Subsupercritical Water Generated by Inductive Heating Inside Flow Reactors Facilitates the Claisen Rearrangement

Article abstract of DOI:10.1055/s-0040-1705945

Claisen rearrangement of electron-deficient O-allylated phenols, including fluorine-modified phenols, is facilitated in aqueous media at high temperatures and pressures under flow conditions, as opposed to organic solvents. The O-allylation of phenols can be coupled with the Claisen rearrangement in an integrated flow system.

Full text of DOI:10.1055/s-0040-1705945

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–E
cluster
A
Integrated Synthesis Using Continuous-
M. Oltmanns, A. Kirschning
Cluster
Synlett
Subsupercritical Water Generated by Inductive Heating Inside
Flow Reactors Facilitates the Claisen Rearrangement
Mona Oltmanns
Andreas Kirschning*
inductive heating
Br
OH
F
0
0
0
0
-
0
0
0
1
-
5
4
3
1
-
6
9
3
0
F
H2O
Na
O
F
Institut für Organische Chemie und Biomolekulares
Wirkstoffzentrum (BMWZ) der Leibniz Universität
Hannover, Schneiderberg 1B, 30167 Hannover,
Germany
F
110 °C
265 °C
64%
Published as part of the Cluster Integrated Synthesis Using
Continuous-Flow Technologies
Corresponding Author
AInnsdtirteuatsfüKrirOscrhganninisgche Chemie und Biomolekulares Wirkstoffzentrum (BMWZ) der Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany
Received: 14.08.2020
Accepted after revision: 16.09.2020
Published online: 27.10.2020
is particularly evident under supercritical or near supercrit-
ical conditions. When the temperature is increased, the rel-
ative static permittivity (polarity) decreases from about
80.1 at 20 °C to a value of 27.5 at 250 °C. This dielectric con-
stant is similar to the dielectric constant of acetonitrile or
methanol. Another property to be mentioned is the dissoci-
ation constant, which drops to a minimum of 11.2 at 250
°C, while the ion product increases with temperature. The
maximum value of the ion product is reached under almost
critical conditions. Consequently, protons and hydroxide
ions are present in higher concentrations, so that this as-
pect paves the way for the use of water as an in situ pro-
duced catalyst for acid- or base-driven reactions. In the near
critical range, there is a decrease of hydrogen bonds in wa-
ter, so that this leads to a decrease of the dielectric constant
to a better solubility or at the critical point even to a com-
plete miscibility of organic compounds with water. And
thus reactions can be accelerated.7,8
DOI: 10.1055/s-0040-1705945; Art ID: st-2020-u0450-c
Abstract Claisen rearrangement of electron-deficient O-allylated
phenols, including fluorine-modified phenols, is facilitated in aqueous
media at high temperatures and pressures under flow conditions, as op-
posed to organic solvents. The O-allylation of phenols can be coupled
with the Claisen rearrangement in an integrated flow system.
Key words Claisen rearrangement, flow chemistry, fluorobenzenes,
inductive heating, supercritical water
The aliphatic version of the Claisen [3,3]-sigmatropic re-
arrangement1 has aroused greater interest among synthetic
chemists than its aromatic counterpart,2 although the latter
version still poses considerable challenges. The first rear-
rangement step of an allyl aryl ether yields an ortho-substi-
tuted dienone, which then enolizes to an ortho-allyl phenol
(Scheme 1). The rearrangement can also take place at an or-
tho position, which carries a substituent, followed by a sec-
ond [3,3]-sigmatropic rearrangement. This Cope rearrange-
ment is sometimes called para-Claisen rearrangement and
yields the corresponding p-allyl phenol.2b
In recent years, we have added inductive heating9 to the
existing portfolio of enabling technologies in organic chem-
istry10 and have shown that it can be ideally combined with
fluid dynamics to create high-temperature and high-pres-
sure conditions.11 First studies on sigmatropic rearrange-
ments under flow conditions in organic solvents at 240 °C
were described by us.12 We also demonstrated that water
can be heated to near supercritical conditions under fluid
dynamics conditions, for example, as a solvent in the con-
tinuous synthesis of the atypical antipsychotic drug iloperi-
done.13 Here we report on Claisen rearrangements with fluo-
rinated allyl phenyl ethers that are not known to succeed
under classical conditions. An earlier publication by Noel
and Hessel already reported on a two-step process for the
preparation of 2-allylphenol using bases such as DBU/Am-
berlyst A21, K2CO3, and Amberlyst A26 and this was tele-
scoped with a Claisen rearrangement carried out at 300 °C.
