A continuous flow solution to achieving efficient aerobic anti-Markovnikov Wacker oxidation

Article abstract of DOI:10.1002/adsc.201300278

An aerobic anti-Markovnikov Wacker oxidation for the flow-synthesis of arylacetaldehydes is reported. In the process, flow chemistry techniques have provided a means to control and minimise the over-oxidation of sensitive products. The reaction showed general applicability to various functionalised styrenes and provided a process capable of a multi-gram scale. Copyright

Full text of DOI:10.1002/adsc.201300278

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DOI: 10.1002/adsc.201300278
A Continuous Flow Solution to Achieving Efficient Aerobic Anti-
Markovnikov Wacker Oxidation
S. L. Bournea and S. V. Leya,*
a
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K.
E-mail: svl1000@cam.ac.uk
Received: April 12, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300278.
Abstract: An aerobic anti-Markovnikov Wacker ox-
idation for the flow-synthesis of arylacetaldehydes
is reported. In the process, flow chemistry tech-
niques have provided a means to control and mini-
mise the over-oxidation of sensitive products. The
reaction showed general applicability to various
functionalised styrenes and provided a process ca-
pable of a multi-gram scale.
(BQ) since the stoichiometry can be more easily con-
trolled.
Several avenues towards achieving an anti-Markov-
nikov Wacker oxidation have previously been investi-
gated. The use of directing groups[4] has been em-
ployed but substrate scope is limited somewhat. An-
other insight by Spencer and co-workers[5] showed
that an increase from catalytic to stoichiometric PdCl2
shifts the selectivity in favour of aldehyde products.
Furthermore, the use of t-BuOH to achieve the de-
sired anti-Markovnikov product was first demonstrat-
ed by Feringa and co-workers.[6] using a catalyst com-
prised of (MeCN)2PdClNO2 and CuCl2 with O2. How-
ever, less than 10% yield was reported for the oxida-
tion of styrene to phenylacetaldehyde.
Keywords: aerobic Wacker oxidation; gas-liquid
flow; microreactors; palladium catalysis; tube-in-
tube
Given our groupꢀs experience with flow chemistry
The use of molecular oxygen as a reagent for the syn- techniques[7] and in particular with gas-flow devices,[8]
thesis of organic compounds is an attractive research we envisioned developing an efficient aerobic anti-
subject and of particular interest to industry. Molecu- Markovnikov Wacker oxidation. Through proper ap-
lar oxygen is inexpensive, readily available and a suita- plication of microreactors and more precise control of
ble green alternative for many oxidising agents cur- reaction parameters, such as oxygen pressure, reaction
rently employed in synthesis.[1] The use of oxygen time and temperature, it is conceivable that any
often requires transition metal catalysts in order to amount of over-oxidation, when using CuCl2 and O2,
promote the rate of reaction and in the majority of may be sufficiently mitigated, a problem which has
cases the desired transformations can be achieved hitherto prevented the development of such an aero-
with high conversion. However, in cases requiring the bic process.
