Continuous-flow Synthesis of Aryl Aldehydes by Pd-catalyzed Formylation of Aryl Bromides Using Carbon Monoxide and Hydrogen

Article abstract of DOI:10.1002/cssc.201802261

A continuous-flow protocol utilizing syngas (CO and H₂) was developed for the palladium-catalyzed reductive carbonylation of (hetero)aryl bromides to their corresponding (hetero)aryl aldehydes. The optimization of temperature, pressure, catalyst and ligand loading, and residence time resulted in process-intensified flow conditions for the transformation. In addition, a key benefit of investigating the reaction in flow is the ability to precisely control the CO-to-H₂ stoichiometric ratio, which was identified as having a critical influence on yield. The protocol proceeds with low catalyst and ligand loadings: palladium acetate (1 mol % or below) and cataCXium A (3 mol % or below). A variety of (hetero)aryl bromides at a 3 mmol scale were converted to their corresponding (hetero)aryl aldehydes at 12 bar pressure (CO/H₂=1:3) and 120 °C reaction temperature within 45 min residence time to afford products mostly in good-to-excellent yields (17 examples). In particular, a successful scale-up was achieved over 415 min operation time for the reductive carbonylation of 2-bromo-6-methoxynaphthalene to synthesize 3.8 g of 6-methoxy-2-naphthaldehyde in 85 % isolated yield. Studies were conducted to understand catalyst decomposition within the reactor by using inductively coupled plasma–mass spectrometry (ICP–MS) analysis. The palladium could easily be recovered using an aqueous nitric acid wash post reaction. Mechanistic aspects and the scope of the transformation are discussed.

Full text of DOI:10.1002/cssc.201802261

Accepted Article
Title: Continuous-flow Synthesis of Aryl Aldehydes by Pd-catalyzed
Formylation of Aryl Bromides Using Carbon Monoxide and
Hydrogen
Authors: Christopher Hone, Pavol Lopatka, Rachel Munday, Anne
O'Kearney-McMullan, and C. Oliver Kappe
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemSusChem 10.1002/cssc.201802261
Link to VoR: http://dx.doi.org/10.1002/cssc.201802261
A Journal of
www.chemsuschem.org

ChemSusChem
10.1002/cssc.201802261
1
Full Paper
Continuous-flow Synthesis of Aryl Aldehydes by Pd-catalyzed
Formylation of Aryl Bromides Using Carbon Monoxide and
Hydrogen
[
a,b]
[b]
[c]
Christopher A. Hone,
Pavol Lopatka, Rachel Munday, Anne O’Kearney-
[
c]
,[a,b]
McMullan, and C. Oliver Kappe*
_
__________________________________
[
a] Dr. C. A. Hone, Prof. Dr. C. Oliver Kappe
Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center
Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010 Graz (Austria)
E-mail: oliver.kappe@uni-graz.at
Homepage: http://goflow.at
[
b]
Dr. C. A. Hone, P. Lopatka, Prof. Dr. C. Oliver Kappe
Institute of Chemistry, University of Graz, NAWI Graz
Heinrichstrasse 28, A-8010 Graz (Austria)
[c]
Dr. R. Munday, A. O’Kearney-McMullan
AstraZeneca, Silk Road Business Park, Macclesfield, SK10 2NA, United Kingdom
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
2
Abstract
A continuous-flow protocol utilizing syngas (CO and H
2
) was developed for the palladium-
catalyzed reductive carbonylation of (hetero)aryl bromides to their corresponding (hetero)aryl
aldehydes. The optimization of temperature, pressure, catalyst and ligand loading, and
residence time resulted in process intensified flow conditions for the transformation. In
addition, a key benefit of investigating the reaction in flow is the ability to precisely control
2
the CO to H stoichiometric ratio, which was identified as having a critical influence on yield.
The protocol proceeds with low catalyst and ligand loadings, palladium acetate (1 mol% or
below) and cataCXium A (3 mol% or below). A variety of (hetero)aryl bromides at a 3 mmol
scale were converted to their corresponding (hetero)aryl aldehydes at 12 bar pressure (CO/H
2
=
1:3) and 120 °C reaction temperature within 45 minutes residence time to afford products
mostly in good to excellent yields (17 examples). In particular, a successful scale-up was
achieved over 415 minutes operation time for the reductive carbonylation of 2-bromo-6-
methoxynaphthalene to synthesize 3.8 g of 6-methoxy-2-naphthaldehyde in 85% isolated
yield. Studies were conducted to understand catalyst decomposition within the reactor by
using inductively coupled mass spectrometry (ICPMS) analysis. The palladium could easily
be recovered using an aqueous nitric acid wash post reaction. Mechanistic aspects and the
scope of the transformation are discussed.
Introduction
Aryl and heteroaryl aldehydes are important intermediates in the synthesis of biologically
active molecules (Figure 1). There are a number of synthetic strategies to form aryl aldehydes
from their corresponding aryl bromides. One strategy is to use halogen-lithium exchange and
[
1]
subsequently react the lithium intermediate with dimethylformamide (DMF) (Scheme 1a).
However, this protocol requires stoichiometric metal and has limited substrate scope due to
the sensitivity of some substrates to decomposition by a strong base such as n-butyllithium (n-
BuLi). Pd-catalyzed formylation of aryl bromides has emerged as a powerful methodology in
[
2]
organic synthesis for the synthesis of carbonyl compounds. In the case of reductive
carbonylations, CO is used in combination with a hydrogen donor source, such as silyl and tin
[
3,4]
hydrides, or formate salts, to achieve formylation at low pressure (Scheme 1b).
However,
these protocols often require high catalyst loadings, and silicon and tin hydrides are relatively
expensive, which limits their use. In particular, Sn is highly undesirable for pharmaceutical
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
3
manufacture due to contamination and toxicity. Whereas, in the case of silyl hydrides, the
silyl hydride is typically added in excess (~2 to 3 equivalents) which increases costs and
complicates post reaction processing.
Figure 1. Important biologically active molecules containing building blocks derived from
(
hetero)aryl aldehydes.
Scheme 1. Synthetic approaches for the formation of aryl aldehydes from aryl bromides.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
4
Anastas developed the 12 principles of green chemistry as a response for the necessity to
[
5]
reduce the environmental impact of chemicals. Perhaps the greenest and most atom
economic source of CO and H is synthesis gas (syngas, CO/H ). Syngas is a highly abundant
and inexpensive feedstock which is available from many sources in the chemicals industry.
2
2
[
6]
Syngas can be produced from the simultaneous splitting of water and activation of carbon
dioxide by electrolysis. Furthermore, virtually all hydrocarbons, derived from natural gas,
petroleum and coal, can be used as a feedstock for the production of syngas via partial
oxidation, steam reforming or gasification. Future sustainable energy policies are likely to see
an increase in the use of biomass or municipal waste for syngas production. The first
palladium-catalyzed formylation utilizing syngas was reported in 1974 by Schoenberg and
3 2 2
Heck using [Pd(PPh ) Cl ] as catalyst at very high pressures (80 to 100 bar) and elevated
[
7]
temperatures (80 to 150 °C). The protocol was not widely adopted for conventional organic
synthesis due to the high pressures required. In 2006, Beller and co-workers reported the
n
formylation of aryl and heteroaryl bromides by Pd(OAc)
2
, P(1-Ad)
2
Bu (cataCXium A),
= 1:1) at relatively
tetramethylethylenediamine (TMEDA) as base, and synthesis gas (CO/H
2
[8]
low pressures (5 to 7 bar) with 16 h reaction time (Scheme 1c). The protocol utilized very
low loadings of catalyst (0.25 mol%) and ligand (0.75 mol%) in most cases and was
demonstrated on a wide substrate scope.
There are many process challenges associated with handling gas-liquid
transformations in batch reactors, particularly at large scales. The interfacial area between the
gas and liquid phases becomes proportionally smaller with increasing reactor size, therefore
the reaction is more likely to be mass transfer limited which leads to reproducibility problems
during scale-up. In addition, most of the gas is in the headspace and therefore the reactor
needs to be pressurized to maximize the amount of gas in solution and reduce mass transfer
2
effects. A large inventory of highly poisonous CO and extremely flammable H needs to be
loaded and pressurized into the batch vessel from a gas cylinder. Typical commercial batch
reactors can operate between 2 to 6 bar thus higher pressures require more specialized and
expensive equipment. These challenges, and that the reaction utilizes toxic and flammable
gases unfortunately renders this transformation increasingly unacceptable in contemporary
organic synthesis within a batch environment. One solution is to form the gas or gases in situ
2
or ex situ from solid or liquid reagents (gas surrogate) which liberate CO/H , therefore
addressing some of the challenges associated with handling gases. The problem is that in situ
formation generally requires the presence of a transition metal catalyst and strong base in
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
5
combination with high temperatures (>100 °C) to release CO, therefore often resulting in
[
9]
compatibility issues between the CO-producing and CO-consuming reaction. Pioneering
research by the Skrydstrup group resulted in the development of a two chamber batch solution
[10]
for forming gases ex situ.
