Design and Performance Validation of a Conductively Heated Sealed-Vessel Reactor for Organic Synthesis

Article abstract of DOI:10.1021/acs.joc.6b02242

A newly designed robust and safe laboratory scale reactor for syntheses under sealed-vessel conditions at 250 °C maximum temperature and 20 bar maximum pressure is presented. The reactor employs conductive heating of a sealed glass vessel via a stainless steel heating jacket and implements both online temperature and pressure monitoring in addition to magnetic stirring. Reactions are performed in 10 mL borosilicate vials that are sealed with a silicone cap and Teflon septum and allow syntheses to be performed on a 2-6 mL scale. This conductively heated reactor is compared to a standard single-mode sealed-vessel microwave instrument with respect to heating and cooling performance, stirring efficiency, and temperature and pressure control. Importantly, comparison of the reaction outcome for a number of different synthetic transformations performed side by side in the new device and a standard microwave reactor suggest that results obtained using microwave conditions can be readily mimicked in the operationally much simpler and smaller conventionally heated device.

Full text of DOI:10.1021/acs.joc.6b02242

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Article
Design and Performance Validation of a Conductively-
Heated Sealed-Vessel Reactor for Organic Synthesis.
David Obermayer, Desiree Znider, Gabriel Glotz, Alexander Stadler, Doris Dallinger, and C. Oliver Kappe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02242 • Publication Date (Web): 07 Nov 2016
Downloaded from http://pubs.acs.org on November 9, 2016
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Design and Performance Validation of a Conductivelyꢀ
Heated SealedꢀVessel Reactor for Organic Synthesis
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David Obermayer,† Desiree Znidar,† Gabriel Glotz,† Alexander Stadler,‡ Doris
Dallinger,*,† and C. Oliver Kappe*,†
† Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Aꢀ8010 Graz, Austria
‡ Anton Paar GmbH, Department Analytical and Synthetic Chemistry, AntonꢀPaarꢀStraße 20, 8054
Graz, Austria
* Doris Dallinger. Eꢀmail: do.dallinger@uniꢀgraz.at
* C. Oliver Kappe. Eꢀmail: oliver.kappe@uniꢀgraz.at.
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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Abstract: A newly designed robust and safe laboratory scale reactor for syntheses under sealed vessel
conditions at 250 °C maximum temperature and 20 bar maximum pressure is presented. The reactor
employs conductive heating of a sealed glass vessel via a stainless steel heating jacket and implements
both onꢀline temperature and pressure monitoring in addition to magnetic stirring. Reactions are
performed in 10 mL borosilicate vials that are sealed with a silicone cap and Teflon septum and allow
syntheses to be performed on a 2ꢀ6 mL scale. This conductively heated reactor is compared to a
standard singleꢀmode sealed vessel microwave instrument with respect to heating and cooling
performance, stirring efficiency, and temperature and pressure control. Importantly, comparison of the
reaction outcome for a number of different synthetic transformations performed side by side in the new
device and a standard microwave reactor suggest that results obtained using microwave conditions can
be readily mimicked in the operationally much simpler and smaller conventionally heated device.
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Introduction
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Highꢀspeed microwaveꢀassisted organic synthesis has attracted considerable interest since its
initial conception in the midꢀ1980s.1 In particular the introduction of dedicated sealedꢀvessel singleꢀ
mode microwave reactors around 2000 has paved the way for the rapid implementation of this enabling
technology into modern synthetic laboratories. Today, microwave reactors are virtually omnipresent in
both academia and industry and the technology has become an indispensable tool for performing
organic synthesis at elevated temperature regimes. The many advantages and benefits of this nonꢀ
classical heating method for various synthetic applications have been thoroughly investigated and
documented in numerous publications, reviews and books.2ꢀ4 Most of the published examples document
a significant reduction of reaction times when performing reactions in sealedꢀvessel microwave
reactors at temperatures well above the boiling point of the solvent at atmospheric conditions
(Arrheniusꢀbased rate acceleration).2ꢀ4 In addition, an increase in yield and product purity can often be
achieved using this technique.2ꢀ4 In contrast to conventionally heated reactions, dedicated microwave
devices also allow a higher degree of process control allowing accurate onꢀline monitoring of
temperature and pressure, and increase the safety by avoiding the use of roundꢀbottom flasks in
combination with waterꢀcooled reflux condensers, oilꢀbaths or other electric heating sources.
Since the early beginnings of microwave chemistry, the dramatic rate accelerations were often
suspected of being caused by soꢀcalled specific or nonꢀthermal microwave effects (in addition to the
wellꢀunderstood Arrheniusꢀbased thermal effects).2 Although occasionally still being controversially
debated,5 most of the allegedly found evidence for such microwave effects can be traced back to
erroneous or incorrect temperature sensing in the microwave setup.6 Clearly, the vast majority of the
effects that can be experienced in microwaveꢀassisted organic synthesis are the result of purely thermal
(Arrheniusꢀbased) bulk temperature phenomena.5 Therefore, the idea of implementing the main
advantages of microwaveꢀassisted synthesis, namely rapid heating and cooling of a reaction mixture in
a sealed vessel environment with adequate process control, into a technically simpler setup – avoiding
microwave technology altogether – appears rather obvious.7
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In 2013 we have reported a novel type of resistanceꢀheated sealedꢀvessel reactor that employed
a modified silicon carbide (SiC) vial as reaction vessel.8,9 This comparatively easy to assemble
resistanceꢀheated SiC autoclave can effectively mimic a standard sealedꢀvessel microwave experiment.
Rapid heating and cooling, superheating of reaction mixtures above their boiling points, and excellent
control over reaction temperature and pressure could all be duplicated in the SiC reactor, in which the
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electrically conductive SiC ceramic served as integrated reactionꢀvessel/heating element. Importantly,
with a series of model reactions and control experiments we could demonstrate that the outcome of the
chemical transformations in the SiC reactor did not differ from the microwaveꢀheated processes under
otherwise identical reaction conditions (temperature profile, reaction time).8
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We now present a technically simplified device that utilizes a standard 10 mL sealed Pyrex
microwave vessel as reaction environment and allows rapid heating and cooling of reaction mixtures to
250 °C and 20 bar pressure at rates not unlike those achieved with modern singleꢀmode microwave
reactors. The reactor employs conductive heating of a stainless steel heating jacket and implements
both onꢀline temperature and pressure monitoring in addition to magnetic stirring. Appropriate software
algorithms ensure proper control over reaction temperature. With a series of model reactions it is
demonstrated that this novel device, based entirely on conductive heating principles, can adequately
mimic the results achieved in modern microwave reactors.
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Results and Discussion
Reactor Design. The basis for the reactor is a standard 10 mL Pyrex microwave vial, which is
immersed in a precisely fitting stainless steel heating jacket (Figure 1). The heating jacket is lagged
with an appropriate heating coil, the pitches between the windings act as cooling fins when cooling the
vial after the reaction. The reaction vial rests on a standard negative temperature coefficient (NTC)
temperature sensor at the bottom of the heating jacket. This contact sensor gives feedback to the
controller, which calculates the actual reaction temperature from the measured surface temperature via
a specifically programmed software algorithm. Comparing the current temperature with the
programmed settings the instrument’s power is regulated between 0 and 315 W to reach and maintain
the target temperature. Additionally, a pressure sensor embedded in the instrument cover measures the
evolving pressure during the reaction up to a maximum of 20 bar (Figure 1). In case of a substantial
pressure buildꢀup the overpressure is safely released via an exhaust port until it drops to below 20 bar.
A key feature for temperature homogeneity and reproducible results is the builtꢀin magnetic stirrer.10
Setting an appropriate stirrer speed (according to the viscosity of the reaction mixture) is essential for
accurate temperature control. Only if sufficient heat distribution by agitation is ensured, the contact
sensor will provide a representative temperature value allowing the controller to determine the reaction
temperature for the entire bulk accordingly.10 To serve a wide scope of homogeneous and
heterogeneous mixtures and various viscosities the stirrer speed can be set between 0 and 1200 rpm.
The reaction vial is closed with a silicone cap containing a Teflon septum and the instrument cover is
manually closed by a handle to seal the vial.
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Figure 1. Schematic drawing depicting the concept of a conductively heated sealed vial reactor
employing a 10 mL glass vial. Apart from temperature and pressure monitoring, magnetic stirring and
air cooling are integrated into the reactor. Image copyright Anton Paar GmbH (ref. 11).
