Development and applications of a practical continuous flow microwave cell

Article abstract of DOI:10.1021/op034181b

A series of synthetic transformations were successfully and safely scaled up to multigram quantities using focused microwave irradiation with a continuous flow reaction cell that was developed in-house and which can be easily adapted to commercially avail

Full text of DOI:10.1021/op034181b

Organic Process Research & Development 2004, 8, 535−538
Communications to the Editor
Development and Applications of a Practical Continuous Flow Microwave Cell
Noel S. Wilson,* Christopher R. Sarko, and Gregory P. Roth
Boehringer Ingelheim Pharmaceuticals, Inc., Department of Medicinal Chemistry, P.O. Box 368, 900 Ridgebury Road,
Ridgefield, Connecticut 06877-0368, U.S.A.
Abstract:
not be linear and may result in the chemist re-optimizing
the reaction prior to scale-up.
A series of synthetic transformations were successfully and
safely scaled up to multigram quantities using focused micro-
wave irradiation with a continuous flow reaction cell that was
developed in-house and which can be easily adapted to com-
mercially available instrumentation. The representative reac-
tions that were investigated included aromatic nucleophilic
substitution (SNAr), esterification, and the Suzuki cross-coupling
reaction. In general, the product yields were equivalent to or
greater than those run under conventional thermal heating
conditions.
Our interest in developing a continuous microwave reactor
(CMR) originates from our need to eliminate the potential
reaction parameter re-optimization (time and temperature)
typically required for scale-up as methods are transferred
from small-volume, single-mode systems to larger (but
limited)-volume multimode systems. Therefore, we focused
our attention on developing a CMR which used commercially
available single-mode systems, such as the Discover5 and
Emrys Synthesizer.6 This would allow us to directly transfer
optimized chemistry from small to large scale without
changing from single- to multimode. The CMR operates by
passing a reaction mixture though a microwave transparent
coil that is held in the cavity of the focused microwave
chamber. In this report we describe the design of the CMR
and present applications demonstrating the synthetic useful-
ness of the tool.
Requirements for the CMR. Unlike the earlier CMRs
that employed multimode systems, we focused our attention
on using a commercially available single-mode microwave,
the Emrys Synthesizer. We felt this would provide us with
the added advantage of focused microwave heating which
would produce an even heating distribution and greater
heating control. A disadvantage of developing a CMR
centered on the single-mode microwave is that the microwave
chamber is considerably smaller than multimode systems.
Therefore, for a CMR to be designed for a single-mode
reactor, the cell must utilize the cavity space to it fullest
potential. To address this issue we developed a CMR
consisting of a series of glass coils (Figure 1).
Introduction
Over the last several years, microwave-assisted organic
synthesis has gained significant recognition among organic
chemists as revealed by the numerous recent reviews.1 This
popularity is primarily due to significant advancements in
single-mode microwave technology that is directed towards
streamlining organic synthesis. Interestingly, given the
significant surge in microwave-based chemistries being
employed and the availability of safe and reliable instru-
ments, it is surprising that very little has been done to
investigate and address downstream issues such as prepara-
tive or large-scale synthesis using microwaves.
Typically, two methods are available for the scale-up of
microwave chemical processes; batch reactors2 and continu-
ous flow systems. The earliest reported system, by Strauss
and co-workers,3 demonstrated that the concept of accelerat-
ing organic reactions in a continuous flow manner with
microwave energy was indeed feasible. Although these
systems have proven to be synthetically useful in scaling up
chemical processes, they depend on the chemist transferring
optimized chemistry from smaller single-mode systems to
either larger batch-type systems or multimode microwaves.4
Unfortunately, this transfer from single- to multimode may
Description of the CMR. The flow cell consists of 22
3-mm (1/8 in.) i.d. borosilicate glass coils encased in a 100
mm × 10 mm protective borosilicate glass sheath. The coiled
glass reactor was found to be an efficient method to
maximize the time the reaction mixture was exposed to
microwave irradiation, and the total flow cell volume was 4
mL. The glass reactor, shown in Figure 1, was fitted with
Omni glass threaded connectors, two fixed-length PTFE end
fittings with porous 25 µm PTFE frits, and silicone O-rings
* To whom correspondence should be addressed. E-mail: nwilson@
rdg.boehringer-ingelheim.com.
