Syngas-mediated C-C bond formation in flow: Selective rhodium-catalysed hydroformylation of styrenes

Article abstract of DOI:10.1055/s-0031-1289292

We report a continuous flow, rhodium-catalysed hydroformylation of various styrenes using a tube-in-tube gas-liquid reactor. The flow process afforded selectively branched aryl aldehydes in good yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289292

2648
LETTER
Syngas-Mediated C–C Bond Formation in Flow: Selective Rhodium-Catalysed
Hydroformylation of Styrenes
H
ydroformyla
i
tion of
v
S
tyrenes arajan Kasinathan,a Samuel L. Bourne,b Päivi Tolstoy,b Peter Koos,b Matthew O’Brien,b Roderick W. Bates,a
Ian R. Baxendale,b Steven V. Ley*b
a
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, 637371 Singapore, Singapore
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
b
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received 19 August 2011
of the gases involved. In addition, the impractical nature
Abstract: We report a continuous flow, rhodium-catalysed hydro-
of using high pressure batch equipment necessitates the
development of alternative approaches.
formylation of various styrenes using a tube-in-tube gas–liquid re-
actor. The flow process afforded selectively branched aryl
aldehydes in good yields.
Flow chemistry has emerged over recent years as an en-
Key words: hydroformylation, rhodium, catalysis, membrane, abling technique that often enhances the safety profile of
flow
synthetic processes, particularly those that involve haz-
ardous conditions (e.g., high temperature or pressures)
and intermediates.8 We have previously reported on the
advantages of using gas-permeable membrane9 based re-
Hydroformylation is a powerful carbon–carbon bond
actors for gas–liquid reactions10 in continuous-flow mode,
compared to other flow chemistry methods.11 The small
internal volume of the reactor greatly enhances the safety
profile of the reaction and makes hydroformylation reac-
tions easy and safe to carry out in research laboratories.
forming reaction,1 whereby one molecule of CO and H2
are added across an olefinic bond to afford synthetically
versatile aldehyde products (Scheme 1).
[Rh], ligand
CHO
syngas (CO:H2)
We report here the hydroformylation of functionalised
styrenes in flow using a tube-in-tube gas–liquid flow reac-
tor, which efficiently delivers gas to a liquid stream. The
study was initiated by evaluating the hydroformylation of
styrene (1a) using the flow setup shown in Figure 1.
CHO
+
R
R
R
solvent
temperature
branched
linear
Scheme 1 General scheme for the rhodium-catalysed hydroformy-
lation of alkenes providing branched and linear aldehydes
The reaction is highly atom-efficient. However, while no
atoms are lost as waste in the reaction itself, hydroformy-
lation processes typically require an excess of both gases
and high pressures to achieve efficient catalyst turnovers.
Fortunately, CO and H2 are plentiful and inexpensive re-
agents, which have enabled hydroformylation to become
the largest-scale application of homogeneous catalysis to-
day.2
Whilst many industrial applications of hydroformylation
afford linear aldehydes,3 the branched isomer,4 which
leads to greater molecular complexity, is less straightfor-
ward to construct and often requires inefficient syntheses.
Varying the electronic nature of substituents attached to
the alkene can strongly influence the selectivity of the re-
action. Aromatic alkenes and vinyl ethers generally pro-
vide branched aldehydes5 with high regioselectivities,
while aliphatic alkenes generally yield linear products.6
Despite the appeal of this efficient C–C bond-forming re-
action, it is not commonly employed in research
laboratories7 owing to the flammable and toxic properties
Figure 1 Gas-flow reactor configuration for optimisation of the
rhodium-catalysed hydroformylation of styrene (1a)
A commercially available flow system was used to pump
the reaction mixture to the gas–liquid reactor from a 1 mL
PTFE sample loop (although any suitable flow chemistry
platform can be used). Styrene (1a; 0.1 mmol) and the
rhodium catalyst were dissolved in solvent (1 mL). The
rhodium pre-catalyst and ligand were premixed in anhy-
drous solvent before adding olefin to the mixture. This re-
agent stream was then pumped at various rates through the
gas–liquid reactor pressurised with syngas (CO/H2 = 1:1),
followed by a heated stainless steel reaction coil. The ex-
iting stream was then passed through a back-pressure reg-
ulator (BPR), which is essential to prevent outgassing
SYNLETT 2011, No. 18, pp 2648–2651
x
x
.x
x
.2
0
1
1
Advanced online publication: 07.10.2011