However, these studies were based on the use of solvents
such as butanol and toluene or were conducted under sol-
vent-free conditions.14,15
OH
O
O
R1
R1
R1
R2
[3,3]
R2
R2
allyl arylether
dienone
o-allylphenol
Scheme 1 The Claisen rearrangement of allyl arylether
It is postulated that the reaction is of polar nature and
therefore can be influenced in polar millieus.3 This is sup-
ported by the fact that the speed of allyl p-tolylether rear-
rangement increases when the polarity of the solvent is in-
creased.4,5 In recent years water has emerged as a nonclassi-
cal solvent for organic reactions and has been studied in
detail. It is inexpensive and environmentally friendly and
shows unusual properties for influencing reactivities.6 This
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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Oltmanns, A. Kirschning
Cluster
Synlett
First, a series of allyl phenyl ethers 9–16 was prepared
from the corresponding phenols 1–8 under standard condi-
tions (Scheme 2). The substituents R1 and R2 were selected
to cover the spectrum from electron withdrawing (2–7) to
neutral (1) to electron releasing (8).
crofluidic devices is already increased, the reaction rates in
water are still not sufficient under conventional conditions.
Under high-temperature/high-pressure conditions, howev-
er, the solvent system can be brought to a point close to
critical conditions. As a result, the phase boundary almost
completely disappears. In addition, the solubility of organic
compounds in the aqueous phase expands, which leads to a
dramatic increase in the reaction rate.14
Br
O
, MeCN,
OH
R1
R1
K2CO3, Δ, 2 d
R2
1, 9: R1 = R2 = H (90% for 9)
R2
2, 10: R1 = Cl, R2 = H (99% for 10)
9–16
1–8
3, 11: R1 = COCH3, R2 = H (85% for 12)
4, 12: R1 = COOCH3, R2 = H (quant. for 13)
5, 13: R1 = F, R2 = H (96% for 13)
6, 14: R1 = H, R2 = F (95% for 14)
7, 15: R1 = R2 = F (90% for 15)
8, 16: R1 = OCH3, R2 = H (92% for 16)
Scheme 2 Synthesis of aromatic allyl phenyl ether derivatives 9–16
The resulting allyl phenyl ethers were next subjected to
high-temperature and high-pressure conditions in a flow-
through system, and the results were compared with the
corresponding Claisen rearrangements under batch condi-
tions. Microwave irradiation was used to achieve high tem-
peratures and high pressures in batch operations, and the
reactions were carried out in a mixture of water/toluene
(2:1) in a sealed vial at up to 200 °C for a period of four
hours (Scheme 3).
Figure 1 Laboratory setup of the flow system
The 1/8′′ steel reactors (coiled, V = 2.4 or 3.2 mL) were
heated by embedding it in the homogeneous electromag-
netic field induced by a coil-shaped electromagnetic induc-
tor. This was operated under high-frequency conditions
(IH-HF 290–320 kHz). The external reactor temperature
was determined with an IR pyrometer. In order to ensure
high pressures inside the flow system, back-pressure regu-
lators are arranged at the outlet of the flow reactor. The allyl
phenyl ethers were fed into the flow system via a sample
loop, and the entire system was operated with a piston
pump. After a short warm-up phase, the temperature inside
the flow system was only affected by the temperature of
the solvent entering the reactor, resulting in a small tem-
perature drop of only 5–10°C at the reactor inlet.13
It was necessary to optimize the flow conditions for all
examples listed in Table 1 and especially for the execution
of Claisen rearrangements in water. For example, for allylat-
ed phenol 9 we found a reactor temperature of 280 °C and a
residence time of 8 min to be ideal, for the chlorine deriva-
tive 10 this was 315 °C and a residence time of 3 min. In
both cases the isolated yields of products 17 and 18 were
90% in water. We found that in two cases (for 12 and 16) the
optimization had to include the avoidance of byproduct for-
mation, especially with respect to para-Claisen products,
but also in the case of allyl phenyl ethers 11 ester hydrolysis
followed by decarboxylation. Under the optimized condi-
tions, the formation of these byproducts was almost com-
pletely suppressed. Fluorinated allyl phenyl ethers 13–15
could also be converted quickly and easily into the Claisen
products in water as solvent.