(1) (a) Krstenansky, J. L.; Cotterill, I. Curr. Opin. Drug DiscoVery DeV. 2000,
454-461. (b) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahe-
dron 2001, 57, 9225-9283. (c) Wilson, N. S.; Roth, G. P. Curr. Opin.
Drug DiscoVery DeV. 2002, 5, 620-629.
(2) Cleophax, J.; Liagre, M.; Loupy, A.; Petit, A. Org. Process Res. DeV. 2000,
4, 498-504.
(3) (a) Cablewski, T.; Faux, A. F.; Strauss, C. R. J. Org. Chem. 1994, 59, 3408-
3412. (b) Marquie, J.; Salmoria, G.; Poux, M.; Laporterie, A.; Dubac, J.
Ind. Eng. Chem. Res. 2001, 40, 4485-4490. (c) Khadilkar, B. M.; Madyar,
V. R. Org. Process Res. DeV. 2001, 5, 452-455.
(4) Sarko, C. R. Abstracts of Papers American Chemical Society 2001; 221st
National Meeting of the American Chemical Society, San Diego, CA, April
1-5, 2001; American Chemical Society: Washington, DC, 2001; ORGN-
049.
(5) CEM Corporation homepage: http://www.cemsynthesis.com.
(6) PersonalChemisty AB hompage: http://www.personalchemistry.com
10.1021/op034181b CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/23/2004
Vol. 8, No. 3, 2004 / Organic Process Research & Development
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535

Table 1. Nucleophilic aromatic substitution of
4-fluoro-3-nitroaniline with phenethylamine
heating temp
flow rate
(mL/min)
time
(h)
entrya method
(°C)
% conversionb
1
2
3
NA
oil bath
CMR
rt
100
120
NA
NA
1
5
18
5
0
20
54
a 50 mL, 0.24 M solution. b Determined by LC-MS.
Scheme 1. Nucleophilic aromatic substitution of
2-fluoro-3-nitrobenzene
Figure 1. Glass coiled flow cell.
Figure 2. Schematic diagram of the CMR in an open-loop
mode. (A) Reaction mixture, (B) HPLC pump, (C) microwave
cavity, (D) flow cell, (E) back-pressure regulator, (F) product
reservoir.
Our studies involved the nucleophilic aromatic substitution
of 4-fluoro-3-nitroaniline with phenethylamine (Table 1). The
reaction did not proceed at room temperature and was
sluggish at reflux temperatures (entries 1 and 2). Only 20%
conversion was observed even after prolonged heating. In
comparison, our closed-loop CMR system provided 54%
conversion after 5 h (entry 3). The total irradiation time per
mL of reaction mixture was 24 min, and the 5 h processing
time reflects the time required to react 12 mmol of material
overall. The methodology was further expanded to the large-
scale synthesis of compound 4 (Scheme 1). Although an 81%
yield of product 4 was obtained, a common limitation of
CMRs was observed. As the reaction progressed, the SNAr
product crystallized from the solution as a fine orange
powder. The result was that the particles eventually clogged
the lines and frits. It was necessary to terminate the reaction
before complete consumption of the starting material.
Esterification. To directly compare the effectiveness of
our CMR system we attempted the esterification of 2,4,6-
trimethylbenzoic acid with methanol (MeOH) as described
by Strauss and co-workers.3 The published example reports
the esterification of 2,4,6-trimethylbenzoic acid, with metha-
nol, in 83% conversion, using only 1.5% sulfuric acid (by
volume) after 1 min. They reported that the temperature of
the system was 80-90 °C above the boiling point of MeOH,
and this was a safety concern to us.
cut from an Omnifit 10-mm i.d. glass chromatography
column. These fittings were connected with 3-mm (1/8 in.)
i.d. TFE Teflon tubing rated for pressures up to 500 psi and
an operating temperature of 200 °C. The inlet tube was
connected to a Rainin HPXL pump, and the outlet was
connected to a 100 psi back-pressure regulator (Figure 2).
