The continuous-flow synthesis of styrenes using ethylene in a palladium-catalysed heck cross-coupling reaction

Article abstract of DOI:10.1055/s-0031-1289291

We report a palladium-catalysed ethylene Heck reaction for the vinylation of aryl iodides using a tube-in-tube gas-liquid reactor. The flow process afforded various styrenes in short reaction times, employing moderate ethylene pressure. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289291

LETTER
2643
The Continuous-Flow Synthesis of Styrenes Using Ethylene in a Palladium-
Catalysed Heck Cross-Coupling Reaction
C
ontinuous-Fl
a
ow Synthes
m
is of
S
tyrenes uel L. Bourne,a Peter Koos,a Matthew O’Brien,a Benjamin Martin,b Berthold Schenkel,b Ian R. Baxendale,a
Steven V. Ley*a
a
Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
E-mail: svl1000@cam.ac.uk
b
Chemical & Analytical Development, Novartis Pharma AG, Werk Klybeck, Klybeckstr. 141, 4057 Basel, Switzerland
Received 19 August 2011
mability and toxicity) are mitigated due to the small inter-
Abstract: We report a palladium-catalysed ethylene Heck reaction
nal volume of the device and its isolation from the main
for the vinylation of aryl iodides using a tube-in-tube gas–liquid re-
cylinder.
actor. The flow process afforded various styrenes in short reaction
times, employing moderate ethylene pressure.
Key words: vinylation, membrane, flow, ethylene, styrene
In recent years the furtherance of green chemistry1 initia-
tives has encouraged the development of more economi-
cally beneficial and environmentally benign processes.
An important consideration therefore, becomes the atom
and step economy2 of new synthetic processes.
As it becomes more apparent that many traditional batch
methods are not sustainable for future applications, new
technologies and tools for synthesis have evolved that dis-
Figure 1 Tube-in-tube semi-permeable membrane gas–liquid reac-
play demonstrable advantages. In particular, flow
chemistry3 has received a great deal of attention from the
scientific community over the past decade. Continuous-
flow techniques can often provide better mixing and heat
transfer, precise control over concentrated or hazardous
reaction streams, reduced solvent waste and synthetic
shortcuts. Moreover, the rapid process optimisation of
synthetic steps on a small scale, combined with the tele-
scoping of steps together in a continuous fashion, enables
far less wasteful multistep sequences to be performed,
leading directly to drug molecules4 or even natural prod-
ucts.5
tor
We report here a Mizoroki–Heck-type cross-coupling of
aryl iodides with ethylene gas to furnish functionalised
styrenes in flow (Scheme 1). Styrenes have been recogn-
ised as useful intermediates that can undergo further trans-
formations such as epoxidation,8 cyclopropanation,9 Heck
coupling10 and hydroformylation.11 However, despite the
many potential applications of styrenes in synthesis and
given the plethora of literature reports on palladium-catal-
ysed C–C bond-forming reactions since the initial work of
Mizoroki12 and Heck,13 the development of a practical
ethylene Heck process14 has been hindered due to the gen-
eral reluctance to use reactive gases in research laborato-
ries. Established high-yielding syntheses of styrenes,
starting from aryl halides, currently involve the palladi-
um-catalysed insertion of vinyl metal species such as po-
tassium vinyltrifluoroborate15 or vinyltributyltin.16
However, these are associated with toxicity, expense, dif-
ficult work-up procedures and significant amounts of
waste.
We envisage combining continuous-flow technologies
with the use of reactive gases as a means to incorporate
small gaseous building blocks into molecules, thereby
simplifying work-up procedures and affording cleaner
overall syntheses.
We have previously reported upon the application of a gas
permeable membrane (Teflon AF-2400)6 reactor, such as
the device in Figure 1, for facilitating the transfer of
ozone,7a oxygen,7b carbon dioxide,7c carbon monoxide7d
or hydrogen7e into a reagent stream in a controlled man-
ner. Consequently, the safety concerns associated with us-
ing reactive gases with conventional high-pressure batch
equipment (such as uncontrolled depressurisation, flam-
I
[Pd]
+
base
R
R
Scheme 1 General Heck cross-coupling reaction of aryl iodides
with ethylene gas to afford styrenes
SYNLETT 2011, No. 18, pp 2643–2647
x
x
.x
x
.2
0
1
1
Advanced online publication: 07.10.2011
DOI: 10.1055/s-0031-1289291; Art ID: D27311ST
© Georg Thieme Verlag Stuttgart · New York