OH
O
µw (280 W), H2O/toluene (2:1),
R1
R1
200 °C, 9.7–14.6 bar, 4 h
R2
17–24
R2
9, 17: R1 = R2 = H (10% for 17)
10, 18: R1 = Cl, R2 = H 42% for 18)a
9–16
11, 19: R1 = COCH3, R2 = H (37% for 19)
12, 20: R1 = COOCH3, R2 = H (35% for 20)
13, 21: R1 = F, R2 = H (26% for 21)
14, 22: R1 = H, R2 = F (21% for 22)
15, 23: R1 = R2 = F (37% for 23)
16, 24: R1 = OCH3, R2 = H (54%, for 24)
Scheme 3 Claisen rearrangement of aromatic allyl phenyl ether deriv-
atives 9–16 under batch conditions using microwave radiation as heat-
ing concept; isolated yields are given. a Determined by NMR
spectroscopy, because 18 could not be separated from 10.
After one, two and four hours, samples were collected
and analyzed by GC–MS. It is remarkable that two hours of
reaction time were not sufficient to achieve a significant
turnover. Thus, allyl phenyl ether 9–16 provided the ortho-
Claisen products 17–24 in only modest yields. Surprisingly,
the conversion with the simplest representative (ally-
loxy)benzene7 resulted in only 10% of the converted prod-
uct 17. The next step was to adapt our findings to a tailor-
made flow system, that is shown in Figure 1 and in Table 1.
Here the question of solubility is relevant when organic re-
actions are carried out in an aqueous medium since flow
channels tend to clog. Although the phase boundary in mi-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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M. Oltmanns, A. Kirschning
Cluster
Synlett
Table 1 Claisen Rearrangement under Flow Conditions in Water and
aqueous solution containing the sodium phenolate (their
preparation is described in the Supporting Information).
Both streams are combined in a T-piece immediately before
the inductively heated steel reactor. Due to the low boiling
point of allyl bromide, the reaction was carried out under
pressure (110–160 bar). The addition of a base to the sodi-
um phenolates resulted in improved yields for the O-allylat-
ed phenols, whereby we chose sodium carbonate and sodi-
um hydroxide, respectively. The latter usually showed bet-
ter results. The optimal conditions for the five examples
regarding base, flow rates, temperature, and pressure are
shown in Scheme 4.
Dry Toluenea
O
R1
R2
9–16
1
st case: bidistilled H2O/toluene (2:1)
2nd case: dry toluene
OH
IH-HF
R1
bpr
steel coil reactor
sample
loop
bpr
pump
R2
V = 3.2 mL or
2.4 mL
17–24
H2O
or dry toluene
pump 1
Br
1 M in
Derivative
R1
In water
In dry toluene
(2nd case)
0.3 mL/min
benzene
(1st case)
flow rate
1/8" steel reactor
(coiled, V = 3.4 mL)
Entryb
R2
Yield ether Yield
(%)
Yield ether Yield Claisen
O
Claisen (%) (%)
(%)c
Na
O
IH-HF
pump 2
R1
R
reactor
9 → 17
H
H
H
H
H
H
F
–
–
–
–
–
–
–
–
90
90
92
92
78
89
89
71
8
83
73
70
62
68
67
24
85
static
mixer
bpr
0.3 mL/min
flow ratea
R2
10 → 18 Cl
–
R1
9, 10, 13, 15
0.1 M in H2O
11 → 19 COCH3
12 → 20 COOCH3
–
sodium salts of
1, 2, 5 and 7
reactor temp. & pressure
A
B
27
19
26
55
–
9
(R = H, R1 = H) 61%
–
71%
–
87%
–
91%
–
120 °C, 133/133 bar
113 °C, 131/130 bar
120 °C, 119/118 bar
13 → 21
14 → 22
15 → 23
F
–
10 (R = Cl, R1 = H) 84%
H
F
–
110 °C, 119/118 bar
130 °C, 148/145 bar
130 °C, 160/156 bar
130 °C, 147/147 bar
110 °C, 124/121 bar
F
13 (R = F, R1 = H) 70%
–
16 → 24 OCH3
H
15 (R = F, R1 = F) 86%
a IH-HF = inductive-heating/high-frequency inductor (300–315 kHz); bpr =
back-pressure regulator.