The system has the flexibility of running either in an open-
or closed-loop mode. The flow cell was inserted into the
cavity of the single-mode microwave from the bottom of
the instrument.7 In this configuration the flow cell temper-
ature was monitored and controlled through the microwave’s
internal IR sensor (located in the cavity) and instrument
software.8
Examples. Nucleophilic Aromatic Substitution. A com-
mon reaction used in the synthesis of medicinally relevant
pharmacophores is the SNAr reaction.9 Typically the SNAr
product is a common intermediate used in library design,
and therefore large-scale synthesis of the intermediate is
required. Although the microwave-assisted methodologies
have been investigated,10 to our knowledge no CMR systems
have been utilized for the preparation of SNAr products.
We first investigated the chemistry using small scale and
the Emrys Synthesizer to evaluate potential safety issues
associated with superheating MeOH above its boiling point.
Since the pressure of MeOH at 150 °C was in excess of 250
psi, we choose to reduce the temperature to 120 °C, resulting
in a pressure of 61 psi. When our CMR was used at 120 °C
for 2 min in an open-loop system, 50% of the 2,4,6-
trimethylbenzoic acid was converted to the methyl ester
(7) The Emrys Synthesizer was raised to gain access to the bottom of the
instrument and flow cell inserted into the microwave cavity from underneath
the instrument.
(8) Caution: bypassing software may result in safety issues.
(9) Cywin, C.; Lee, J.; Roth, G. P.; Sarko, C. R.; Snow, R. J.; Wilson, N. S.;
Pullen, S. S. Preparation of amido-substituted benzimidazoles useful as
protein kinase inhibitors. PCT Int. Appl. WO 0341708, 2003.
(10) (a) Cherng, Y.-J. Tetrahedron 2002, 58, 887-890. (b) Cherng, Y.-J.
Tetrahedron 2002, 58, 1125-1129. (c) Cherng, Y.-J. Tetrahedron 2000,
56, 8287-8289.
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Table 2. Esterification of 2,4,6-trimethylbenzoic acid
mirror on the surface of the flow cell, no clogging of the
lines and no temperature effects were observed. Upon raising
the temperature, results comparable to those reported by
O¨ hlberg and Westman were obtained (entries 1, 4, and 5).
To verify that the reaction did not proceed prior to treatment
with microwave irradiation an equivalent reaction stirring
at room temperature was performed (entry 2). Only an 11%
yield of the Suzuki product was obtained after 6 h. The
workup of the reaction is very straightforward and does not
require an aqueous wash. The mixture is simply filtered
through a plug of silica gel to remove the Pd catalyst and
the product then crystallizes directly from the filtrate.
heating temp flow rate
entrya method (°C) (mL/min)
time
1 h
70 h
2 min
% conversionb
1
2
3
NA
rt
80
NA
NA
1
0
14
50
oil bath
CMR
120
a 100 mL, 0.15 M solution. b Determined by LC-MS.
Table 3. Suzuki coupling results
Conclusions
A variety of chemical processes were successfully and
safely scaled up to multigram quantities using our continuous
flow microwave cell. The CMR can be easily fabricated and
proved to be a cost-effective alternative to purchasing
commercially available microwave scale-up systems since
it is adaptable for a variety of single-mode microwaves. The
representative chemistries explored included SNAr, esterifi-
cation, and the Suzuki cross-coupling reaction. In all cases
product yields were equivalent to or greater than conventional
heating methods and scaled up to multigram quantities with
clogging of the lines and over-pressurization as the only
limitations observed. Nonetheless, our CMR does have the
advantage that it does not require a re-optimization step when
transferring chemistries from small to large scale.
heating
method
temp flow rate
(°C) (mL/min) time % conversion
entry
1
sealed
microwave tube
140
NA
6 min
86a
2c NA
rt
120
130
140
NA
6 h
11b
73b
82b
84a
3c CMR
4c CMR
5c CMR
0.25
0.25
0.25
8 min
8 min
8 min
a Isolated yield. b Determined by 1H NMR, 250 MHz. c 50 mL, 0.11 M
solution.
Experimental Section
(Table 2). In comparison, with prolonged heating only a low
conversion (14%) was obtained using traditional heating
techniques.
1
All H NMR were recorded on either a Bruker Biospin
AC250 (250 MHz) or a Bruker Biospin DPX-400 (400 MHz)
instrument in CDCl3. The 1H NMR spectra were referenced
Suzuki Reaction. The Suzuki reaction has become one of
the most important carbon-carbon bond formation reactions
in organic synthesis. During the past few years several
microwave conditions have been developed;11 however,
typically these methods require an aqueous workup. Recently,
O¨ hlberg and Westman obtained compound 9 without an
aqueous workup and in excellent yield when ethanol (EtOH)
was used for the solvent and triethylamine (TEA) for the
base.12 The coupled product 9 was obtained in excellent yield
upon treatment of 1.1 equiv of aryl halide with 1 equiv of
the boronic acid in the presence of 20 mol % PdCl2(PPh3)2
and 2 equiv of TEA while heating at 140 °C for 6 min (Table
3, entry 1). However, at the time of their report the only
methods for scale-up of a microwave Suzuki reaction
obtained in a single mode was via batch production or re-
optimization using conventional heating techniques or a
multimode microwave.
1
to the H resonance of residual chloroform (δ 7.26). Data
are reported as follows: chemical shift in ppm (δ), multiplic-
ity (s ) singlet, d ) doublet, t )triplet, q ) quartet, m )
multiplet, br ) broad signal), coupling constant (Hz), and
integration. All LC-MS data were analyzed by an HPLC/
UV/MS system utilizing a Gilson 215, Agilent HP 1100 LC,
a Sedex 55 ELSD (evaporative light-scattering detector), and
a Micromass Platform II mass spectrometer. The ionization
mode utilized was positive electrospray ionization. The
HPLC column employed was Zorbax SB-C8 (4.6 mm × 30
mm).
A Typical Procedure for the Nucleophilic Aromatic
Substitution of 2-Fluoro-3-nitrobenzene. A 250-mL Er-
lenmeyer flask was charged with 1-fluoro-2-nitrobenzene (5
mL, 47.4 mmol), ethanol (67 mL), phenethylamine (2 equiv,
11.9 mL, 94.8 mmol), and DIEA (2 equiv, 16.5 mL, 94.8
mmol). The CMR was primed with ethanol, and the single-
mode microwave was programmed to heat the sample to 120
°C for 5 h. The intake line to the HPLC pump was placed
in the reaction mixture, along with the outtake line from the
flow cell, creating a closed-loop system. The HPLC was set
to pump at 1 mL/min, and the microwave was turned on.
The solution changed from yellow to dark red after 1 h, and
an orange precipitate developed. After 5 h the solution was
cooled, and the precipitate was collected, providing the
To validate the safety issues associated with transferring
the optimized chemistry to our CMR we decided to lower
temperature for our initial run (Table 3, entry 3). Although
some palladium did not dissolve and precipitated out as a
(11) (a) Kabalka, G. W.; Pagni, R. M.; Wang, L.; Namboodiri, V.; Hair, C. M.
Green Chem. 2000, 2, 120-122. (b) Blettner, C. G.; Konig, W. A.; Stenzel,
W.; Schotten, T. J. Org. Chem. 1999, 64, 3885-3890. (c) Larhed, M.;
Lindeberg, G.; Hallberg, A. Tetrahedron Lett. 1996, 37, 8219-8222.