In particular, 9-methylfluorene-9-carbonyl chloride was
employed to generate stoichiometric CO and potassium formate as the hydride source within a
[
11]
two chamber system (COware) for reductive carbonylation of aryl iodides. Madsen and co-
workers also demonstrated a two batch chamber configuration for the ex situ formation CO
and H
was fed into a second chamber for the formylation of aryl bromides.
pioneered the tube-in-tube reactor gas-loading concept to enable the safer introduction of
2
using an iridium-catalysed dehydrogenative decarbonylation of hexane-1,6-diol which
[
12]
The Ley group
[13]
gases into the liquid-phase from gas cylinders. Teflon AF-2400 (a fluoropolymer) is used
as a semi-permeable membrane, which is permeable to gases but impermeable to liquids. The
tube-in-tube flow reactor was successfully applied for hydroformylation and some
[
14]
carbonylation reactions, but not specifically for reductive carbonylation reactions.
Furthermore, Ley and co-workers have recently shown that oxalyl chloride can be hydrolyzed
by using NaOH to form CO in situ in flow and subsequently used the generated CO in
[15]
carbonylation reactions. The aforementioned strategies are good options for research scale
experimentation, however both approaches suffer from limited scalability in terms of atom
[
16,17]
inefficiency, poorer performance at scale-up or are simply too expensive.
Tubular plug flow reactors have emerged as a platform for the safe, efficient and
[
17]
scalable utilization of gases direct from gas cylinders by using mass flow controllers. Gas-
liquid flow reactions have successfully been applied for API synthesis by using continuous-
[
18]
flow reactors.
The improved safety features of continuous-flow reactors enable the safe
operation at higher pressures and temperatures, including above the boiling point of the
[
19]
solvent. A continuous-flow reactor only needs a relatively small pressurized reactor volume
containing the reaction mixture, and when properly designed can sustain the pressure of an
[
20]
unexpected combustion. Gas-liquid segmented (Taylor) flow regimes generated in flow
microchannels provide a high interfacial area between the gas and liquid phases within a
tubular flow reactor, therefore mass transfer effects are minimized. The utilization of CO in
[
21]
flow for organic synthesis has been demonstrated by a number of groups. In particular, Ryu
and co-workers demonstrated a microflow process for a radical-based carbonylation reaction
[
22]
of alkyl iodides and bromides to aldehydes and ketones. However, this procedure utilized
environmentally unfriendly and expensive Bu SnH and very high CO pressures (80 bar). Eli
3
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
6
Lilly and Co have successfully demonstrated the successful and safe scale-up of
hydroformylation and reductive amination by using CO and H within a large scale tubular
2
[
23–25]
reactor, with one example demonstrated at a 2 MT scale.
We were inspired by the low pressure batch protocol reported by Beller and co-
workers for the reductive carbonylation of (hetero)aryl bromides with synthesis gas as a
8
sustainable and cost effective reagent. We herein report the development of a continuous-
flow protocol for the reductive carbonylation of (hetero)aryl bromides to (hetero)aryl
aldehydes using synthesis gas. To our knowledge, this is the first reported flow procedure for
the reductive carbonylation of (hetero)aryl bromides using syngas.
Results and Discussion
The gas-liquid continuous-flow reactor setup consisted of two high pressure liquid pumps
(HPLC) (P, Uniqsis) for introducing the liquid feeds (see Figure 2a; see also Figure S1 in the
ESI). CO gas and H gas were introduced in a controlled manner into the system from gas
2
cylinders via calibrated mass flow controllers (MFC, Bronkhorst-EL). The liquid and gaseous
streams were combined in a simple four-way inlet mixer (M) at room temperature. The mixer
was connected to the tubular reactor via a fluoropolymer tubing (PFA, 1/8” o.d., 1/16” i.d.).
The PFA tubing allowed for visual inspection of the flow profile. The residence time reactor
was a 60 mL stainless steel coil reactor (ID: 1/8” o.d., 1/16”) heated on an aluminum heating
block (Uniqsis FlowSyn). The reaction mixture exited the system through a short cooling loop
and an adjustable back pressure regulator (BPR, Swagelok, 0 to 25 bar) which maintained a
constant system pressure. A nitrogen purge was installed at the outlet. A pressure sensor
(
PS1) was integrated directly after one of the liquid pumps before entering the mixer to
measure the system pressure.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
7
Figure 2. (a) Continuous-flow configuration for reductive carbonylation optimization; (b)
gas-liquid segmented (Taylor) flow regime.
Optimization experiments were performed with 4-bromoanisole (1a) as a model
substrate under conditions close to those reported by Beller and co-workers (Table 1) using
[
8]
Pd(OAc)
2
and cataCXium A, but at residence times more appropriate to flow processing (<
1
h). We expected that 4-bromoanisole (1a) would display relatively low reactivity towards
the transformation due to the electron donating effect of the methoxy substituent, because
oxidative addition of the aryl bromide to the active palladium(0) species is typically the rate-
[
26]
determining step in this transformation.
.75 equivalents of base were dissolved in toluene and introduced as one feed, and Pd(OAc)
5 mol%) and cataCXium A (15 mol%) were dissolved in toluene and introduced as the
For these reactions, 2.5 mmol of substrate and
0
2
(
second feed, to provide homogeneous solutions. Pd(0) precipitate formation occurred over
time if the palladium catalyst and base were introduced in the same feed, from reduction of
[
14b]
Pd(II) to Pd(0) particles.
Sample loops and injection valves were used to load the liquid
feeds. The liquid feeds were each pumped at equal flow rates. When the reaction was started,
the injection valves were switched and the feed mixtures were carried into the mixer, where
2
they combined with CO and H to give a segmented gas-liquid (Taylor) flow regime under the
flow rates used in this study (Figure 2b).
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
8
Initially, the influence of temperature, pressure and gas flow rate were investigated to
identify appropriate reaction conditions for the continuous-flow reductive carbonylation of 4-
bromoanisole (1a). For the temperature and pressure optimization (Table 1), CO and H were
2
fed in excess at equal flow rates to give ~2.2 equivalents of each gas relative to the substrate.
The flow rates were adjusted at different pressures to provide comparative residence times.
The conversion was relatively low at 5 bar pressure (entry 1), which was most likely caused
by insufficient mass transfer of CO and H
drop in conversion was observed at 15 bar, probably due to catalyst deactivation by CO (entry
). 10 bar pressure was identified providing the best compromise between reaction rate and
avoiding unwanted catalyst deactivation (entry 2). The reaction proceeded smoothly giving
5% conversion and 89% desired product yield at 120 °C, 10 bar pressure and 36 min
2
from the gas phase to the liquid phase. However, a
3
9
residence time (entry 4). Conversion was significantly lower at 100 °C (entry 5) from a slower
reaction rate. A higher reaction temperature resulted in higher conversion but did not improve
yield due to the accelerated catalyst decomposition observed (entry 6).
We knew from the outset that a well-known phenomenon, and often unavoidable
process, is the aggregation of Pd(0) to form clusters, which ultimately and irreversibly
[27]
precipitate in the form of Pd black, which can then deposit onto the reactor wall. Deposited
Pd can be recovered from a stainless steel coil by washing with 20% aqueous nitric acid
solution at 60 °C. The reactor coil was always washed in-between experiments (unless
otherwise specified) with aqueous nitric acid solution to remove residual Pd. Washing with
aqueous nitric acid solution demonstrated that considerable amounts of Pd were lost from
solution and deposited onto the reactor wall. No Pd(0) black particles were observed in the
collected reaction mixtures, but Pd(0) particles were observed when the solutions were kept
overnight indicating not all the Pd was deposited on the reactor channels. Running a reaction
2
without fresh Pd(OAc) and without washing the deposited palladium indicated that the
deposited Pd is catalytically inactive to the desired transformation (entry 7). The amount of
deposited Pd was measured by inductively coupled plasma mass spectrometry (ICPMS) for
the optimized conditions (vide infra). No desired transformation occurred in the absence of
catalyst (entry 8).