Methods programming for temperature controlled experiments in the reactor termed Monowave 50
(Figure 2, Anton Paar GmbH)11 is carried out via a builtꢀin capacitive touchscreen and allows
experiments up to 250 °C for a maximum of 4 h. Reaction mixtures can be heated in an “as fast as
possible” mode (AFAP) or by applying a defined ramp time to reach the target temperature. After an
experiment is completed the vial is automatically cooled within minutes by an integrated heat
exchanger. The heating and cooling characteristics of the instrument are comparable to the performance
of standard singleꢀmode microwave reactors. The most significant difference to a microwave device is
probably the initial delay of the heating phase, since the sealed vessel reactor needs a preꢀheating time
to heat up the heating jacket. Once the working temperature is reached (after ca. 30 s) the heating
profiles appear nearly identical to those experienced with a singleꢀmode microwave instrument (Figure
3). The more polar the utilized solvent (i.e., the higher its tan δ value)12 the more significant is the
difference in heating rate between microwave dielectric heating and the convective heating principle
used in the Monowave 50 device. The cooling concept is also slightly different to standard singleꢀmode
microwave reactors. Instead of a jet stream of compressed air alongside the vessel surface the heat is
withdrawn from the heating jacket by a standard heat exchanger fan. Cooling fins in the heating jacket
enlarge its surface ensuring efficient heat transfer to cool down the reaction mixture efficiently. In case
of a potentially remaining overpressure after cooling the safety measures of the instrument ensure a
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safe release when opening the instrument cover. When the handle is unlocked the pressure piston
slightly moves to allow the silicon cap to expand. The overpressure is immediately released via an
exhaust channel to the rear of the instrument. After complete manual opening of the instrument cover
the vial is at atmospheric pressure and can be safely removed from the heating jacket (Figure 2).
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Figure 2. Monowave 50 reactor (Anton Paar GmbH) with open cover and 10 mL glass vials with
silicone cap, septa and stirring bar. Image copyright Anton Paar GmbH (ref. 11).
a
Figure 3. Temperature and pressure profiles for heating and cooling a sample of toluene (6 mL) AFAP
to 200 °C (5 min hold time, target temperature for cooling 50 °C) comparing the performance of a
standard singleꢀmode microwave reactor (Monowave 300, MW, blue) with the conventionally heated
Monowave 50 reactor (CONV, red). The ca. 30 s preꢀheating phase of the Monowave 50 reactor is not
shown for better comparison.
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Heating and Cooling Performance. In order to evaluate the heating performance and the quality of
temperature control in the newly designed reactor a series of standard solvents for organic synthesis
was processed. First, to validate the principle of the contact thermometer and the algorithm to
determine the reaction temperature, preliminary heating experiments have been conducted with
simultaneous internal temperature sensing in an instrument prototype setup. As shown in Figure 4 the
calculated reaction temperature derived from the measurement of the surface temperature of the glass
vial agrees nicely with the actual temperature inside the reaction vial determined by an internal
temperature probe. Furthermore, the filling volume has no significant influence on the heating profile.
Heating the minimum filling volume (2 mL) and the maximum filling volume (6 mL) only differs by a
few seconds.
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Figure 4. Temperature profiles for heating 2 mL and 6 mL of ethanol to 180 °C (5 min hold time) in
the Monowave 50 reactor: calculated reaction temperature (blue) and measured internal temperature
(red). The power graphs (green) indicate that significant energy is required only to heat up the heating
coil and that power consumption is virtually independent of the vial content. A NiCrꢀNi type K
thermoelement (500 × 0.5 mm) was used as internal temperature probe.
With this optimized algorithm in hand, the performance of the new reactor regarding heating efficiency
of frequently used organic solvents was compared to a standard singleꢀmode microwave reactor. The
small matrix comprises polar (high tan δ) as well as nonꢀpolar solvents (low tan δ) to demonstrate that,
unlike applying microwave dielectric heating,12 the dielectric properties of the solvents have no
influence on the heating efficiency. In the operation range of 2 to 6 mL most tested solvents are heated
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virtually within the same time frame of approximately 3.5ꢀ5 min (corrected time without ca. 30 s
preheating phase) to the respective target temperatures (Figure 5).
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Figure 5. Heating profiles (AFAP) of common solvents (6 mL) to individual target temperatures: DCM
(green), 140 °C; EtOH (red), 160 °C; THF (orange) and water (blue), 180 °C; MeCN (yellow) and
toluene (light blue), 200 °C; NMP (black), 250 °C. For clarity, monitored pressure is not shown.
In order to ensure a high degree of accuracy in achieving the programmed target temperature heating
efficiency was sacrificed. Since when applying convective heating the heating process will continue
even when power is already reduced it appeared advantageous to regulate the power more
conservatively to prevent any significant thermal overshoots, especially when exothermic reactions are
processed. This invariably leads to the comparatively slow heating ramps of ca. 3.5ꢀ5 minutes as shown
in Figure 5. Notably, polar solvents with high heat capacity (such as NMP, ethanol, H2O) still tend to
slightly exceed the programmed target temperatures. In contrast, using microwave reactors the inꢀcore
heating immediately stops when the power is off, therefore target temperatures are reached faster and
more accurately, although slight overshoots can also be observed for some solvents (see Figure S1,
Supporting Information). Consequently, in direct comparison heating with microwave reactors,
(dielectric) heating will always be more rapid. Notably, the cooling principle of the Monowave 50
reactor utilizing a standard heat exchanger fan is less complex than the one used in standard singleꢀ
mode microwave reactors (compressed air flow). The efficiency of the integrated fan, which makes the
instrument independent of external sources of compressed air, is still sufficient to cool most solvents
within 4ꢀ5 min, but lacks the speed of the compressed air support. Therefore, overall cycle times
including heating, hold time and cooling are invariably longer compared to a microwave experiment.
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Standard Chemistry Examples. The assumption that slower heating and minor thermal overshoots
have no significant influence on the reaction outcome has been validated with selected model
transformations. All chemical transformations performed during this validation (Scheme 1) are known
in the literature and have been previously investigated and optimized in our laboratories using
microwave dielectric heating and/or using the SiC reactor mentioned above.8,9 The results obtained
with the conductively heated Monowave 50 reactor demonstrate that the only relevant parameter is the
hold time at the target temperature, rather than the time required to achieve the target temperature
(ramp time). The efficiency of other features like stirring (influence of scale/filling volume) and
pressure build up/release were also verified with appropriate chemical transformations.
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Scheme 1. Model reactions for performance validation. Reactions were performed in the Monowave 50
reactor (CONV) based on optimization data previously obtained using microwave conditions (hold
time, temperature). For detailed reaction conditions in the singleꢀmode microwave reactor, see ref 8.
For detailed reaction conditions in the Monowave 50, see the Experimental Section.
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For all model reactions shown in Scheme 1 virtually identical results in terms of conversion, purity
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profile, and/or product yields were obtained using the Monowave 50 reactor based on conventional
heating principles (CONV) compared to experiments utilizing dielectric heating in a singleꢀmode
microwave reactor (MW).8,9 Although the heating jacket reaches very high temperatures to ensure a
rapid heating of the vessel contents, wall effects due to the hot vessel surface apparently do not play a
significant role in the outcome of the model reactions. This is in agreement with earlier investigations
and findings from our laboratory comparing conventional heating with microwave dielectric heating.9,13
As an initial example, the formation of 2ꢀmethylbenzimidazole (1) from oꢀphenylenediamine
and acetic acid (Scheme 1a) was performed at different scales.8 Utilizing a reaction temperature of 200
°C the resulting autogenic pressure is close to the 20 bar limit of the Monowave 50 instrument. At both
of the applied scales (2 and 6 mL, respectively) identical product yields (93%) were obtained.
Additionally, a gas evolving Knoevenagel condensation (Scheme 1b) was performed demonstrating the
feasibility of the instrument’s pressure control system.8 At small scale (2 mL) the overpressure from
CO2 remaining in the vial after cooling (~7 bar) was not an issue. Even on larger scales (6 mL) the
overpressure (~15 bar) was safely released upon opening of the instrument cover (see above). Of
particular interest in this evaluation were exothermic reactions such as the nitro group reduction shown
in Scheme 1c, to assess how the control system is able to handle these types of transformations in terms
of temperature accuracy. Even on small scale this reaction is difficult to control under microwave
conditions leading to a significant exotherm that is accompanied by a pressure rise close to the 30 bar
limit of the microwave reactor (Figure S2, Supporting Information).14 As outlined above, applying the
conductive heating principles realized in the new reactor (Figure 1) the thermal overshoot cannot be
expected to be controlled. Under identical reaction conditions as in the microwave reactor on a 2 mmol
scale, a similar exotherm and pressure buildꢀup above the instrument´s limit of 20 bar was observed,
which led to the termination of the experiment (Figure S3, Supporting Information). For the nitro
reduction to be performed successfully in the Monowave 50, the scale had to be reduced to 1 mmol
leading to a more diluted reaction mixture. Using these conditions the temperature overshoot could be
completely prevented and the pressure remained in the operational range of the Monowave 50 (Figure
S3, Supporting Information). In any event, virtually identical product yields were obtained for both
processes. Finally, the influence of filling volume and solid material on stirring efficiency was
investigated using a DielsꢀAlder reaction involving large quantities of solid starting materials (Scheme
1d), and a substitution reaction where potassium carbonate (1.5 equiv) is used as heterogeneous base
(Scheme 1e).15 On small scale (2 or 3 mL, respectively) the DielsꢀAlder reaction furnishes identical
high yields in both reactor types. When moving to larger scale (6 mL) efficient stirring to quickly
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dissolve the substrates becomes more an issue due to the amount of solid material (>1.5 g) present,
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which may lead to inhomogeneous temperature distribution within the vial and consequently to
diminished yield (very similar to the situation under microwave conditions).10 Higher stirring speed
(1200 rpm) overcomes this problem and the yield can be even increased to >90 % (Table 1). In the
substitution reaction K2CO3 remains present as solid material in the reaction mixture during the entire
process.15 The observable trend is similar to the DielsꢀAlder reaction: on smaller scale the amount of
K2CO3 can be agitated efficiently and the reaction proceeds smoothly furnishing high yields (83%). In
the 6 mL range (>600 mg K2CO3) stirring becomes important to allow accurate temperature control. If
the stirring speed is too low the admixing of the solid base with the reaction mixture is insufficient,
resulting in lower yields (ca. 60%).15 Furthermore, a significant thermal overshoot can be observed due
to inaccurate temperature measurement caused by the solid base being immobilized on the bottom of
the vial.10 With a stirring speed of 1200 rpm yields can be improved again, but are still lower (70ꢀ80%)
compared to the smaller scale. With the information from these initial experiments further chemistry
examples with respect to educational purpose and also medicinal chemistry relevance have been
investigated.
