The impact of Novel Process Windows on the Claisen rearrangement

Article abstract of DOI:10.1016/j.tet.2013.02.038

The impact of Novel Process Windows on the Claisen rearrangement in microflow was investigated. Elevated temperatures (up to 300 °C) were crucial to achieve full conversion of allyl phenyl ether in the Claisen rearrangement. We observed that 1-butanol was the optimal reaction solvent for this transformation in flow. Solvent-free reaction conditions were feasible for the Claisen rearrangement and provided quantitative yields of the target product at 280 °C and 100 bar. Also elevated reaction pressures (up to 300 bar) were investigated in the Claisen rearrangement. We found that thermal expansion and pressure-related compression phenomena cannot be ignored at such harsh reaction conditions. These phenomena lead to large deviations of the desired residence time (as calculated from the nominal flow rate) and have a clear impact on the observed reaction trends. Finally, we also investigated the temperature effect on the Johnson-Claisen rearrangement of cinnamyl alcohol. Quantitative yields were obtained at 200 °C and at 100 bar.

Full text of DOI:10.1016/j.tet.2013.02.038

Tetrahedron 69 (2013) 2885e2890
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The impact of Novel Process Windows on the Claisen rearrangement
,
Hiroki Kobayashi a b, Brian Driessen a, Dannie J.G.P. van Osch a, Ali Talla a,
b
a
,
a,
*
*
€
Shinichi Ookawara , Timothy Noel , Volker Hessel
a Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, Den Dolech 2, 5600 MB Eindhoven, The Netherlands
b Department of Chemical Engineering, Graduate School of Science and Engineering, Tokyo Institute of Technology, Meguroku, Tokyo 152-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The impact of Novel Process Windows on the Claisen rearrangement in microflow was investigated.
Elevated temperatures (up to 300 ꢀC) were crucial to achieve full conversion of allyl phenyl ether in the
Claisen rearrangement. We observed that 1-butanol was the optimal reaction solvent for this trans-
formation in flow. Solvent-free reaction conditions were feasible for the Claisen rearrangement and
provided quantitative yields of the target product at 280 ꢀC and 100 bar. Also elevated reaction pressures
(up to 300 bar) were investigated in the Claisen rearrangement. We found that thermal expansion and
pressure-related compression phenomena cannot be ignored at such harsh reaction conditions. These
phenomena lead to large deviations of the desired residence time (as calculated from the nominal flow
rate) and have a clear impact on the observed reaction trends. Finally, we also investigated the tem-
perature effect on the JohnsoneClaisen rearrangement of cinnamyl alcohol. Quantitative yields were
obtained at 200 ꢀC and at 100 bar.
Received 5 December 2012
Received in revised form 19 January 2013
Accepted 11 February 2013
Available online 15 February 2013
Keywords:
Microreactors
Novel Process Windows
Flow chemistry
Claisen
High temperature
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
reactions are typically initiated at high reaction temperatures and
require in batch several hours reaction time to reach full conver-
In 2005, continuous manufacturing was selected by the ACS GCI
Pharmaceutical Roundtable as the number one ‘Key Green Engi-
neering Research Area for Sustainable Manufacturing’.1 While
continuous manufacturing is a mainstay in chemical industries,
such as the confectionary and petroleum industry, it has only re-
cently received more interest from the pharmaceutical industry.2,3
More specifically, microreactor technology has attracted attention
as an enabling tool for novel reaction development and scale-up.
The use of such microreactor devices has enabled synthetic
chemists and process engineers to perform reactions with an un-
precedented control over mixing, mass- and heat-transfer, safety,
reaction/residence time, and other process parameters, which re-
sults in an enhanced reproducibility.4 In addition, it allows the
practitioner to utilize harsh reaction conditions (e.g., high tem-
perature, pressure, and reactant concentration), which are far from
the common laboratory practice, in a safe and reliable fashion.