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
9
a
Table 1. Initial flow optimization of reductive carbonylation of 4-bromoanisole (1a).
liq. total flow
CO
H
2
T
P
t
res
Conv. 1a Yield 1b Selec.
Entry
b
b
[
mL/min]
[mL /min] [mL
n
n
/min] [°C] [bar]
[min]
[%]
45
66
63
95
50
96
1
[%]
38
61
58
89
46
79
0
[%]
84
92
92
94
92
82
0
1
2
3
4
5
6
0.4
5
5
120
120
120
120
100
140
120
120
5
18
0.8
10
14
5
10
14
5
10
15
10
10
10
10
10
18
1.10
0.4
18
36
0.4
5
5
40
0.4
5
5
33
c
7
0.4
5
5
36
d
8
0.4
5
5
36
0
0
0
a
2
Conditions: 1a (0.25 M) in anhydrous PhMe, 5 mol% Pd(OAc) , 15 mol% cataCXium A, 0.75 equiv. TMEDA,
1
5 mol% Ph O as internal standard (IS). The liquid pumps were set at equal flow rates. Reactor coil was washed
2
with 20% aqueous nitric acid at 60 °C in-between experiments with the exception of entry 7. Conversion and
yield determined by GC-FID using Ph O as IS, selectivity (%) = [prod. (mol) / 1− SM remaining (mol)] × 100%.
2
c
2
No Pd(OAc) within feed and no pre-reaction wash with aqueous nitric acid from previous run to remove
d
2
deposited Pd black. No Pd(OAc) added to feed.
We next investigated different catalyst systems which might provide better performance under
the process intensified conditions utilized in a continuous-flow environment (Table S1).
2
Pd(OAc) /cataCXium A gave the highest conversion and yield when compared to a selection
of other phosphine ligands. The structure of the ligand appears to be very specific to the
success of the reaction: two bulky alkyl groups and the long aliphatic tail are very important
for the high efficiency of the catalyst system in terms of electron-richness and steric shielding
[
28]
of the complexes. The catalyst system is critical to the reaction given the limited stability
of the corresponding palladium(0) complexes in presence of base and carbon monoxide,
especially under high temperatures and pressures.
−3
−1
2
The solubility of CO and H in toluene is relatively poor 7.59 × 10 mol L and 3.31
−3
−1
×
10 mol L respectively under standard conditions (20 °C and 1 bar). Thus, elevated
pressures are necessary to dissolve a sufficient quantity of the gases in solution to provide a
reasonable reaction rate and therefore an appropriate residence time (<1 h) for processing
within a tubular reactor. There are a number of reports measuring the solubility of CO and H
2
[
31]
in organic solvents, however data available for high T/p regimes are limited. Delmas and
co-workers measured the solubility of CO and H in toluene at relative high temperatures (up
2
This article is protected by copyright. All rights reserved.

to 100 °C) and pressures (up
to 15 bar
).
The solubility of each gas in the liquid-phase
ChemSusChem
10.1002/cssc.201802261
1
0
[
31c]
obeys Henry’s law whereby the amount of dissolved gas is proportional to its partial pressure
[32]
in the gas phase, therefore the reaction rate should be directly proportional to the amount of
gas dissolved in solution. The data from Delmas and co-workers was simulated in DynoChem
(
Scaleup Systems) to predict the solubility of CO and H
solubility of CO in the liquid phase was approximately double than for H
competing with CO for dissolution in the liquid phase and when these are used in equimolar
amounts then the amount of H dissolved in solution will be lower than CO, so the effective
concentration of CO will be higher. Increasing the reaction temperature would only have a
small influence on the amount of dissolved H (Figure 3b), whereas the solubility of CO in the
liquid phase displayed only marginal temperature dependence (not shown).
2
as a function of pressure. The
2
(Figure 3a). H is
2
2
2
2
Figure 3. (a) Simulated concentration of H and CO dissolved in the liquid phase as a
2
function of pressure at 120 °C; (b) Simulated concentration of H dissolved in the liquid phase
at different temperatures and pressures.
2
The ability to carefully control the relative stoichiometric ratio of CO to H through varying
the gas flow rates by using mass flow controllers is a key benefit of using continuous-flow
reactors (Table 2). The influence of gas stoichiometry has not previously been studied for
reductive carbonylations. The conversion and yield significantly drops when CO to H
2
was
used at a 3:1 ratio, corresponding to 3.3 equiv. of CO and 1.1 equiv. of H (entries 1 and 2).
2
The Pd became easily deactivated by the CO present, because CO is a strong π-acceptor
ligand, and therefore forms palladium carbonyl clusters which can irreversibly form Pd black.
The rate of oxidative addition is significantly reduced due to the loss of active catalyst. The
clustering of Pd atoms is facile in the presence of CO resulting in nonactive palladium
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
1
1
[
29]
carbonyl complexes.
close-to-stoichiometric quantity. Very good conversion and yields were obtained at a 1:1
CO to H ratio (~2.2 equiv. of each gas). A CO to H ratio of 1:3 resulted in even better
One approach to prevent catalyst deactivation is to utilize CO at a
[
30]
2
2
results with 99% conversion and 98% yield at 35 min residence time (entry 6). Under these
conditions, the system becomes highly starved on CO towards the end of reaction. In these
circumstances, at the beginning of the reactor there is a higher CO concentration present while
towards the end the concentration is very low because almost all the CO has been consumed,
thus improving process safety at the outlet due to the low concentration of CO present.
a
Table 2. Optimization of gas stoichiometry for the reductive carbonylation of 1a.
liq. total flow
CO/H2
ratio
CO
H2
tres
Conv. 1a
[%]
Yieldb Selec.
Entry
b
[
mL/min]
[mL /min]
[mL /min] [min]
1b [%]
[%]
91
93
92
94
94
99
n
n
1
2
3
4
5
6
0.8
3/1
3/1
1/1
1/1
1/3
1/3
15
7.5
10
5
19
37
18
36
17
35
32
54
66
95
70
99
29
0.4
2.5
10
50
0.8
61
0.4
5.0
5.0
2.5
5.0
15
89
0.8
66
0.4
7.5
98
a
2
Conditions: 1a (0.25 M) in anhydrous PhMe, 5 mol% Pd(OAc) , 15 mol% cataCXium A, 0.75 equiv. TMEDA,
1
5 mol% Ph O (IS) T = 120 °C, Psys = 10 bar, 30 min collection time. The liquid pumps were set at equal flow
2
rates. Reactor coil was washed with 20% aqueous nitric acid at 60 °C in-between experiments. Conversion and
yield determined by GC-FID using Ph O as IS.
2
The main limitation of CataCXium A is that it is a proprietary ligand and therefore relatively
expensive compared to many other phosphine ligands. Consequently, it was important to
identify flow conditions that provided low ligand loadings to reduce costs and minimize
waste. The catalyst and cataCXium A loadings were lowered to more commecially-viable
levels, 1 mol% and 3 mol% respectively, for subsequent optimization. The conversion and
yield dropped signicantly on reducing the catalyst and ligand loadings which could be
improved by increasing the base to 3 equivalents (Table S2, entry 6). Further optimization at
a lower catalyst loading demonstrated that increasing the pressure from 10 to 12 bar resulted
in a significant improvement in conversion and yield (Table 3, entries 3 and 5). However,
there was a drop in conversion at 14 bar, indicating elevated catalyst deactivation from CO
poisoning at higher pressures (entry 6). The optimal system pressure was identified as 12 bar
(
2
entry 7). The ratio of CO to H became even more important when the catalyst and ligand
loadings were lowered to more commecially viable levels, 1 mol% and 3 mol% respectively
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
1
2
(
entries 1 to 3). For the reaction in a segmented gas-liquid flow pattern, only a small excess of
CO (1.1 equiv.) and H (3.3 equiv.) are needed, whereas the reaction in a batch autoclave
would require much more (ca. more than 90 equiv. of CO and 280 equiv. of H ) due to the
2
2
[8]
reactor headspace. The low dosing of gases using continuous-flow reactors is a key benefit
of continuous-flow reactors in terms of reducing usage and wastage, and improving safety.
a
2
Table 3. Influence of CO/H ratio, pressure and residence time on conversion and yield.
