Flow Synthesis in Hot Water: Synthesis of the Atypical Antipsychotic Iloperidone

Article abstract of DOI:10.1002/chem.201504409

Inductively heated steel reactors continuously perform organic transformations in water under high temperature conditions, utilizing the unique physiochemical properties of water at subcritical conditions. We demonstrated the power of this set-up in the continuous synthesis of the atypical antipsychotic drug iloperidone, in which we performed four out of five steps under aqueous conditions.

Full text of DOI:10.1002/chem.201504409

DOI: 10.1002/chem.201504409
Full Paper
&
Industrial Chemistry
Flow Synthesis in Hot Water: Synthesis of the Atypical
Antipsychotic Iloperidone
Jan Hartwig and Andreas Kirschning*[a]
Abstract: Inductively heated steel reactors continuously per-
form organic transformations in water under high tempera-
ture conditions, utilizing the unique physiochemical proper-
ties of water at subcritical conditions. We demonstrated the
power of this set-up in the continuous synthesis of the atyp-
ical antipsychotic drug iloperidone, in which we performed
four out of five steps under aqueous conditions.
Introduction
Synthesis under supercritical or subcritical conditions is
highly attractive with water as the solvent of choice. From an
industrial perspective, the cost issues and the safety and envi-
ronmental concerns make water an interesting alternative to
traditional organic solvents.[8] In selected cases, the solvent
water provides unique reactivity properties for organic com-
pounds or promotes accelerated reaction rates.[9] When water
is used under superheated conditions (>1008C) its properties
change drastically. The dielectric constant (e’) drops from 78.5
at 258C to 27.5 at 2508C, and therefore it shows a similar solu-
bility for organics as do acetonitrile or methanol. Furthermore,
the ion product increases with temperature. The dissociation
constant of (pKw) decreases from 14 at 258C to a minimum of
11.2 at 2508C. Above that temperature the pKw increases
again.[8] Consequently, the solvent can act simultaneously as an
acid and a base, without the need for neutralization or catalyst
regeneration when terminating the reaction.[10] Solubility prob-
lems can be overcome by organic co-solvents forming aque-
ous suspensions that dissolve starting materials as well as
products, and such mixtures can ideally be handled in micro-
fluidic reactors. Principally, the phase boundary is already en-
larged in mircofluidic devices but reaction rates are still not
sufficient in water under conventional conditions. Under high
temperature/high pressure conditions the solvent system can
be brought to a point close to critical conditions, removing
almost completely the phase boundary and at the same time
raising the solubility of organic compounds in the aqueous
phase leading to hugely increased reaction rates.[6,11] In this
context, pioneering work on the utilization of subcritical water
in organic synthesis was published by the groups of Ikushima
and Polikaoff.[10,12]
High temperature/high pressure reactions have recently at-
tracted increased interest because the emergence of new ena-
bling technologies for organic synthesis allow us to create
technical devices and chemical environments that facilitate this
type of chemistry.[1] Traditionally, flash vacuum pyrolysis (FVP)
has been used, in which precursor molecules are exposed
under gas-phase conditions to short thermal shocks at high
temperatures.[2] In contrast, flow reactors are an ideal tool for
performing high temperature/high pressure transformations in
solution phase, provided that pressure resistant reactors are
utilized that can rapidly be heated to temperatures around
and well above 2008C.[3] It was shown by us[4] and others[5]
that the scope of synthetic applications is much broader for
such continuous set-ups than for those of FVP. Indeed, under
such conditions, fluids including aqueous solutions as well as
reaction mixtures become near- or supercritical.[6]
In previous years we introduced inductive heating to organic
synthesis and disclosed that this technique can ideally be com-
bined with continuous flow processes.[4,7] During inductive
heating, an externally located medium (15–100 MHz) or high
frequency (100–800 MHz) electromagnetic field induces heat in
conductive materials or alternatively in superparamagnetic
nanostructured particles. The latter usually serve as a fixed bed
material in flow devices, whereas copper or steel reactors can
directly be heated under these conditions. This fast heating
technique broadens the scope of synthetic high temperature
applications because residence times in flow devices and thus
the time of exposure under high temperature conditions can
be controlled by means of the flow rate.
In this report, we disclose the first applications of aqueous
suspensions conducted in an inductively heated high-tempera-
ture and high-pressure flow environment. We also disclose an
improved way to measure and control the temperature inside
the reactor in the presence of an external oscillating electro-
magnetic field. Finally, we demonstrate that this set-up is well
suited for the synthesis of the commercially used atypical anti-
psychotic drug iloperidone.
[a] J. Hartwig, Prof. Dr. A. Kirschning
Institut für Organische Chemie, und Biomolekulares Wirkstoffzentrum
(BMWZ), Leibniz Universität Hannover, Schneiderberg 1B
30167 Hannover (Germany)
E-mail: andreas.kirschning@oci.uni-hannover.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504409.
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higher power inputs needed to heat water up to 3008C. Still,
this is achieved within 20 seconds and with a relative inductor
power input of only 30% (300% PWM=pulse width modula-
tion).
Results and Discussion
Reactor design
So far, we had encountered difficulties to reliably and accurate-
ly determine and control the temperature inside the reactor in
the presence of an external electromagnet field. A permanent-
ly installed IR-pyrometer has been one option. Alternatively,
we now show that direct temperature measurements inside
the reactor can be realized for inductively heated reactors
under medium frequencies conditions using a thermocouple
(K-element) connected to a T-joint located inside a 1/4“ flow
reactor (Figure 1). Gratifyingly, the error of these measurements
compared to self-heating of the thermocouple inside the oscil-
lating magnetic field was below 1% (for details see the Sup-
porting Information).
Next, the AC-generator was equipped with a computer-con-
trolled on/off-switch to control the temperature, either by the
signal transmitted from the thermocouple being located in the
solvent stream in the last quarter segment of the reactor or
the signal transmitted from the IR-pyrometer, which measures
the temperature on the reactor surface. In Figure 3 the heating
profiles for temperatures preset at 100, 150, 200, and 2508C,
respectively, at 50% maximum energy input are listed. Water
was pumped through the reactor at
a flow rate of
1.0 mLminÀ1 and the heating was controlled either by the
thermocouple or by the IR-pyrometer. Remarkably, the desired
temperature was reached within 30 s in all cases. Thermocon-
trol with the thermocouple revealed some overheating of the
reactor surface, for which the larger heat capacity of water
compared with steel is responsible. In contrast, when we per-
formed the thermocontrol with the IR-pyrometer, the set tem-
perature of the stream is reached after prolonged time, be-
cause overheating does not occur.