These new processing conditions, which can be attained by means
of microreactor technology, have been called ‘Novel Process
Windows’.5
sion.6 Therefore, catalytic versions of sigmatropic rearrangements
were developed to reduce reaction times, to perform the reaction
under milder conditions and to avoid side reactions.7 To avoid the
use of such toxic catalysts, green alternatives are strongly desired,
which can accelerate sigmatropic rearrangements efficiently. One
such strategy involves the use of microwave-assisted heating.8
Whereas short reaction times and minimal by-product formation
are obtained, limited scale-up potential of microwave chemistry
remains a problem. Recently, flow chemistry has been employed to
accelerate the sigmatropic rearrangement.9
Because of its unimolecular reaction mechanism, we have
identified the Claisen rearrangement of allyl phenyl ether as an
ideal reaction platform to investigate several parameters with re-
spect to the Novel Process Windows concept. In this paper, we will
discuss the influence of high temperature, high pressure, high
concentration, and solvent effects on the Claisen rearrangement
and the JohnsoneClaisen rearrangement.
2. Results and discussion
One reaction class that can benefit significantly from Novel
Process Windows is the sigmatropic rearrangement. Such pericyclic
In order to study the influence of the different aspects of Novel
Process Windows on the outcome of the Claisen rearrangement of
allyl phenyl ether, a microfluidic system was assembled as depicted
in Figs. 1 and 2. Solutions of allyl phenyl ether were pumped into
the microreactor system by means of HPLC pumps. The capillary
* Corresponding authors. Tel.: þ31 40 247 2973; e-mail addresses: t.noel@tue.nl
€
(T. Noel), v.hessel@tue.nl (V. Hessel).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.038

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H. Kobayashi et al. / Tetrahedron 69 (2013) 2885e2890
Fig. 1. Schematic representation of the microfluidic setup for the Claisen rearrange-
ment of allyl phenyl ether to produce 2-allyl phenol.
Scheme 1. Influence of solvent and temperature on the Claisen rearrangement of allyl
phenyl ether. Reaction conditions: 0.1 M allyl phenyl ether in solvent, 100 bar, 4 min
residence time, benzonitrile as internal standard. The yield was determined via HPLC
analysis of the reaction mixture by comparison of the signal of the target product with
the signal of the internal standard.
In order to reach higher yields, further reaction optimization
was performed by varying the solvent system (Scheme 1). It is
known that Claisen rearrangements are very dependent on solvent
effects.11,12 We found that by conducting the reaction in polar sol-
vents, such as ethanol and 2-propanol, similar results were ob-
tained as compared to toluene. However, a significant increase in
yield was observed when 1-butanol was used as a solvent. There-
fore, further investigation toward the nature of polar protic sol-
vents was performed and is shown in Scheme 2. At 280 ꢀC, the best
results are obtained with primary alcohols with a longer carbon
chain, i.e., 1-butanol and 1-hexanol. Secondary alcohols, such as 2-
propanol and 2-butanol, are less efficient. The acceleration of the
Claisen rearrangement in polar protic solvents can be attributed to
their hydrogen-bonding capacity.13 However, in contrast with ob-
servations under conventional batch conditions, the best results are
in flow obtained with longer chain alcohols. Based on our experi-
mental data, we have been able to calculate the activation energies
for the Claisen rearrangement and this follows the same reaction
order as observed in batch: ethanol>1-butanolz1-hexanol.14
Fig. 2. Microfluidic setup used for sigmatropic rearrangements in continuous-flow: (1)
HPLC pumps, (2) heating bath with stainless steel capillary microreactor, (3) cooling
bath, (4) sample loop, (5) back pressure regulator (BPR), (6) collection.
microreactor has a volume of 1 mL (stainless steel, 500 mm inner
diameter, 5 m length) and was placed in a heating bath. After
exiting the capillary reactor, the reaction medium is cooled to 15 ꢀC
in a 400 mL cooling unit (stainless steel, 500 mm inner diameter, 2 m
length). The pressure in the microfluidic setup can be regulated by
means of a back pressure regulator (BPR). The BPR utilized in this
system can be varied in a range from 1 to 400 bar, thereby allowing
to study the effect of pressure on the sigmatropic rearrangement.