(12) O¨ hlberg, L.; Westman, J. Synlett 2001, 12, 1893-1896.
Vol. 8, No. 3, 2004 / Organic Process Research & Development
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537

1
product in 81% yield. H NMR (CDCl3, 400 MHz) δ 8.16
TEA (2 equiv, 11.4 mmol, 1.6 mL). The CMR was primed
with ethanol, and the single-mode microwave was pro-
grammed to heat the sample to 140 °C for 5 h. The intake
line to the HPLC pump was placed in the reaction mixture,
and the outtake line from the flow cell was placed into a
second 100-mL Erlenmeyer flask, creating an open-loop
system. The HPLC was set to pump at 0.25 mL/min, and
the microwave was turned on. The collected sample was
filtered through a plug of silica to remove the Pd catalyst,
and the product was crystallized from the filtrate in 84%
(dd, 1H, J ) 8.61 Hz, J ) 1.56 Hz), 8.10 (brs, 1H), 7.43
(ddd, 1H, J ) 8.61 Hz, J ) 7.04 Hz, J ) 1.76), 7.37 (m,
2H), 7.29 (m, 3H), 6.86 (dd, 1H, J ) 8.8 Hz, J ) 1.17 Hz),
6.64 (ddd, 1H, J ) 8.22 Hz, J ) 6.65 Hz, J ) 1.18 Hz)
3.59 (dt, 2H, J ) 7.24 Hz, J ) 5.28 Hz) 3.05 (t, 2H, J )
7.24 Hz).
A Typical Procedure for the Esterification of 2,4,6-
Trimethylbenzoic Acid. A 250-mL Erlenmeyer flask was
charged with 1.5% H2SO4 (by volume) in MeOH (total
volume 100 mL) and the acid (2.5 g, 15 mmol). The CMR
was primed with methanol, and the single mode microwave
was programmed to heat the sample to 120 °C for 5 h. The
intake line to the HPLC pump was placed in the reaction
mixture, and the outtake line from the flow cell was placed
into a second 100-mL Erlenmeyer flask, creating an open-
loop system. The HPLC was set to pump at 1 mL/min, and
the microwave was turned on (2-min resonance time). After
5 h the solution was cooled, and concentrated under reduced
pressure. The crude material was diluted with ethyl acetate,
washed with water (2×), and brine (1×), dried over MgSO4,
1
yield. H NMR (CDCl3, 400 MHz) δ 10.04 (s, 1H), 7.93
(dd, 4H, J ) 8.41 Hz, J ) 8.22 Hz), 7.74 (d, 1H, J ) 7.83
Hz), 7.56 (d, 1H, J ) 8.42 Hz), 7.35 (dt, 1H, J ) 8.41 Hz,
J ) 1.37 Hz), 7.27 (t, 1H, J ) 7.63 Hz), 7.22 (s, 1H)
Acknowledgment
We thank Adolf P. Gunther of Advanced Glass Technol-
ogy for the fabrication of the flow microwave cells along
with Dr. Heewon Lee and George Lee for their assistance
in obtaining analytical data.
1
and concentrated to provide the product in 50% yield. H
NMR (CDCl3, 400 MHz) δ 6.85 (s, 2H), 3.90 (s, 3H), 2.29
(s, 9H).
A Typical Procedure for the Suzuki Coupling of
4-Bromobenzaldehyde. A 100-mL Erlenmeyer flask was
charged with PdCl2(PPh3)2 (0.20 mol %, 80 mg, 1.14 mmol)
and 48.4 mL of ethanol. To the stirring suspension was added
2-benzofuranboronic acid (1 equiv, 5.7 mmol, 0.93 g),
4-bromobenzaldehyde (1.1 equiv, 6.3 mmol, 1.16 g), and
Supporting Information Available
Outlined procedure for the continuous flow cell setup and
operation. This material is available free of charge via the
Internet at http://pubs.acs.org.
Received for review December 3, 2003.
OP034181B
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