CO/H2 Liq. total flow
CO
H2
[mL /min]
P
tres
Conv.b Yield 1b Selec.
b
Entry
ratio
3/1
1/1
1/3
1/5
1/3
1/3
1/3
[mL/min]
[mL
n
/min]
n
[bar] [min] 1a [%]
[%]
26
44
76
53
57
75
86
[%]
76
92
95
96
96
96
99
1
2
3
4
5
6
7
0.8
15
10
5
5
12
12
12
12
10
14
12
23
22
22
17
19
24
44
34
48
80
55
60
78
87
0.8
10
15
25
15
15
7.5
0.8
0.8
5
0.8
5
0.8
5
0.4
2.5
a
Conditions: 1a (0.25 M) in anhydrous PhMe, 1 mol% Pd(OAc)
2
, 3 mol% cataCXium A, 3 equiv. TMEDA, 15
mol% Ph O (IS) T = 120 °C Reactor coil was washed with 20% aqueous nitric acid at 60 °C in-between
2
b
experiments. Conversion and yield determined by GC-FID using Ph O as internal standard.
2
Another strategy to prevent deactivation by CO is to utilize phosphine ligands at high
[
33]
ligand−Pd ratios (Table 4). A ligand to catalyst ratio of 2:1 resulted in a drop in conversion
and yield (entry 1), probably due to catalyst poisoning from overcoordination of CO. The
utilization of a ligand to catalyst ratio of 4:1 only resulted in a marginal improvement in yield
(
entry 4) from a 3:1 ratio. In contrast, an increase in the ligand to catalyst ratio to 5:1 retards
the reaction and decreased the aldehyde yield to 71% (entry 5). The slight increase in yield
obtained when using a ligand to catalyst ratio of 4:1 compared to 3:1 often cannot be justified
based on the increase in cost associated with using a higher ligand excess. We also
investigated the use of stabilizing solvents to prevent the formation of black Pd(0) particles.
[
34]
Even though environmentally their use should be minimized, polar aprotic solvents DMF
[
27b]
and (dimethylacetamide) DMA, can stabilize Pd(0) species in solution.
However, using
these solvents as co-solvents did not improve conversion or yield (Table S3), therefore were
not investigated further.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
1
3
a
Table 4. Optimization of catalyst and ligand loadings for reductive carbonylation.
Ligand
tres
[min]
Conv. 1a
[%]
Yieldb
Selec.
Entry
Cat. [mol%]
L/C ratio
b
[
mol%]
1b [%]
[%]
97
96
98
96
91
1
2
3
4
5
1
1
2
3
4
5
2
2
3
4
5
4
44
45
46
46
47
72
90
91
74
58
70
86
89
71
53
1
1
0.5
a
2
Conditions: 1a (0.25 M) in anhydrous PhMe, 3 equiv. TMEDA, 15 mol% Ph O (IS) T = 120 °C, Psys = 12 bar,
3
0 min collection time. Reactor coil was washed with 20% aqueous nitric acid at 60 °C in-between experiments.
Conversion and yield determined by GC-FID using Ph O as internal standard.
2
b
The applicability of the continuous-flow protocol for the Pd-catalyzed reductive carbonylation
of aryl bromide substrates with syngas was demonstrated on a 3 mmol scale and is shown in
Table 5 (18 examples). 4-Bromobenzotrifluoride, possessing an electron deficient
trifluoromethyl group, displayed high reactivity giving full conversion and 97% product yield
(
entry 2). The catalyst and ligand loadings could be lowered to 0.5 mol% and 1.5 mol%
respectively to afford the product in 78% yield. 1-Bromo-4-chlorobenzene also showed high
reactivity giving quantitative conversion and 97% product yield (entry 3). Whereas, 1-bromo-
4
-fluorobenzene (entry 5) displayed slightly lower reactivity than 1-bromo-4-chlorobenzene.
Aryl bromides bearing electron donating alkyl groups in the para position displayed moderate
reactivity (entries 6 and 7). In particular, 4-isobutylbenzaldehyde, an intermediate in the
synthesis of ibuprofen, was afforded in 53% yield (entry 7). 4-Bromo-N-N-dimethylaniline
(entry 8), possessing an electron donating group, showed similar reactivity to 4-bromoanisole.
Heteroaryl bromides proved to be more challenging than bromobenzene substituted
compounds (entries 9 to 12). Beller and co-workers proposed that, in the case of 2-
bromopyridine, the catalyst was deactivated through the formation of inactive dimers after the
[
8]
oxidative addition step. We attempted to synthesize pyrimidine-5-carbaldehyde as a
[
35]
precursor compound for a myeloperoxidase (MPO) inhibitor,
but only a poor 13% yield
was obtained (entry 10). In the instance of 3-bromoquinoline, full conversion and 75% yield
were obtained but dehalogenation of the starting material was also observed (entry 11). As the
CO insertion step into the Pd−Aryl bond can be slow with aromatic ring systems possessing
electron-deficient substituents, this resulted in the competitive reduction of the aryl bromide
[
36]
in some cases (entries 11 to 18).
A reduction in catalyst loading did not decrease the
selectivity for the dehalogenated product. Aryl bromides containing carbonyl compounds
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
1
4
displayed good reactivity under the flow protocol (entries 16 to 18). The conversions and
yields were relatively stable for a 30 min operation time (Tables S2 and S3). Overall the
conversions and yields compared favorably to other reductive carbonylation batch protocols,
see Table S6.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
1
5
a
Table 5. Scope and limitations of reductive carbonylation flow protocol.
Entry
Substrate (a)
Product (b)
Pd(OAc)
2
cataCXium
A [mol%]
Conv.
[%]
Yield
[%]
Select.
[%]
Dehal. (c)
[%]
[
b]
[b]
[b]
[b]
[
mol%]
1
2
3
1
1
3
90
86
96
−
3
1.5
3
100
81
97
78
96
56
98
97
96
97
97
98
−
−
−
−
−
0
.5
1
100
58
0
0
.5
1.5
3
1
100
4
5
.5
1.5
99
95(84)
97
−
1
3
88
86
98
−
6
7
1
1
3
3
70
55
69(61)
53
99
96
−
−
8
9
1
1
3
74
73(67)
99
−
3
3
100
99
45
13
45
13
−
−
10
11
12
13
1
1
3
100
92
75
75
77
23
19
0
.5
1.5
71(66)
1
1
3
3
100
100
0
0
33
20
18
18
1
1
4
5
1
1
3
3
100 69(47)
100 65(59)
69
65
28
34
1
6
1
3
100 85(59)
85
12
1
1
7
8
1
1
3
3
100 78(70)
100 87(84)
78
87
20
12
a
Reaction conditions: 3 mmol scale (hetero)arylbromide (0.25 M solution in anhydrous toluene), TMEDA (3 equiv.), Ph
internal standard, 15 mol%), CO:H = 1:3, CO flow rate = 2.5 mL /min, H flow rate = 7.5 mL /min, catalyst feed flow rate
0.2 mL/min, substrate feed flow rate = 0.2 mL/min, Psys = 12 bar, T = 120 °C, tres ~45 min. outlet was fractionated at 10
2
O
(
=
2
n
2
n
b
min intervals over a 30 min period, yields and conversion are average from 30 min collection time and determined by GC-
FID, see Tables S4 and S5 for conversions and yields for individual fractions. Molecular weights were confirmed by GC-MS.
Values given in parentheses are isolated yields after silica gel chromatography. The somewhat lower isolated yields
compared to the GC yields in some cases may be due to the volatility of the product.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
1
6
A scale-up experiment was conducted for the reductive carbonylation of 2-bromo-6-
methoxynapthalene (4a) to 6-methoxy-2-naphthaldehyde (4b). 6-methoxy-2-naphthaldehyde
(
4b) is a possible intermediate in the synthesis of Naproxen, a nonsteroidal anti-inflammatory
[
37]
drug.
The total operation time was 415 minutes (from start-up to shutdown) with the
product collected over 370 minutes (Figure 4). It was necessary to submerge the outlet tubing
and BPR within an ultrasound bath and heat at 80 °C to prevent accumulation of a white solid
near-or at- the BPR, which was from TMEDA−HBr salt precipitation. No pressure increase or
fluctuations were observed for the duration of the experimental run. Only a very marginal
drop in conversion or yield was observed for the first ~170 minutes of runtime. However, the
conversion and yield slowly decreased over the course of the run, with a drop of
approximately 15% over 350 min of runtime. The crude product was purified by column
chromatography to give pure product in 85% isolated yield which enabled preparation of 3.8 g
of product giving a throughput of 0.7 g/h from the continuous-flow process.
Figure 4. Long run profile. For reaction conditions and analytics, see Table 4, entry 4, with
0
2
.5 mol% Pd(OAc) and 1.5 mol% cataCXium A used for the long run. No samples were
taken until color (reaction mixture) was observed at the BPR. Samples were fractionated at 20
min intervals. The first and last samples were less concentrated due to dilution by the “push-
out” solvent.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
1
7
Reactor contamination (fouling) is a critical issue in flow chemistry that is often
[38]
overlooked.