Although this BPR is very versatile for our purposes, it has a large
internal volume of approximately 6 mL. Therefore, after the cooling
unit, a sample loop is placed, which facilitates results gathering. In
this fashion, results can be collected very rapidly and directly after
the cooling unit. After the BPR, the product can be collected.
Our initial investigations focused on studying the temperature
effect on the Claisen rearrangement. The use of high temperatures
in sigmatropic rearrangement chemistry allows to reduce reaction
times significantly.10 However, such processing is rather difficult to
attain under conventional batch conditions. In contrast, the com-
bination of sealed microreactor technology and back pressure
regulators provides opportunities to heat reaction mixture far
above the boiling point of the solvent. Consequently, solvent se-
lection for high temperature Novel Process Windows is not re-
stricted anymore by the solvent’s boiling point. We started with
toluene as a solvent (concentration of allyl phenyl ether 0.1 M) and
a residence time of 4 min.9g From Scheme 1, we can see that tem-
perature has a very pronounced effect on the formation of the
Claisen product, i.e., 2-allyl phenol. Below 240 ꢀC, almost no
product formation is observed. However, at high temperatures the
Claisen rearrangement is much more efficient: 62% yield of 2-allyl
phenol is obtained at 280 ꢀC.
Scheme 2. Influence of polar protic solvents and temperature on the Claisen
rearrangement of allyl phenyl ether. Reaction conditions: 0.1 M allyl phenyl ether in
solvent, 100 bar, 4 min residence time, benzonitrile as internal standard. The yield was
determined via HPLC analysis of the reaction mixture by comparison of the signal of
the target product with the signal of the internal standard.

H. Kobayashi et al. / Tetrahedron 69 (2013) 2885e2890
2887
Therefore, we surmise that the observed trend in continuous-flow
experiments is due to a different thermal expansion of the sol-
vents.15 Such thermal expansions are often neglected in many flow
chemistry papers. However, as is evident from Scheme 3, large
deviations of the desired residence time (i.e., 4 min as calculated
from the nominal flow rate) are observed at high temperatures.16,17
In addition, it is found that ethanol is much more expanded at high
temperatures than 1-butanol and 1-hexanol, leading to signifi-
cantly shorter residence time than the desired residence time. This
finding can explain the observed trend in Schemes 1 and 2.
Scheme 4. Influence of the residence time on the Claisen rearrangement. Reaction
conditions: 0.1 M allyl phenyl ether in 1-butanol, 100 bar, 300 ꢀC, benzonitrile as in-
ternal standard. The yield was determined via HPLC analysis of the reaction mixture by
comparison of the signal of the target product with the signal of the internal standard.
solvent consumption is however crucial to reduce waste genera-
tion. To address this need, we investigated if the Claisen rear-
rangement of allyl phenyl ether is affected by the concentration of
the substrate. From Scheme 5, it is immediately clear that an in-
crease of the concentration does not influence the reaction per-
formance. However, the best solution to avoid any solvent issues is
simply to perform the reaction under solvent-free reaction condi-
tions. To realize this goal under continuous-flow microprocessing
conditions, both reagents and products need to be in a liquid state
to avoid clogging of the microchannels.19,20 These requirements are
met in the Claisen rearrangement of allyl phenyl ether; both the
substrate and the target product are an oil at room temperature. To
our delight, we observed that the Claisen rearrangement under
neat reaction conditions proceeded well and afforded even in-
creased yields when compared to diluted conditions (Scheme 5).
Scheme 3. Estimated residence time at elevated temperatures for 1-butanol,
1-hexanol, and ethanol.16,17
It is noteworthy that in all the experiments performed in this
study no by-product formation could be detected via NMR, GCeFID,
and HPLCeUV studies (Fig. 3). This was also evident by the good
match between the calculated HPLC conversion and yield. We hy-
pothesized that by-product formation is prevented by minimizing
the exposure time in the heated zone to what is kinetically needed
for the Claisen rearrangement itself. Extended reaction times at
such elevated temperatures would result in the formation of iso-
mers, e.g., by a double bond migration.
