Continuous flow synthesis of aryl aldehydes by Pd-catalyzed formylation of phenol-derived aryl fluorosulfonates using syngas

Article abstract of DOI:10.1039/d0ra04629a

This communication describes the palladium-catalyzed reductive carbonylation of aryl fluorosulfonates (ArOSO2F) using syngas as an inexpensive and sustainable source of carbon monoxide and hydrogen. The conversion of phenols to aryl fluorosulfonates can be conveniently achieved by employing the inexpensive commodity chemical sulfuryl fluoride (SO2F2) and base. The developed continuous flow formylation protocol requires relatively low loadings for palladium acetate (1.25 mol%) and ligand (2.5 mol%). Good to excellent yields of aryl aldehydes were obtained within 45 min for substrates containing electron withdrawing substituents, and 2 h for substrates containing electron donating substituents. The optimal reaction conditions were identified as 120 °C temperature and 20 bar pressure in dimethyl sulfoxide (DMSO) as solvent. DMSO was crucial in suppressing Pd black formation and enhancing reaction rate and selectivity. This journal is

Full text of DOI:10.1039/d0ra04629a

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Continuous flow synthesis of aryl aldehydes by Pd-
catalyzed formylation of phenol-derived aryl
fluorosulfonates using syngas†
Cite this: RSC Adv., 2020, 10, 22449
ab
ab
Paul Hanselmann,c Guixian Hu,c Christopher A. Hone
*
Manuel Kockinger,
and C. Oliver Kappe
¨
ab
*
This communication describes the palladium-catalyzed reductive carbonylation of aryl fluorosulfonates
(ArOSO2F) using syngas as an inexpensive and sustainable source of carbon monoxide and hydrogen.
The conversion of phenols to aryl fluorosulfonates can be conveniently achieved by employing the
inexpensive commodity chemical sulfuryl fluoride (SO2F2) and base. The developed continuous flow
formylation protocol requires relatively low loadings for palladium acetate (1.25 mol%) and ligand
(2.5 mol%). Good to excellent yields of aryl aldehydes were obtained within 45 min for substrates
containing electron withdrawing substituents, and 2 h for substrates containing electron donating
substituents. The optimal reaction conditions were identified as 120 ꢀC temperature and 20 bar pressure
in dimethyl sulfoxide (DMSO) as solvent. DMSO was crucial in suppressing Pd black formation and
enhancing reaction rate and selectivity.
Received 25th May 2020
Accepted 5th June 2020
DOI: 10.1039/d0ra04629a
rsc.li/rsc-advances
Aryl aldehydes are ubiquitous intermediates and building with the commodity chemical sulfuryl uoride (SO2F2) and
blocks in the chemical and pharmaceutical industry. As such, base.
their convenient and cost-efficient synthesis is of high interest.
Previously, Beller and co-workers successfully demonstrated
One of the simplest ways of forming aldehydes is through the the Pd-catalyzed formylation of aryl triates with syngas as
Pd-catalyzed formylation of Ar–X (where X ¼ I, Br, or OTf) using a sustainable and cost effective reagent under batch conditions
syngas (CO and H2).1 The main limitations in the case of aryl (Scheme 1a).11 We were interested in the synthesis of aryl
iodides and bromides are the price and availability of the aldehydes from aryl uorosulfonates, which could be derived
starting materials. In the case of triates, tri-
uoromethanesulfonic anhydride (Tf2O) is the reagent most
commonly employed to prepare triates from alcohols, but it is
relatively expensive, prone to hydrolysis and atom uneconomic.2
Fluorosulfonates (–OSO2F) have been proposed as an alternative
leaving group to triates because their reactivity is considered
largely the same,2,3 or placed in-between bromides and chlo-
rides.4 The uorosulfonate leaving group is an emerging
chemical motif5 that has been used in many types of chemical
transformations including reduction,6 metal catalyzed cross-
coupling,3,5,7 deoxyuorination,8 amination,9 and methox-
ycarbonylation.10 Aryl uorosulfonates can be conveniently and
inexpensively prepared by treating readily available phenols
aCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center
Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
bInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz,
Austria. E-mail: christopher.hone@rcpe.at; oliver.kappe@uni-graz.at
cR&D Chemistry, LPBN, Lonza AG, CH-3930 Visp, Switzerland
† Electronic supplementary information (ESI) available: Experimental procedures,
further optimization data and characterization of all compounds. See DOI:
10.1039/d0ra04629a
Scheme 1 Pd-catalyzed reductive carbonylation using syngas for (a)
triflates (Beller)11 and (b) fluorosulfonates (this work) as leaving groups.