partial oxidation of compounds, over-oxidation can be
a significant problem and one which is more easily and CuCl2 with O2 in batch mode (Table 1). When
controlled by employing alternative oxidants. using BQ as oxidant 4-chlorostyrene gave almost full
We initiated our investigation by comparing BQ
One such process, brought to our attention by conversion and good selectivity as previously report-
a paper from Grubbs and co-workers,[2] involves the ed,[2] although some over-oxidation was also observed
anti-Markovnikov Wacker oxidation of styrenes to (entry 1). The more electron-rich 4-methoxystyrene
sensitive arylacetaldehyde products wherein the use gave a lower conversion and a poorer selectivity for
of sterically hindered tert-butyl alcohol as reaction the arylacetaldehyde (entry 2). Again, some over-oxi-
solvent accounts for the excellent aldehyde selectivity. dation was observed but to a lesser extent with the
To prevent over-oxidation of the desired products at electron-rich derivative. Substituting BQ for CuCl2
the benzylic position, ultimately leading to cleavage (5 mol%) and O2 (10 bar) led to complete conversion
of the olefinic bond to form benzaldehydes, copper of both electronically varying examples. However, as
and oxygen which are traditionally employed in the expected, significantly increased over-oxidation of the
Wacker oxidation[3] were substituted for bezoquinone desired products to the corresponding benzaldehydes
was observed.[9] Decreasing the oxygen pressure
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Table 1. Anti-Markovnikov Wacker oxidation of various functionalized styrenes in batch mode.[a]
Entry
R
[Ox]
Amount
Conv.[b] [%]
Selec.[b] (2/3/4)
1
2
3
4
5
4-Cl
4-OMe
4-Cl
4-OMe
4-OMe
BQ
BQ
CuCl2 +O2
CuCl2 +O2
CuCl2 +O2
1.15 equiv.
1.15 equiv.
5 mol%
5 mol%
1 mol%
94
75
99
99
98
84:3:7
66:6:3
70:5:24
67:4:28
79:7:12
[a]
Reaction conditions: substrate (1.25 mmol), (MeCN)2PdCl2 (2.5 mol%), H2O (1.1 equiv.), t-BuOH (10 mL), O2 (10 bar),
858C, 1 h. A stainless steel autoclave (v=50 mL) was used.
Ratio of products 2:3:4 determined by GC analysis.
[b]
(5 bar) led to both incomplete conversion and contin-
ued formation of the respective benzaldehydes, possi-
bly due to the competing rate of over-oxidation lead-
ing to oxygen depletion within the autoclave. Howev-
er, it was possible to reduce the extent of over-oxida-
tion by reducing the co-catalyst loading five-fold to
1 mol% (entry 5, Table 1). Further decreasing the co-
catalyst loading resulted in longer reactions times.
It is also important to note that stirred-tank auto-
claves that exist in the pharmacutical industry can be
used to perform aerobic oxidation with dilute air mix-
tures (5–8% O2 in N2) requiring a constant flow of
gas through the reactor to prevent oxygen deple-
tion.[1d] Therefore, despite small improvements in the
aerobic batch process, further batch optimisations
would be of little relavance and a flow-mode process
was quickly pursued.
Scheme 1. Reaction conditions: PhMe/t-BuOH (1:6), flow
rates (0.25+0.25 mLminÀ1), reaction coil (v=30 mL), gas
reactor (v=0.7 mL) AF2400 (l=1.5 m). Injection loop A
(2 mL): substrate 1a (0.4 mmol, 0.2M). Injection loop B
(2 mL): (MeCN)2PdCl2, CuCl2, H2O.
The reaction was found to proceed rapidly with
CuCl2 and O2 giving reaction times of approximately
15 min using 5 mol% catalyst loadings allowing for
extensive reaction optimisations in a short time
frame. We began by addressing which co-solvent loaded into injection loop B. A Uniqsis FlowSyn reac-
would be appropriate to prevent t-BuOH freezing in tor was used to pump the reagents through the inner
the flow tubes and pumps at room temperature. A tube of a tube-in-tube gas reactor pressurised with
mixture of PhMe/t-BuOH (1:6) gave the best results pure oxygen. The reaction stream was then passed
compared to other co-solvents which caused the for- through a 30-mL stainless steel reaction coil main-
mation of other by-products. Following this the cata- tained at constant temperature, after which the reac-
lyst loadings of palladium and copper were briefly in- tion stream passed through a 25-bar back-pressure
vestigated and
a catalyst loading of [Pd]/[Cu] regulator (BPR). This was required to maintain a ho-
(5 mol%/5 mol%) was found to give good conversions mogeneous solution by preventing out-gassing of
and selectivities while allowing for some variation in oxygen at pressures up to 25 bar. Finally, the exiting
reaction time and oxygen pressure to obtain the best product stream is collected in a small vial under a con-
results for specific substrates.
stant flow of nitrogen to remove excess oxygen.