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Table 1. Influence of Filling Volume and Stirrer Speed on the Diels-Alder Cycloadditiona
reactor scale (mmol) toluene (mL) stirring (rpm) yield (%)
CONV
CONV
CONV
MW
2.45
7.35
7.35
2.45
7.35
7.35
2
6
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2
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6
600
600
88
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94
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92
1200
600
MW
600
MW
1200
a
Conditions: equimolar amounts of anthracene and maleic anhydride, heating AFAP to 200 °C, hold
time 5 min, yield refers to isolated product. For detailed reaction conditions on a 2.45 mmol scale in the
Monowave 50 (CONV), see the Experimental Section.
Educational Chemistry Examples. For synthetic organic reactions that are implemented in an
undergraduate laboratory course several criteria need to be met: they have to be operationally
straightforward, relatively inexpensive and should cover standard organic reaction mechanisms. Owing
to the simplicity of use and small footprint of the Monowave 50 reactor, its use in undergraduate (and
graduate) teaching laboratories appears to be of significant potential interest. In Universityꢀtype
teaching laboratories the long reaction times experienced for many standard synthetic organic chemical
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transformations (even at reflux conditions) often form a significant obstacle for their implementation
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into a laboratory course. Microwave instruments have therefore become increasingly popular in many
undergraduate teaching laboratories.16 We have therefore investigated the adaptation of several proven
microwave chemistry protocols currently used in an undergraduate teaching laboratory to the
Monowave 50 reactor.17 These involve Williamson ether syntheses, oxidation of double bonds and
alcohols, a Knoevenagel and a Grignard reaction. All reactions were conducted under identical
conditions (scale, hold time, temperature) in both a singleꢀmode microwave reactor (MW) and the
Monowave 50 instrument (CONV).
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4ꢀNitrophenetol (6) and propoxybenzene (7) were synthesized via the Williamson ether
synthesis from the corresponding phenols using bromoethane or 1ꢀbromopropane, respectively
(Scheme 2). The employed method was adapted from a protocol where a biphasic system of K2CO3 in
MeOH was found to be effective.18 An equimolar amount of the phenol and base (5 mmol) were
reacted with 1.2 equiv of alkyl bromide in EtOH as solvent. For the more volatile bromoethane (bp 38
°C) a temperature of 120 °C had to be selected in order not to exceed the pressure limit of the
instruments (20 bar), whereas for 1ꢀbromopropane (bp 71 °C) 140 °C were possible. To approach the
set temperature more smoothly in the Monowave 50 the “ramp to temp” setting was selected and
virtually identical isolated yields for both experiments were obtained (Scheme 2). In addition, to
emphasize that only thermal effects and thus the Arrhenius equation applies, a standard reflux (EtOH at
78 °C) experiment under otherwise identical conditions as described above was performed for the
synthesis of propoxybenzene (7). After 2 h an HPLC conversion of 50 % to the product was reached.
Further heating overnight did not improve the reaction progress (for a kinetic study, see Figure S4 in
Supporting Information) and 39% of ether 7 was isolated, indicating that 1ꢀbromopropane is
presumably vaporized and therefore removed from the reaction mixture already after 2 h.
Consequently, a closed vial approach is beneficial in cases, where volatile reagents are involved.
EtBr, K2CO3
OH
OEt
EtOH
CONV 74%
MW 75%
O2N
O2N
120 °C, 10 min
6
n-PrBr, K2CO3
O
OH
EtOH
CONV 62%
MW 61%
140 °C, 5 min
7
Scheme 2. Williamson ether syntheses. For detailed reaction conditions, see the Experimental Section.
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The direct oxidation of cyclohexene to adipic acid using aqueous hydrogen peroxide (H2O2) as a
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green and cheap oxidation reagent (only water is formed as byꢀproduct) and tungstic acid (H2WO4) as
catalyst using highꢀtemperature microwave chemistry was demonstrated in 2013.19 If stirring is not
sufficient in this biphasic system, H2O2 decomposes to H2O and O2 which is a highly exothermic
process. Furthermore, the rise in temperature from the exotherm increases the rate of decomposition.19
To prevent these events, a ramp time of 5 min to reach the 130 °C reaction temperature was mandatory.
Under these conditions, a temperature overshoot of only 8 °C and a maximum pressure of 11 bar was
experienced (for the heating profiles, see Figure S5 in Supporting Information) and adipic acid (8) was
isolated in 40% after heating for 30 min (Scheme 3a). A similar protocol was applied for the oxidation
of the secondary alcohol 1ꢀphenylꢀ1ꢀpropanol to propiophenone (9), however, 1 mol% of the phaseꢀ
transfer catalyst (PTC) methyltrioctylammonium hydrogen sulfate was necessary (Scheme 3b).20
Initially, a 3 min ramp was tested, but a rapid temperature increase − resulting in an overshoot of 22 °C
− was experienced accompanied with a pressure rise (for the Monowave 50 heating profiles, see Figure
S6 in Supporting Information). Therefore, also the 5 min ramp was applied and 9 could be generated
successfully.
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Scheme 3. Oxidation reactions. For detailed reaction conditions, see the Experimental Section.
For the Knoevenagel condensation of benzaldehyde and ethyl cyanoacetate, we transferred the original
undergraduate laboratory protocol21 to a microwave heated version. Toluene was employed as solvent
and 1 mol% of βꢀalanine was used as catalyst. After 8 min at 150 °C (AFAP) 75% of cinnamic ester 10
was isolated under microwave conditions and 73% when performed under identical conditions in the
Monowave 50 instrument (Scheme 4). Also in this case a conventional reflux experiment was
conducted: after 2 h, full conversion was achieved and 70% of product 5 was isolated (for a kinetic
study, see Figure S7 in Supporting Information).
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Scheme 4. Knoevenagel condensation of benzaldehyde and ethyl cyanoacetate. For detailed reaction
conditions, see the Experimental Section.
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Performing a Grignard reaction in a microwave reactor is not a trivial affair, since arcing phenomena of
magnesium turnings during the formation of the Grignard reagent may occur.22 For this very reason, no
direct comparison of microwave and conventional sealed vial heating in the Monowave 50 reactor was
attempted. The Grignard reaction of bromobenzene and ethyl benzoate to form triphenylmethanol (7)
was therefore only performed in the Monowave 50 instrument (Scheme 5), with conditions adapted
from previously published work using microwave conditions.17 The generation of the Grignard reagent
11 was performed in dry THF as solvent, taking advantage of the higher boiling point compared to
traditional Et2O. After cooling, ethyl benzoate was added to the vial containing phenylmagnesium
bromide (11) and the reaction mixture further heated for an additional 15 min at 85 °C to provide
triphenylmethanol (12) in 58% isolated yield. This reaction showcases one of the few examples, where
microwave heating cannot be generally applied and thus the conventionally heated sealed vial reactor
proved to be the better solution.
Scheme 5. Synthesis of triphenylmethanol via the Grignard reaction. For detailed reaction conditions,
see the Experimental Section.
A more advanced example represents generation of a derivative of a pyrazoleꢀbased NFAT
transcription factor regulator, which – due to costꢀefficiency reasons for educational laboratory courses
– is a modification of a three step microwave protocol originally developed for the synthesis of related
amide analog (Scheme 6).23 The first step implements the generation of pyrazole 14 from hydrazine 13
and acetylacetone. 4ꢀNitrophenylpyrazole 14 is then further converted to the corresponding amine 15
via a catalytic transfer hydrogenation employing 2 mol% Pd/C as catalyst and cyclohexene as hydrogen
donor. To prevent a temperature overshoot in the Monowave 50 due to the exothermic reaction, a ramp
time of 3 min is necessary. The final amidation step involves heating of aromatic amine 15 with
carboxylic acid 16 in the presence of phosphorus trichloride (PCl3), furnishing amide 17 in 50%
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isolated yield using microwave conditions and 55% in the Monowave 50 reactor. Again, in this 3ꢀ
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step synthesis of amide 17 virtually the same isolated yields were obtained for each single step in both
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the microwave instrument and the conventionally heated Monowave 50.
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Scheme 6. Threeꢀstep synthesis of amide 17. For detailed reaction conditions, see the Experimental
Section.
