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lectivities, which was far from a continuous process. We had
attributed this to the diffusion of gas from the surrounding sol-
vent stream into the 1 mL reaction plug. As no optimisations
were conducted after introducing methanol as co-solvent,
which resulted in the dramatic increase in conversions, several
parameters were reconsidered and it was discovered that de-
creasing the substrate concentration to 0.05m allowed for
larger injection plugs and continuous flow. Furthermore, the
change in concentration improved conversions whilst main-
taining high selectivities. A range of branched aldehydes were
synthesised directly from aryl iodides by using this tandem 2-
step 3-gas process, as shown in Table 12.
mixture was inhibiting the second reaction. This incompatibili-
ty was resolved by the incorporation of our recently developed
in-line liquid–liquid extraction system to remove the offending
component between the two steps. The overall yields of
branched aldehydes from the two-step telescoped process are
comparable to those achieved in the hydroformylation of pure
styrene starting materials. This is only possible with the high
conversions achieved in the ethylene Heck process and effi-
cient washing and separation operations in-line prior to the
hydroformylation step.
The rapid optimisation of these processes and their incorpo-
ration into telescoped tandem flow processes highlights the
importance (especially in the context of the research laborato-
ry) of the flexibility and modularity that these newly developed
flow chemistry technologies provide.
Iodides (entries 1–4, Table 12) showed improved conversions
in the hydroformylation step with a lower substrate concentra-
tion. Particularly high selectivity (97:3) was observed for the 3-
iodobenzonitrile derivative 2a. We had anticipated low overall
isolated yields for two reasons: material could be lost either
side of the collected fraction after LLS (unlikely, given the size
of the fraction collected to halve the effective concentration)
or the extraction of methanol into the aqueous phase could
have improved the solubility of styrene in the polar phase re-
sulting in the loss of some material by extraction. Despite
these concerns, the isolated yields for the telescoped process
were only marginally below those obtained from the single
step process.
Experimental Section
Synthesis of unsymmetrical stilbenes from aryl iodides
General procedure: The first aryl iodide (0.6 mmol), Cy2NMe
(2.2 equiv.), Pd(OAc)2 (1 mol%) and tBu3P·HBF4 (2 mol%) were dis-
solved in MeOH/PhMe (1:9, 3 mL, 0.2m). The 3 mL reaction mixture
was injected into a Uniqsis Flowsyn reactor through a 10 mL PEEK
injection loop A. The reaction plug was pumped at 1 mLminÀ1
(stock solvent MeOH/PhMe 1:9) by using a tube-in-tube gas reactor
(l=1.5 m, AF 2400) pressurised with 10 bar ethylene followed by
a 20 mL PTFE reaction coil at 1308C (residence time=20 min). The
exiting reaction stream passed through a BPR (P=20 bar) and
a 6 mL fraction (containing the reaction plug and any dispersion)
was collected and flushed with argon. After degassing with argon
for 5 min, the 6 mL reaction mixture was injected a second time
through injection loop A at a flow rate of 0.2 mLminÀ1 and com-
bined with a 6 mL solution of the second aryl iodide from injection
loop B at a flow rate of 0.2 mLminÀ1 at a T piece mixer. The reac-
tion stream entered a 20 mL reaction coil at 1308C (residence
time=50 min) and exited through a BPR (P=20 bar). The crude re-
action solution was worked up with aqueous HCl and brine in
batch mode, followed by column chromatography.
Conclusions
We have developed a gas–liquid flow system for the palladi-
um-catalysed ethylene Heck process that, by delivering gas to
flow streams as homogeneous solutions, facilitated the rapid
screening and optimisation of conditions in a safe and control-
lable manner. The optimised conditions were used to trans-
form a variety of aryl and heteroaryl iodides into synthetically
valuable styrene derivatives in high conversions and yields. Re-
actions were performed on scales from 0.3 to 120.0 mmol by
using the same system, highlighting the ease of scale-out for
these continuous flow devices. The permeation and take-up of
ethylene by the solvent was quantitatively measured by using
an in-line ReactIR flow cell calibrated by using a gas burette. It
was found that the gas concentration was linearly proportional
to pressure and exhibited saturation behaviour with respect to
time, as might be expected. By using controlled depressurisa-
tion and argon flushing, the excess ethylene gas could be re-
moved to facilitate a second Heck cross-coupling with no addi-
tional catalyst to afford unsymmetrical stilbenes in a tandem
two-step telescoped flow process. By using the same gas–
liquid flow devices, an efficient and highly selective continuous
flow hydroformylation process was developed that facilitated
the rapid and scalable synthesis of synthetically useful a-
branched aldehydes from styrene precursors. As only small vol-
umes of pressurised syngas (CO/H2 1:1) were present in the re-
actor at any one time, the safety profile of the process was en-
hanced greatly, highlighting one of the key advantages of flow
chemistry compared with batch mode. Initial attempts to tele-
scope the two transformations into a 3-gas 2-step tandem
flow process identified that a component of the first reaction
Synthesis of branched aldehydes from aryl iodides
General procedure: The procedure for the formation of styrene
from aryl iodides was identical to that used for the synthesis of un-
symmetrical stilbenes, except that 1.2 equiv. instead of 2.2 equiv. of
base was used. The exiting reaction stream from the reaction
1 (1 mLminÀ1) was combined with an aqueous HCl (1m) stream
(1 mLminÀ1) at a T piece. The combined biphasic stream was then
passed through an in-line mechanical mixer followed by an in-line
liquid–liquid separator (full details in the Supporting Information).
(At this stage the styrenes could be purified by small-scale distilla-
tion.) A 6 mL organic fraction was collected from the LLS and flush-
ed with argon in a holding flask for 5 min. The reaction mixture
was then injected through injection loop A at a flow rate of
0.3 mLminÀ1 (stock solvent MeOH/PhMe 1:1) and combined with
a 6 mL solution of Ru(CO)2(acac) (3 mol%) and PPh3 (18 mol%) dis-
solved in MeOH/PhMe (1:1), which was injected through injection
loop B at a flow rate of 0.3 mLminÀ1 at a T piece mixer. The reac-
tion stream then entered a tube-in-tube gas reactor (l=1.5 m,
AF 2400) pressurised with syngas (CO/H2 1:1, P=25 bar) followed
by a 30 mL stainless steel reaction coil at 708C (residence time=
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