The conditions for the anti-Markovnikov Wacker
The flow set-up used for the optimisation experi-
ments is shown in Scheme 1. A substrate solution con- oxidation of 4-methoxystyrene 1a were varied with re-
taining 4-methoxystyrene 1a (0.4 mmol, 0.2M) was spect to temperature (Figure 1, A), H2O equivalents
loaded into injection loop A and a catalyst solution (Figure 1, B) and pressure of pure oxygen (Figure 1,
containing (MeCN)2PdCl2, CuCl2 and H2O was C). Catalyst loadings, solvent mixture and the resi-
2
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A Continuous Flow Solution to Achieving Efficient Aerobic Anti-Markovnikov Wacker Oxidation
selectivity above 808C. Following this, the equivalents
of water were investigated (Figure 1, B). Since trace
amounts of water in the t-BuOH used in these reac-
tions could contribute to the reaction, sub-stoichio-
metric amounts of water were also investigated. In-
complete conversion of the starting material was ob-
served within the 1-h residence time frame up until
the addition of 1.2 equiv. of water. However, given
the ease which with residence time can be controlled
using flow we considered 1.4 equiv. as optimum for
the overall reaction rate and to avoid incomplete con-
version when varying the substrates. Next we studied
the influence of oxygen pressure on the reaction
(Figure 1, C). At a constant combined flow rate
(0.5 mLminÀ1) through the gas reactor, complete con-
version was not observed until an oxygen pressure of
8 bar was applied. Further increasing the pressure of
oxygen resulted in significant over-oxidation and deg-
radation of the reaction selectivity. Gas burette meas-
urements determined the oxygen concentration at
8 bar to be 0.097M, not surprisingly close to the 0.1M
reaction concentration. This demonstrates nicely the
ease and accuracy with which controlling the oxygen
concentration using flow-technologies enables reac-
tions that would prove particularly challenging in
batch-mode.
As a means of isolating and purifying the arylacet-
AHCTUNGTREGaNNUN ldehyde products we chose to crystallize them as the
bisulfite adducts.[10] This was only possible due to the
relatively pure product stream. The product fraction
was collected directly from the reactor into a stirred
beaker of sodium bisulfite solution in EtOH/H2O
leading to preferential crystallisation of the aryl-
AHCTUNGTRENNUNG
the recovery of arylacetaldehyde sulfite adduct crys-
tals by vacuum filtration. The free aldehyde can be re-
generated from the bisulfite adduct in the normal
way, by addition of aqueous sodium bicarbonate, or
under non-aqueous conditions by addition of chloro-
trimethylsilane.[10c]
With optimised conditions in hand for the aldehyde
selective anti-Markovnikov Wacker oxidation of 1a
and a simple, efficient means of isolation, we investi-
gated the reaction with a variety of functionalised
styrenes, shown in Table 2, using the same flow set-up
Figure 1. The effect of varying parameters on selectivity and
by-product formation. (A) Temperature: H2O (2 equiv.), O2
(10 bar). (B) H2O equivalents: T=808C, O2 (10 bar). (C)
Oxygen pressure: H2O (1.4 equiv.), T=608C. General reac-
tion conditions: PhMe/t-BuOH (1:6), flow rates (0.25+
0.25 mLminÀ1), reaction coil (stainless steel, v=30 mL), gas
reactor (v=0.7 mL) AF2400 (l=1.5 m). Injection loop A
(2 mL): 4-vinylanisole 1a (0.4 mmol). Injection loop B
(2 mL): (MeCN)2PdCl2 (5 mol%), CuCl2 (5 mol), H2O
(X equiv.).
dence time (via flow rate) remained constant through- used in Scheme 1. Not surprisingly, the electronic
out these optimisations. properties of the aryl substituents significantly affect
The reaction temperature was first studied the selectivities and the propensity for over-oxidation.