DOI: 10.1055/s-0031-1289292; Art ID: D27411ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hydroformylation of Styrenes
2649
from the solution in the reactor and to maintain a homoge-
neous solution, thus avoiding segmented flow. The initial
optimisation reactions are summarised in Figure 2. In this
screening process we focused on reaction parameters in-
cluding rhodium catalyst/loading, gas pressure, reaction
temperature, flow rate and solvent. The results of the
rhodium pre-catalyst and ligand12 screening showed that
[Rh(CO)2(acac)] gave the best conversions compared to
Rh(OAc)2 and Rh(PPh3)4 when Ph3P was used as a ligand.
Furthermore, Ph3P proved to be the most effective
ligand13 for our system when compared to other phospho-
rous ligands [P(OPh)3, P(o-Tol)3, P(2-fur)3], which gave
low conversions.
Having established the optimal catalyst and its loading (3
mol%) for flow hydroformylation, the reaction
temperature14 was then investigated (Figure 2, A). Higher
conversions were observed with increasing temperature
up to 80 °C. However, the selectivity was adversely af-
fected beyond 60 °C. The optimal combination of high
conversion and high selectivity was achieved at 65 °C. In
a screen to determine the optimal catalyst to ligand ratio,
it was found that increasing the amount of Ph3P ligand led
to a regioselectivity improvement from 85:15 to 92:8 of
branched to linear aldehydes (Figure 2, C).15 Thereafter,
the effect of varying the pressure of syngas in the tube-in-
tube reactor was investigated (Figure 2, D).16 Modest con-
versions were achieved at lower pressures, while at 25 bar
of syngas the conversion of styrene to aldehyde improved
significantly (with increased selectivity). Varying the
flow rate between 0.1 mL/min and 1.0 mL/min (Figure 2,
B) revealed that the conversion was optimal between 0.5
and 0.7 mL/min. At higher flow rates the conversion de-
creased, possibly due to a combination of shorter reaction
time and insufficient dissolution of gas into the liquid
stream. Reactions performed at lower flow rates gave un-
expectedly low conversion into the desired aldehydes. Af-
ter this initial screening, the best conversion obtained was
57% (Figure 2, conditions D, 25 bar of syngas) with 93:7
regioselectivity.
Figure 2 Temperature (A), flow rate (B), ligand loading (C) and
pressure of syngas (D) influence on selectivity and conversion in con-
tinuous flow styrene hydroformylation. General reaction conditions:
styrene (0.1 mmol), [Rh(CO)2(acac)] (3 mol%), 1 mL loop, 20 bar
(CO/H2 = 1:1) (if not stated otherwise), 20 mL heating coil, 60 °C (if
not stated otherwise), toluene; A: AF-2400 1 m, Ph3P (30 mol%) (ca-
talyst prepared using toluene), flow rate: 0.2 mL/min, reaction time:
100 min; B: AF-2400 1 m, Ph3P (24 mol%) (catalyst prepared using
toluene); C: AF-2400 1 m, Ph3P (6–30 mol%) (catalyst prepared
using toluene), flow rate: 0.2 mL/min, reaction time: 100 min.; D:
AF-2400 2 m, Ph3P (18 mol%) (catalyst prepared using THF), flow
rate: 0.6 mL/min, reaction time: 33 min.
The influence of solvent was then examined. Changing
the reaction solvent from toluene to methanol resulted in
a dramatic increase in conversion to 79% without loss of
selectivity. Although methanol is not traditionally used in
hydroformylations due to its tendency to form acetal prod-
ucts through further reaction with the aldehydes,17 no such
by-products were observed and only the desired alde-
hydes were obtained. Further adjustments to the reaction
time (35 mL coil, 58 min) and the solvent used for catalyst
preparation (MeOH–toluene, 1:1) gave excellent conver-
sion (93%) of styrene (1a) into the desired aldehyde with
high selectivity (B/L = 94:6). With optimised reaction
conditions in hand, the scope of the process was investi-
gated. Yields and selectivities for the hydroformylation of
a variety of styrene derivatives are shown in Table 1. The
flow setup used for the synthesis of the examples was the
same as that used in Figure 1 for the optimisation reac-
tions.
The electronic properties of the aryl substituents on the
styrene compounds had an effect on the reaction conver-
sions and selectivities.18 Styrene substrates with electron-
withdrawing groups gave the desired aldehydes in higher
conversions and better regioselectivities than those bear-
ing electron-donating groups. Furthermore, two different
heteroaromatic styrenes were tested. Hydroformylation of
2-vinyl pyridine (11a) gave predominantly the branched
aldehyde, however, a significant amount of the hydroge-
nated by-product 2-ethylpyridine was observed (Table 1,
entry 11). Hydroformylation of 4-methyl-5-vinylthiazole
Synlett 2011, No. 18, 2648–2651 © Thieme Stuttgart · New York