Medicinal Chemistry Examples. Microwave heating has become a fundamental enabling technology
in the pharmaceutical industry, in particular for rapid reaction optimization on laboratory scale and for
the fast development of synthetic steps towards the synthesis of APIs (active pharmaceutical
ingredients).2,24 In this context, we herein describe rapid processꢀintensified synthetic protocols for the
synthesis of Olanzapine (18), Imatinib (19) and Glibenclamide (20), approved drugs of high
importance for the pharmaceutical industry. The reaction conditions were first optimized employing
standard singleꢀmode microwave heating, followed by additionally performing all synthetic steps in the
Monowave 50 instrument. Compared to the conventional (often reflux) protocols a dramatic reduction
in reaction times from several days to only a few minutes could be achieved, along with high product
yields and simplified overall processes.
Synthesis of Olanzapine. Olanzapine or Zyprexa, a thienobenzodiazepine, is a second generation
(atypical) antipsychotic agent which is prescribed for the treatment of schizophrenia and bipolar
disorder.25 It was developed and launched in 1996 by Eli Lilly and is still among the topꢀten bestꢀ
selling drugs and generics.26 Albeit different synthetic approaches towards the molecule have been
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reported in the literature,25 we decided to adapt the continuous flow route deployed by Kirschning
and coworkers (Scheme 7).27
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Scheme 7. Synthesis of Olanzapine 18. For detailed reaction conditions, see the Experimental Section.
For the initial BuchwaldꢀHartwig reaction involving aryliodide 21 and 2ꢀaminothiophene 22 different
Pd catalysts, two metal chelating ligands (XPhos and Xantphos), and organic and inorganic bases were
screened. It was found that selectivity is highly dependent on the catalyst and ligand system. The best
results concerning conversion and selectivity could be achieved by using Pd(OAc)2 as a catalyst,
Xanthphos as a ligand and sterically hindered DBU as base. After heating at 130 °C for 10 min and
filtration through a plug of silica, intermediate 23 could be directly used for the next step, the reduction
of the NO2 group. For this purpose the hydrazineꢀmediated reduction catalyzed by in situ formed iron
oxide nanocrystals was employed.14 Workup involved simple filtration through a plug of silica
providing aniline 24 in 96 % product yield and in sufficient purity for the subsequent step. Gratifyingly,
the acidꢀpromoted cyclization of aniline 24 to benzodiazepine 25 proceeded smoothly following the
published protocol.27 Heating a solution of compound 24 under acidic conditions at 120 °C for 10 min
led to full conversion. For the final reaction step, the batch protocol of Kirschning was adapted to
.
microwave conditions. In our hands, employing BF3 Et2O as Lewis acid catalyst27 in EtOH at various
temperatures and reaction times mainly resulted in hydrolyzation of 25 to the corresponding
diazepinone. Finally, it was found that simply heating of intermediate 25 in neat Nꢀmethylpiperazine at
160 °C for 30 min and subsequent purification by flash chromatography provided pure olanzapine (18)
in 96 % yield. Performing the 4ꢀstep synthesis of 18 in the Monowave 50 using identical conditions and
instrument settings as for the MW experiments resulted in a virtually identical isolated overall yield of
Olanzapine.
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Synthesis of Imatinib. Imatinib (19), the API in the drug Gleevec, is an anticancer agent which is
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used for the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor
(GISTs).28 It has proven to be a popular target drug for synthetic chemistry, thus several processes have
been published.29 We essentially used the synthetic route published by Ley and coworkers,29b but had
to replace some of the original procedures with protocols more compatible with microwave synthesis
(see Scheme 8). The building blocks 29 and 32 for the final coupling step were synthesized via two
different synthetic routes. For the initial amidation step toward building block 29, commercially
available aniline 26 and acyl chloride 27 were subjected to microwave heating in MeCN for 3 min at
130 °C. After a simple extraction the condensation product 28 was obtained in 91% yield with >99 %
purity (HPLC). Running the exothermic reaction in the Monowave 50 reactor applying the same
settings as in the microwave instrument (AFAP mode) led to a significant temperature overshoot of 25
°C (see Figure S8 in Supporting Information). Nevertheless, the amidation remained clean and 28
could be isolated in very similar yields and high purity. Full conversion of benzylic chloride 28 to 29
was obtained by reaction with 3 equiv of Nꢀmethylpiperazine and 3 equiv of triethyl amine at 170 °C
for 5 min. To further simplify the protocol, both steps could be performed as a sequential oneꢀpot
reaction, and after crystallization from water, 29 was obtained in 93% overall yield. Although amine 32
is commercially available, it was readily synthesized starting from acetylpyridine (30) and DMFDMA
within a few minutes.29,30
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N
Cl
Br
Br
Cl
N
Br
MeCN
Et3N, MeCN
+
+
130 °C, 3 min
170 °C, 5 min
HN
HN
N
NH2
H
O
Cl
O
O
29
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N
NH2
O
O
N
N
NaOH, n-BuOH
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H2N
NH2
O
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N
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+
+
NH2 Cl
170 °C, 3 min
O
N
N
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N
N
H
N
N
.
Pd2(dba)3 CHCl3 XPhos, KOtBu
toluene:t-BuOH (1:1)
N
N
CONV 58%
MW 60%
29 + 32
HN
160 °C, 10 min
19
O
Scheme 8. Synthesis of Imatinib 14. For detailed reaction conditions, see the Experimental Section.
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This condensation was performed under neat conditions due to side product formation upon reaction
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with the solvent; e.g., in case of MeOH >30% of nicotinic acid methyl ester was detected by GCꢀMS.
Clean and complete condensation of 31 producing the heterocyclic key intermediate 32 was obtained
using guanidine hydrochloride, NaOH as base and nꢀBuOH as solvent at 200 °C within 5 min.
Crystallization from ice/water provided 32 in 70% yield and sufficient purity for the final step.
Intermediates 29 and 32 were coupled via a BuchwaldꢀHartwig reaction using Pd2(dba)3 with XPhos as
catalystꢀligand system according to the Ley protocol.29b For reaction optimization, a number of
different bases and solvent mixtures were tested. Performing the reaction in the presence of the
commonly employed base Cs2CO3 caused stirring problems and the coupling was almost completely
suppressed. KOtꢀBu was found to be a more suitable base and in toluene/tꢀBuOH (1:1) as solvent
mixture complete conversion to 19 (HPLC) in high selectivity was achieved. For the Buchwaldꢀ
Hartwig coupling a 3 min ramp to reach and keep the set target temperature of 160 °C was necessary in
the Monowave 50, since under AFAP conditions a temperature overshoot of ca. 20 °C was
experienced. Pure Imatinib (19) was obtained after automated flash chromatography. Whilst the yield
of the last step was similar to that described in the flow procedure (69 vs 71%),29b the overall yield
could be increased significantly (32 vs 58%).
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Synthesis of Glibenclamide. Glibenclamide or Glyburide is a hypoglycemic agent, which decreases the
blood sugar level, therefore it is used in the treatment of diabetes mellitus type II.31 We first
transformed the synthetic route reported Velingkar and coworkers32 from conventionallyꢀheated open
vessel to sealedꢀvessel microwave conditions and were able to significantly reduce reaction times from
many hours down to several minutes (Scheme 9). For the initial amidation step leading to amide 35 the
original method was slightly modified. Instead of a 2ꢀstep procedure including a preceding acid
chloride formation of carboxylic acid 33 and subsequent amidation with 34, we applied the oneꢀstep
protocol already described in Scheme 6 employing phosphorous trichloride as reagent. Isolation by
simple extraction provided pure 35 in 95% yield. Intermediate 36 was obtained in high purity (HPLC)
and 88% yield by sulfonation of 35 using chlorosulfonic acid as sulfonation agent and CHCl3 as solvent
within 10 min at 60 °C. The subsequent formation of sulfonamide 37 was performed with NH4OH as
amination reagent and dioxane as solvent. Isolation by extraction provided sulfonamide 37 in 68%
yield. For the last step, the synthesis of sulfonylurea Glibenclamide (20), we followed a protocol that
was originally performed at room temperature for 24 h employing Cu(I)Cl as catalyst.33 Using 0.5
equiv of K2CO3, 2.4 equiv of cyclohexylisocyanate and heating at 80 °C for 10 min, 80% conversion
and a 54% isolated yield of 20 could be obtained. Performing the fourꢀstep synthesis of 20 in the
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Monowave 50 reactor using exactly the same reaction conditions and instrument settings as in the
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microwave instrument provided Glibenclamide (20) in exactly the same overall yield (see Scheme 9).
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Scheme 9. Synthesis of Glibenclamide 20. For detailed reaction conditions, see the Experimental
Section.
Conclusion
In summary, we have demonstrated the design and construction of a conventionallyꢀheated sealedꢀ
vessel reactor (Monowave 50) that is capable of mimicking many of the features common to modern
singleꢀmode microwave reactors with respect to heating and cooling efficiency, temperature and
pressure monitoring and the ability to efficiently agitate the reaction mixture in a cylindrical vessel
using magnetic stirring. Similar to a standard sealed vessel microwave instrument, reaction temperature
and time (hold time) is programmed via a graphical interface, with vessel handling (sealing, opening,
introduction to the cavity) all being very similar to a standard microwave instrument. Although heating
and cooling cycles are somewhat slower in the new device compared to a standard microwave
instrument (leading to extended processing times), no direct impact on the outcome of the investigated
chemical transformations in terms of conversion, selectivity or purity profiles could be observed.