–
85%
b Details on conditions (temperature and flow rate): 9 → 17: 280 °C, 0.4
mL/min; 10 → 18: 315 °C, 0.8 mL/min; 11 → 19: 305 °C, 0.9 mL/min; 12 →
20: 265 °C, 0.3 mL/min; 13 → 21: 270 °C, 0.5 mL/min; 14 → 22: 273 °C, 0.5
mL/min; 15 → 23: 245 °C, 1.3 mL/min; 16 → 24: 265 °C, 0.3 mL/min.
c Isolated yields are reported (for further details and workup, see the Sup-
porting Information).
Scheme 4 O-Allylation of phenols under flow conditions. Method A:
phenolates are supplemented with 0.1 M sodium carbonate; method B:
phenolates supplemented with 0.1 M sodium hydroxide were pumped
at a flow rate of 0.3 mL/min while the allyl bromide was pumped at a
flow rate of 0.3 mL/min).
Finally, we turned our focus on the development of a
flow system that combines the O-allylation step with the
Claisen rearrangement. The correct choice of base was cru-
cial, and it should be noted that an excess of allyl bromide
(it decomposes to hydrogen bromide under pyrolytic condi-
tions) proved to be problematic.15 To achieve the best re-
sults, the addition of a hydrochloric acid solution was es-
sential, followed by continuous liquid–liquid extraction to
remove the base DBU, and several fixed bed reactors filled
with Amberlyst 21 to bind the excess hydrochloric acid
were other processes to be included. A two-stage process in
water as developed here would avoid these obstacles.
As both individual steps are optimized as continuous
processes, these could be telescoped as exemplified for the
difluorophenol 7. The first stage was performed in a coil re-
actor (V = 3.4 mL) at 110 °C. Sodium phenolate 7 and a 1 M
allyl bromide solution were combined via a static mixer and
then inductively heated in the first steel reactor. The Claisen
rearrangement was then carried out in a second reactor (V
= 3.2 mL), which was inductively heated to 265 °C, and 2-
In Table 1, Claisen rearrangements in water are directly
compared with the corresponding transformations per-
formed in dry toluene. In most cases the reactions in tolu-
ene were not complete, and the isolated yields of the rear-
rangement products 17–23 were lower than those obtained
in water as a solvent. Only the electron-rich allyl phenyl
ether 16 gave better yields of the rearrangement product 24
in toluene compared to water as solvent. These results re-
veal a promoting effect of water for Claisen rearrangements
of allyl phenyl ethers particularly those with electron defi-
ciency.
Next, we investigated the realization of the first step,
the O-allylation. Due to the very good mass transfer of flow
systems, these are suitable for phase-transfer reactions
such as the allylation of sodium phenolates with allyl bro-
mide without the addition of a phase-transfer catalyst. For
the O-allylation we designed a flow system consisting of
two HPLC pumps. One pump transports allyl bromide in
benzene, while the second pump is responsible for the
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
M. Oltmanns, A. Kirschning
Cluster
Synlett
allyl-4,6-difluorophenol (23) was obtained in 64% isolated
yield (Scheme 5).Our studies demonstrate the positive ef-
fect of water under almost supercritical conditions on the
aromatic Claisen rearrangement. Theoretical calculations
have already been made on this topic.16 These showed that
the hydrogen bond between the oxygen atom of the dis-
solved starting compound and two water molecules is more
pronounced in the transition state. Consequently, the pres-
ence of water leads to looser, more dissociative, and more
polarized transition states. The prerequisite for this would
be the formation of a zwitterionic transition state.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1705945. Included are experimental
procedures, spectral data and copies of 1H and 13C NMR spectra of all
new compounds and intermediates. Su
p
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orti
n
gInformatio
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ortingInformatio
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References and Notes
(1) Claisen, L. Ber. Dtsch. Chem. Ges. 1912, 45, 3157.