Heating profiles of water in a Steel 316 reactor (1/4“, length
of 14 cm, 1.5 mL volume) at different flow rates (1.0, 2.0, and
5.0 mLminÀ1) at 4.5 MPa were conducted for different energy
inputs of the external inductor. Noteworthy, the limiting factor
for heating beyond 2708C is the boiling point of water at
4.5 MPa, a pressure that is determined by the choice of the
backpressure regulator (Figure 2).
If a 1/8“ steel reactor is heated under high frequency condi-
tions, it became necessary to coil up the tube to reach ade-
quate reactor volumes being exposed to the inductor. The
void volume of this reactor was 1.2 mL (60 cm
length) and the heating profile at a flow rate of
1.0 mLminÀ1 at 100, 150, 200, and 2508C set temper-
ature was determined (Figure 4, top graph). Again,
the IR-pyrometer was linked to the computer-con-
trolled AC generator. For reaching 100 or 1508C, re-
spectively, 30% of the maximum power input was
applied and for reaching 200 or 2508C, respectively,
50% of the maximum power input was applied. In all
cases, the set temperature was reached within 20
seconds. The heating profile of water at a flow rate
of 0.5, 1.0, 2.0, 3.0, and 5.0 mLminÀ1 at different tem-
peratures (RT to 2008C) revealed that the flow rate
has only a minimal effect on the heating rate under
high frequency conditions (Figure 4, bottom graph).
To evaluate the effect of these harsh conditions on
the reactor material, we opened the reactors after
these test runs and then cut in half. Although the re-
actor surface had changed colour due to slight oxida-
tion, no substantial corrosion was observed even
after 36 h of operation time.
The difference of heating profiles at 1.0 and 2.0 mLminÀ1 is
marginal. Only at high flow rates of around 5.0 mLminÀ1 are
Organic synthesis under high pressure/high tem-
perature conditions
With a reliable computer-assisted temperature con-
trol in hand, we tested selected organic transforma-
tions under high temperature aqueous conditions
under flow conditions. The Brçnstedt- or Lewis acid-
promoted trimerization of 4-methoxy-3-butene-2-one
Figure 1. Set-up for inductive heating under continuous flow conditions in an aqueous
suspension under high temperature/high pressure conditions (top) and K-element for
temperature measurements inside flow reactors (bottom).
1 in water is known to yield triacetyl benzene 2 at
around 1508C.[13] We found that this reaction also
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Figure 3. Temperature profile over time for differently preset temperatures;
temperatures determined by thermocouple (top) and by IR-pyrometer
(bottom) [1/4“ steel reactor at 15.0 kHz, 100, 150, 200, 2508C temperature
set].
Figure 2. Temperature versus power input for a 1/4“ steel reactor at
15.0 kHz; the temperature was measured at the outlet of the reactor using
the K-element (top); 1/4” steel reactor encased in middle frequency inductor
(bottom left); 1/8“ coil reactor encased in high frequency inductor (bottom
right).
smoothly proceeds in an aqueous suspension with toluene in
the absence of any acid under high temperature conditions.[14]
Triacetyl benzene 2 was isolated in 89% yield at 2408C in less
than 2 min residence time and in the absence of a phase-trans-
fer catalyst. Noteworthy, most byproducts remain in the aque-
ous phase, and a simple extraction was sufficient to collect the
pure product (Scheme 1).
Scheme 1. Continuous preparation of triacetyl benzene 2 in water under
near supercritical conditions (1/H2O=1:10, toluene was added to the reac-
tion mixture at the outlet of the reactor to dissolve the product; threefold
with respect to H2O; the pumps were operated with pure water).
Ketone 1 was also employed in a multicomponent reaction
with benzaldeyhdes and benzyl amines to yield dihydropyri-
dines.[15] The use of a Lewis acid such as scandium triflate was
necessary and reaction times were reported to vary between 2
to 20 days, providing the product in 13–86% yield. We found
that under aqueous high temperature conditions, dihydropyri-
dine 5 can be prepared under flow conditions from ketone 1,
benzaldehyde 3, and benzylamine 4 in the absence of a Lewis
acid.
At temperatures above 2008C, substantial polymerization
and formation of a polar byproduct was observed. However,
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yields after long reaction times. In previous work we demon-
strated that inductive heating at high frequencies significantly
accelerates the formation of phenol 8 (91%, 4 min residence
time).[4b] We found that this type of rearrangement also pro-
ceeds well in high temperature aqueous media under flow
conditions to yield phenol 7 isolated in 86% yield (Scheme 3).
Remarkably, the residence time was about 3 min.
Scheme 3. Claisen rearrangement of 6 in aqueous medium (toluene/
H2O=1:5; pumps were operated with pure water; inner reactor diame-
ter=1/16“, 60 cm length).
In essence we encountered no major influence of the pres-
sure (2.0 to 8.0 MPa) on the yields of these three reactions. The
pressure only needs to be high enough to prevent evaporation
of the solvent within the reactor.
Having established the principles of continuous synthesis in
water at high temperature conditions using water as solvent,
we extended our studies to the synthesis of a pharmaceutically
relevant goal. Iloperidone 9 is an atypical antipsychotic that is
used for the treatment of schizophrenia. It was commercialized
in 2009 under the name Fanaptꢁ (Figure 5).
Figure 4. Temperature over time for different preset temperatures (1/8“ steel
reactor at 300.0 kHz and preset temperatures at 100, 150, 200 and 2508C)
and flow rates (0.5, 1.0, 2.0, 3.0 and 5.0 mLminÀ1); determined with an IR-py-
rometer.
the reaction proceeded smoothly at 1808C with full conver-
sion, and we isolated dihydropyridine
5 in 81% yield
(Scheme 2). Remarkably, the residence time was well below
eight minutes.
Thirdly, we investigated the electronically disfavored Claisen
rearrangement of allyl ether 6, which proceeds in very low
Figure 5. Synthetic plan towards iloperidone 9.
The multistep flow synthesis is based on two aro-
matic building blocks 10 and 12 that are connected
with 3-bromo-1-chloropropane 11. The first step, the
Fries rearrangement of aryl acetate 10 is the only re-
action that could not work in water but dichlorome-
thane was the solvent of choice. The rearrangement
was conducted in the presence of methane sulfonic
acid (3.2 equiv) in a flow reactor made of polyether
ether ketone (PEEK) (Scheme 4). The choice of reactor
material hampered its operation above a pressure of
Scheme 2. Synthesis of dihydropyridine 5 in an aqueous suspension (toluene/H2O=4:3;
pumps were operated with pure water).