Temperature overshoots as a result of exothermic reactions can typically be overcome by adding a
ramp time to the set temperature. Since using conductive heating principles the heating efficiency of
the reaction mixture/solvent is not dependent on its dielectric properties, also nonꢀpolar solvents can be
employed conveniently in this reactor. In addition, the main advantages of microwave heating, such as
superheating of reaction mixtures above their boiling points accompanied by faster reaction rates, and
excellent control over reaction temperature and pressure, are all duplicated with the new reactor.
Therefore, sealedꢀvessel microwave conditions on laboratory scale (2ꢀ6 mL reaction volume, 250 °C,
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20 bar) can easily be mimicked in a reactor of much reduced complexity, smaller footprint (no
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compressed air required) and lower cost. It can thus be argued that in both teaching and research labs
this technology will be very useful, providing a simplified and more affordable solution for carrying
out sealed vessel microwave experiments.
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Experimental Section
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General Methods. HꢀNMR spectra were recorded on a 300 MHz instrument. CꢀNMR spectra were
recorded on the same instrument at 75 MHz. Chemical shifts (δ) are expressed in ppm downfield from
TMS as internal standard. The letters s, d, t, q, and m are used to indicate singlet, doublet, triplet,
quadruplet, and multiplet. GCꢀMS spectra were recorded using a GC coupled with a DSQ II (EI, 70
eV). A HP5ꢀMS column (30 m × 0.250 mm × 0.25 ꢁm) was used with Helium as carrier gas (1 mL
minꢀ1 constant flow). The injector temperature was set to 280 °C. After 1 min at 50 °C the temperature
was increased in 25 °C minꢀ1 steps up to 300 °C and kept at 300 °C for 4 min. The MS conditions were
as follows: positive EI ionization, ionization energy 70 eV, ionization source temperature 280 °C,
emission current 100 ꢁA, fullꢀscanꢀmode. GCꢀFID analysis was performed on a GC with a flame
ionization detector using a HP5 column (30 m x 0.250 mm x 0.025 ꢁm). After 1 min at 50 °C, the
temperature was increased in 25 °C minꢀ1 steps up to 300 °C and kept at 300 °C for 4 min. The
detector gas for the flame ionization was H2 and compressed air (5.0 quality). Analytical HPLC
analysis was carried out on a C18 reversedꢀphase (RP) analytical column (150 x 4.6 mm, particle size 5
ꢁm) at 37 °C using a mobile phase A (water/MeCN 90:10 (v/v) + 0.1% TFA) and B (MeCN + 0.1%
TFA) at a flow rate of 1.5 mL minꢀ1. The following gradient was applied: linear increase from solution
30% B to 100% B within 10 min. LCꢀMS analysis was carried out on a C18 reversedꢀphase (RP)
analytical column (150 x 4.6 mm, particle size 5 ꢁm) at 37 °C using a mobile phases A (water/ MeCN
90:10 (v/v) + 0.1% HCOOH) and B (MeCN + 0.1% HCOOH) at a flow rate of 0.6 mL minꢀ1. The
following gradient was applied: linear increase from solution 30% B to 100% B in 17 min, hold at
100% solution B for 4 min. HRMS analysis was performed on a TOF LC/MS instrument using APCI
in positive mode. Melting points were obtained on a standard melting point apparatus in open capillary
tubes. Microwave irradiation experiments were carried out in a Monowave 300 singleꢀmode
microwave reactor using 10 mL borosilicate glass vials. The reaction temperature was monitored by an
external infrared sensor (IR) that was housed in the sideꢀwalls of the microwave cavity, measuring the
surface temperature of the reaction vessel. Reaction times refer to hold times at the temperature
indicated, not to total irradiation times. All previously optimized syntheses were additionally carried
out in a Monowave 50 reactor11 using 10 mL borosilicate glass vials with silicone caps. The
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temperature was monitored by an external contact sensor placed at the cavity bottom, measuring the
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surface temperature of the reaction vessel (Figure 1). All solvents and chemicals were obtained from
standard commercial vendors and were used without any further purification. Products were
1
characterized by H NMR and identified by comparison of the spectra with those reported in the
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literature. All compounds synthesized herein, except for compounds 15 and 17, are known in the
literature. Proof of purity was obtained by 1H NMR, GCꢀFID and HPLCꢀUV spectroscopy.
The experimental procedures given below refer to syntheses performed in the Monowave 50.
The experiments have additionally been performed in a singleꢀmode microwave reactor under identical
conditions (temperature and hold time), unless otherwise stated.
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2-Methylbenzimidazole (1). Into a 10 mL process vial, equipped with a stir bar, were placed oꢀ
phenylenediamine (10 mmol, 1.08 g) and 2 mL of acetic acid. The vial was closed and the reaction
mixture was heated to 200 °C with a 5 min ramp and 600 rpm stirring speed and was then kept at this
temperature for further 3 min. After cooling, AcOH was removed under reduced pressure, the product
was precipitated using a saturated K2CO3 solution and further extracted with EtOAc. The organic phase
was dried over Na2SO4 followed by evaporation of EtOAc under reduced pressure. After drying
overnight at 50 °C, 2ꢀmethylbenzimidazole was obtained as pink solid in 93% yield (1.23 g) and >99%
purity (HPLC at 215 nm).
1
Mp 178ꢀ180 °C, (lit.8 177ꢀ178 °C). H NMR (300 MHz, DMSOꢀd6) δ 12.20 (brs, 1H), 7.44 (brs, 2H),
7.13 – 7.07 (m, 2H), 2.48 (s, 3H). The spectral data are in agreement with the previously published
values.8
trans-Cinnamic Acid (2). Into a 10 mL process vial, equipped with a stir bar, were placed
benzaldehyde (4 mmol, 410 ꢁL), malonic acid (6 mmol, 624 mg), piperidine (6 mmol, 590 ꢁL) and 1
mL of EtOH. The vial was closed and the reaction mixture was heated to 140 °C with a 3 min ramp and
1200 rpm stirring speed and was then kept at this temperature for further 10 min. After cooling, the
reaction mixture was poured into water and acidified under agitation by the addition of 1M HCl. The
resulting slurry was cooled in an iceꢀbath for 1 h, after which the precipitate was isolated by filtration
and washed with cold water. The product was dried overnight at 50 °C and 2 was obtained in 78%
yield and >99% purity (HPLC at 215 nm).
1
Mp 136ꢀ137 °C, (lit.8 136ꢀ138 °C). H NMR (300 MHz, DMSOꢀd6) δ 12.42 (brs, 1H), 7.70 – 7.67 (m,
2H), 7.60 (d, J = 16.1 Hz, 1H), 7.43 – 7.39 (dd, J = 6.6, 3.7 Hz, 3H), 6.54 (d, J = 16.0 Hz, 1H). The
spectral data are in agreement with the previously published values.8
Aniline (3). Into a 10 mL process vial, equipped with a stir bar, were placed nitrobenzene (1 mmol, 103
ꢁL), 1.25 mL of MeOH, 125µL of a 0.02 M stock solution of Fe(acac)3 in MeOH (0.25 mol% catalyst
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loading), and 1.8 equiv of N2H4 H2O (1.8 mmol, 88 ꢁL). The vial was closed and the reaction mixture
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was heated at 150 °C for 5 min with 600 rpm stirring speed. After cooling, the solvent was evaporated
under reduced pressure, the crude mixture was dissolved in EtOAc and filtered through a plug of silica gel.
After evaporation of EtOAc, pure aniline was obtained in 98% (91 mg) isolated yield and >99% purity
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HPLC at 215 nm).
1H NMR (300 MHz, CDCl3) δ 7.23 – 7.16 (m, 2H), 6.82 – 6.77 (m, 1H), 6.72 (dd, J = 8.5, 1.0 Hz, 2H),
3.52 (brs, 2H). The spectral data are in agreement with the previously published values.8
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(9R,10S,11R,15S)-9,10-Dihydro-9,10-[3,4]furanoanthracene-12,14-dione (4). Into a 10 mL process
vial, equipped with a stir bar, were placed anthracene (2.45 mmol, 437 mg), maleic anhydride (2.45
mmol 242 mg) and 2 mL of toluene. The vial was closed and the reaction mixture was heated at 200 °C
for 5 min with 600 rpm stirring speed. After cooling, the reaction mixture was further cooled in a
refrigerator (~ 5 °C) for 3ꢀ4 h to enable complete crystallization of the cycloaddition product. The
precipitate was filtered, washed with cold toluene, and dried at 50 °C to provide 596 mg (88%) of the
colorless product in 97% purity (HPLC at 215 nm).