As discussed above, Pd(0) species aggregate to generate Pd clusters, which
ultimately irreversibly precipitate in the form of Pd black which deposits on metal surfaces.
ICPMS analysis was conducted to measure the amount of Pd deposited on the reactor walls
compared to the amount of Pd remaining in solution and to obtain a more thorough
understanding of the slow decrease in conversion and yield over operation time for some
substrates. ICPMS analysis was conducted on samples fractionated at 20 min intervals for a
separate experimental run for the reductive carbonylation of 2-bromo-6-methoxynapthalene
(
4a) over ~2 hours. Control experiments confirmed that the untreated steel material itself
cannot catalyze the reductive carbonylation (videa supra). The amount of Pd measured in the
collected reaction solution decreased over operation time which indicated that the presence of
existing “inactive” deposited catalyst accelerated the deposition of further catalyst (Table 6).
ICPMS measurements, along with the slow decrease in conversion and yield through the run,
demonstrated that the rate of decomposition of catalyst increases over the duration of the run.
The catalyst can either enter the catalytic cycle or aggregate to form initially soluble
palladium clusters, which at some point will turn into insoluble palladium black. ICPMS
analysis confirmed that ~80% of the Pd was deposited on the walls over the duration of the
experiment and that Pd is easily recovered by washing the reactor with 20% aqueous nitric
acid. The formation of Pd black is self-catalyzed and leads to the withdrawal of Pd from the
catalytic cycle. ICPMS analysis also confirmed that no Fe or Co leached from the stainless
steel into the reaction solution or from the aqueous nitric acid wash (Table S5).
Table 6. ICPMS analysis of a flow experiment for the formylation of 2-bromo-6-
a
methoxynapthalene.
Sample
mg]
Pd determined Pd determined
Pd expected Pd determined
Entry
[
[mg/kg]
[mg]
0.594
0.245
0.125
0.071
0.053
3.48
[mg]
0.929
0.929
0.929
0.929
0.929
[%]
64
26
13
8
Fraction 1
Fraction 2
Fraction 3
Fraction 4
Fraction 5
253
303
2352
811
342
366
611
117
111
194
5
Aq. HNO wash
12 (mL)
290 (mg/L)
Sum
3
4.57
4.65
98
a
For reaction conditions and analytics, see Table 4, entry 4, with 0.5 mol% Pd(OAc)
A. Samples were fractionated at 20 min intervals.
2
and 1.5 mol% cataCXium
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
1
8
The catalytic cycle for Pd-catalyzed formylation between aryl bromides and synthesis gas
[
26]
(
2
CO/H 1:1) proposed by Beller and co-workers is shown in Scheme 2. The catalytic cycle
involves the oxidative addition of the aryl bromide with the active palladium(0) species,
migratory insertion of CO into the Ar−Pd bond, coordination of a hydrogen molecule, and
subsequent base-mediated hydrogenolysis of the resulting acyl complex to give the desired
aldehyde. The catalytic cycle is completed by the reaction of the palladium hydrobromide
complex with base to regenerate Pd(0). In the study by Beller and co-workers, the
n m n 2
carbonylpalladium(0) complex [Pd (CO) L ] and hydrobromide complex [Pd(Br)(H)L ] were
identified as catalytic resting states, these complexes were not directly involved in the
catalytic cycle. Consequently, the active catalyst [PdL] is always at low levels throughout the
reaction, thus making the oxidative addition the rate-determining step, therefore aromatics
containing an electron donating group are slower to react than the corresponding aromatics
containing an electron withdrawing group. The efficiency of the Pd(0) catalyst is dependent
on the relative rate of the oxidative addition to the decomposition of Pd(0), the agglomeration
eventually leads to the formation of palladium black which coats the reactor channels. The
rate of the agglomeration process is second order in Pd or higher, whereas oxidative addition
is usually first order in palladium(0), therefore the rate of Pd decomposition accelerates
throughout over operation time due to the presence of Pd on the reactor channels. The ICPMS
showed that increasing amounts of catalyst were lost from solution over operation time,
therefore indicating the presence of existing deposited Pd catalyzes the agglomeration
process. The very slow decrease in conversion and yield which was observed over time for
some substrates is caused by the increasing rate of catalyst decomposition over operation
time.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
1
9
Scheme 2. Mechanism for the Pd-catalyzed reductive carbonylation of aryl bromides.
Conclusion
Green and sustainable chemical processes rely not only on effective chemistry but also on the
implementation of reactor technologies, which enhance reaction performance and overall
safety. We have developed a continuous-flow protocol for Pd-catalyzed reductive
carbonylation of (hetero)aryl bromides to aldehydes, with syngas as an inexpensive, atom
2
economic and environmentally friendly source of CO and H . Relatively low catalyst loadings
(
0.5 mol% to 1 mol%) and ligand loadings (1.5 to 3 mol%) provided moderate to excellent
product yields. The reaction consumes only carbon monoxide, hydrogen, and base as
stoichiometric reagents. The continuous-flow protocol enabled the reaction time to be
significantly reduced compared to the batch protocols available. For continuous flow
reactions, gaseous reagents can be easily and accurately dosed into the system by using mass-
flow controllers, therefore enabling precise control over the CO to H stoichiometric ratio.
2
2
The investigation of gas stoichiometric ratio demonstrated that using CO/H at a 1:3 ratio
prevented the formation of non-active Pd carbonyl clusters and therefore increased product
yield. The flow reaction uses pure gases as feedstock to generate gas−liquid segmented flow
patterns which allows the reaction to be completed within 45 min residence time with much
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
2
0
smaller excess (1.1 equiv of CO, 3.3 equiv of H ) of gases than batch. Under the flow
2
conditions, at the end of the reactor the CO concentration is very low because almost all the
CO has been consumed, thus improving process safety at the outlet due to the low amount of
CO present. The presence of deposited catalyst within the reactor was shown to have a
negative effect on the reductive carbonylation. ICPMS analysis demonstrated that the amount
catalyst deposition on the reactor channels increased over the duration of run. The deposited
catalyst could be recovered using an aqueous nitric acid wash. In order to improve safety,
recent batch examples have attempted to use liquid and solid reagents as gas surrogates for
2 2
CO and H . The continuous-flow protocol with H and CO offers a safe, atom economic and
environmentally benign alternative to these gas surrogate procedures. The developed process
is especially appealing for industrial applications, where atom economy, sustainability,
reagent cost and reagent availability and safety are important factors. Several key API
intermediates were synthesized in a continuous and environmentally benign manner. In
particular, a continuous-flow protocol was operated for a 6 hour run time to produce 3.8 g of
an important active pharmaceutical intermediate. A major advantage of the continuous flow
2
protocol is the ability to handle pure H and CO under process intensified conditions in a safe
and scalable manner. Nevertheless, the long run and ICPMS analysis demonstrated that there
are challenges associated with catalyst decomposition over time. Further work is necessary to
find improved catalyst systems that allow reaction to occur without any decomposition over
time under process intensified conditions.
Experimental
1
3
General Methods. NMR spectra were recorded on a 300 MHz instrument (75 MHz for C).
Chemical shifts (δ) are expressed in ppm downfield from TMS as internal standard. The
letters s, d, t, q and m stand for singlet, doublet, triplet, quadruplet and multiplet. GC-FID
analysis was performed using a HP5 column (30 m × 0.250 mm × 0.025 μm). After 1 min at
-1
-1
5
0 °C the temperature was increased in 2 °C min stepped up to 80 °C, then in 25 °C min
stepped up to 300 °C and kept at 300 °C for 4 minutes. The detector gas for the flame
ionization is H and compressed air (5.0 quality). GC−MS spectra were recorded using a HP5-
2
MS column (30 m × 0.250 mm × 0.25 μm) with helium as carrier gas (1 mL/min constant
flow) coupled with a mass spectrometer (EI, 70 eV). After 1 min at 50°C, the temperature was
increased in 25 °C/min steps up to 300 °C and kept at 300 °C for 1 min. All solvents and
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
2
1
chemicals were obtained from standard commercial vendors and were used without any
further purification. All compounds synthesized herein are known in the literature.
CAUTION: CO is highly toxic and flammable, therefore extreme care must be taken when
2 2
handling. H is extremely flammable. CO alarms must be installed and N purge used at the
outlet. All equipment must be set up in a well-ventilated fume hood. A thorough safety
assessment should be made before conducting any experiments.