Fig. 3. A typical HPLC chromatogram of the crude reaction mixture after Claisen
rearrangement of allyl phenyl ether. Reaction conditions: 0.1 M allyl phenyl ether in
1-butanol, 100 bar, 300 ꢀC, 4 min residence time, benzonitrile as internal standard.
Since full conversion and quantitative yields were obtained
within 4 min residence time, we examined whether even shorter
residence times were feasible for the Claisen rearrangement of allyl
phenyl ether (Scheme 4). However, lowering the residence time to
2 min is not sufficient to obtain full conversion; 82% yield of 2-allyl
phenol was obtained.
Solvents play a key role in the development of many organic and
inorganic synthetic transformations. In the pharmaceutical and fine
chemical industry, solvent use constitute a share of 80e90% of the
total mass utilization.18 As we described above, solvent effects are
also very pronounced in the Claisen rearrangement. Reducing the
Scheme 5. Influence of reagent concentration on the Claisen rearrangement of allyl
phenyl ether. Reaction conditions: 1-butanol or solvent-free, 100 bar, 4 min residence
time, benzonitrile as internal standard. The yield was determined via HPLC analysis of
the reaction mixture by comparison of the signal of the target product with the signal
of the internal standard.

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H. Kobayashi et al. / Tetrahedron 69 (2013) 2885e2890
Another important physical parameter that can affect the re-
Encouraged by the results obtained in the Claisen rearrange-
ment of allyl phenyl ether, we next examined the JohnsoneClaisen
rearrangement in our microfluidic setup. This type of sigmatropic
rearrangements involves the heating of an allylic alcohol and an
excess of ethyl orthoacetate in the presence of an acid catalyst to
yield an olefinic ester.25 Our microfluidic setup was expanded with
one additional HPLC pump for the addition of ethyl orthoacetate
(Fig. 4).
action rate of the Claisen rearrangement is pressure.21,22 Typically,
transformations that are accompanied by a decrease in volume
(activation volume) are accelerated by an increase in pressure. It
has been shown in batch that the Claisen rearrangement can be
accelerated by elevated pressures since high pressure favors the
cyclic transition state.23 The ability to change the back pressure in
our microfluidic system prompted us to investigate the pressure
dependence of the Claisen rearrangement of allyl phenyl ether in
continuous-flow (Scheme 6). Hereto, we lowered the reaction
temperature to 260 ꢀC, which allows us to visualize potential var-
iations in yield more clearly than at full conversion. We observed
a significant increase in yield when we raised the pressure from
50 bar (53% yield) to 300 bar (68% yield). Although liquids are
generally considered as incompressible fluids, at the elevated
pressures and temperatures employed in this study this simplifi-
cation is not valid anymore (Scheme 7).24 We can conclude from
Scheme 7 that there exists a significant difference in residence time
of almost 30 s between the experiments performed at 50 bar and
300 bar. It is therefore difficult to attribute the increase in yield
exclusively to pressure effects and we must take into account that
part of the yield increase is due to prolonged reaction times.
Fig. 4. Schematic representation of the microfluidic setup for the JohnsoneClaisen
rearrangement of cinnamyl alcohol to afford ethyl 3-phenylpent-4-enoate.
We found rapidly that the best reaction conditions involved the
use of toluene as a solvent. In the absence of an acid catalyst, low
conversions were usually obtained even at higher reaction tem-
peratures. Optimal conversions were obtained within 4 min in the
presence of 1.2 equiv of triethyl orthoacetate and 20 mol % acetic
acid at high temperatures (Scheme 8). Full conversion was obtained
at 200 ꢀC.
Scheme 6. Influence of pressure on the Claisen rearrangement of allyl phenyl ether.
Reaction conditions: 0.1 M allyl phenyl ether in 1-butanol, 260 ꢀC, 4 min residence
time, benzonitrile as internal standard. The yield was determined via HPLC analysis of
the reaction mixture by comparison of the signal of the target product with the signal
of the internal standard.