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soxazole 15 in 72% yield, again at a flow rate of 0.2 mLminÀ1
(7.5 min residence time).
Unfortunately, though both processes require similar flow
rates, these two steps could not be telescoped because the in
situ masking of the secondary amine as acetate is necessary
for oxime formation. Therefore, we investigated the coupling
of the ring closure with the alkylation process. Thus, oxime 14
was N-alkylated with 3-bromo-1-chloropropane 11, and intra-
molecular subsitution as well as nucleophilic substitution took
place under these conditions. However, the multistep process
required optimization because ring closure and alkylation did
not lead to full transformation in a single pass. Therefore, we
first performed the ring closure in the presence of 3-bromo-1-
chloropropane 11, which provided a mixture of the benzisoxa-
zole 15 and the desired alkylation product 16. The reaction
mixture was mixed with a second portion of 3-bromo-1-chloro-
propane 11 at the outlet of the reactor, and the mixture was
submitted to the flow system again, which increased the
degree of conversion (Scheme 6).
Scheme 4. Fries rearrangement of acetate 10 under flow conditions.
2.0 MPa. The reactor was filled with steel beads (0.8 mm) that
were heated under medium frequency conditions while the
starting material 10 was passed through the reactor. The flow
rate was 0.2 mLminÀ1 (15 min residence time) to yield the de-
sired acetophenone 13 in 75% (7.3 mmol producthÀ1).
The western fragment was elaborated by first transforming
ketone 12 into the corresponding oxime 14 and an intramolec-
ular aromatic nucleophilic substitution occurred in the follow-
ing (Scheme 5). Oxime 14 was prepared in an acidic aqueous
medium; the product was isolated in 87% yield by simple fil-
tration of the solid material, which only formed at the reactor
outlet because the pressure had dropped. The process was
conducted with a 1/4“-reactor at a flow rate of 0.166 mLminÀ1
and 1758C, which corresponds to a residence time of 9 min.
Then, oxime 14 underwent ring closure at 110 8C in the pres-
ence of potassium hydroxide (50 wt% in water) to yield benzi-
At the same time it was possible to switch the organic sol-
vent to CH2Cl2 to increase the solubility of the salts. Under
these conditions, 1.2m LiOH-solution was sufficient for initiat-
ing the ring closure compared with the reaction in 13m KOH-
solution mentioned above (Scheme 5). The reaction was car-
ried out at a flow rate of 0.2 mLminÀ1 (15 min residence time)
at 1308C. We also envisaged and studied the O-alkylation of
phenol 13 first, but all such attempts only yielded in-
separable product mixtures.
Finally, the N-alkylated product 16 was coupled
with phenol 10 to yield iloperidone 9 in 78% yield
(Scheme 7). Decomposition of the N-alkylation prod-
uct 16 was suppressed when using the 1/8“-reactor,
which was heated to 1808C under high frequency
conditions. For purification, we developed a “catch
and release” protocol. After formation, iloperidone 9
was loaded and trapped on silica gel, which was
used as fixed bed material in a steel pipe cartridge.
Next, this cartridge was washed with EtOAc and final-
ly release of 9 was achieved by flushing the silica gel
with 2% MeOH in CH2Cl2. We collected the target
molecule after concentration in vacuo.
Scheme 5. Oxime formation and intramolecular, nucleophilic substitution in aqueous
media and formation of benzisoxazole 15.
Scheme 6. Telescoped cyclization/N-alkylation in aqueous media.
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6.5/95; 6.6/5; 8/5). Ion mass signals (m/z) are reported as values in
atomic mass units. Retention times (tR) are given in the experimen-
tal part.
Flash column chromatography was performed using MACHEREY-
NAGEL silica gel (grain size 40–63 mm).
Commercially available reagents and solvents were used as re-
ceived or purified by conventional methods prior to use, described
in the literature.[17] For thin-layer chromatography precoated silica
gel 60 F254 plates (MERCK, Darmstadt) were used and the spots
were visualized with UV light at 254 nm or alternatively by staining
with ninhydrine or permanganate solutions.
Flow synthesis components
Scheme 7. Iloperidone 9 formation and purification by a “catch and release”
protocol.
HPLC-pumps: Solvent or reaction mixture pumping was performed
by HPLC PUMP K-120, K-1001, Smartline Pump 100 and Azura P
4.1S from Knauer (Berlin, Germany).
Conclusions
Tubing and capillaries: Standardly, steel capillaries with 1/16“
outer diameter and 1.0 mm inner diameter made of stainless steel
316 from Techlab GMBH (Braunschweig, Germany) was used in all
systems. Additional, PTFE-tubing from Bohlender GMBH (Grünsfeld,
Germany) with 0.8”1.6”0.4 was used in room-pressured areas.
We have disclosed the first applications of continuously oper-
ated organic transformations in high temperature aqueous
media using inductively heated steel reactors. This set-up
allows us to rapidly achieve high temperature/high pressure
conditions. We studied selected examples such as the trimeri-
zation of 4-methoxy-3-butene-2-one and its use in a multicom-
ponent reaction towards dihydropyridines, in which water as
a solvent reveals its unique properties at near supercritical con-
ditions by acting as an acidic promoter. To showcase this tech-
nology, we implemented it in a process for preparing the neu-
rolepticum iloperidone 9. Importantly, four out of five steps
could be carried out in an aqueous medium under high tem-
perature/high pressure continuous flow conditions. We are cer-
tain that inductive heating in combination with flow reactors
has great potential to open up many other avenues for organic
synthesis under pyrolytic solution phase conditions.[16]
Injection valve: Starting materials were injected to the pressurized
system via a Rheodyneꢁ 6-way valve from Idex Corporation (Lake
Forest, USA).
Temperature measurement: The temperature of inductively
heated system was measured with a digital IR pyrometer CTLLTCF3
with laser light tag from Optris GMBH (Berlin, Germany) or a NiCr-
Ni type K thermocouple from B+B Thermo-Technik GMBH (Do-
naueschingen, Germany). For accurate temperature measurement,
the reactor was coated with temperature stable black varnish and
the emission factor was set to 0.95.