(2) (a) Bennett, G. B. Synthesis 1977, 589. (b) Ziegler, F. E. Acc. Chem.
Res. 1977, 10, 227. (c) Bartlett, P. A. Tetrahedron 1980, 36, 2.
(d) Ryan, J. P.; O’Connor, P. R. J. Am. Chem. Soc. 1952, 74, 5866.
(3) Reviews: (a) Martín Castro, A. M. Chem. Rev. 2004, 104, 2939.
(b) The Claisen Rearrangement: Methods and Applications;
Hiersemann, M.; Nubbemeyer, U., Ed.; Wiley-VCH: Weinheim,
2007.
Br
1 M/C6H6
0.3 mL/min
(4) Kincaid, J. F.; Tarbell, D. S. J. Am. Chem. Soc. 1939, 61, 3085.
(5) (a) Hurd, C. D.; Pollack, M. A. J. Org. Chem. 1939, 3, 550.
(b) Goering, H. L.; Jacobson, R. R. J. Am. Chem. Soc. 1958, 80,
3277. (c) White, W. N.; Gwynn, D.; Schlitt, R.; Girard, C.; Fife, W.
J. Am Chem. Soc. 1958, 80, 3271.
OH
IH-HF
IH-HF
F
bpr
static
mixer
3.4 mL reactor
3.2 mL reactor
110 °C
265 °C
F
23 (64%)
(6) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68.
(7) Savage, P. E. Chem. Rev. 1999, 99, 603.
(8) (a) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew. Chem. Int. Ed. 2005, 44, 3275. (b) Vogel,
H.; Krammer, P. J. Supercrit. Fluids 2000, 16, 189.
0.3 mL/min
Na
O
F
F
(9) Kirschning, A.; Kupracz, L.; Hartwig, J. Chem. Lett. 2012, 41, 562.
(10) Kirschning, A.; Solodenko, W.; Mennecke, K. Chem. Eur. J. 2006,
12, 5972.
7 (Na salt)
0.098 M/H2O
(11) Wang, W.; Tuci, G.; Duong-Viet, C.; Liu, Y.; Rossin, A.; Luconi, L.;
Nhut, J.-M.; Nguyen-Dinh, L.; Pham-Huu, C.; Giambastiani, G.
ACS Catal. 2019, 9, 7921.
Scheme 5 Telescoped flow protocol of O-allylation and Claisen rear-
rangement for the continuous synthesis of difluorophenol 23
(12) (a) Ceylan, S.; Friese, C.; Lammel, C.; Mazac, K.; Kirschning, A.
Angew. Chem. Int. Ed. 2008, 47, 8950; Angew. Chem.; 2008, 120,
9083. (b) Ceylan, S.; Coutable, L.; Wegner, J.; Kirschning, A.
Chem. Eur. J. 2011, 17, 1884.
(13) Hartwig, J.; Kirschning, A. Chem. Eur. J. 2016, 22, 3044.
(14) (a) Chemical Synthesis Using Supercritical Fluids; Jessop, P. G.;
Leitner, W., Ed.; Wiley-VCH: Weinheim, 1999. (b) Kruse, A.;
Dinjus, E. J. Supercrit. Fluids 2007, 39, 362. (c) Marre, S.; Roig, Y.;
Aymonier, C. J. Supercrit. Fluids 2012, 66, 251.