2650
S. Kasinathan et al.
LETTER
(12a) gave the branched aldehyde with high conversion Table 1 Rhodium-Catalysed Hydroformylation of Styrene Deriva-
tives 1a–12aa
and regioselectivity (Table 1, entry 12). It is noteworthy
that all the reactions were highly reproducible in terms of
conversion as well as regioselectivity.
Rh(CO)2(acac)
CHO
PPh3
CHO
+
Ar
Ar
Ar
CO:H2 (1:1) 25 bar
MeOH–toluene
65 °C, 58 min
Concurrent investigations in our group have led to the de-
velopment of an efficient method for the preparation of
functionalised styrenes via a palladium-catalysed cross-
B
L
1a–12a
1b–12b
coupling of aryl iodides with ethylene gas.19 To demon- Entry Substrate
strate the potential of transition-metal-catalysed C–C
Conv. (%)b,d B/Lb,d
Yield (%)c,d
71
bond-forming reactions in flow, we envisaged the direct
conversion of aryl iodides into the corresponding
branched aldehydes via two sequential C–C bond-form-
ing reactions using reactive gases (Figure 3).
1
90
89
13:1
12:1
2
82
86
94
75
F
3
4
5
95
97
81
16:1
31:1
9:1
F
F3C
MeO
6
7
93
92
13:1
10:1
85
80
OMe
MeO
Cl
OMe
8
9
96
90
86
–
18:1
6:1
11:1
–
70
69
69
10
11
N
e
–
Figure 3 Flow setup for the Pd-catalysed vinylation of aryl iodides
followed by Rh-catalysed hydroformylation to afford linear and bran-
ched aldehydes
12
95
23:1
81
N
S
Although alternative complexes that maintain complete
homogeneity throughout the reaction can be used to catal-
yse the Heck reaction, the palladium JohnPhos complex
forms significant amounts of palladium black as it cataly-
ses the vinylation of 4-iodoanisole to 4-vinylanisole; how-
ever, this can be easily removed through simple in-line
filtration, thereby providing a reaction stream that can be
fed directly into the continuous flow hydroformylation af-
ter the removal of ethylene gas.20 Subsequently, the reac-
tion stream containing 4-vinylanisole (5a) was added to a
third stream containing [Rh(CO)2(acac)] (3 mol%) and
Ph3P (18 mol%) in MeOH and toluene (1:1). The stream
was then passed through a second gas–liquid reactor pres-
a Reaction conditions: substrate (1 mmol), [Rh(CO)2(acac)] (3 mol%),
Ph3P (18 mol%), 25 bar of CO/H2 (1:1), substrate dissolved in 10 mL
of toluene–MeOH (1:1 mixture), flow solvent: MeOH (0.6 mL/min).
b Determined by GC analysis.
c Isolated yield of the branched regioisomer after purification by flash
chromatography on silica gel.
d Values correspond to results obtained after two runs with each sub-
strate.
e Complex reaction mixture: a significant amount of the 2-ethylpyri-
dine was observed.
surised with syngas (CO/H2 = 1:1) at 25 bar before enter-
ing a second heated stainless steel reaction coil. This
preliminary experiment, involving three different gases,
Synlett 2011, No. 18, 2648–2651 © Thieme Stuttgart · New York

LETTER
Hydroformylation of Styrenes
2651
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Acknowledgment
We thank the following for financial support: Singapore Ministry of
Education Academic Research Fund Tier 1 (grant RG 62/10) (S.K.,
R.W.B.), Novartis (S.L.B.), Astra Zeneca (P.T.), Georganics Ltd
(P.K.), EPSRC (M.O.B.), the Royal Society (I.R.B.) and the BP
1702 Professorship (S.V.L.).
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