Inductor/Generator medium frequency: The generator for
medium frequency was acquired from IFF GMBH (Ismaning, Germa-
ny). The water-cooled device allows a stepless adjustment of the
frequency in the range of 8 to 25 kHz with a maximum power
output of 10.0 kW. Pulse width modulation is possible steplessly
from 100 to 1000 promille. The prototype inductor provided fol-
lowing features of performance: 368 mH, N=20 w, pack=2.9 mm2.
Experimental Section
Inductor/Generator high frequency: The high frequency genera-
tor HU 2000+ and the compatible inductor were acquired from
Himmel (Tübingen, Germany). Both devices are water-cooled and
allow a maximum power output of 2.0 kW at 280–310 and 780–
850 kHz. The power output is adjustable between 5–100% in 0.1%
steps.
General information
1H NMR spectra were recorded with
a Bruker Avance-400
(400 MHz) with DPC console and Bruker DRX-500 (500 MHz) with
DRX-console at room temperature. Multiplicities are described with
the following abbreviations: s: singlet; d: doublet; t: triplet; q:
quartet; m: multiplet; b: broad.
13C NMR spectra were recorded at 100 MHz with a Bruker Avance-
400 and at 125 MHz with a Bruker DRX-500. Chemical shifts of H-
and 13C NMR spectra are reported in d (ppm) relative to TMS as the
internal standard. Multiplicities are described with the following
abbreviations: s: singlet (due to quaternary carbon), d: doublet
(methine), t: triplet (methylene), q: quartet (methyl), m: multiplet.
All coupling constants J are expressed in Hertz. Supporting H-1H
correlation (COSY) and 1H-13C correlation (HSQC, HMBC) experi-
ments were performed for interpretation of mutaproducts spectra.
Back pressure modules: For pressure regulation in-line back pres-
sure modules, BPR Assembly from Upchurch Scientific (Oak Harbor,
USA) with different cartridges 250 psi (1.72 MPa), 500 psi
(3.45 MPa), 750 psi (5.17 MPa) and 1000 psi (6.90 MPa) were used.
1
Reactors: PEEK-reactors were fabricated in the workshop of the in-
stitute of technical chemistry at the Leibniz University Hannover.
Ketron PEEK rods 1000 Natur (1 m, Ø 25 mm) were purchase from
Arthur Krüger KG (Barsbüttel, Germany). Steel reactors and fittings
made of stainless steel 316 from Swagelok (Salon, Ohio USA) were
acquired from best fluid gmbh (Hamburg, Germany) with 1/8“”
0.028”, 1/4“”0.049” and 3/8“”0.049” measurements.
1
Mass spectra were recorded with a type QTOF premier (MICRO-
MASS) spectrometer (ESI mode) in combination with a Waters Acq-
uity S2 UPLC system equipped with a Waters Acquity UPLC BEH
C18 1.7 mm (SN 01473711315545) column (solvent A: water+0.1%
(v/v) formic acid, solvent B: MeOH+0.1% (v/v) formic acid; flow
rate=0.4 mLminÀ1; gradient (t [min]/solvent B [%]): 0/5; 2.5/95;
Computer software: The computer assisted reaction control was
realized with LabView 2014, 14.0 32-bit from National Instruments
(Austin, USA).
Computer hardware: Digital and analog input and output was
performed with a USB-6001 from National Instruments (Austin,
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USA) and a Photomos 1A 2500 MA 60V AQV252G from Panasonic
Corporation (Kadoma, Japan).
in vacuo. Purification by flash chromatography (petroleum ether!
petroleum ether/ethyl acetate 1:9 to 3:7) gave the target molecule
as slightly brown crystals (208 mg, 1.25 mmol, 74%).
Synthesis in
a flow system: 2-Methoxyphenylacetate (250 mL,
Procedures and analytical data
1.70 mmol, 1.0 equiv, 0.81m) was dissolved in a mixture of CH2Cl2
(1.5 mL) and methane sulfonic acid (350 mL, 5.39 mmol, 3.2 equiv).
The solution was injected into the loop and pumped through
a PEEK-reactor filled with steel bead (0.8 mm) at a flow rate of
0.2 mLminÀ1 CH2Cl2. The reactor was heated by a medium frequen-
cy inductor at 360% PWM and pressurized to 2.1 MPa. The reaction
mixture was washed three times with bicarbonate solution. The or-
ganic layer was dried over magnesium sulfate, filtered, and concen-
trated in vacuo. Purification by using flash chromatography (petro-
leum ether!petroleum ether/ethyl acetate=1:9 to 3:7) gave the
target molecule as slightly brown crystals (213 mg, 1.28 mmol,
The numerical assignment for the spectra signals are displayed in
the Supporting Information.
Triacetylbenzene (2): Synthesis in a flow system: Trans-4-methoxy-
3-butene-2-one (100 mL, 1.0 mmol, 1.0 equiv, 1.0m) was dissolved
in distilled water (1.0 mL). The solution was injected in front of tol-
uene (3.0 mL) into the loop and pumped through a 1/4“-steel reac-
tor (V=1.5 mL) with distilled water at 0.8 mLminÀ1. The reactor
was heated by a medium frequency field to 2408C and pressurized
to 4.5 MPa. The collected reaction solution was extracted with tolu-
ene (3”5 mL), the combined organic layers were dried over mag-
nesium sulfate, filtered and concentrated in vacuo. Drying in high
vacuum gave the target molecule as colorless crystals (60 mg,
1
75%). H NMR (400 MHz, CDCl3, CHCl3 =7.26 ppm): d=7.52 (td, J=
4.4, 1.9 Hz, 1H), 6.98–6.88 (m, 1H), 6.39 (s, 1H), 3.92 (s, 2H), 2.54 (s,
2H) ppm; Tmp: 113.58C; HRMS (EI): m/z calcd C9H10O3+: 166.0630
[M+H]+; found: 166.0626.
1
0.29 mmol, 89%). H NMR (400 MHz, CDCl3, CHCl3 =7.26 ppm): d=
8.70 (s, 3H), 2.71 ppm (s, 9H).