Scheme 8. Influence of temperature on the JohnsoneClaisen rearrangement of cin-
namyl alcohol to afford ethyl 3-phenylpent-4-enoate. Reaction conditions: cinnamyl
alcohol (0.1 M), triethyl orthoacetate (0.12 M), acetic acid (0.02 M), toluene, 100 bar,
4 min residence time, 1,3-dimethoxybenzene as internal standard. The yield was de-
termined via HPLC analysis of the reaction mixture by comparison of the signal of the
target product with the signal of the internal standard.
3. Conclusions
We have developed
a high temperature, high pressure
continuous-flow microreactor setup for the investigation of several
aspects of the Novel Process Windows concept on the Claisen
rearrangement of allyl phenyl ether (See Table 1 for an overview).
Scheme 7. Estimated residence time at elevated pressures for 1-butanol.

H. Kobayashi et al. / Tetrahedron 69 (2013) 2885e2890
2889
Table 1
were performed on Varian 430-GC with an FID detector using
a Varian capillary column CP-Sil 5 CB (60 m, 0.25 mm, 1 m). HPLC
Overview of the investigated aspects of the Novel Process Windows concept in the
m
Claisen rearrangement of allyl phenyl ether5
analyzes were performed on Shimadzu UFLC XR (205 nm) using
a GraceSmart RP 18 5u column (150 mm, 4.2 mm). Benzonitrile was
used as an internal standard for determination of HPLC yield and
conversion in the Claisen rearrangement of allyl phenyl ether. 1,3-
Dimethoxybenzene was used as an internal standard for both GC
and HPLC measurement in the JohnsoneClaisen rearrangement to
determine the HPLC yield and conversion.
Novel Process
Windows
Results obtained in this study
Full conversion was achieved at 300 ꢀC
15% Yield increase by increasing pressure
- High concentrations are feasible
without efficiency loss
- Solvent-free conditions result in
full conversion at 280 ꢀC
High T processing
High p processing
Routes at much increased
concentration
4.3. Experimental setup
- Solvent effects: n-butanol optimal
for flow processing
The experimental setup used for the Claisen rearrangement is
shown in Fig. 1, while the one for the JohnsoneClaisen rearrange-
ment in flow is described in Fig. 4. Reaction solutions were fed by
two HPLC pumps (Knauer, Smartline 1050) and mixed by an SS T-
mixer (IDEX Health & Science, bore size 0.5 mm). The mixer is
connected to SS capillary tube reactor (ID 0.5 mm, OD 1/1600, 5 m),
which was submerged in a temperature controlled oil bath (Lauda,
Proline P8). The reactor is connected to the cooling section made by
SS capillary tube (ID 0.5 mm, OD 1/1600, 2 m), which was submerged
in a water bath (Lauda, ECO Silver RE620S) at 15 ꢀC. The cooling
section is connected to a 6 port valve (VICI) equipped with a sam-
pling loop. The reactor pressure is controlled by the back pressure
regulator (Bronkhorst, EL-PRESS).
Safety and hazardous
operations
High p and T processing can be done
in microflow without comprimising
safety of the environment
Full conversion can be obtained in
4 min under solvent free-conditions and
in the absence of a catalyst
Process simplification
We have found that elevated temperatures (up to 300 ꢀC) are
mandatory to achieve full conversion and quantitative yields
within 4 min residence time. In addition, interesting solvents ef-
fects were observed; with 1-butanol as the best solvent in micro-
flow processing. This observation was in contrast with batch
experiments. Explanation for this apparent mismatch is provided
by solvent expansion phenomena, which lead to large deviations of
the desired residence time (as calculated from the nominal flow
rate). Solvent-free reaction conditions were feasible for the Claisen
rearrangement of allyl phenyl ether; quantitative yields for 2-allyl
phenol were obtained at 280 ꢀC and 100 bar. The influence of re-
action pressure (up to 300 bar) was also investigated. An increase of
15% yield was observed at 260 ꢀC by increasing the pressure from
50 to 300 bar. Due to solvent compression at such elevated pres-
sures, we believe that this yield increase cannot be entirely at-
tributed to pressure effects. Finally, we also studied the
temperature influence on the JohnsoneClaisen rearrangement of
cinnamyl alcohol to afford ethyl 3-phenylpent-4-enoate. Optimal
reaction conditions involved the use of toluene as a solvent, acetic
acid as a catalyst, 200 ꢀC, 100 bar, and 4 min residence time.