2644
S. L. Bourne et al.
LETTER
The study reported here was initiated by evaluating the vi- dimethylformamide to completely dissolve the additives.
nylation of 3-iodoanisole (1a) using the flow chemistry It was found that the addition of N,N-dimethylformamide
arrangement shown in Figure 2. A commercially avail- alone improved the conversion to 54%, and the addition of
able flow system was used to pump the reagents to the tetrabutylammonium iodide (TBAI, 1 equiv; Table 1, en-
gas–liquid reactor from a 5 mL PEEK sample loop. Iodide try 9) gave 96% conversion. Minor amounts of Pd black
1a (0.5 mmol), triethylamine (2 equiv), additive (1 equiv) formation presented no problems.
and the catalyst (5 mol%) were dissolved in solvent (5
mL). This reagent stream was then pumped at a rate of 1
Table 1 Optimisation of the Reactiona
mL/min through the gas–liquid reactor, pressurised with
ethylene at 15 bar, followed by a 20 mL heated PFA reac-
tion coil at 120 °C, after which the exiting stream passed
through a plug of cotton wool, to remove Pd black, then
through a 20 bar back-pressure regulator (BPR; Figure 2).
Entry Ligand (mol%)
Additive (equiv) Conv. (%)b
1
XantPhos
JohnPhos
SPhos
(6)
(12)
(12)
(12)
(15)
(15)
(12)
(12)
(12)
–
36
46
5
2
–
3
–
4
XPhos
–
10
25
–
5
t-Bu3P
–
6c
7d
8d
9d
Ph3P
–
JohnPhos
JohnPhos
JohnPhos
–
54
60
96
n-Bu4NOAc (1)
n-Bu4NI (1)
a Et3N (2 equiv), Pd(OAc)2 (5 mol%), dioxane (0.1 M), 120 °C,
50 min, ethylene (15 bar)
b Conversions determined by 1H NMR analysis.
c No reaction was observed.
d DMF in dioxane (1:4) was used as solvent.
A brief investigation into alternative solvent systems re-
vealed that toluene gave equivalent or better conversions
than dioxane. Therefore, the solvent system was changed
to N,N-dimethylformamide in toluene (1:4).
Figure 2 Flow set-up for the ethylene Heck optimisation using 3-
iodoanisole
Our initial optimisations focused on preventing Pd black
formation to achieve completely homogeneous reaction
solutions. Previous work in our group on carbonylation
reactions7e in flow had shown that the palladium Xant-
Phos complex resisted rapid formation of Pd black. Al-
though the XantPhos ligand is not popularly used for
Heck-type reactions, it did allow for a rapid initial optimi-
sation without the added complication of blockages and
filter-changes in a sealed, super-heated system. Condi-
tions were varied according to reaction time, reaction con-
centration, ethylene pressure and temperature. The best
conditions from this initial optimisation were used to
screen alternative ligands more commonly employed in
Heck-type reactions (Table 1).
A variety of substituted aryl iodides were examined in the
coupling reaction with ethylene, as shown in Table 2.
Substrates with both electron-withdrawing and electron-
donating substituents furnished the corresponding styrene
products in good isolated yields. Hydroxy groups, includ-
ing benzyl alcohols, were also compatible with the reac-
tion (Table 2, entries 7–9). Substrate 6a, with a strongly
electron-withdrawing para-nitro group, gave the styrene
product in only 60% conversion.
The reactions shown in Table 2 had residence times of 20
min. We had found earlier that a 50 min residence time
(using a lower flow rate), counter-intuitively led to de-
creased conversions. To investigate the dissolution of eth-
ylene in the solvent stream as a function of pressure and
flow rate, an in-line ReactIR® flow cell was used.19 The
asymmetrical CH2 bend observed in the IR spectra at 952
cm–1 was used to measure the ethylene concentrations
[calibrating the IR data with gas burette measurements
showed that a difference in absorption of 0.01 A.U. corre-
sponds to a concentration difference of 1.48 mL (0.066
M) of ethylene gas per 1 mL of toluene].
The monodentate ligands t-Bu3P and Ph3P also prevented
any formation of Pd black (Table 1, entries 5 and 6). How-
ever, low conversion was observed for both. The Buch-
wald-type ligands17 XPhos and SPhos also gave low
conversions, with the exception of JohnPhos, which gave
a 46% conversion, although accompanied by the forma-
tion of minor amounts of Pd black. Thereafter, the use of
tetraalkylammonium salts18 was investigated, for which it
was necessary to use a mixed solvent system with N,N-
Synlett 2011, No. 18, 2643–2647 © Thieme Stuttgart · New York