(2,4-Difluorophenyl)(piperidin-4-yl)methanone oxime acetate
(14): Synthesis in a round-bottom flask: Hydroxylamine hydrochlo-
ride (240 mg, 3.45 mmol, 1.5 equiv) was dispersed in a mixture of
ethanol (2.4 mL) and distilled water (0.5 mL). Sodium hydroxide
(230 mg, 5.75 mmol, 2.5 equiv) was added to the mixture and
stirred for 10 min at room temperature. Subsequently, 4-(2,4-di-
Dihydropyridine (5): Synthesis in a flow system: Trans-4-methoxy-3-
butene-2-one (100 mL, 1.0 mmol, 1.0 equiv, 0.5m), 4-nitrobenzalde-
hyde (150 mg, 1.0 mmol, 2 equiv), and benzylamine (75 mL,
0.75 mmol, 1.5 equiv) were dissolved in toluene (2.0 mL) and dis-
tilled water (1.5 mL) was added. The mixture was injected into the
loop and pumped through a 1/4“-steel reactor (V=1.5 mL) with
distilled water at 0.2 mLminÀ1
. The reactor was heated by
fluorbenzoyl)piperidinehydrochloride
(600 mg,
2.29 mmol,
1.0 equiv, 0.66m) and acetic acid (0.5 mL, 8.7 mmol, 3.8 equiv) were
added. The reaction mixture was stirred for 6 h at 908C then
cooled down and stirred additionally for one hour at room temper-
ature. The precipitated solid was filtered off and washed with etha-
nol (2”1.0 mL). Drying under high vacuum gave the product as
colorless crystals (640 mg, 2.13 mmol, 93%).
a medium frequency field to 1808C and pressurized to 4.5 MPa.
The collected reaction solution was extracted with toluene (3”
15 mL), the combined organic layers were dried over magnesium
sulfate, filtered, and concentrated in vacuo. Purification by using
flash chromatography (petroleum ether/ethyl acetate=3:1–1:1)
gave the target molecule as a yellow oil (152 mg, 0.40 mmol,
81%). 1H NMR (400 MHz, CDCl3, CHCl3 =7.26 ppm): d=8.08–7.99
(m, 2H), 7.51–7.38 (m, 5H), 7.32 (dd, J=11.1, 9.6 Hz, 2H), 7.22 (s,
2H), 5.29 (s, 1H), 4.72 (s, 2H), 2.14 ppm (s, J=5.5 Hz, 6H).
Synthesis in a flow system: 4(2,4-Difluorbenzoyl)piperidiehydrochlor-
ide (1.2 g, 4.58 mmol, 1.0 equiv, 0.66m) and hydroxylamine hydro-
chloride (480 mg, 6.90 mmol, 1.5 equiv) were dissolved in a mixture
of CH2Cl2 (5.4 mL) and sodium hydroxide (0.62 mL) solution (50%
in water, 11.46 mmol, 2.5 equiv). Acetic acid (1.0 mL, 17.6 mmol,
3.8 equiv) was added and the solution was injected into the loop
and pumped through a 1/4“ steel reactor (V=1.5 mL) with distilled
water at 0.166 mLminÀ1. The reactor was heated by a medium fre-
quency field to 1758C and pressurized to 2.0 MPa. The reaction so-
lution was stored for one hour at room temperature after the reac-
tion and the precipitated solid was filtered off. The remaining solu-
tion was stored for additional 16 h and the precipitated solid was
filtered off. The combined solids were washed with ethanol (2”
3.0 mL). Drying under high vacuum gave the product as colorless
crystals (1.2 g, 4.00 mmol, 87%). 1H NMR (400 MHz, DMSO,
CD2HSOCD3 =2.49 ppm): d=7.29–7.21 (m, 2H, H-5,6), 7.11 (td, J=
8.5, 2.5 Hz, 1H, H-2), 2.96 (d, J=12.3 Hz, 2H, H-10), 2.57–2.44 (m,
3H, H-8,10), 1.82 (s, 3H, H-14), 1.71–1.61 (m, 2H, H-9), 1.37 ppm
(qd, J=12.3, 3.9 Hz, 2H, H-9); 13C NMR (100 MHz, DMSO,
CD2HSOCD3 =40.45 ppm): d=174.1 (C-13), 163.04 (dd, J=246.7,
12.1 Hz, C-3), 159.52 (dd, J=247.8, 12.4 Hz, C-1), 154.57 (d, J=
3.2 Hz, C-7), 131.32 (dd, J=10.2, 6.4 Hz, C-5), 119.70 (dd, J=19.2,
4.2 Hz, C-6), 112.34 (dd, J=21.3, 4.1 Hz, C-4), 104.79 (t, J=26.2 Hz,
C-2), 45.4 (C-10), 41.7 (C-8), 29.7 (C-9), 23.6 ppm (C-14); Tmp: decom-
position at 2108C; HRMS (LCT): m/z calcd for C12H15F2N2O+:
241.1152 [MÀOAc]+; found: 241.1149.
2-Allyl-6-nitrophenol (7): Synthesis in a flow system: 1-(Allyloxy)-2-
nitrobenzene (50 mg, 0.28 mmol, 1.0 equiv) were dissolved in tolu-
ene (0.2 mL) and distilled water (1.0 mL). The mixture was injected
into the loop and pumped through a 1/8“ steel reactor (V=1.2 mL)
with distilled water at 0.4 mLminÀ1. The reactor was heated by
a high frequency field (300 kHz) to 2608C and pressurized to
4.5 MPa. The collected reaction solution was extracted with ethyl
acetate (3”15 mL), the combined organic layers were dried over
magnesium sulfate, filtered, and concentrated in vacuo. Purification
by using flash chromatography (petroleum ether!petroleum
ether/ethyl acetate=99:1–98:2) gave the target molecule as
a yellow oil (43 mg, 0.24 mmol, 86%). 1H NMR (400 MHz, DMSO,
CD2HSOCD3 =2.49 ppm): d=10.95 (s, 1H), 7.99 (dd, J=8.6, 1.7 Hz,
1H, H-3), 7.46 (dd, J=7.3, 1.1 Hz, 1H, H-5), 6.92 (dd, J=8.5, 7.4 Hz,
1H, H-4), 6.06–5.90 (m, 1H, H-8), 5.14 (t, J=1.3 Hz, 1H, H-9), 5.11
(dq, J=8.3, 1.5 Hz, 1H, H-9), 3.48 ppm (d, J=6.6 Hz, 2H, H-7);
13C NMR (100 MHz, CDCl3, CHCl3 =77.16 ppm): d=153.4 (C-1),
137.6 (C-5), 135.2 (C-8), 133.7 (C-2), 131.5 (C-6), 123.2 (C-3), 119.6
(C-4), 116.9 (C-9), 33.8 ppm (C-7); HRMS (LCT): m/z calcd for
C9H10N1O3+: 180.0655 [M+H]+, found: 180.0656.