Representative Procedure for Reductive Carbonylation of (Hetero)aryl Bromides
Reported in Table 7. Flow experiments were performed using the continuous-flow setup
depicted in Figure 2 (also see Figure S1 for a labeled image). The continuous-flow setup is
described in detail in the Results and Discussion section. The solution of substrate (0.5 M in
PhMe), corresponding to 0.25 M within the reactor, tetramethylethylenediamine (TMEDA) (3
2
equiv.) and diphenylether (15 mol%) as an internal standard (stream 1) and Pd(OAc) (1
mol% or 0.5 mol%) and cataCXium A (3 mol% or 1.5 mol%) in PhMe (stream 2) were
loaded into their corresponding sample loops. The liquid feeds were pumped using two high
pressure liquid pumps (HPLC) (P, Uniqsis) with a flow rate of 0.2 mL/min for each pump,
using toluene as a carrier solvent. The flow rates of the gas streams were measured and
controlled by two calibrated mass flow controllers (MFCs) using CO = 2.5 mL
n 2
/min, H = 7.5
mL /min. The system was maintained at 120 °C and 12 bar pressure to provide ~45 min
n
residence time. The residence time was measured from the four streams mixing at the mixer
until color was observed at the BPR. The liquid pump flow rates, temperature and pressure
were measured and monitored by the control platform of the pumping system. Once color was
observed at the BPR, fractions were collected for 10 min intervals over a 40 min period.
Collection was stopped once no color was observed at the BPR. Yields and conversion were
determined by GC-FID using diphenylether as internal standard and the reported values are an
average from 30 min collection time. In some cases fractions were combined for purification
by silica gel chromatography.
4
-Methylbenzaldehyde (6b). The title compound was prepared according to the general
procedure as a colorless oil in 61% yield after silica gel chromatography (petroleum
1
ether/EtOAc: 100/0 to 99/1 then isocratic petroleum ether/EtOAc: 99/1). H NMR (300 MHz,
1
3
CDCl
3
) δ: 9.96 (s, 1H), 7.83-7.72 (m, 2H), 7.33 (d, J 8.0 Hz, 2H), 2.44 (s, 3H); C NMR (75
[39]
MHz, CDCl
3
) δ: 192.1, 145.7, 134.3, 130.0, 129.8, 22.0 (lit. ).
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
2
2
4-Dimethylaminobenzaldehyde (8b). The title compound was prepared according to the
general procedure as white crystals in 67% yield after silica gel chromatography (petroleum
ether/EtOAc: 100/0 to 85/15 then isocratic petroleum ether/EtOAc: 85/15). m.p 74.2-74.6 °C
[
41]
1
(
(
(
lit. 72-73 °C); H NMR (300 MHz, CDCl
3
) δ: 9.74 (s, 1H), 7.78-7.68 (m, 2H), 6.76-6.65
1
3
m, 2H), 3.08 (s, 6H). C NMR (75 MHz, CDCl ) δ = 190.5, 154.4, 132.1, 125.3, 111.1, 40.2
3
[
39]
lit. ).
Quinoline-3-carbaldehyde (11b). The title compound was prepared according to the general
procedure as an off-white solid in 66% yield after silica gel chromatography (petroleum
ether/EtOAc: 100/0 to 80/20 then isocratic petroleum ether/EtOAc: 80/20). m.p 69.6-69.9 °C
[39]
1
(
lit. 70 °C); H NMR (300 MHz, CDCl
3
) δ: 10.26 (s, 1H), 9.37 (d, J 1.8 Hz, 1H), 8.64 (d, J
1
7
1
.8 Hz, 1H), 8.20 (d, J 8.5 Hz, 1H), 8.00 (d, J 8.1 Hz, 1H), 7.89 (ddd, J 8.5, 7.0, 1.5 Hz, 1H),
1
3
3
.67 (ddd, J 8.1, 7.0, 1.5 Hz, 1H); C NMR (75 MHz, CDCl ) δ 190.9, 150.7, 149.3, 140.3,
[39]
32.8, 129.8, 129.6, 128.7, 128.0, 127.2 (lit. ).
4
-Cyanobenzaldehyde (14b). The title compound was prepared according to the general
procedure as white crystals in 47% yield after silica gel chromatography (petroleum
ether/EtOAc: 100/0 to 92/8 then isocratic petroleum ether/EtOAc: 92/8). m.p 100.8-101.3 °C
[42]
1
(
lit. 100-101 °C); H NMR (300 MHz, CDCl
3
) δ: 10.09 (s, 1H), 8.05-7.94 (m, 2H), 7.89-
13
7
.80 (m, 2H); C NMR (75 MHz, CDCl ) δ: 190.8, 138.8, 133.0, 130.0, 117.9, 117.7
3
[
39]
(
ref. ).
1
-Naphthaldehyde (15b). The title compound was prepared according to the general
procedure as a yellow liquid in 59% yield after silica gel chromatography (petroleum
1
ether/EtOAc: 100/0 to 99/1 then isocratic petroleum ether/EtOAc: 99/1). H NMR (300 MHz,
CDCl
3
) δ: 10.41 (s, 1H), 9.26 (d, J 8.8 Hz, 1H), 8.11 (d, J 8.2 Hz, 1H), 8.00 (dd, J 7.0, 1.3 Hz,
1
H), 7.93 (d, J 8.2 Hz, 1H), 7.70 (ddd, J 8.5, 7.0, 1.5 Hz, 1H), 7.67-7.62 (m, 1H), 7.62-7.56
1
3
(
3
m, 1H); C NMR (75 MHz, CDCl ) δ 193.7, 136.8, 135.4, 133.9, 131.5, 130.7, 129.2, 128.6,
[39]
1
27.1, 125.1, 125.0 (lit. ).
4
-Acetylbenzaldehyde (16b). The title compound was prepared according to the general
procedure as a pale yellow low melting solid in 59% yield after silica gel chromatography
1
(
(
petroleum ether/EtOAc: 100/0 to 91/9 then isocratic petroleum ether/EtOAc: 91/9). H NMR
1
3
3
300 MHz, CDCl ) δ: 10.10 (s, 1H), 8.14-8.05 (m, 2H), 8.01-7.94 (m, 2H), 2.66 (s, 3H); C
[
40]
NMR (75 MHz, CDCl
3
) δ: 197.5, 191.7, 141.3, 139.2, 130.0, 128.9, 27.1 (lit. ).
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
2
3
Benzene-1,4-dicarboxaldehyde (17b). The title compound was prepared according to the
general procedure as white crystals in 70% yield after silica gel chromatography (petroleum
ether/EtOAc: 100/0 to 90/10 then isocratic petroleum ether/EtOAc: 90/10). m.p 116.8-117.3
[39]
1
13
°
3
C (lit. 115 °C); H NMR (300 MHz, CDCl ) δ: 10.13 (s, 2H), 8.05 (s, 4H); C NMR (75
[
39]
3
MHz, CDCl ) δ: 191.7, 140.1, 130.3 (lit: ).
4
-Ethoxycarbonylbenzaldehyde (18b). The title compound was prepared according to the
general procedure as a colorless oil in 84% yield after silica gel chromatography (petroleum
1
ether/EtOAc: 100/0 to 95/5 then isocratic petroleum ether/EtOAc: 95/5). H NMR (300 MHz,
CDCl
3
) δ: 10.09 (s, 1H), 8.23-8.14 (m. 2H), 7.98-7.88 (m, 2H), 4.40 (q, J 7.1 Hz, 2H), 1.40 (t,
1
3
J 7.1 Hz, 3H). C NMR (75 MHz, CDCl
3
) δ: 191.8, 165.7, 139.2, 135.5, 130.2, 129.6, 61.7,
[
39]
1
4.4 (ref. ).
Long Run Procedure for the Preparation of 6-Methoxy-2-naphthaldehyde (4b) Using
Continuous-flow.
Preparation of catalyst feed: Pd(OAc)
2
(42.1 mg, 0.188 mmol, 0.5 mol%) and cataCXium A
(
201.7 mg, 0.563 mmol, 1.5 mol%) were weighed into 100 mL two-necked round bottom
flask containing a magnetic stirrer. The flask was enclosed with a rubber septa and a balloon
filled with argon was attached. Anhydrous toluene (75 mL) was added to the flask and the
mixture was stirred for 15 minutes to provide a homogeneous yellow solution (75 mL).
Preparation of substrate feed: 2-bromo-6-methoxynaphtalene (4a) (7.113 g, 30 mmol, 1
equiv.) was weighed into a 100 mL two-necked round bottom flask containing a magnetic
stirrer. The flask was enclosed with rubber septa and a balloon filled with argon was attached.