LETTER
Continuous-Flow Synthesis of Styrenes
2645
Table 2 Scope of the Reactiona
Entry
1
Substrate
Product
Yieldb
(conv.)
80%
MeO
I
MeO
(94%)
1a
1b
2
3
4
5
83%
(99%)
NC
NC
I
Figure 3 (a) Intensity of ethylene stretching frequency at 952 cm–1
against pressure at constant flow rate (1.0 mL/min). (b) Absorbance
of ethylene against flow rate at constant pressure (10 bar).
2b
AcO
2a
AcO
71%
(82%)
I
To further demonstrate the potential of homogeneous
transition-metal-catalysed C–C bond-forming reactions
performed in flow, we envisaged telescoping the ethylene
Heck into a second Heck reaction (Figure 4), whereby the
easy removal of ethylene gas followed by the addition of
a second aryl iodide would afford unsymmetrical stil-
benes using catalyst turned over from the initial step. Con-
sequently, it was necessary to prevent the formation of Pd
black. The ligands t-Bu3P and Ph3P were reinvestigated
and it was found that t-Bu3P gave equivalent or better con-
versions than JohnPhos in the presence of TBAI and
Cy2NMe without the formation of Pd black. This provided
a robust catalyst system that could be turned over and used
to catalyse the second Heck reaction without loss of activ-
ity due to palladium black formation.
The reaction stream containing the styrene product of Ar1I
was collected in a vented flask and degassed by flushing
with excess argon. The solution was then combined with
a second stream containing Ar2I (1 equiv) at a T-piece be-
fore entering a second heated reaction coil to effect a sec-
ond Heck cross-coupling reaction.
3b
4b
3a
AcO
73%
(87%)
I
4a
85%
(98%)
I
MeO
MeO
5b
5a
6
43%
(60%)
I
O2N
O2N
6b
6a
7
8
78%
(88%)
I
HO
HO
7b
7a
76%
(94%)
I
OH
OH
8b
8a
HO
9
75%
I
HO
(92%)
9a
9b
10
81%
I
(95%)
CN
CN
10b
10a
a Reaction conditions: Aryl iodide (0.5 mmol), Et3N (2 equiv),
Pd(OAc)2 (5 mol%), JohnPhos (12 mol%), TBAI (1 equiv), DMF in
toluene (1:4), 120 °C, 20 min, 1 mL/min, ethylene (15 bar), AF-2400
(0.7 m).
b Isolated yield after distillation.
As can be seen from the results shown in Figure 3, a high-
er ethylene concentration is obtained at lower flow rates,
and the ethylene concentration at a fixed flow rate increas-
es linearly with ethylene pressure, as expected. The reason
lower conversions were observed at longer retention times
is not yet clear, investigations are continuing.
Figure 4 Flow set-up for the vinylation Ar1I followed by a second
Heck reaction with Ar2I to afford unsymmetrical stilbenes
Synlett 2011, No. 18, 2643–2647 © Thieme Stuttgart · New York

2646
S. L. Bourne et al.
LETTER
Table 3 Unsymmetrical Stilbenes
optimising the second telescoped reaction. Furthermore, it
has been possible to link the ethylene Heck reaction with
a hydroformylation in flow to prepare branched alde-
hydes, thereby demonstrating the sequential use of reac-
tive gases (see the succeeding paper).20
Entry Starting iodide
Product
Yielda
(Conv.)
1
72%
(92%)
NC
I
NC
Acknowledgment
2a
We thank the following for financial support: Novartis (S.L.B.),
Georganics Ltd (P.K.), EPSRC (M.O.B.), the Royal Society
(I.R.B.) and the BP 1702 Professorship (S.V.L.).
12
2
73%
(81%)
NC
I
OMe
OMe
NC
2a
References and Notes
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68%
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F3C
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Continuous-Flow Synthesis of Styrenes
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