 7). The
ratio of dppp to Pd(OAc)2 was also investigated. The formation of
Pd black was observed for experiments with a dppp to Pd ratio of
below 1.25:1 which demonstrated that some of the catalyst was
lost from the catalytic cycle, although, no difference in yield was
observed (Table S3). The optimal ligand to catalyst ratio was
determined to be 1.25:1.
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10.1002/cctc.201801974
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Table 2. Results of the ligand screening.a
of equivalents of base was also studied (Table S6). By doubling
the equivalents of base from 2 to 4 at 5 mol% catalyst loading, the
yield was improved to 78%. However, when performing the same
increase in base equivalents at 2.5 mol% catalyst loading, no
change in yield was observed. These results indicate that the
optimal amount of base is not related to the substrate but to the
catalyst, a ratio of 80 between base to catalyst was determined to
be optimal.
The influence of CO stoichiometry was investigated by
varying the CO flow rate (Figure 2). The utilization of sub-
stoichiometric amounts of CO resulted in the formation of large
quantities of the dechlorinated side product 3a. However, the
equivalents of CO did not influence the reaction when used in
excess to the substrate. It is important to note that over a
prolonged operation time a more reproducible pressure control
could be achieved by using 2 equiv of CO when operating at 23
bar and 3 equiv of CO at higher pressures.
O
Pd(OAc)2
Cl
N
CO, Et3
O
MeOH/MeCN
CN
CN
1a
2a
Yield 2a
[%]b
Entry
1
Ligand
PPh3
Structure
Ph
Ph
P
<1
<1
Ph
P
2
3
P(C6H11)
3
Conversion (A)
Yield (B)
Byproduct (C)
PPh2
PPh2
100
80
60
40
20
0
<1
(S)-BINAP
63
62
60
38
60
60
Ph2P
38
38
18
20
4
5
dppe
PPh2
36
23
14
PPh2
dppbe
2
2
2
2
PPh2
0,7
1,2
1,5
CO equiv
Figure 2. Influence of CO equivalents on the reaction outcome. Reaction
conditions are described in Table 2, entry 8, CO (1 equiv) = 6 mLn min−1
2
3
6c
7d
Xantphos
Xantphos
31
32
O
.
PPh2
Ph2P
PPh2
PPh2
The general applicability of the continuous-flow protocol for the
carbonylation of aryl chloride substrates is shown in Table 3.
Electron poor aromatics displayed the highest reactivity, with
substrates possessing an electron withdrawing group or electron
deficient N-heterocycles affording the highest yields. N-
heterocycles gave higher conversions than benzene derivatives
with 100% conversion at 170 °C observed in most cases (entries
7 to 12). The reactivity of the benzene derivatives could be
increased through the utilization of higher temperatures and
pressures as shown with the model substrate 1a. 2-
Chlorobenzonitrile 1b displayed poorer reactivity than 4-
chlorobenzonitrile 1a. 4-Chloronitrobenzene 1e did not react to
give the desired product, but the nitro group was reduced to the
corresponding amino derivative 4. The Pd-catalyzed reduction of
nitro groups to amino groups by CO is well known, and was the
focus of a recent study by our group.[17] The reactions for
chloropyrazine 1g and 3-chloro-6-methylpyridazine 1h resulted in
the formation of solids which blocked the reactor, which could be
prevented by using MeOH/MeCN at a 1:9 solvent ratio. Full
conversion of 2-chloropyrazine 1g could be achieved at 180 ºC at
34 bar pressure. The reaction of 4,7-dichloroquinoline 1j resulted
in significant formation of the double substituted derivative. The
selectivity for the monosubstituted product 2j was improved by
changing the MeOH/MeCN solvent ratio to 1:9. The catalyst
loading could be lowered for more reactive substrates, for
instance full conversion was achieved for 2-chloro-4-
8
dppp
60
a
Reaction conditions: 4-chlorobenzonitrile 1a (1 mmol), Pd(OAc)2 (5 mol%),
ligand (10 mol%), Et3N (2 equiv) in MeOH/MeCN 1:1 (10 mL), liquid flow rate =
2.4 mL min−1, CO flow rate = 12 mLn min−1, T = 170 °C, p = 23 bar. b Yields were
measured by HPLC area% integration. c CO (1.5 equiv). d CO (1.2 equiv).
A study of the residence time showed that the conversion halts at
~16 min (Table S4). No Pd black formation was observed in the
outlet solution in the experiments with dppp. However, Pd black
can deposit onto the reactor wall on its formation.[14i] Pd can be
readily recovered from the reactor by washing with 20% aqueous
nitric acid solution at 60 °C. Inductively coupled plasma mass
spectrometry (ICPMS) analysis was used to measure the amount
of Pd remaining in solution compared to the amount deposited on
the reactor channels. The results showed that nearly all the Pd
remained in solution with only 6% of the Pd deposited on the
reactor channels during the experiment (Table S8). Thus, the
analysis demonstrated that only a small amount of Pd black was
formed. A control experiment demonstrated that the residual
deposited Pd was catalytically inactive when a feed solution, in
the absence of Pd(OAc)2, provided a yield below 1%. The results
therefore indicated that the active catalyst is converting to an
inactive form which is soluble in solution.