1-(4-Hydroxy-3-methoxyphenyl)ethan-1-one (13): Synthesis in
a round-bottom flask: 2-Methoxyphenylacetate (250 mL, 1.70 mmol,
1.0 equiv, 0.68m) was added to a mixture of 2.0 mL CH2Cl2, meth-
ane sulfonic acid (440 mL, 6.73 mmol, 4.0 equiv) and phosphor(V)-
oxide (62 mg, 0.43 mmol, 0.25 equiv) and stirred for 16 h at room
temperature. The reaction mixture was diluted with CH2Cl2 (10 mL)
and washed three times with bicarbonate solution. The organic
layer was dried over magnesium sulfate, filtered, and concentrated
6-Fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (15): Synthesis in
a round-bottom flask: (2,4-Difluorophenyl)piperidine-4-ylmethano-
noxim acetate (100 mg, 0.33 mmol, 1.0 equiv, 0.66m) was dissolved
in potassium hydroxide-solution (0.5 mL, 50% in water, 5.35 mmol,
20 equiv). The mixture was stirred for 1 h at 110 8C then diluted
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with distilled water (3.0 mL) and the aqueous layer was extracted
with toluene (3”5.0 mL). The combined organic layers were dried
over magnesium sulfate, filtered, and concentrated in vacuo. Re-
crystallization from diethyl ether gave the target molecule as color-
less crystals (20.3 mg, 0.092 mmol, 28%).
(dd, J=8.5, 2.1 Hz, 1H, H-2), 7.04 (td, J=8.8, 2.1 Hz, 1H, H-4), 3.62
(t, J=6.5 Hz, 2H, H-13), 3.12–2.99 (m, 3H, H-8,10), 2.53 (t, J=
7.1 Hz, 2H, H-11), 2.23–2.09 (m, 2H, H-10), 2.09–2.02 (m, 4H, H-9),
1.98 ppm (q, J=6.8 Hz, 2H, H-12); 13C NMR (100 MHz, CDCl3,
CHCl3 =77.16 ppm): d=164.2 (d, J=250.6 Hz, C-3), 164.0 (d, J=
13.6 Hz, C-1), 161.18 (d, J=0.8 Hz, C-7), 122.7 (d, J=11.1 Hz, C-5),
117.4 (d, J=1.3 Hz, C-6), 112.4 (d, J=23.3 Hz, C-4), 97.5 (d, J=
26.7 Hz, C-2), 55.8 (C-11), 53.7 (C-10), 43.4 (C-13), 34.7 (C-8), 30.7 (C-
9), 30.2 ppm (C-12); Tmp: slow decomposition starting at 1708C;
HRMS (LCT): m/z calcd for C15H19FN2OCl+: 297.1170 [M+H]+;
found: 297.1168.
Synthesis in a flow system: (2,4-Difluorophenyl)piperidine-4-ylme-
thanonoxim acetate (500 mg, 1.67 mmol, 1.0 eq, 0.21m) was dis-
solved in ethanol (6.0 mL) and potassium hydroxide (2.0 mL) solu-
tion (50% in water, 21.60 mmol, 12.9 equiv) was added. The solu-
tion was injected into the loop and pumped through a 1/4“ steel
reactor (V=1.5 mL) with distilled water at 0.2 mLminÀ1. The reactor
was heated by a medium frequency field to 110 8C and pressurized
to 2.0 MPa. The collected reaction solution was extracted with tolu-
ene (3”25 mL), the combined organic layers were dried over mag-
nesium sulfate, filtered, and concentrated in vacuo. Recrystalliza-
tion from diethyl ether gave the target molecule as colorless crys-
tals (323 mg, 1.46 mmol, 88%). 1H NMR (400 MHz, DMSO,
CD2HSOCD3 =2.49 ppm): d=8.41 (s, 1H, H-11), 8.05 (dd, J=8.8,
5.3 Hz, 1H), 7.69 (dd, J=9.1, 2.1 Hz, 1H), 7.34–7.27 (dd, J=8.8,
2.1 Hz, 1H), 3.44 (tt, J=11.4, 3.8 Hz, 1H), 3.28 (d, J=12.7 Hz, 2H),
2.95 (td, J=12.4, 2.8 Hz, 2H), 2.10 (dd, J=13.5, 2.6 Hz, 2H),
1.99 ppm (ddd, J=15.7, 12.8, 3.9 Hz, 2H); 13C NMR (100 MHz,
DMSO, CD2HSOCD3 =40.45 ppm): d=164.3 (dd, J=131.1, 116.9 Hz,
C-3), 164.0 (d, J=14.2 Hz, C-1), 161,6 (C-7) 124.6 (d, J=11.3 Hz, C-
5), 117.9 (d, J=1.2 Hz, C-6), 113.6 (d, J=25.3 Hz, C-4), 98.4 (d, J=
27.4 Hz, C-2), 44.0 (C-10), 32.6 (C-8), 28.4 ppm (C-9); Tmp: 119.38C;
HRMS (LCT): m/z calcd C12H14FN2O+ 221.1090 [M+H]+; found:
221.1091.
Iloperidone (1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperi-
dinyl]propoxy]-3-methoxy-phenyl]ethanone) (9): Synthesis in
a flow system (purification by flash chromatography): 3-(1-(3-Chloro-
propyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole
(120 mg,
0.40 mmol, 1.2 equiv) was dissolved in CH2Cl2 (1.5 mL) and 4-acyl-
2-methoxyphenol (56 mg, 0.34 mmol, 1.0 equiv) and lithium hy-
droxide solution (850 mL, 1.2m, 1.01 mmol, 3.0 equiv) were added.
The solution was injected into the loop and pumped through a 1/
4“ steel reactor (V=1.5 mL) with distilled water at 0.2 mLminÀ1
.
The reactor was heated by a medium frequency field to 1808C and
pressurized to 4.5 MPa. The collected reaction solution was extract-
ed with CH2Cl2 (3”15 mL), the combined organic layers were dried
over magnesium sulfate, filtered and concentrated in vacuo. Purifi-
cation by using flash chromatography (ethyl acetate!ethyl ace-
tate/methanol 1:0 to 95:5) gave the target molecule as slightly
yellow crystals (112 mg, 0.27 mmol, 78%).