(Figure 1, A). A relatively low temperature of 508C Electron-rich styrenes gave slightly worse selectivity
led to better selectivities and less by-product forma- with more of the methyl ketone being formed in con-
tion before full conversion could be reached in the trast to substrates bearing halogen substituents which
desired 1-h residence time frame. Increasing the tem- preferred formation of the desired arylacetaldehyde
perature progressively led to an increased reaction products. However, the electron-rich species had less
rate and full conversion with good selectivity and of a tendency to over-oxidise before complete conver-
minimal by-product formation at an optimal 608C. sion was reached. For example; the reaction of 4-(tri-
This was followed by a drop-off in reaction rate and fluoromethyl)styrene 1k formed significant amounts
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Table 2. Anti-Markovnikov Wacker oxidation of various
However, despite the high conversions to desired
products for this process, the crystallisation of some
products proved more difficult, particularly due to the
small scale of the crystallisation process. Those exam-
ples with ortho substituents proved particularly diffi-
cult to recover using this technique.
Using the reaction concentration and conditions op-
timised up to this stage in the investigation, 0.4 mmol
of substrate is typically employed using the injection
loop system. To demonstrate the scalability of this
process we planned to increase the throughput and
run the reaction continuously for several hours. A
second optimisation of conditions was necessary to
find the optimum oxygen pressure at the higher sub-
strate concentration. (Table 3). Initial attempts to in-
crease the reaction concentration to 0.5M led to pal-
ladium black precipitation (entry 1). This did not
cause the reactor to block, however the concentration
was subsequently decreased to 0.3M for the following
experiments as a precautionary measure.
functionalized styrenes.[a]
Entry Arylacetaldehyde 2 Selec.[b] (2/3/4) Yield[c] [%]
a
83:7:7
74
75
b
77:13:7
c
82:6:11
78
d
e
f
82:3:12
92:2:3
88:4:4
79:6:8
84:4:11
72[d]
56
77
Somewhat surprisingly, significant amounts of both
unreacted starting material and over-oxidised by-
product were observed together, similar to the obser-
vation made when lowering the oxygen pressure in
the batch autoclave. Lowering the co-catalyst loading
to 1 mol% (entry 3) decreased the rate of competing
over-oxidation and gave almost full conversion.
g
h
66
80
When increasing the reaction concentration back to
0.5M palladium black formation was no longer a prob-
lem, however, oxygen depletion continued to prevent
i
82:4:9
88:2:6
77:2:14
84:3:3
80
j[e]
77
Table 3. Selected optimisation experiments for scale up.[a]
k[f]
59
Entry Conc. [Pd]:[Cu]
O2
Conv.[b] Selec.[b]
[M]
[mol%]
[bar]
[%]
(2/3/4)
l
80[d]
1[c]
2
3
0.5
0.3
0.3
0.5
0.5
0.5
0.5
0.3
5:5
5:5
5:1
5:1
5:1
5:1
5:2
5:2
5:2
10
15
20
20
30
37
79
98
73
95
20:4:13
49:5:25
69:11:18
50:7:16
64:10:21
49:5:20
64:15:15
70:6:23
76:4:19
[a]
Reaction conditions: substrate (0.4 mmol, 0.2M),
(MeCN)2PdCl2 (5 mol%), CuCl2 (5 mol%), H2O
(1.4 equiv.), solvent=PhMe/t-BuOH (1:6), flow rates
(0.25+0.25 mLminÀ1), residence time=60 min, gas reac-
tor (v=0.7 mL) AF2400 (l=1.5 m), O2 (p=8 bar), reac-
tion coil (stainless steel, v=30 mL), T=608C.
Product ratios add up to the overall conversion and were
determined by GC analysis of the crude product mixture.