Subsequently, the influence of the base type on the reaction
was studied (Table S5). Several organic soluble bases were
screened with triethylamine affording the best yield. The influence
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10.1002/cctc.201801974
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hydroxymethylpyridine 11a at 2.5 mol% and 2-chloro-5- The scalability of the continuous-flow protocol was demonstrated
cyanopyridine 12a at 1.25 mol% Pd(OAc)2 loading.
through a scale-out experiment using 2-chloro-5-cyanopyridine 1l
as the substrate and 1.5 mol% Pd(OAc)2 loading. The system was
operated over a period of 100 min (5 reactor volumes worth), with
the output fractionated at 25 min intervals. Analysis of the
fractions demonstrated that the system could be operated
consistently over a longer operation time (Figure S5), thus the
protocol can be used to synthesize larger quantities. The collected
output solutions were combined and purified by column
chromatography to afford pure methyl 5-cyanopicolinate 2l in
84% isolated yield.
In conclusion, we have described a continuous-flow protocol
for the carbonylation of aryl chlorides using CO gas under high
T/p conditions. Among all the catalytic systems studied,
Pd(OAc)2/dppp provided the best performance due to its high
stability under high T/p conditions. The flow protocol uses 5 mol%
catalyst loading. This loading is higher than in some batch
protocols, however the reaction time is significantly reduced to
only 16 min in flow compared to the long reaction times necessary
under typical batch conditions. The protocol was most successful
for the carbonylation of electron deficient aromatics, in particular
N-heterocycles. The catalyst and ligand loadings could be
decreased further for more reactive substrates through the
utilization of high T/p conditions which are readily accessed in a
continuous-flow environment. In contrast to operation within batch,
there was no vapor phase or headspace in flow because all of the
gas was dissolved in solution, since a very low amount of CO (2
to 3 equiv) could be utilized, thus improving the inherent safety
and potential scalability of the developed protocol.
Table 3. Scope and limitations of flow protocol.a
Pd(OAc)2
N
CO, Et3
Me
(Het)Ar-Cl
(Het)Ar-CO2
MeOH/MeCN
2a-l
1a-l
Conv. 1 Yield 2
[%]b
Entry
1d
Substrate 1
Cl
Product 2
COOMe
[%]c
96
81
NC
NC
2a
1a
COOMe
CN
Cl
45
91
45b
70
20b
-
2
3
4
5
CN
1b
2b
Cl
COOMe
OHC
H2N
OHC
H2N
1c
2c
COOMe
Cl
80
1d
2d
O
O
Cl
Cl
100
H2N
N
O2
1e
4
Cl
Cl
COOMe
6g
N
100
100
96
61
N
N
2f
1f
COOMe
COOMe
N
Acknowledgements
N
7e,f
N
2g
1g
The CCFLOW Project (Austrian Research Promotion Agency
FFG No. 862766) is funded through the Austrian COMET
Program by the Austrian Federal Ministry of Transport, Innovation
and Technology (BMVIT), the Austrian Federal Ministry of
Science, Research and Economy (BMWFW), and by the State of
Styria (Styrian Funding Agency SFG). We thank Prof. W.
Goessler (Graz University) for performing ICPMS analysis.
Cl
8f
9
N
N
100
100
87
84
N
2h
N
1h
N
Cl
N
Cl
1i
2i
Cl
N
Cl
N
Keywords: continuous flow • carbonylation • (hetero)aryl
chlorides • carbon monoxide • Pd-catalyzed • gas-liquid
transformation
10f
90
70
1j
COOMe
COOMe
2j
Cl
N
Cl
11g
12h
HO
100
100
73
82
HO
N
2k
1k
[1]
[2]
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COOMe
Cl
N
N
NC
NC
1l
2l
[3]
a
Reaction conditions: substrate 1a-l (2.5 mmol), Pd(OAc)2 (5 mol%),
ligand:catalyst 1.25:1, Et3N (4 equiv) in MeOH/MeCN 1:1 (25 mL), liquid flow
rate = 2.4 mL min−1, CO flow rate = 12 mLn min−1 (2 equiv), T = 170°C, P = 23
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b
c
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rate =18 mLn min−1 (3 equiv). e T = 180 ºC, p = 34 bar ,CO flow rate =18 mLn
f
min−1
.
MeOH/MeCN 1:9. g Pd(OAc)2 (2.5 mol%), Et3N (2 equiv). h Pd(OAc)2
(1.25 mol%), Et3N (1 equiv).
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COMMUNICATION
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[16] At high pressures, more reproducible CO flow rates and pressure control
were achieved by using a Swagelok BPR.
[17] G. Glotz, B. Gutmann, P. Hanselmann, A. Kulesza, D. Roberge, C. O.
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[13] B. Gutmann, C. O. Kappe, J. Flow Chem. 2017, 7, 65–71.
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10.1002/cctc.201801974
ChemCatChem
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Alejandro Mata,[a,b] Christopher Hone,[a,b]
Luc Moens[c] and C. Oliver Kappe*[a,b]
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BPR1
Continuous-flow Pd-catalyzed
Carbonylation of Aryl Chlorides with
Carbon Monoxide at Elevated
Temperature and Pressure
Collection
BPR2
Aryl chlorides are underutilized in organic synthesis due to their very poor reactivity.
The development of an intensified continuous-flow protocol for a Pd-catalyzed
methoxycarbonylation of aryl chlorides employing carbon monoxide gas and high T/p
conditions is described. The applicability of the continuous-flow protocol is
demonstrated on several substrates providing moderate to good yields. The flow
process enables safe and scalable aryl chloride carbonylation using CO.
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