Mp 267ꢀ268 °C, (lit.8 265ꢀ266 °C). 1H NMR (300 MHz, DMSOꢀd6) δ 7.51 – 7.45 (m, 2H), 7.37 – 7.31
(m, 2H), 7.23 – 7.15 (m, 4H), 4.88 (s, 2H), 3.66 – 3.65 (m, 2H). The spectral data are in agreement with
the previously published values.8
2-Chloro-1-(4-methoxyphenoxy)-4-nitrobenzene (5). Into a 10 mL process vial, equipped with a stir
bar, 1,2ꢀdichloroꢀ4ꢀnitrobenzene (1 mmol, 191 mg) and 1.1 equiv of 4ꢀmethoxyphenol (1.1 mmol, 136 mg),
were dissolved in 2 mL DMA. After the addition of 1.5 equiv of K2CO3 (Sigma Aldrich 347825, ~325
mesh, 1.5 mmol, 207 mg), the vial was closed and the reaction mixture was heated at 150 °C for 10
min with 600 rpm stirring speed. After cooling, the reaction mixture was transferred to an Erlenmeyer
flask and 2 mL of water were added slowly while stirring the reaction mixture vigorously. A precipitate
was formed which was intensified by scratching with a glass rod. After further 1 h stirring in the iceꢀ
bath, the precipitate was filtered and washed with cold water. Drying overnight at 50 °C gave 5 as
yellow solid in 83% yield (232 mg) and 99% purity (HPLC at 215 nm).
Mp 97ꢀ99 °C, (lit.8 91ꢀ93 °C). 1H NMR (300 MHz, DMSOꢀd6) δ 8.44 (d, J = 2.8 Hz, 1H), 8.15 (dd, J =
9.2, 2.8 Hz, 1H), 7.21 – 7.15 (m, 2H), 7.09 – 7.03 (m, 2H), 6.90 (d, J = 9.2 Hz, 1H), 3.79 (s, 3H). The
spectral data are in agreement with the previously published values.8
4-Nitrophenetol (6). Into a 10 mL process vial, equipped with a stir bar, were placed 4ꢀnitrophenol (5
mmol, 696 mg), K2CO3 (5 mmol, 691 mg), bromoethane (6 mmol, 448 µL), and 1.5 mL of EtOH. The
vial was closed and the reaction mixture was heated to 120 °C with a 5 min ramp and 600 rpm stirring
speed and was then kept at this temperature for further 10 min. After cooling, the contents of the vial
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were transferred to a separatory funnel and partitioned between diethyl ether (15 mL) and 2%
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aqueous NaOH (15 mL). The aqueous layer was again extracted twice with diethyl ether (25 mL). The
organic layers were then combined, dried over MgSO4, and concentrated in vacuo. The product was
obtained as beige solid in 74% yield (618 mg) and ≥99% purity (HPLC at 215 nm). MW procedure:
Heating at 120 °C for 10 min without ramp, 75% yield.
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Mp 62ꢀ63 °C, (lit. 16b 60 °C). H NMR (300 MHz, CDCl3) δ 8.21 (d, J = 9.3 Hz, 2H), 6.95 (d, J = 9.3
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Hz, 2H), 4.15 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H). The spectral data are in agreement with the
previously published values.16b
Propoxybenzene (7). Into a 10 mL process vial, equipped with a stir bar, were placed phenol (5 mmol,
471 mg), K2CO3 (5 mmol, 691 mg), 1ꢀbromopropane (6 mmol, 545 µL), and 1.5 mL of EtOH. The vial
was closed and the reaction mixture was heated to 140 °C with a 3 min ramp and 600 rpm stirring
speed and was then kept at this temperature for further 5 min. After cooling, the contents of the vial
were transferred to a separatory funnel and partitioned twice between diethyl ether (15 mL) and 2%
aqueous NaOH (15 mL). The aqueous layer was again extracted twice with diethyl ether (25 mL). The
organic layers were then combined, dried over MgSO4, and concentrated in vacuo. The product was
obtained as colorless oil in 62% yield (422 mg) and 98% purity (HPLC at 215 nm). MW procedure:
Heating at 140 °C for 5 min without ramp, 61% yield.
1H NMR (300 MHz, CDCl3) δ 7.35 – 7.29 (m, 2H), 6.99 – 6.91 (m, 3H), 3.95 (t, J = 6.6 Hz, 2H), 1.90
– 1.79 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H). The spectral data are in agreement with the previously
published values.34
Adipic Acid (8). Into a 10 mL process vial, equipped with a stir bar, were placed cyclohexene (4
mmol, 406 µL), 4.4 equiv H2O2 (25% aqueous, 2.2 mL) and 1 mol% of tungstic acid (0.04 mmol, 10
mg). The vial was closed and the reaction mixture was heated to 130 °C with a 5 min ramp and 800
rpm stirring speed and was then kept at this temperature for further 30 min. After cooling, the contents
of the vial were transferred to a round bottomed flask and the residue in the vial was washed into the
flask with MeCN. The liquid was removed under reduced pressure at 70 °C and the solid crude product
was dried at 50 °C. The product was washed with ca. 5 mL cold 1N HCl and dried overnight at 50 °C
to obtain adipic acid as colorless solid in 40% yield (234 mg). MW procedure: 40% yield.
Mp 148ꢀ149 °C, (lit. 19 151ꢀ152 °C).1H NMR (300 MHz, DMSOꢀd6) δ 12.02 (brs, 2H), 2.21 (t, J = 6.4
Hz, 4H), 1.52 – 1.47 (m, 4H). The spectral data are in agreement with the previously published
values.19
Propiophenone (9). Into a 10 mL process vial, equipped with a stir bar, were placed 1ꢀphenylꢀ1ꢀ
propanol (4 mmol, 548 µL), 4.4 equiv H2O2 (25% aqueous, 2.2 mL), 1 mol% of sodium tungstate
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dihydrate (0.04 mmol, 13 mg) and 1 mol% of methyltrioctylammonium hydrogen sulfate (0.04
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mmol, 19 mg). The vial was closed and the reaction mixture was heated to 135 °C with a 5 min ramp
and 800 rpm stirring speed and was then kept at this temperature for further 5 min. After cooling, the
reaction mixture was extracted with diethyl ether (3 × 5 mL). To remove any peroxides, the organic
phase was washed with a saturated solution of NaHSO3 (2 x 5 mL). The combined organic phases were
dried over MgSO4, and concentrated in vacuo to give the product as yellow oil in 79% yield (424 mg)
and 97% purity (HPLC at 215 nm). MW procedure: 80% yield.
1H NMR (300 MHz, CDCl3) δ 8.00 – 7.97 (m, 2H), 7.60 – 7.54 (m, 1H), 7.50 – 7.44 (m, 2H), 3.02 (q, J
= 7.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H). The spectral data are in agreement with the previously
published values.35
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α-Cyanocinnamic Acid Ethyl Ester (10). Into a 10 mL process vial, equipped with a stir bar, were
placed benzaldehyde (5 mmol, 505 µL), ethyl cyanoacetate (5 mmol, 534 µL), 1 mol% of βꢀalanine
(0.05 mmol, 4.5 mg), and 2.5 mL of toluene. The vial was closed and the reaction mixture was heated
at 150 °C for 8 min with 600 rpm stirring speed. After cooling, the solvent was evaporated and 5 mL of
cold EtOH added. Upon stirring, the product precipitated. The precipitate was isolated by filtration and
washed with cold water. The product was dried overnight in a desiccator and was obtained as a
colorless solid in 73% yield (1.38 g) and 99% purity (HPLC at 215 nm). MW procedure: 80% yield.
Mp 48ꢀ49 °C, (lit. 21 48ꢀ49 °C).1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 8.02 – 8.00 (m, 2H), 7.61 –
7.49 (m, 3H), 4.41 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). The spectral data are in agreement with
the previously published values.21
Triphenylmethanol (12). Into a 10 mL process vial, equipped with a stir bar, were placed
bromobenzene (4 mmol, 420 µL), magnesium turnings (4.1 mmol, 100 mg) and 2 mL of extra dry
THF. The vial was quickly sealed with the cap and heated to 85 °C with a 3 min ramp and 600 rpm
stirring speed and was then kept at this temperature for a further 20 min. After cooling, ethyl benzoate
(2 mmol, 286 µL) dissolved in 1 mL of extra dry THF was added to the reaction mixture. Again, the
vial was quickly resealed with the cap and heated to 85 °C within a 3 min ramp and 600 rpm stirring
speed and was then kept at this temperature for 15 min. After cooling, the reaction mixture was
transferred to a round bottom flask; residues from the vial were washed into the flask with 1 mL of
THF. 10 mL of 10 % HCl were added in order to dissolve any unreacted magnesium. THF was
evaporated and a yellow slurry remained in the flask, which was extracted with DCM (3 × 25 mL). The
combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was
recrystallized from hexane or petroleum ether, to obtain the colorless product in 58% yield (302 mg)
and ≥99% purity (HPLC at 215 nm).