2
Subsequently, Ph O (709 µL, 4.5 mmol, 15 mol %), TMEDA (13.5 mL, 90 mmol, 3 equiv.)
and anhydrous toluene (60 mL) were added under argon atmosphere. The resulting mixture
was stirred for 15 minutes to provide homogeneous pale yellow solution (80.5 mL).
Flow procedure: Flow experiments were performed using the continuous-flow setup
depicted in Figure 1 (also see Figure S1 for a labeled image). Before the reaction, the entire
flow system was washed with 20% aqueous nitric acid solution at 60 °C to ensure no residual
Pd deposited on the reactor channels, and then subsequently washed with acetonitrile and then
toluene. Calibrated mass flow controllers (MFC, EL-Bronkhorst) were set to the desired flow
rates, CO = 2.5 mL /min, H = 7.5 mL /min, and gases started to flow into the reactor. The
n
2
n
pressure was slowly increased at the BPR (Swagelok). The gas flow rate was measured in
units of mL
n
n n
/min (n represents measurement under standard conditions: T = 0 °C, P = 1.01
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
2
4
bar). When the system reached 3 bar, the liquid pumps were started P1 = 0.2 mL/min and P2
0.2 mL/min, with both pumping toluene. The pressure was slowly increased to 12 bar and
=
the temperature set to 120 °C. Once at the desired temperature and pressure, the streams were
switched to the feed solutions. The feeds were introduced directly through the pumps. The
streams were mixed using a four-way inlet mixer at room temperature to give a segmented
flow regime and then flowed through the reactor. The residence time ~45 min was the time
measured from the four streams mixing at the mixer until color was observed at the BPR. The
tubing after the stainless steel coil and the Swagelok BPR were immersed in an ultrasound
bath and heated at 80 °C to prevent of accumulation solids in front of- and within- the BPR.
The feed solutions were pumped for 350 min, then toluene was pump for the remaining time
as a carrier solvent. A total of 18 fractions were collected, a fraction was collected every 20
minutes (approx. 8 mL) and conversion and yield measured by GC-FID using diphenylether
as an internal standard (see Fig. 4 for conversion and yield over operation time).
Isolation procedure. All fractions were combined (except the first and last) to give 128 mL
(
max. yield would give 23.9 mmol based on 64 mL substrate feed) and the volatiles were
removed under reduced pressure. The residue was dissolved in EtOAc and absorbed on silica
gel (43 to 60 μm particle size). Purification of the crude product by silica chromatography
(
petroleum ether/EtOAc 100/0 to 95/5 then isocratic petroleum ether/EtOAc 95/5).
Subsequent removing of solvent under reduced pressure afforded 6-methoxy-2-
naphthaldehyde (4b) (85% yield, 3.77 g, 20.2 mmol) as white crystals. m.p 83.4-83.8 °C
[43]
1
(
lit. 80-82 °C); H NMR (300 MHz, CDCl
3
) δ: 10.01 (s, 1H), 8.17 (d, J 1.7 Hz, 1H), 7.84
(
dd, J 8.5, 1.7 Hz, 1H), 7.81 (d, J 9.0 Hz, 1H), 7.73 (d, J 8.5 Hz, 1H), 7.16 (dd, J 9.0, 2.5 Hz,
1
3
1
H,), 7.10 (d, J 2.5 Hz, 1H), 3.88 (s, 3H); C NMR (75 MHz, CDCl ) δ: 192.2, 160.4, 138.4,
3
[39]
1
34.4, 132.5, 131.2, 128.1, 127.9, 123.8, 120.1, 106.2, 55.6 (lit. ).
ICPMS. The amount of Pd deposited within the reactor compared to remaining in solution
was determined by ICPMS analysis. The crude reaction solution was collected from the
reactor was evaporated under reduced pressure to remove all volatile compounds. The
resulting residue was dissolved in acetonitrile/concentrated nitric acid to give a homogeneous
solution. The deposited Pd from the reactor channels was collected by washing with 20%
aqueous nitric acid at 60 °C. The solutions were diluted with nitric acid to 40 mL and placed
in a vial for microwave digestion. Microwave-assisted acid digestion was carried out in an
MLS UltraClave IV instrument. The temperature was ramped up in 30 min to 250 °C and kept
at this temperature for a further 30 min. After appropriate dilution Pd was quantitatively
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
2
5
determined at m/z 105 with an Agilent 7500ce inductively coupled plasma mass spectrometer.
A calibration was performed with an external calibration curve established from 1.000 g of
Pd/L standard (CPI International). Indium served as the internal standard.
Acknowledgements
The CC Flow 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. P.L.
acknowledges Slovak Academic Information Agency (SAIA) for his research mobility grant.
References
[
[
1]
2]
W. F. Bailey, J. J. Patricia, J. Organomet. Chem. 1988, 352, 1–36.
For a background on Pd-catalyzed carbonylation reactions, see: (a) A. Brennführer, H.
Neumann, M. Beller, Angew. Chem. Int. Ed. 2009, 48, 4114–4133; (b) M. Beller, X.-F.
Wu, in Transition Metal Catalyzed Carbonylation Reactions, Ch. 3 Reductive
Carbonylations, Springer-Verlag, Berlin Heidelberg, 2013.
[
3] (a) F. K. Sheffy, J. K. Stille, J. Am. Chem. Soc. 1983, 105, 7173–7175; (b) V. P.
Baillargeon, J. K. Stille, J. Am. Chem. Soc. 1986, 108, 452–461.
[
4] (a) I. Pri-Bar, O. Buchman, J. Org. Chem. 1984, 49, 4009–4011; (b) Y. Misumi, Y.
Ishii, M. Hidai, Organometallics 1995, 14, 1770–1775; (c) L. Ashfield, C. F. J.
Barnard, Org. Process Res. Dev. 2007, 11, 39–43.
[5] P. T. Anastas, M. M. Kirchoff, Acc. Chem. Res. 2002, 35, 686–694
[6]
S. R. Foit, I. C. Vinke, L. G. J. de Haart, R. A. Eichel, Angew. Chem. Int. Ed. 2017, 56,
402–5411.
5
[7] A. Schoenberg, R. F. Heck, J. Am. Chem. Soc 1974, 96, 7761–7764.
[
8] (a) S. Klaus, H. Neumann, A. Zapf, D. Strübing, S. Hübner, Juan Almena, T.
Riermeier, P. Groß, M. Sarich, W.-R. Krahnert, K. Rossen and M. Beller Angew.
Chem. Int. Ed. 2006, 45, 154–158; (b) A. Brennführer, H. Neumann, S. Klaus, T.
Riermeier, J. Almena, M. Beller, Tetrahedron 2007, 63, 6252–6258.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
2
6
[
9] J. Wannberg, M. Larhed, in Modern Carbonylation Methods; Ch. 4, L. Kolla, Ed.;
Wiley & Sons: Germany, 2008.
[
[
[
[
10] P. Hermange, A. T. Lindhardt, R. H. Taaning, K. Bjerglund, D. Lupp, T. Skrydstrup, T.
J. Am. Chem. Soc. 2011, 133, 6061–6071.
11] S. Korsager, R. H. Taaning, A. T. Lindhardt, T. Skrydstrup, J. Org. Chem. 2013, 78,
6
112–6120.
12] S. H. Christensen, E. P. K. Olsen, J. Rosenbaum, R. Madsen, Org. Biomol. Chem 2015,
3, 938–945.
13] M. Brzozowski, M. O’Brien, S. V. Ley, A. Polyzos, Acc. Chem. Res. 2015, 48, 349–
62.
1
3
[
14] (a) S. Kasinathan, S. L. Bourne, P. Tolstoy, P. Koos, M. Obrien, R. W. Bates, I. R.
Baxendale, S. V. Ley, Synlett 2011, 2648− 2651; (b) U. Gross, P. Koos, M. O’Brien,
A. Polyzos, S. V. Ley, Eur. J. Org. Chem. 2014, 6418–6430.
[15] S V. F. Hansen, Z. E. Wilson, T. Ulven, S. V. Ley, React. Chem. Eng., 2016, 1, 280–
2
87.
[
[
[
16] L. Yang, K. F. Jensen, Org. Process Res. Dev., 2013, 17, 927–933
17] C. J. Mallia, I. R. Baxendale, Org. Process Res. Dev. 2016, 20, 327–360.
18] For general reviews on flow chemistry, see: (a) M. B. Plutschack, B. Pieber, K.