4.4. Typical experimental procedure for Schemes 1, 2 and 4e6
A volumetric flask (100 mL) was charged with allyl phenyl ether
(1.34 g, 10.0 mmol), benzonitrile (206 mg, 2.0 mmol), and n-BuOH
was added to make the solution volume 100 mL. The solution was
introduced in the microfluidic experimental setup at 0.250 mL/min
(Space time: 4 min) by means of a single HPLC pump. The samples
were collected via the sample loop at 30 and 40 min after each
experiment to ensure steady state data collection. The samples
were analyzed with HPLCeUV for quantification via the internal
standard method. Each data point in the plot constitutes the aver-
age of two samples. Key experiments were performed at least twice
by two different persons to enhance the reproducibility of our
experiments.
4.5. Isolated yield of 2-allyl phenol
4. Experimental section
A volumetric flask (100 mL) was charged with allyl phenyl ether
(1.34 g, 10.0 mmol) and n-BuOH was added to make the solution
volume 100 mL. The solution was introduced in the microfluidic
experimental setup at 0.250 mL/min (Space time: 4 min) by means
of a single HPLC pump. The reaction temperature was set at 300 ꢀC,
the pressure at 100 bar. The whole experimental setup was flushed
for 90 min at the reaction condition in order to achieve steady state.
The difference with the above mentioned experiments is attributed
due to the large internal volume of the back pressure regulator.
After that, a sample was collected at the exit of the experimental
setup for exactly 100 min (2.50 mmol of product). Solvent was
evaporated in vacuo and pure product was obtained as a colorless
4.1. General reagent information
Allyl phenyl ether, cinnamyl alcohol, benzonitrile 1,3-dimetho-
xybenzene, 1-butanol, 1-hexanol, ethanol, isopropanol, toluene,
and diethyl ether were purchased from SigmaeAldrich chemical
company and used as received. Acetic acid and triethyl orthoacetate
were purchased from Fluka and used as received. Sodium hydrogen
carbonate was purchased from Merck and used as received. For the
flow experiment, solutions were prepared in volumetric flasks.
4.2. General analysis information
oil (0.319 g, 95% yield). 1H NMR (400 MHz, CDCl3)
d: 3.42 (d,
The isolated reaction product was characterized by GC/MS, 1H
NMR, 13C NMR, and IR spectroscopy. Mass spectra were measured
on a Shimadzu, GCMS-QP2010 Ultra. Nuclear Magnetic Resonance
spectra were recorded on a Varian 400 MHz instrument. All 1H NMR
J¼6.2 Hz, 2H), 5.00 (s, 1H), 5.14e5.18 (m, 2H), 5.98e6.08 (m, 1H),
6.81 (d, J¼7.6 Hz, 1H), 6.89 (t, J¼7.6 Hz, 1H), 7.11e7.16 (m, 2H) ppm.
13C NMR (100 MHz, CDCl3)
d: 35.1, 115.8, 116.5, 121.0, 125.3, 127.9,
130.5, 136.4, 154.1 ppm. IR (ATR, cmꢁ1): 3455, 1638, 1591, 1489,
1455, 1214, 1169, 996, 914, 749. EI-MS: 134 [Mþ].