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Mp 165ꢀ166 °C, (lit. 36a 161ꢀ162 °C). H NMR (300 MHz, CDCl3) δ 7.40 – 7.26 (m, 15H), 2.84 (s,
1H). The spectral data are in agreement with the previously published values.36b
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3,5-Dimethyl-1-(4-nitrophenyl)-1H-pyrazole (14). Into a 10 mL vial, equipped with a stir bar, 4ꢀ
nitrophenylhydrazine hydrochloride (2 mmol, 379 mg), 1.05 equiv of acetylacetone (2.1 mmol, 215
µL) and 4 mL of EtOH were added. The vial was closed and the reaction mixture was heated at 160 ºC
for 2 min with 600 rpm stirring speed. After cooling, the content of the vial was transferred to a
separatory funnel, 1N NaOH (50 mL) was added and the aqueous phase was extracted with EtOAc (3 ×
50 mL). The organic layers were combined and dried over MgSO4. After filtration, the solvent was
evaporated and the product was obtained as a yellow/light brown precipitate in 76% yield (330 mg) and
≥99% purity (HPLC at 215 nm). MW procedure: 76% yield.
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Mp 104ꢀ105 °C, (lit. 37 101ꢀ103 °C). 1H NMR (300 MHz, CDCl3) δ 8.33 (d, J = 9.1 Hz, 2H), 7.69 (d, J
= 9.1 Hz, 2H), 6.09 (s, 1H), 2.44 (s, 3H), 2.32 (s, 3H). The spectral data are in agreement with the
previously published values.37
4-(3,5-Dimethyl-1H-pyrazol-1-yl)aniline (15). Into a 10 mL vial, equipped with a stir bar, 14 (1.2
mmol, 261 mg), 2 mol% of Pd/C (10 wt% Pd, 0.024 mmol, 26 mg), 4 mL of EtOH and 2 equiv of
cyclohexene (2.4 mmol, 243 µL) were added. The vial was closed and the reaction mixture was heated
to 170 ºC with a 3 min ramp and 800 rpm stirring speed and kept at this temperature for a further 4
min. After cooling, an HPLC for determining the conversion was obtained. If the conversion was
<95%, an additional amount of Pd/C was added and the vial was reheated at the same conditions. If the
conversion is ≥95%, the content of the vial was filtered through a plug of Celite. The filtrate was
evaporated, 1N NaOH (25 mL) was added and the aqueous phase was extracted with EtOAc (3 × 20
mL). The organic layers were combined and dried over MgSO4. After filtration, the solvent was
evaporated and the product was obtained as brown, sticky oil in 95% yield (213 mg) and 99% purity
(HPLC at 215 nm). MW procedure: Heating at 170 °C for 4 min without ramp, 96% yield.
1H NMR (300 MHz, DMSOꢀd6) δ 7.06 – 7.01 (m, 2H), 6.62 – 6.59 (m, 2H), 5.94 (s, 1H), 5.29 (brs,
13
2H), 2.15 + 2.13 (ds, 6H). C NMR (75 MHz, DMSOꢀd6) δ 148.5, 146.8, 139.1, 128.9, 126.1, 113.9,
106.0, 13.8, 12.3. HRMS (APCI): (M+H)+, ([C11H13N3]+H)+: m/z found 188.11810, calcd 188.11822.
4-Chloro-N-(4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)benzamide (17). Into a 10 mL vial equipped
with a stir bar 1.1 equiv of 4ꢀchlorobenzoic acid (1.25 mmol, 196 mg) were added. 15 (1.14 mmol, 213
mg) was taken up in 5 mL MeCN and transferred to the vial. 1.1 equiv of phosphorus trichloride (1.25
mmol, 109 µL) were added dropwise. The vial was closed and the reaction mixture was heated at 150
ºC for 1 min with 600 rpm stirring speed. After cooling, the content of the vial was transferred to a
separatory funnel, 1N NaOH (25 mL) was added and the aqueous phase was extracted with EtOAc (3 ×
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20 mL). The organic layers were combined and reꢀextracted with saturated NaCl (25 mL), then
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combined and dried over MgSO4. After filtration, the solvent was evaporated and the product was
obtained as light yellow precipitate which was further washed with a small amount of cold toluene.
After filtration, the product was obtained as white precipitate in 55% yield (204 mg) and 97% purity
(HPLC at 215 nm). MW procedure: 50% yield.
Mp 193ꢀ194 °C. 1H NMR (300 MHz, CDCl3) δ 8.58 (brs, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.8
Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 6.01 (s, 1H), 2.29 (s, 3H), 2.27 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 165.0, 149.0, 139.7, 138.2, 137.0, 136.1, 133.1, 129.0, 128.7, 125.4, 121.0,
106.9, 13.5, 12.3. HRMS (APCI): (M+H)+, ([C18H16ClN3O]+H)+: m/z found 326.10570, calcd
326.10547.
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5-Methyl-2-(2‘-nitrophenylamino)thiophene-3-carbonitrile (23). Into a 10 mL vial equipped with a
stir bar were placed 1ꢀiodoꢀ2ꢀnitrobenzene (0.5 mmol, 125 mg), 1 equiv of 2ꢀaminoꢀ5ꢀ
methylthiopheneꢀ3ꢀcarbonitrile (0.5 mmol, 70 mg), 5 mol% of Pd(OAc)2 (2.5 µmol, 5.5 mg) and 10
mol% of Xanthphos (0.05 mmol, 29 mg). The mixture was suspended in 4 mL of EtOAc/toluene (3:1)
and 2 equiv of DBU (1 mmol, 150 µL) were added. The vial was closed and the reaction mixture was
heated at 130 °C for 10 min with 800 rpm stirring speed. After cooling to 55 °C, the crude reaction
mixture was washed with ca. 20 mL of water and the aqueous phase extracted with 3 × 15 mL of DCM.
The combined organic phases were dried over Na2SO4. Filtration over a plug of silica and evaporation
of the solvent provided 123 mg (95 %) of product as a dark violetꢀred solid in 97% purity (HPLC at
215 nm).
1H NMR (300 MHz, CDCl3) δ 9.63 (brs, 1H), 8.27 (d, J = 8.5, 1.5 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H),
7.21 (d, J = 8.5 Hz, 1H), 6.99 (t, J = 7.9 Hz, 1H), 6.80 (s, 1H), 2.49 (s, 3H). The spectral data are in
agreement with the previously published values.27
2-[(2-Amino]-5-methylthiophene-3-carbonitrile (24). Into a 10 mL vial equipped with a stir bar were
.
placed nitroarene 23 (0.475 mmol, 123 mg), 1.5 mL of absolute EtOH, 2.5 equiv of N2H4 H2O (1.8
mmol, 88 µL), and 3 mol% of Fe(acac)3 (756 µL of a 0.02 mM ethanolic solution). The vial was closed
and the reaction mixture was heated at 150 °C for 5 min with 800 rpm stirring speed. After cooling to
55 °C, the solvent was evaporated under reduced pressure, the crude mixture was dissolved in EtOAc
and filtered through a plug of silica gel (10 g). The solvent was evaporated to provide 105 mg (96 %)
of product in 91% purity (HPLC at 215 nm). The product was pure enough to be used for the next step.
24 in ≥99% purity (HPLC at 215 nm) and 70% yield was obtained by purification by flash
chromatography using a 10 g SNAP ULTRA cartridge and petroleum ether/EtOAc (85:15) as eluent.
1H NMR (300 MHz, CDCl3) δ 7.23 (dd, J = 7.8, 1.3 Hz, 1H), 7.11 (td, J = 7.8, 1.4 Hz, 1H), 6.90 – 6.76
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(m, 2H), 6.48 (d, J = 1.3 Hz, 1H), 6.22 (brs, 1H), 3.84 (brs, 2H), 2.28 (d, J = 1.2 Hz, 3H). The
spectral data are in agreement with the previously published values.27
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2-Methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-amine (25). Into a 10 mL vial equipped with a
stir bar were placed aniline 24 (0.45 mmol, 105 mg), 4 mL of EtOAc/EtOH (2:1), and 5 drops of
concentrated HCl. The vial was closed and the reaction mixture was heated at 120 °C for 10 min with
800 rpm stirring speed. After cooling to 55 °C, precipitation by EtOAc, filtration and additional
washing with EtOAc provided 110 mg (91%) of product 25 as a yellow solid in ≥99% purity (HPLC at
215 nm).
1H NMR (300 MHz, MeOD) δ 7.16 (td, J = 7.7, 1.6 Hz, 1H), 7.07 (td, J = 7.6, 1.5 Hz, 1H), 6.96 (dd, J
= 7.9, 1.5 Hz, 1H), 6.83 (dd, J = 7.9, 1.4 Hz, 1H), 6.71 (d, J = 1.3 Hz, 1H), 2.33 (d, J = 1.3 Hz, 3H).
The spectral data are in agreement with the previously published values.27
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Olanzapine (18). Into a 10 mL vial equipped with a stir bar were placed benzodiazepine 25
(0.41 mmol, 110 mg) and 3 mL of Nꢀmethylpiperazine. The vial was closed and the reaction mixture
was heated at 160 °C for 30 min with 800 rpm stirring speed. After cooling to 55 °C, the crude reaction
mixture was washed with ca. 30 mL of water and the aqueous phase was extracted with 3 × 20 mL
DCM. The combined, organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by flash chromatography using a 25 g SNAP ULTRA cartridge and DCM/MeOH
as eluent. Evaporation of the solvent provided 122 mg (96 %) of Olanzapine in ≥99% purity (HPLC at
215 nm) as offꢀwhite crystals. MW procedure: 94% yield.