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from their corresponding phenols. Our group previously re- were used to deliver the substrate solution (2 mL) and catalyst
ported the continuous ow Pd-catalyzed formylation of (hetero) feed solution (3 mL). The gases, H2 and CO, were introduced
aryl bromides within a continuous ow system.12 Carbonylation into a four-way mixer by using two mass ow controllers
reactions benet from the highly efficient mixing, enhanced (MFCs). The ow system was pressurized to 10 bar by using
mass and heat transfer characteristics, precise residence time, a back pressure regulator (BPR). Substrate 1a was mixed with
accessibility to high pressure and temperature regimes, and the triethylamine (Et3N) as base and diphenyl ether (Ph2O) as
high operational safety of continuous ow reactors.13–16 Herein, internal standard for preparation of the substrate feed.
we describe the development of a continuous ow protocol for Pd(OAc)2 and dppp were used as the catalyst feed. Initially, we
the synthesis of aryl aldehydes from their corresponding aryl evaluated toluene (PhMe), tetrahydrofuran (THF), acetonitrile
uorosulfonates (Scheme 1b).
(MeCN) and dimethylformamide (DMF) as solvents for the
We commenced our investigation by evaluating the catalytic carbonylation reaction (Table 1).
system palladium(II) acetate (Pd(OAc)2) and 1,3-bis(diphenyl-
Higher conversion was typically observed when using 120 ꢀC
phosphino)propane (dppp), which was utilized by Beller and co- instead of 100 ꢀC. Using PhMe and THF as solvent gave only
workers for the batch formylation of aryl triates.11,17 The minimal conversion and trace amount of product (Table 1,
reaction was optimized within a continuous ow reactor for 4- entries 1–4). MeCN as solvent gave higher conversions but still
methoxyphenyl sulfurouoridate (1a) as model substrate. We very low selectivity towards product (Table 1, entry 5 & 6). Using
used a Uniqsis FlowSyn ow system consisting of two HPLC DMF gave the best preliminary results (entry 7–9). By using
pumps and a heated reactor coil (32 mL). Two sample loops pyridine as base, selectivity could be improved, from approxi-
mately 20% to 60%, albeit with a drop in conversion (entry 10).
We selected to optimize conditions using pyridine since higher
selectivity is more desirable. The throughput of the reaction
Table 1 Solvent, base and temperature screening for the continuous
could be almost tripled by using equimolar amounts of gas (1.4
equiv.) and higher liquid ow rates without high loss in yield
(entry 11).
flow formylation of aryl fluorosulfonatesa
During the initial trials with DMF as solvent, we noticed that
the obtained results were irreproducible without pre-washing
ꢀ
the reactor coil with 20% aqueous nitric acid (HNO3) at 60 C
in-between experimental runs. Subsequent reaction runs
without a wash run in-between resulted in a drop of 4-
methoxybenzaldehyde (2a) yield and ultimately resulted in
a black output solution (Fig. 1). The drop in yield and black
output solution indicates a well-known phenomenon of Pd0 –
agglomerating and forming clusters.18 These clusters then
irreversibly precipitate as Pd black particles. These Pd black
particles coat the reactor wall and can catalyze further Pd black
formation.12,19 In order to tackle this issue, we looked for an
additive or a method to prevent or slow the rate of Pd black
agglomeration.