Isolated yields are based on the recovery of arylacetalde-
hyde sulfite adduct crystals.
4
5
6[d]
7[d]
8[d]
20+20 74
20+20 94
20+20 99
20+20 99
[b]
[c]
9[d,e] 0.3
[a]
Reaction conditions: substrate 1h, (MeCN)2PdCl2, CuCl2,
H2O (1.4 equiv.), solvent=PhMe/tBuOH (1:6), flow rates
(0.25+0.25 mLminÀ1), residence time=60 min, gas reac-
tor (v=0.7 mL) AF2400 (l=1.5 m), O2 (p=X bar), reac-
tion coil (stainless steel, v=30 mL), T=608C.
Conversions and product ratios were determined by GC
analysis of the crude product mixture.
Palladium black was observed.
Flow set-up as used in Scheme 2 using a 5-mL injection
loop for substrate, flow rates of 0.2+0.6 mLminÀ1 were
used with the catalyst stream being pumped continuously
giving a combined reaction plug volume of 20 mL.
A flow rate of 0.3+0.9 mLminÀ1 was used.
[d]
[e]
[f]
Isolated yield after column chromatography.
A residence time of 75 min was used.
A residence time of 40 min was used.
[b]
of by-product before all of the starting material had
been consumed. Therefore, reducing the residence
time led to lower conversion and lower by-product
formation thereby improving the overall yield. Sub-
strates 1e and 1j with ortho substituents both gave ex-
cellent selectivity and less by-product formation.
[c]
[d]
[e]
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A Continuous Flow Solution to Achieving Efficient Aerobic Anti-Markovnikov Wacker Oxidation
Scheme 2. Flow scheme for multi-gram preparation of 2h utilising a second gas-reactor to provide adequate oxygen supply.
The 5-mL injection loop was used during optimisations but not during the scale-up process whereby reagents were intro-
duced continuously through the pumps.
full conversion from being reached. A similar prob- zation of the desired products by formation of the bi-
lem encountered in our group involving hydrogen de- sulfite adducts. This aerobic oxidation is applicable to
pletion was solved by introducing a second gas reac- both electron-rich and electron-poor styrenes. In addi-
tor into the set-up.[8f] We decided therefore to investi- tion, the removal of spent oxidants such as hydroqui-
gate a similar set-up in this process.
none or metal based oxidants by expensive separation
The effect of double dosing the reaction stream techniques is not necessary. Furthermore, the use of
with oxygen (Scheme 2) showed some improvements a tube-in-tube gas reactor to charge a pressurised re-
in favour of the desired product (entry 6). Oxygen de- action stream with only the necessary volume of pure
pletion continued to hinder the reactions progress at oxygen improves the safety of such a process in flow.
high concentration (entry 7) and increasing oxygen No effective reactor headspace prevents the combina-
pressures further only led to unacceptable over-oxida- tion of solvent and oxygen in the gas-phase to form
tion. Using a 0.3M reaction concentration allowed for explosive mixtures, lessening chances of auto-ignition.
99% conversion and increasing the combined flow Additionally, with no incentive to use diluted oxygen
rate to 1.2 mLminÀ1 (40 min residence time) eventual- mixtures; lower, safer reactor pressures can be em-
ly provided acceptable conditions for scale-up ployed to obtain the same oxygen concentrations in
(entry 9).
solution.
Scalability of the process was tested when oxygen
The overall continuous throughput of the reaction
was increased from 3 mmolhÀ1 using the set-up in depletion at the higher reaction concentrations
Scheme 1 to 21.6 mmolhÀ1 using the set-up in became a problem. However, rapid optimisations and
Scheme 2 and optimised scale-up conditions (entry 9, employment of a double gas-reactor set-up allowed us
Table 3). In total 96 mmol of substrate 1h were pro- to obtain similar reaction selectivities with over 7
cessed over the course of a 6-hour run period (allow- times the initial throughput and subsequently led to
ing for collection of all material contained within the successful synthesis on a multi-gram scale.
reactor and dispersion effects). The exiting product
stream was collected into a large stirred beaker con-
taining sodium bisulfite solution and the resulting
crystals were collected by vacuum filtration at the end
of the experiment. An overall isolated yield of 71%
Experimental Section
yield (17.62 g, 68 mmol) for the pure crystalline 4-
chlorophenylacetaldehyde sulfite adduct of 2h with
a selectivity of 76:4 (2h/3h) for the crude product mix-
ture was achieved.