Mp 192ꢀ193 °C, (lit. 38 193ꢀ194 °C). 1H NMR (300 MHz, CDCl3) δ 7.05 (dd, J = 7.8, 1.4 Hz, 1H), 6.96
(dt, J = 7.5, 1.5 Hz, 1H), 6.88 (dt, J = 7.5, 1.7 Hz, 1H), 6.64 (dd, J = 7.7, 1.1 Hz, 1H), 6.28 (d, J = 1.1
Hz, 1H), 5.30 (s, 1H), 3.68 – 3.56 (m, 4H), 2.64 – 2.53 (m, 4H), 2.39 (s, 3H), 2.31 (d, J = 1.1 Hz, 3H).
The spectral data are in agreement with the previously published values.27,38
N-(3-Bromo-4-methylphenyl)-4-(chloromethyl)benzamide (28). Into a 10 mL vial equipped with a
stir bar were placed 3ꢀbromoꢀ4ꢀmethylaniline (0.5 mmol, 93 mg), 1.01 equiv of 4ꢀ
(chloromethyl)benzoyl chloride (0.505 mmol, 94 mg) and 2 mL of MeCN. The vial was closed and the
reaction mixture was heated at 130 °C for 3 min with 800 rpm stirring speed. After cooling to 55 °C,
the crude reaction mixture was washed with approximately 10 mL of 1N aqueous NaOH and the
aqueous phase was extracted with 3 × 10 mL EtOAc. The combined organic phases were dried over
Na2SO4. The solvent was evaporated to provide 154 mg (91 %) of product 28 in ≥99% purity (HPLC at
215 nm) as a colorless solid.
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1H NMR (300 MHz, DMSOꢀd6) δ 10.34 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.3 Hz, 2H),
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7.67 (dd, J = 8.3, 2.1 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 1H), 4.85 (s, 2H), 2.32 (s,
3H). The spectral data are in agreement with the previously published values.29b
N-(3-Bromo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (29). Into a 10 mL
vial equipped with a stir bar were placed benzamide 28 (0.44 mmol, 149 mg), 3 equiv of Nꢀ
methylpiperazine (1.32 mmol, 146 µL), 3 equiv of triethyl amine (1.32 mmol, 183 µL) and 2 mL of
MeCN. The vial was closed and the reaction mixture was heated at 170 °C for 5 min with 800 rpm
stirring speed. After cooling to 55 °C, the crude reaction mixture was poured on ca. 10 mL of water.
After crystallization, the product was filtered and washed with additional 10 mL iceꢀcold water. The
white crystals were dried overnight at 50 °C to provide 150 mg (85 %) of product 29 in ≥99 % purity
(HPLC at 215 nm).
1H NMR (300 MHz, DMSOꢀd6) δ 10.28 (s, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.67
(dd, J = 8.3, 2.1 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.6 Hz, 1H), 3.53 (s, 2H), 2.39 (brs,
8H), 2.31 (s, 3H), 2.19 (s, 3H). The spectral data are in agreement with the previously published
values.29b
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4-(Pyridin-3-yl)pyrimidin-2-amine (32). Into a 10 mL vial equipped with a stir bar are placed 3ꢀ
acetylpyridine (6 mmol, 673 µL) and N,Nꢀdimethylformamide dimethyl acetal (DMFDMA, 6 mmol,
797 µL). The vial is closed and the reaction mixture is heated at 170 °C for 3 min with 800 rpm stirring
speed. After cooling to 55 °C, the crude reaction mixture is poured on ca. 30 mL cold diethyl ether.
After crystallization, the product is filtered and washed with additional 10 mL cold diethyl ether. 718
mg (68%) of enone 31 are obtained as red crystals in 93% purity (GCꢀFID).
Into a 10 mL vial, equipped with a stir bar, were placed enone 31 (1 mmol, 176 mg), 1.1 equiv of
guanidine hydrochloride (1.1 mmol, 105 mg), 1.1 equiv of NaOH (1.1 mmol, 44 mg) and 2 mL of nꢀ
BuOH. The vial was closed and the reaction mixture was heated at 200 °C for 5 min with 800 rpm
stirring speed. After cooling to 55 °C, the crude reaction mixture was poured on ca. 20 mL ice/water.
After crystallization, the product was filtered and washed with additional 5 mL cold water and 5 mL of
cold EtOAc. The slightly yellow crystals were dried overnight at 50 °C to provide 120 mg (70 %) of
compound 32 in 97% purity (GCꢀFID).
1H NMR (300 MHz, DMSOꢀd6) δ 9.23 (dd, J = 2.3, 0.7 Hz, 1H), 8.68 (dd, J = 4.8, 1.6 Hz, 1H), 8.41 –
8.35 (m, 2H), 7.53 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 6.80 (s, 2H). The spectral
data are in agreement with the previously published values.29b
Imatinib (19). Into a 10 mL vial equipped with a stir bar were placed benzamide 29 (0.41 mmol,
164 mg), 1 equiv of amine 32 (0.41 mmol, 70 mg), 1.4 equiv of KOtBu (0.57 mmol, 65 mg), 8 mol%
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Page 29 of 34
The Journal of Organic Chemistry
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XPhos (33 µmol, 16 mg), 4 mol% Pd2(dba)3 CHCl3 (16 µmol, 17 mg) and 2 mL of toluene/tꢀBuOH
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(1:1). The vial was closed and the reaction mixture was heated to 160 °C with 3 min ramp and 800 rpm
stirring speed and kept for 10 min at this temperature. After cooling to 55 °C, the solvent was
evaporated and the residual crude mixture was purified by flash chromatography using a 25 g SNAP
ULTRA cartridge and pure methanol as eluent. The desired fractions were combined and the solvent
was evaporated under reduced pressure. The residue was dissolved in ca. 10 mL of DCM and filtered.
Evaporation of the solvent provided 143 mg (71 %) of Imatinib as colorless solid in ≥99 % purity
(HPLC at 215 nm). MW procedure: Heating at 160 °C for 10 min without ramp,73% yield.
Mp 206ꢀ209 °C (lit.29b 206ꢀ207 °C).1H NMR (300 MHz, DMSOꢀd6) δ 10.17 (s, 1H), 9.28 (s, 1H), 8.99
(s, 1H), 8.68 (d, J = 3.8 Hz, 1H), 8.52 – 8.46 (m, 2H), 8.08 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.54 –
7.42 (m, 5H), 7.20 (d, J = 8.3 Hz, 1H), 3.52 (s, 2H), 2.34 (brs, 8H), 2.22 (s, 3H), 2.14 (s, 3H). The
spectral data are in agreement with the previously published values.29b
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5-Chloro-2-methoxy-N-(2-phenethyl) benzamide (35). Into a 10 mL vial equipped with a stir bar are
placed of 5ꢀchloroꢀ2ꢀmethoxy benzoic acid (0.5 mmol, 93 mg), 2 mL of dry THF, 1.1 equiv of 2ꢀ
phenylethylamine (0.55 mmol, 69 µL) and 1.1 equiv of phosphorous trichloride (0.55 mmol, 49 µL).
The vial is closed and the reaction mixture is heated at 150 °C for 5 min with 800 rpm stirring speed.
After cooling to 55 °C, the crude reaction mixture is washed with ca. 20 mL of aqueous NaOH and the
aqueous phase was extracted with 3 × 15 EtOAc. The combined organic phases are dried over Na2SO4.
The solvent is evaporated to provide 138 mg (95 %) of product 35 as a light yellow solid in ≥99 %
purity (HPLC at 215 nm).
1H NMR (300 MHz, CDCl3) δ 8.17 (d, J = 2.8 Hz, 1H), 7.37 – 7.18 (m, 7H), 6.84 (d, J = 8.8 Hz, 1H),
3.78 – 3.74 (m, 2H), 3.72 (s, 3H), 2.92 (t, J = 6.7 Hz, 2H). The spectral data are in agreement with the
previously published values.39
4-[(5-Chloro-2-methoxybenzamido)ethyl] benzene sulfonyl chloride (36). Into a 10 mL vial
equipped with a stir bar were added benzamide 35 (0.48 mmol, 138 mg) and 3 mL of CHCl3. The vial
was placed on ice and 0.44 mL sulfonic acid chloride was added dropwise while stirring. The vial was
closed and the reaction mixture is heated at 60 °C for 10 min with 800 rpm stirring speed. After cooling
to 55 °C, the crude reaction mixture was washed with ca. 20 mL of a brine/ice mixture and the aqueous
phase was extracted with 3 × 15 mL of diethyl ether. The combined organic phases were dried over
Na2SO4. The solvent was evaporated to provide 171 mg (88 %) of product 36 as a light yellow sticky
oil in 88% purity (HPLC at 215 nm).
1H NMR (300 MHz, DMSOꢀd6) δ 8.23 (t, J = 5.5 Hz, 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 8.1 Hz,
2H), 7.49 (dd, J = 8.9, 2.8 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.9 Hz, 1H), 3.80 (s, 3H), 3.53
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