(15) (a) Noel, T.; Hessel, V.; Shahbazali, E.; Spapens, M.; Kobayashi,
H.; Ookawara, S. Chem. Eng. J. 2015, 281, 144. (b) Noel, T.;
Hessel, V.; Kobayashi, H.; Driessen, B.; van Osch, D. J. G. P.; Talla,
A.; Ookawara, S. Tetrahedron 2013, 69, 2885.
(16) Hammes-Schiffer, S.; Hu, H.; Kobrak, M. N.; Xu, C. J. Phys. Chem.
A 2000, 104, 8058.
(17) White, W. N.; Wolfarth, E. F. J. Org. Chem. 1970, 35, 3585.
(18) Two-Step Flow Synthesis of 2-Allyl-4,6-difluorophenol (23)
An allyl bromide solution in benzene (1 M) was combined with
a 0.1 M aqueous sodium phenolate solution (7, sodium salt) via
a static mixer. An additional 0.5 mol/L of sodium hydroxide was
added to the aqueous sodium phenolate solution. Both reagents
were pumped at a flow rate of 0.3 mL/min through a 1/8′′ steel
reactor (coiled, V = 3.4 mL). The reactor was heated to 110 °C in
an oscillating electromagnetic high-frequency field. The reac-
tion mixture was then passed through a second reactor (3.2
mL), which was heated to a temperature of 265 °C at a pressure
of 183–184 bar. The reaction mixture was collected over a
period of 25 min and extracted with diethyl ether (3 × 10 mL).
The combined organic phases were dried over magnesium sul-
It also becomes clear that the rate constant depends on
the nature of the substituent. White et al. reported that
when the para position bears an electron-donating me-
thoxy group and not an electron-withdrawing nitro group,
the rate constant (for EtOH/H2O) increases by a factor of 6.8.
Thus, not only the use of a polar solvent but also electron-
donating groups lead to an increase in the reaction rate.17
In conclusion, the Claisen rearrangement is another ex-
ample of how water can be used advantageously as a sol-
vent in organic reactions under near supercritical condi-
tions.18 Flow arrangements with high-speed heating tech-
nology based on electromagnetic induction provide the
ideal environment for achieving rapid Claisen rearrange-
ments of allyl phenyl ethers, including previously unknown
examples. Since fluid mechanics is a fundamental technolo-
gy for modern organic synthesis, this work should open
new avenues for applications in the pharmaceutical and
perfume industries.
Funding Information
This work was supported in part by the Symrise AG, Holzminden, Ger-
many.()
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

E
M. Oltmanns, A. Kirschning
Cluster
Synlett
fate, filtered, and concentrated under reduced pressure and co-
evaporated with methanol. The residue obtained was purified
by flash chromatography (pentane to pentane/diethyl ether
10%).
CDCl3, CDCl3 = 77.16 ppm):  = 156.5–154.8 (q, dd, J = 240.6 Hz,
11.5 Hz, C-6), 151.4–149.7 (q, dd, J = 238.7 Hz, 12.7 Hz, C-8),
138.0–137.9 (q, dd, J = 14.0 Hz, 3.5 Hz, C-9), 135.3 (t, C-2),
129.6–129.5 (q, dd, J = 8.3 Hz, 2.6 Hz, C-4), 116.9 (s, C-1), 112.0–
111.8 (t, dd, J = 22.6 Hz, 3.4 Hz, C-5), 102.0–101.7 (t, dd, J = 27.2
Hz, 23.0 Hz, C-7), 34.0–33.9 (s, dd, J = 3.1 Hz, 1.4 Hz C-3). HRMS
(EI): m/z calcd for C9H8OF2: 170.0543; found: 170.0543; Rf =
0.24 (pentane/Et2O = 9:1).
2-Allyl-4,6-difluorophenol (24)
Yellow oil (80.2 mg, 0.47 mmol; 64%). 1H NMR (600 MHz, CDCl3,
CHCl3 = 7.26 ppm):  = 6.75–6.71 (1 H, m, H-7), 6.68–6.66 (1 H,
m, H-5), 5.98–5.92 (1 H, m, H-2), 5.14–5.10 (2 H, m, H-1), 4.99
(1 H, br s, OH), 3.41–3.40 (2H, m, H-3). 13C NMR (150 MHz,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E