In conclusion, we have developed an efficient and
reproducible, aerobic, flow synthesis for arylacetalde-
hydes from functionalized styrenes. Only through the
Batch Mode Synthesis of Arylacetaldehydes from
Styrenes
Oxidant p-benzoquinone (1.15 equiv.) and catalyst
(MeCN)2PdCl2 (2.5 mol%) were added to t-BuOH (10 mL)
which was heated to 858C. Olefin (1.25 mmol) and H2O
(1.1 equiv.) were then added to the reaction mixture
(0.125M) and stirred for 60 min at 858C. Alternatively, p-
application of flow technologies such as the tube-in-
benzoquinone was replaced with CuCl2 (5 mol%) and the
tube gas reactor was it possible to accurately charge
reaction vessel was pressurised with pure O2 (10 bar). After
60 min the reaction vessel was rapidly cooled in ice water
and depressurised. A sample was immediately taken for GC
a reaction stream with a stoichiometric amount of
gaseous oxygen. In addition, the relative purity of the
product stream allowed for simple, selective, crystalli- analysis.
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COMMUNICATIONS
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Flow Mode Synthesis of Arylacetaldehydes from
Styrenes
Olefin (0.4 mmol) was dissolved in PhMe/t-BuOH (1:6,
2 mL, 0.2M) and loaded into injection loop A (2 mL).
(MeCN)2PdCl2 (5 mol%), CuCl2 (5 mol%) and H2O
(1.4 equiv.) were dissolved in PhMe/t-BuOH (1:6, 2 mL) and
loaded into injection loop B (2 mL). The reagents were
pumped using a Uniqsis Flowsyn reactor via the 2-mL
PEEK injection loops A and B at a flow rate of 0.25+
0.25 mLminÀ1 [using PhMe/t-BuOH (1:6) as stock solvent]
through a T-piece mixer which combines the two streams.
The reaction mixture then flowed through a tube-in-tube
gas reactor (v=0.7 mL) AF2400 (l=1.5 m) pressurised with
pure O2 (8 bar) followed by a 30-mL stainless steel reaction
coil at 608C (residence time: 60 min). The exiting product
stream passed through a BPR (15 bar) and a 6 mL fraction
(containing the reaction plug and any dispersion) was col-
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2011, 2648–2651; k) S. L. Bourne, M. OꢀBrien, S. Kasi-
nathan, P. Koos, P. Tolstoy, D. X. Hu, R. W. Bates, B.
Martin, B. Schenkel, S. V. Ley, ChemCatChem 2013, 5,
159–172.
lected into
a vial (flushed with nitrogen) containing
NaHSO3 (0.4 mmol) dissolved in H2O/EtOH (1:1, 1 mL).
Crystallisation of the arylacetaldehyde sulfite adduct occurs
slowly over the time that the fraction was collected
(12 min). (Further dilution of the product fraction with
EtOH sometimes helped to encourage crystallisation if nec-
essary.) The adduct crystals were collected by Buchner fil-
tration, washed with EtOH followed by Et2O and finally
dried under vacuum. A small sample can be collected for
GC analysis to determine conversions and selectivities
before addition to the sodium sulfite solution.
Acknowledgements
We would like to thank Dr. Benjamin Martin, Dr. Berthold
Schenkel and Novartis Pharma AG, Basel, Switzerland, for
guidance and financial support.
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