In 2005, Zierkiewicz and Privalov studied the Pd(OAc)2/
dimethyl sulfoxide (DMSO) system and identied that DMSO
can coordinate to free Pd0, which can help the re-oxidation of
Pd0 to PdII.20 When applied to our reaction system using 4-
Entry Solvent Temp. [ꢀC] Conv. 1ab [%] Sel.b [%] Yieldb 2a [%]
1
PhMe
PhMe
THF
100
120
100
120
100
120
100
120
120
120
7.7
17.1
9.6
0
0
2
2.2
0.4
3
6.9
0.7
4
5
6
7
8
9
10
11
THF
17.0
20.7
42.7
67.1
79.1
50.3
36.7
32.8
4.9
3.0
5.9
19.1
22.1
22.6
59.0
50.0
0.8
5.9
3.4
12.8
17.5
11.4
21.6
16.4
MeCN
MeCN
DMF
DMF
DMFc
DMFd
DMFd,e 120
a
General conditions: feed 1: 0.2 M 4-methoxy sulfurouoridate (1a), 1.0
equiv. Et3N and 0.15 equiv. Ph2O in solvent; feed 2: 5 mol% Pd(OAc)2
and 10 mol% dppp in solvent. Feed 1/feed 2/H2/CO ¼ 0.1 : 0.1 : 5 : 5
mL minꢁ1 resulting in a 27 min residence time (tres). 10 bar system
b
c
d
pressure. Analyzed by GC-FID. 13.5 min tres
.
1 equiv. of pyridine
e
Fig. 1 Drop in 4-methoxybenzaldehyde (2a) GC yield after repeated
reaction runs without wash runs in-between. Conditions used are
provided in Table 1, entry 11.
as base. Flow rates for feed 1/feed 2/H2/CO ¼ 0.3 : 0.3 : 1.87 : 1.87
mL minꢁ1, tres 35 min.
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Fig. 3 Substrate scope for aryl fluorosulfonates containing electron
withdrawing groups. Yields were determined by GC-FID using Ph2O as
internal standard. Yields in parentheses were isolated yield. Conditions
are the same as given in Scheme 2a.
Fig. 2 Influence of DMSO on conversion and yield for Pd-catalyzed
formylation of 4-chloro sulfurofluoridate (1b) with syngas measured by
GC-FID (Ph2O as internal standard). For 0–80 vol% DMSO, 0.2 M 4-
chloro sulfurofluoridate (1b), 1.0 equiv. pyridine and 0.15 equiv. Ph2O in
DMF/DMSO; feed 2: 5 mol% Pd(OAc)2 and 10 mol% dppp in DMF/
DMSO. 120 ꢀC temperature and 10 bar system pressure. Flow rates for
feed 1/feed 2/H2/CO ¼ 0.3 : 0.3 : 1.87 : 1.87 mL minꢁ1, corresponding
to tres 35 min. 100 vol% DMSO experiment was performed using
1.25 mol% Pd(OAc)2 and 2.5 mol% dppp.
group (-OSO2F). Increased pressure (20 bar) and base (1.5
equiv.) resulted in higher selectivity to the aldehyde product 2b
(Fig. S1†). The fraction of DMSO solvent could be increased to
no more than 80% owing to catalyst solubility.
The reaction conditions in terms of residence time and
catalyst loading were then re-optimized for using DMSO as
solvent. The catalyst loading was lowered to 1.25 mol%
Pd(OAc)2 and 2.5 mol% dppp to ensure full dissolution of the
catalyst system. A further decrease in loading did not provide
satisfactory results, with a drop in yield observed (Fig. S2†).
Under these conditions 40 min of residence time was sufficient
to achieve a high yield of 4-chlorobenzaldehyde (2b) (Fig. S3†).