Gilmore and P. H. Seeberger, Chem. Rev. 2017, 117, 11796–11893; (b) M. Movsisyan,
E. I. P. Delbeke, J. K. E. T. Berton, C. Battilocchio, S. V Ley, Chem. Soc. Rev. 2016,
4
5
5, 83–117; (c) B. Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2015,
4, 6688–6728.
[
19] N. Kockmann, P. Thenée, C. Fleischer-Trebes, G. Laudadio, T. Noël, React. Chem.
Eng. 2017, 2, 258–280.
[20] C. A. Hone, D. M. Roberge, C. O. Kappe, ChemSusChem 2017, 10, 32–41.
[
21] For a recent review of the use of CO in flow, see: (a) T. Fukuyama, T. Totoki, I. Ryu,
Green Chem. 2014, 16, 2042–2050; for selected examples of CO use in flow, see: (b)
Md. T. Rahman, T. Fukuyama, N. Kamata, M. Sato, I. Ryu, Chem. Commun. 2006,
2
236–2238; (c) E. R. Murphy, J. R. Martinelli, N. Zaborenko, S. L. Buchwald, K. F.
Jensen, Angew. Chem., Int. Ed. 2007, 46, 1734–1737; (d) X. Gong, P. W. Miller, A. D.
Gee, N. J. Long, A. J. Mello, R. Vilar, Chem. –Eur. J. 2012, 18, 2768–2772; (e) P. W.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
2
7
Miller, N. J. Long, A. J. de Mello, R. Vilar, J. Passchier, A. Gee, Chem. Commun.
006, 546–548; (f) P. W. Miller, N. J. Long, A. J. de Mello, R. Vilar, H. Audrain, D.
2
Bender, J. Passchier, A. Gee, Angew. Chem., Int. Ed. 2007, 46, 2875–2878; (g) P. W.
Miller, L. E. Jennings, A. J. deMello, A. D. Gee, N. J. Long, R. Vilar, Adv. Synth.
Catal. 2009, 351, 3260–3268; (h) G. Glotz, B. Gutmann, P. Hanselmann, A. Kulesza,
D. Roberge, C. O. Kappe RSC Adv. 2017, 7, 10469–10478 (i) Y. Chen, C. A. Hone, B.
Gutmann, C. O. Kappe, Org. Process Res. Dev. 2017, 21, 1080–1087.
[
22] T. Fukuyama, M. T. Rahman, N. Kamata, I. Ryu, Beilstein J. Org. Chem. 2009, 5, 30.
23] M. D. Johnson, S. A. May, J. R. Calvin, G. R. Lambertus, P. B. Kokitkar, C. R. Landis,
B. R. Jones, M. L. Abrams, J. R. Stout, Org. Process Res. Dev. 2016, 20, 888–900.
[
[
24] M. L. Abrams, J. Y. Buser, J. R. Calvin, M. D. Johnson, B. R. Jones, G. Lambertus, C.
R. Landis, J. R. Martinelli, S. A. May, A. D. McFarland, J. R. Stout, Org. Process Res.
Dev. 2016, 20, 901−910.
[
25] S. A. May, M. D. Johnson, J. Y. Buser, A. N. Campbell, S. A. Frank, B. D. Haeberle,
P. C. Hoffman, G. R. Lambertus, A. D. McFarland, E. D. Moher, T. D. White, D. D.
Hurley, A. P. Corrigan, O. Gowran, N. G. Kerrigan, M. G. Kissane, R. R. Lynch, P.
Sheehan, R. D. Spencer, S. R. Pulley, J. R. Stout, Org. Process Res. Dev. 2016, 20,
1
870−1898.
[
26] A. G. Sergeev, A. Spannenberg, M. Beller, J. Am. Chem. Soc. 2008, 139, 15549–
5563.
1
[
27] (a) A. H. M. de Vries, J. M. C. A. Mulders, J. H. M. Mommers, H. J. W. Henderickx, J.
G. de Vries, Org. Lett. 2003, 5, 3285–3288; for examples of Pd black deposition in
flow, see: (b) C. A. Hone, A. O’Kearney-McMullan, R. Munday, C. O. Kappe,
ChemCatChem, 2017, 9, 3298–3302; (c) ref [21h].
[
28] (a) J. Schranck, F. Spindler, Chim. Oggi 2016, 34, 48–54; (b) C. A. Fleckenstein, H.
Plenio, Chem. Soc. Rev. 2010, 39, 694–711; (c) K. A. Agnew-Francis, C. M. Williams,
Adv. Synth. Catal. 2016, 358, 675–700; (d) H. Neumann, A. Brennführer, P. Groß, T.
Riermeier, J. Almena, M. Beller Adv. Synth. Catal. 2006, 348, 1255–1261.
[
[
[
29] T. A. Stromnova, I. I. Moiseev, Russ. Chem. Rev. 1998, 67, 485–514.
30] C. M. Kormos, N. E. Leadbeater, Synlett 2007, 2006–2010.
31] (a) V. S. Nair, S. P. Mathew, R. V. Chaudhari, J. Mol. Catal. A Chem. 1999, 143, 99–
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
2
8
1
10; (b) Purwanto, R. M. Deshpande, R. V. Chaudhari, H. Delmas, J. Chem. Eng. Data
1
996, 41, 1414–1417; (c) U. J. Jáuregui-Haza, E. J. Pardillo-Fontdevila, A. M.
Wilhelm, H. Delmas, Lat. Am. Appl. Res. 2004, 34, 71–74; (d) J.-Z. Yin 1, C.-S. Tan,
Fluid Phase Equilib. 2006, 242, 111–117.
[
[
[
32] W. Henry, Phil. Trans. R. Soc. Lond. 1803, 93, 29–274.
33] A. Zapf, M. Beller, Chem. Commun. 2005, 431–440.
34] C. M. Alder, J. D. Hayler, R. K. Henderson, A. M. Redman, L. Shukla, L. E. Shuster,
H. F. Sneddon, Green Chem. 2016, 18, 3879–3890.
[
35] (a) T. Lazarevi, L. Andreja, V. Vasic, Curr. Drug Metab. 2015, 16, 168–190; (b) C. W.
Holyoke, W. Zhang, T. F. Pahutski, G. P. Lahm, M. H. T. Tong, D. Cordova, M. E.
Schroeder, E. A. Benner, J. J. Rauh, R. F. Dietrich, et al., in ACS Symp. Ser. 2015, pp.
3
65–378.
[
36] T. Ishiyama, H. Kizaki, T. Hayashi, A. Suzuki, N. Miyaura, J. Org. Chem. 1998, 63,
726–4731.
4
[
[
37] S. J. Mahmood, C. Brennan, M. M. Hossain, Synthesis 2002, 2, 1807–1809.
38] (a) B. Gutmann, T. N. Glasnov, T. Razzaq, W. Goessler, D. M. Roberge, C. O. Kappe,
Beilstein J. Org. Chem. 2011, 7, 503–517; For a comprehensive review on fouling in
microstructured devices, see: (b) M. Schoenitz, L. Grundemann, W. Augustin, S.
Scholl, Chem. Commun. 2015, 51, 8213–8228
[
[
39] T. Ueda, H. Konishi, K. Manabe, Angew. Chem. Int. Ed. 2013, 52, 8611–8615.
40] H. Huang, X. Li, C. Yu, Y. Zhang, P. S. Mariano, W. Wang, Angew. Chem. Int. Ed.
2
017, 56, 1500–1505.
[41] S. Pan, S. Yan, T. Osako, Y. Uozumi, Synlett 2018, 29, 1152–1156.
[
[
42] M. Holan, U. Jahn, Org. Lett. 2014, 16, 58–61.
43] C. Prabhakar, G. B. Reddy, Ch. M. Reddy, D. Nageshwar, A. S. Devi, J. M.Babu, K.
Vyas, M. R. Sarma, G. O. Reddy, Org. Process Res. Dev. 1999, 3, 121–125.
This article is protected by copyright. All rights reserved.

ChemSusChem
10.1002/cssc.201802261
2
9
Keywords: reductive carbony
lation; for
mylation; aldehydes; Pd-catalyze
d; continuous-flow;
carbon monoxide; gas-liquid transformation.
Text for TOC: The development of a continuous-flow protocol for a Pd-catalyzed
formylation of (hetero)aryl bromides using carbon monoxide and hydrogen is described. The
applicability of the continuous-flow protocol is demonstrated on several (hetero)aryl bromide
substrates. The intensified continuous-flow process enables safe and scalable Pd-catalyzed
formylation using gases.
Graphical Contents Entry
This article is protected by copyright. All rights reserved.