3-(1-(3-Chloropropyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole
(16): Synthesis in a flow system: 6-Fluor-3-(piperidin-4-yl)benzo[d]-
isoxazole (200 mg, 0.91 mmol, 1.0 equiv, 0.061m) and 1-bromo-3-
chloropropane (167 mL, 1.82 mmol, 2.0 equiv) were dissolved in
a mixture of CH2Cl2 (10.0 mL) and distilled water (5.0 mL) and lithi-
um hydroxide solution (0.9 mL, 1.2m, 1.09 mmol, 1.2 equiv) was
added. The solution was injected into the loop and pumped
through a 1/4“ steel reactor (V=1.5 mL) with distilled water at
0.5 mLminÀ1. The reactor was heated by a medium frequency in-
ductor to 1258C (125% PWM) and pressurized to 2.0 MPa. The col-
lected reaction solution was extracted with ethyl acetate (3”
10 mL), the combined organic layers were dried over magnesium
sulfate, filtered and concentrated in vacuo. Purification via flash
chromatography (petroleum ether!petroleum ether/ethyl acetate
1:9 to 3:7) gave the target molecule as slightly yellow crystals
(180 mg, 0.61 mmol, 67%).
Synthesis in a flow system (catch and release purification): 3-(1-(3-
Chloropropyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole
(200 mg,
0.67 mmol, 1.0 equiv) was dissolved in toluene (1.0 mL), and 4-acyl-
2-methoxyphenol (111 mg, 0.67 mmol, 1.0 equiv), lithium hydrox-
ide-solution (2.8 mL, 1.2m, 3.37 mmol, 5.0 equiv) and 1.5 mL petro-
leum ether were added. The mixture was injected into the loop
and pumped through a 1/8“ steel reactor (V=1.2 mL) with distilled
water at 0.1 mLminÀ1. The reactor was heated by a high frequency
field to 1808C and pressurized to 4.5 MPa. The reactor was flushed
with additional CH2Cl2 (3.0 mL) after the reaction and CH2Cl2
(5.0 mL) was added to the reaction mixture. The organic layer was
separated from the aqueous layer, injected into a loop and
pumped through a 1/4” steel reactor (V=2.5 mL) filled with silica
gel at 1.0 mLminÀ1 with ethyl acetate. The product was washed
with ethyl acetate (20 mL) and then released by pumping a mixture
of ethyl acetate/methanol 98:2 (8 mL) through the plug silica. Con-
centration in vacuo gave the target molecule as slightly yellow
crystals (184 mg, 0.43 mmol, 64%). 1H NMR (400 MHz, DMSO, not
calibrated because DMSO signal was overlayed): d=7.98 (dd, J=
8.7, 5.3 Hz, 1H, H-5), 7.66 (dd, J=9.1, 1.9 Hz, 1H, H-2), 7.60 (dd, J=
8.4, 1.9 Hz, 1H, H-18), 7.44 (d, J=1.8 Hz, 1H, H-16), 7.26 (td, J=9.3,
2.1 Hz, 1H, H-4), 7.07 (d, J=8.4 Hz, 1H, H-19), 4.11 (t, J=6.3 Hz, 2H,
H-13), 3.83 (s, 3H, H-15’), 3.18–3.05 (m, 1H, H-8), 2.98 (d, J=
11.2 Hz, 2H, H-10), 2.52 (s, 3H, H-17’’), 2.54–2.44 (m, 2H, H-11), 2.11
(t, J=10.9 Hz, 2H, H-10), 2.06–1.74 ppm (m, 6H, H-9, 11, 12);
13C NMR (100 MHz, DMSO, CD2HSOCD3 =40.45 pp): d=197.2 (C-
17’), 164.5 (d, J=247.8 Hz, C-3), 163.9 (d, J=14.2 Hz, C-1), 162.3 (C-
7), 153.4 (C-14), 149.6 (C-15), 130.7 (C-17), 124.6 (d, J=11.4 Hz, C-5),
124.0 (C-18), 118.16 (d, J=1.1 Hz, C-6), 113.3 (d, J=25.3 Hz, C-4),
112.6 (C-19), 111.3 (C-16), 98.2 (d, J=27.3 Hz, C-2), 67.7 (C-13), 56.4
Synthesis in a flow system (2 steps): (2,4-Difluorophenyl)piperidine-
4-ylmethanonoximacetate (400 mg, 1.33 mmol, 1.0 equiv, 0.21m)
and 1-bromo-3-chloropropane (230 mL, 2.33 mmol, 1.75 equiv)
were dissolved in CH2Cl2 (4.0 mL) and lithium hydroxide-solution
(2.8 mL, 1.2m, 3.30 mmol, 2.5 equiv) was added. The solution was
injected into the loop and pumped through a 1/4“ steel reactor
(V=1.5 mL) with distilled water at 0.2 mLminÀ1. The reactor was
heated by a medium frequency field to 1308C and pressurized to
2.0 MPa. 1-bromo-3-chloropropane (230 mL, 2.33 mmol, 1.75 equiv)
and lithium hydroxide solution (1,1 mL, 1.2m, 1.33 mmol, 1.0 equiv)
were added to the collected solution and the mixture was injected
a into the loop for a second run at the same conditions. The col-
lected reaction solution was extracted with ethyl acetate (3”
30 mL), the combined organic layers were dried over magnesium
sulfate, filtered and concentrated in vacuo. Purification by using
flash chromatography (petroleum ether!petroleum ether/ethyl
acetate 1:9 to 3:7) gave the target molecule as slightly yellow crys-
tals (300 mg, 1.01 mmol, 76%). 1H NMR (400 MHz, DMSO,
CD2HSOCD3 =2.49 ppm): d=7.68 (dd, J=8.7, 5.1 Hz, 1H, H-5), 7.23
(C-15’), 55.5 (C-11), 53.9 (C-10), 34.4 (C-8), 31.1 (C-9,12), 27.2 ppm
+
(C-17’’); Tmp: 120–1228C; HRMS (LCT): m/z calcd for C24H28FN2O4
:
427.2028 [M+H]+; found: 427.2026.
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4583–4592; h) T. N. Glasnov, C. O. Kappe, J. Heterocycl. Chem. 2011, 48,
11 –29; i) D. Webb, T. F. Jamison, Chem. Sci. 2010, 1, 675–680.
[6] a) Chemical Synthesis using Supercritical Fluids (Eds.: P. G. Jessop, W. Leit-
ner), Wiley-VCH, Weinheim, 1999; b) A. Kruse, E. Dinjus, J. Supercrit.
Fluids 2007, 39, 362–380.
Acknowledgements
This work was supported by the Fonds der Chemischen Indus-
trie (PhD scholarship for J.H.).