With these new conditions (Scheme 2a), a long run was
successfully operated which was stable for 4 hours with no
apparent drop in yield, thus demonstrating no or minimal
catalyst decomposition (Scheme 2b).
chloro sulfurouoridate (1b) as substrate, the use of DMSO as
co-solvent alleviated the issues associated with Pd black
formation (Fig. 2). Furthermore, we could drastically increase
the yield of desired product 2b, due to reduced catalyst
decomposition. The only side product in all cases was the
hydrogenated product 3b, with the loss of the uorosulfonate
The applicability of the optimized conditions, shown in
Scheme 2a, was demonstrated on a range of substrates. In most
cases, substrates bearing an electron withdrawing group (EWG)
in the para position underwent full conversion and the corre-
sponding aryl aldehyde was formed in moderate to excellent
yields (Fig. 3). The hydrogenated product was the sole side
product observed. However, the reaction of substrates 1e and 1f
resulted in the formation of a mixture of double formylation
and hydrogenated products. The formylation of 4-nitro sulfur-
ouoridate (1 m) was problematic because of deactivation of the
catalyst.
Less reactive substrates, 1k and 1l, were only fully converted
when modied reaction conditions were applied. In these cases,
the liquid ow rates were lowered, which prolonged the resi-
dence time to approximately 2 h (Fig. 4a). Moreover, the H2 ow
rate was modied to deliver 4.2 equiv. The same modied
conditions were also used for substrates containing electron
donating groups (EDG). The formation of the hydrogenated side
product was not a signicant problem for substrates containing
EDG substituents with the aldehyde products obtained in good
to excellent yields (Fig. 4b). Gratifyingly, 6-methoxy-2-
naphthalaldehyde (2p) could be isolated in 82% yield aer
purication by column chromatography. Substrate 2b is
a potential precursor to naproxen, an important non-steroidal
anti-inammatory active pharmaceutical ingredient.
Scheme 2 (a) Continuous flow setup for the Pd-catalyzed formylation
of 4-chloro sulfurofluoridate (1b) long run. (b) 4-Chlorobenzaldehyde
(2b) GC yield at 30 min intervals over 4 h operation time. 0.15 equiv.
Ph2O was used as an internal standard.
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Program by the Austrian Federal Ministry of Transport, Inno-
vation and Technology (BMVIT), the Austrian Federal Ministry
of Digital and Economic Affairs (BMDW), and the State of Styria
(Styrian Funding Agency SFG).
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Fig. 4 (a) Unreactive substrates containing electron withdrawing
groups; (b) substrates containing electron donating groups. For 43 min
conditions, see Scheme 2a. Conditions: feed 1: 0.2 M fluorosulfonate,
1.5 equiv. pyridine and 0.15 equiv. Ph2O in DMSO; feed 2: 1.25 mol%
Pd(OAc)2 and 2.5 mol% dppp in DMSO. 120 ꢀC temperature and 10 bar
system pressure. Feed 1/feed 2/H2/CO
¼
0.08 : 0.08 : 1.5 : 0.5
mL minꢁ1, corresponding to a tres ¼ 123 min.
Substrates bearing a substituent in ortho position to the u-
orosulfonate group afforded the corresponding aldehyde either
in low yield, for 1r and 1u, or no yield, for 1d and 1o. The drop in
yield could be caused by steric hindrance from the ortho-
substituent. The steric block on the catalytic center will favor the
addition of the much smaller hydrogen molecule instead of
a larger CO molecule, resulting in the hydrogenated product.
In conclusion, we have described a continuous ow method
for the Pd-catalyzed synthesis of valuable aryl aldehyde building
blocks from aryl uorosulfonates and syngas as an inexpensive,
atom-economic, and environmentally friendly source of CO and
H2. The continuous ow approach enabled the precise addition
of gas by using mass ow controllers. Meta and para substituted
aryl uorosulfonates could be converted to their corresponding
aldehydes in good to excellent yields. Catalyst decomposition
was successfully avoided by using DMSO as solvent. DMSO
coordinates to Pd0 and facilitates the re-oxidation to PdII.
Additionally, reaction rates and selectivity could be enhanced by
the use of DMSO. Starting materials for the reductive carbon-
ylation could be conveniently derived in excellent yields from
readily-available phenols and the commodity chemical sulfuryl
uoride. The developed process is especially appealing for the
chemical industry, where reagent cost and availability are
important factors in process feasibility.
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Conflicts of interest
The authors declare no competing nancial interest.
Acknowledgements
The CCFLOW project (Austrian Research Promotion Agency
FFG No. 862766) is funded through the Austrian COMET
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