are reported in d units, parts per million (ppm), and were measured
relative to the signal for tetramethylsilane (0 ppm) in the deuter-
ated chloroform. The following abbreviations were used to ex-
plain the multiplicities: s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet. IR spectra were taken on a PerkineElmer Spectrum
One equipped with a Universal ATR sampling accessory. GC analyzes
4.6. Typical experimental procedure for Scheme 8
A volumetric flask (50 mL) was charged with cinnamyl alcohol
(1.34 g, 10.0 mmol), acetic acid (0.12 g, 2.0 mmol), 1,3-

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H. Kobayashi et al. / Tetrahedron 69 (2013) 2885e2890
dimethoxybenzene (0.27 g, 2.0 mmol), and toluene was added to
make the solution volume 50 mL. A second volumetric flask (50 mL)
was charged with triethyl orthoacetate (1.95 g, 12.0 mmol) and tol-
uene was added to make the solution volume 50 mL. Both solutions
were flowed through the microfluidic experimental setup at
0.125 mL/min (Space time: 4 min) by means of two HPLC pumps. The
samples were collected via the sample loop at 30 and 40 min after
each experiment to ensure steady state data collection. The samples
were analyzed with HPLCeUV for quantification of cinnamyl alcohol
via the internal standard method. Another sample was collected and
extracted with 1 M aqueous NaHCO3; the organic phase was analyzed
by GCeFID for the quantification of reaction product. Each data point
in the plot constitutes the average of two samples. Key experiments
were performed at least twice by two different persons to enhance
the reproducibility of our experiments.
References and notes
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4.7. Isolated yield of ethyl 3-phenylpent-4-enoate
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Isolated yield was obtained at optimum reaction condition
(220 ꢀC, 100 bar). A volumetric flask (50 mL) was charged with
cinnamyl alcohol (1.35 g, 10.0 mmol), acetic acid (0.13 g, 2.2 mmol),
and toluene was added to make the solution volume 50 mL. A
second volumetric flask (50 mL) was charged with triethyl
orthoacetate (1.95 g, 12.0 mmol) and toluene was added to make
the solution volume 50 mL. Both solutions were fed at 0.125 mL/
min and whole experimental setup was flushed for 90 min at the
reaction condition in order to achieve steady state. The difference
with the above mentioned experiments is attributed due to the
large internal volume of the back pressure regulator. After that,
a sample was collected at the exit of the experimental setup for
exactly 100 min (2.50 mmol of product). The collected sample was
washed 1 M aqueous sodium hydrogen (25 mL) carbonate and the
aqueous layer was washed with same amount of diethyl ether
(25 mL) twice. The combined organic layers were dried by MgSO4.
After filtration of MgSO4, solvents were evaporated in vacuo and
pure product was obtained as a colorless oil (0.475 g, 93% yield). 1H
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NMR (400 MHz, CDCl3)
15.0 Hz,1H), 2.75 (dd, J¼8.2, 15.0 Hz,1H), 3.86 (q, J¼7.1 Hz, 1H), 4.07
(q, J¼7.1 Hz, 2H), 5.05 (s, 1H), 5.09 (s, 1H), 5.94e6.02 (m, 1H),
d
: 1.17 (t, J¼7.1 Hz, 3H), 2.68 (dd, J¼7.5,
7.20e7.32 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3)
d: 14.1, 40.3,
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given by Cibulka and Zikovh, see Ref. 17b. These equations are valid until 250 ꢀC
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for higher temperatures. The densities of ethanol were obtained from Ref. 17c.
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cmꢁ1): 2982, 1733, 1493, 1453, 1371, 1255, 1157, 1031, 918, 757. EI-
MS: 204 [Mþ].
Acknowledgements
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Funding by the Advanced European Research Council Grant
‘Novel Process Windows e Boosted Micro Process Technology’
under grant agreement number 267443 is kindly acknowledged.
H.K. and S.O. would like to thank the Graduate School of Engi-
neering, Tokyo Institute of Technology for financial support. T.N.
would like to acknowledge the support of the Netherlands Orga-
nization for Scientific Research (NWO) for a VENI grant. We would
like to thank Svetlana Borukhova for her help in the assembly of the
experimental setup and Bruno Cortese for advice in the kinetic
analysis of the experimental results.
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Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.02.038.