[7] a) S. Ceylan, L. Coutable, J. Wegner, A. Kirschning, Chem. Eur. J. 2011,
17, 1884–1893; b) J. Wegner, S. Ceylan, C. Friese, A. Kirschning, Eur. J.
Org. Chem. 2010, 4372–4375; c) S. Ceylan, T. Klande, C. Vogt, C. Friese,
A. Kirschning, Synlett 2010, 2009–2013; d) S. Ceylan, C. Friese, C.
Lammel, K. Mazac, A. Kirschning, Angew. Chem. Int. Ed. 2008, 47, 8950–
8953; Angew. Chem. 2008, 120, 9083–9086.
[8] a) P. Krammer, H. Vogel, J. Supercrit. Fluids 2000, 16, 189–206; b) P.
Krämer, S. Mittelstädt, H. Vogel, Chem. Eng. Technol. 1999, 22, 494–500;
c) V. Hessel, D. Kralisch, N. Kockmann, T. Nol, Q. Wang, ChemSusChem
2013, 6, 746–789.
Keywords: flow synthesis · high temperature · industrial
chemistry · synthetic methods · medicinal chemistry
[1] a) A. Loppinet-Serani, C. Aymonier, F. Cansell, ChemSusChem 2008, 1,
486–503; b) C. S. Martínez-Cisneros, S. G. Pedro, M. Puyol, J. García-
García, J. Alonso-Chamarro, Chem. Eng. J. 2012, 211–212, 432–441; c) A.
Kirschning, W. Solodenko, K. Mennecke, Chem. Eur. J. 2006, 12, 5972–
5990.
[9] a) S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb, K. B. Sharp-
less, Angew. Chem. Int. Ed. 2005, 44, 3275–3279; Angew. Chem. 2005,
117, 3339–3343; b) U. M. Lindstrçm, Chem. Rev. 2002, 102, 2751–2772.
[10] Y. Ikushima, K. Hatakeda, M. Sato, O. Sato, M. Arai, Chem. Commun.
2002, 2208–2209.
[11] a) P. E. Savage, Chem. Rev. 1999, 99, 603–621; b) D. Dallinger, C. O.
Kappe, Chem. Rev. 2007, 107, 2563–2591; c) S. Marre, Y. Roig, C. Aymon-
ier, J. Supercrit. Fluids 2012, 66, 251–264.
[12] a) Y. Ikushima, K. Hatakeda, O. Sato, T. Yokoyama, M. Arai, Angew. Chem.
Int. Ed. 1999, 38, 2910–2914; Angew. Chem. 1999, 111, 3087–3091; b) Y.
Ikushima, K. Hatakedo, O. Sato, T. Yokoyama, M. Arai, Angew. Chem. Int.
Ed. 2001, 40, 210–213; Angew. Chem. 2001, 113, 216–219.
[13] T. Iwado, K. Hasegawa, T. Sato, M. Okada, K. Sue, H. Iwamura, T. Hiaki, J.
Org. Chem. 2013, 78, 1949–1954.
[14] First attempts to run this reaction led to a blockage in the flow system
because of the insolubility of the product in pure water.
[15] P. R. Girling, A. S. Batsanov, H. C. Shen, A. Whiting, Chem. Commun.
2012, 48, 4893–4895.
[16] A. Kirschning, L. Kupracz, J. Hartwig, Chem. Lett. 2012, 41, 562–570.
[17] J. Leonard, B. Lygo, G. Procter, Praxis in der organischen Chemie, VCH,
Weinheim, 1996.
[2] a) C. Wentrup, Aust. J. Chem. 2014, 67, 1150–1165; b) C. O. Kappe, G.
Färber, C. Wentrup, G. Kollenz, J. Org. Chem. 1992, 57, 7078–7083;
c) J. C. Gilbert, D. H. Giamalva, U. Weerascooriya, J. Org. Chem. 1983, 48,
5251–5256; d) B. R. Henke, A. J. Kouklis, C. H. Heathcock, J. Org. Chem
1992, 57, 7056–7066; e) H. Briehl, A. Lukosch, C. Wentrup, J. Org. Chem.
1984, 49, 2772–2779; f) P. F. Britt, A. C. Buchanan, M. J. Cooney, D. R.
Martineau, J. Org. Chem. 2000, 65, 1376–1389; g) G. I. Yranzo, N. R.
Reartes, J. D. PØrez, I. Iwataki, H. Adachi, J. Anal. Appl. Pyrolysis 1998, 46,
101–112; h) A. E.-A. M. Gaber, H. McNab, J. Anal, Appl. Pyrolysis 2009,
86, 369–374; i) R. A. Aitken, N. Karodia, Liebigs Ann./Recueil 1997, 779–
783; j) J. A. Campbell, G. Mcdougald, H. McNab, L. V. C. Rees, R. G. Tyas,
Synthesis 2007, 3179–3184.
[3] T. Razzaq, C. O. Kappe, Chem. Asian J. 2010, 5, 1274–1289.
[4] a) S. R. Chaudhuri, J. Hartwig, L. Kupracz, T. Kodanek, A. Kirschning, Adv.
Synth. Catal. 2014, 356, 3530–3538; b) J. Hartwig, S. Ceylan, L. Kupracz,
L. Coutable, A. Kirschning, Angew. Chem. Int. Ed. 2013, 52, 9813–9817;
Angew. Chem. 2013, 125, 9995–9999; c) L. Kupracz, A. Kirschning, Adv.
Synth. Catal. 2013, 355, 3375–3380.
[5] a) M. Brzozowski, M. O’Brian, S. V. Ley, A. Polyzos, Acc. Chem. Res. 2015,
48, 349–362; b) B. Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int.
Ed. 2015, 54, 6688–6729; Angew. Chem. 2015, 127, 6788–6832; c) G. Jü-
rjens, A. Kirschning, D. Candito, Nat. Prod. Rep. 2015, 32, 723–737;
d) J. C. Pastre, D. L. Browne, S. V. Ley, Chem. Soc. Rev. 2013, 42, 8849–
8869; e) J. Wegner, S. Ceylan, A. Kirschning, Adv. Synth. Catal. 2012, 354,
17–57; f) T. N. Nol, S. L. Buchwald, Chem. Soc. Rev. 2011, 40, 5010–
5029; g) J. Wegner, S. Ceylan, A. Kirschning, Chem. Commun. 2011, 47,
Received: November 2, 2015
Published online on January 25, 2016
Chem. Eur. J. 2016, 22, 3044 – 3052
www.chemeurj.org
3052
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim