A microcapillary system for simultaneous, parallel microwave-assisted synthesis

Article abstract of DOI:10.1002/chem.200500820

A continuous flow, microwave-assisted, parallel-capillary microreactor has been developed. Libraries of drug candidates were prepared on the milligram scale with this reactor by injecting plugs of reagents from separate syringes into common reaction capil

Full text of DOI:10.1002/chem.200500820

FULL PAPER
DOI: 10.1002/chem.200500820
A Microcapillary System for Simultaneous, Parallel Microwave-Assisted
Synthesis
[
a]
Eamon Comer and Michael G. Organ*
Abstract: A continuous flow, microwave-assisted, parallel-capillary microreactor
has been developed. Libraries of drug candidates were prepared on the milligram
scale with this reactor by injecting plugs of reagents from separate syringes into
common reaction capillaries, thereby producing discrete compounds in excellent
yield and purity. Microwave irradiation provides the necessary energy that existing
room-temperature microreactor technology lacks for higher activation barrier
transformations, producing the required amounts of desired compounds in minutes
or less.
Keywords: combinatorial chemis-
try · cross-coupling · microreactors ·
microwaves · parallel synthesis
Introduction
miniaturization in a flow format incorporating the reaction-
rate-promoting benefits and higher yields of MAOS.
[18,19]
High-throughput synthetic strategies used in the discovery
of new drug candidates, materials, and catalysts have relied
on two prevailing methods, namely mix and split, and paral-
Results and Discussion
[1,2]
lel synthesis.
These so-called “high-speed synthesis”ap-
proaches actually have slower chemical transformations be-
cause they are often heterogeneous. To address this, various
techniques have been applied including microwave-assisted
Most flow-through, microscale combinatorial reaction sys-
tems have used a sequential-flow approach to the prepara-
tion of libraries, whereby compounds were produced, one
[3–6]
[13,14]
organic synthesis (MAOS),
and higher yielding reactions.
which provide faster, cleaner
after another, through the same reactor channel.
Signifi-
[6–12]
[20]
However, the one-at-a-
cantly, virtually all libraries prepared by this approach
have been synthesized at room temperature by using glass
microchips that carry the associated limitations discussed
above. With the aim of greatly improving this process we
designed and prepared a single capillary reactor (Fig-
time nature of preparing reactions in single, specialized (and
expensive) microwave vials does much to offset the benefits
of faster chemical conversion. One way to overcome these
handling issues is to perform reactions in a flow format. Ad-
ditionally, there is merit in miniaturizing the combinatorial
[21]
[22]
ure 1A). The assembly consists of a stainless steel mixing
chamber with three inlets that merge to a single outlet that
can be connected to capillary tubes of various internal diam-
eters (200–1150 mm) and, ultimately, to collection vessels.
We prepared a demonstration array of compounds using a
consecutive-flow/MW-irradiation strategy based on the
[
13,14]
process,
which has been achieved by microflow systems
[15–17]
called microreactors.
However, the fabrication of chip-
type microreactors requires specialized, expensive facilities,
and the laminar flow associated with microchannel devices
[17]
can lead to poor reactivity. Further, existing microfluidic
technology does not address fully the issue of heating in
these reaction systems, which limits application. The goals
of high-throughput synthesis might be better served through
[23]
Suzuki–Miyaura cross-coupling reaction (Table 1). A con-
stant stream of phenyl boronic acid (1) and base (syringe A)
was fed into the reaction chamber (Figure 1A), while plugs
of aryl halides 2–6 and catalyst (syringes B1–B5) were intro-
duced sequentially through a second lead into the reaction
capillary to afford the biaryl library, separated by time, in
very good to excellent conversion.
[
a] E. Comer, Prof. M. G. Organ
The Department of Chemistry, York University
This methodology was then applied to the nucleophilic
4
700 Keele Street, Toronto, Ontario, M3J 1P3 (Canada)
substitution of aromatic fluorides (S Ar) with primary
Fax : (+1)416-735-5936
N
E-mail: organ@yorku.ca
amines that produced the anilines shown in Table 2. It is
Chem. Eur. J. 2005, 11, 7223 – 7227
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Having established the con-
cept of a MW-assisted continu-
ous/sequential-flow library syn-
thesis and prepared two small
libraries, we felt we were in a
unique position to significantly
advance microscale, flow paral-
lel synthesis using our capillary
[25]
reactor approach. The multi-
reactor assembly (shown in Fig-
ures 1B and C) was designed
specifically for library prepara-
tion and consists of a stainless
steel holder with four pairs of
two inlet ports (8 ports in
total), in which the channels of
each pair merged to afford four
Figure 1. Continuous flow, capillary MW microreactors. A) Schematic of the single capillary reactor system.
B) Schematic of the parallel, capillary multireactor system. C) Photograph of the parallel, capillary multireac- outlet ports. Capillary tubes
tor system.
were connected to each of
these outlets to form a multi-
reactor system and all reactions could be heated simultane-
ously while they flowed through each capillary. We elected
Table 1. A cross-coupling library prepared by sequential injection of
stock solutions by continuous flow capillary microwave irradiation.
N
Table 2. A S Ar library prepared by sequential injection of stock solutions
by flow capillary microwave irradiation.
Conversion
Stream A
Product
[
a]
[%]
Stream
A
Conversion
[%]
Product
[
a]
stream
B1
9
7
9
7
6
0
stream
B1
1
00
stream
B2
stream
B3
stream
B2
56
stream
B4
72
stream
B3
1
00
stream
B5
100
1
[
a] Percent conversion was determined by H NMR spectroscopy and is stream
67
relative to residual starting halide 2–6.
B4
worth noting that despite the small channel size, no laminar
stream
[17]
55
flow
of the two reacting streams was observed and no B4
blockage of the reactor occurred where products crystal-
lized, which was shown to be problematic in other, even
larger diameter flow systems.
1
[
a] Percent conversion was determined by H NMR spectroscopy and is rela-
[24]
tive to residual starting fluoride 12.
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Microwave-Assisted Synthesis
FULL PAPER
stream A1 or A2 and were sub-
jected to microwave irradiation
to afford all possible products.
Streams B1 and B2 were then
simply switched to B3 and B4
giving rise to a sequential, par-
allel synthesis. By using this
technique the number of prod-
ucts was doubled relative to the
example in Table 3. The total
Figure 2. Top view of multireactor system schematic for a 2”2 parallel library.
number of products obtainable
by this methodology is only lim-
ited by the number of reagents
employed, and, once again, the
Table 3. Preparing libraries of compounds simultaneously by parallel capillary irradiation using the multi-inlet
reactor (shown in Figure 2).
products are separated by time.
This strategy demonstrates
fluoride A1
fluoride A2
that the number of products ob-
tainable in this parallel synthe-
sis strategy is no longer limited
to the number of reaction ves-
sels as is the case with conven-
tional parallel synthesis. To pre-
pare the library shown in
Table 4 by using a conventional
microreactor approach would
require a single channel reactor
[
a]
[a]
amine B1
amine B2
product A1B1 (78%)
product A2B1 (100%)
[
a]
[a]
product A1B2 (90%)
product A2B2 (100%)
to perform eight continuously
flowing separate reactions, one
after another, in the same chan-
1
nel; this series of reactions
would require minimally four
[
a] Percent conversion was determined by H NMR spectroscopy and is relative to residual starting fluoride.
times the amount of time to
complete. This aside, our
to use the S Ar reaction for the parallel synthesis in which
system represents the first MW-
N
fluorides 12 and 23 (syringes A1 and A2) and amines 24 and
(or indeed thermally)-assisted parallel synthesis in a contin-
uous flow format and, as such, marks a potentially new di-
rection for high-throughput synthesis.
In summary, we have developed a new capillary-based ap-
proach to parallel synthesis, whereby the reagents flow in se-
quence into a multicapillary reactor device and the transfor-
mations are accelerated by microwave irradiation to provide
collections of compounds in a very rapid, clean, and efficient
manner.
2
5 (syringes B1 and B2) were the two reagent pairs (see
Figure 2 and Table 3). Thus, for example, a stream of amine
5 from syringe B2 was split into two and fed equally into
2
different inlets whereby one stream could combine with
fluoride 12 (from syringe A1), while the other mixed with 23
(
from syringe A2). By using this technique four streams con-
taining all possible combinations were collected separately
and the conversion ranged from very good to excellent.
A perceived drawback of flow parallel synthesis is the ne-
cessity to have as many syringe pumps as starting reagents
[13]
and as many reaction channels as products. Additionally,
it is a common belief that once a parallel reaction system
has been built, the number of components in the library are
Experimental Section
Preparation of cross-coupling library prepared by sequential injection of
stock solutions using a flow capillary reactor with microwave irradiation
[13]
fixed.
These concerns could be eliminated, or at least
(
(
1
Table 1): Stock solutions containing aryl halides
stream B2), 4 (stream B3), 5 (stream B4) and 6 (stream B5) (0.3 mmol,
equiv) and Pd(PPh (17 mg, 0.015 mmol, 5 mol%) in DMF (1 mL)
2 (stream B1), 3
minimized, through the new concept of continuous-flow, se-
quential, parallel synthesis using the multireactor assembly
shown in Figures 1B, 1C, and 3 (for results see Table 4).
Aryl bromides 6 and 2 were continuously fed into inlet ports
A1 and A2 using syringes A1 and A2, respectively. The bor-
onic acids from syringes B1 and B2 were each split into two
streams and pumped into their respective inlets as denoted
in Figure 3. There they mixed with either bromide
3 4
)
were prepared and loaded into Hamilton gas-tight syringes B1 to B5, re-
spectively. A stock solution containing phenylboronic acid (1; stream A)
(
0
48 mg, 0.39 mmol, 1.3 equiv), and 2m KOH (0.45 mL, 3.0 equiv,
.9 mmol) in DMF (1 mL) was prepared and loaded into Hamilton gas-
tight syringe A. The continuous flow microwave system was primed with
DMF and syringes A and B1 were connected to the reactor system as
TM
shown in Figure 1A, with the aid of Microtight fittings. The syringes
Chem. Eur. J. 2005, 11, 7223 – 7227
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7225

M. G. Organ and E. Comer
into Hamilton gas-tight syringe A. The
continuous flow microwave system
was primed with DMF and syringes A
and B1 were connected to the reactor
system as shown in Figure 1A, with
TM
the aid of Microtight
fittings. The
syringes were placed in a Harvard 22
syringe pump that was set to deliver
À1
1
5 mLmin and the single mode mi-
crowave (Biotage Smith Creator Syn-
TM
thesizer ) was programmed to heat
constantly at 170 W. The syringe pump
and MW were turned on and the
output from the reactor was fed into
collection tubes and was analyzed di-
Figure 3. Top view of multireactor system schematic for a 2”4 parallel, sequential synthesis.
1
rectly by H NMR spectroscopy imme-
diately after reaction. When 0.15 mL
of B1 had been fed into the reactor,
the syringe was switched to one con-
taining just DMF that was ran for 30 s
to clean the lines. The syringe was then
switched to B2 and the process repeat-
ed until all stock solutions had passed
Table 4. Preparing libraries of compounds by sequential, parallel capillary irradiation using the multi-inlet re-
actor (shown in Figure 3).
bromide A1
bromide A2
[
29]
[
[
a]
a]
[a]
[a]
through the reactor. Products 18,
boronic acid B1
boronic acid B2
product A1B1 (67%)
product A1B2 (91%)
product A2B1 (100%)
product A2B2 (100%)
[30] [31]
2
0,
and 21
are known and the
1
H NMR spectra obtained were consis-
tent with literature data. Compounds
1
1
9 and 22 gave H NMR data consis-
tent with samples prepared previously
in our laboratories. All compounds in
this study were isolated by silica gel
chromatography for the purpose of
spectroscopic identification.
[
[
a]
a]
[a]
[a]
boronic acid B3
boronic acid B4
product A1B3 (92%)
product A2B3 (100%)
product A2B4 (100%)
Preparation of libraries of compounds
by simultaneous parallel capillary irra-
diation using the multi-inlet reactor
(
Table 3): Two separate stock solutions
product A1B4 (91%)
containing the aryl amines 24
(
amine B1),
and
25
(amine B2)
(
1.2 mmol, 2 equiv) in DMF (1.21 mL)
were prepared and loaded into Hamil-
ton gas-tight syringes B1 and B2, re-
spectively. Similarly, two separate stock
1
[
a] Percent conversion was determined by H NMR spectroscopy and is relative to residual starting fluoride.
solutions containing fluoronitroben-
zene 12 (fluoride A1) and 23 (fluori-
de A2) (0.6 mmol, 1 equiv), each con-
taining diisopropylamine (0.21 mL,
.2 mmol) in DMF (1 mL), were prepared and loaded into Hamilton gas-
tight syringes A1 and A2, respectively. The continuous flow, multi-inlet
microwave system was primed with DMF and syringes A1, A2, B1, and
were placed in a Harvard 22 syringe pump that was set to deliver
1
À1
1
5 mLmin , and the single mode microwave (Biotage Smith Creator Syn-
TM
thesizer ) was programmed to heat constantly at 170 W. The syringe
pump and MW were turned on and the effluent from the reactor was fed
into collection tubes and analyzed directly by H NMR spectroscopy im-
B2 were connected to the reactor system as shown in Figures 1B and 1C
1
TM
and Table 3 with the aid of Microtight
fittings. The syringes were
mediately after the reaction. When 0.15 mL of B1 had been fed into the
reactor, the syringe was switched to one containing just DMF that was
ran for 30 s to clean the lines. The syringe was then switched to B2 and
the process repeated until all stock solutions B1 to B5 had passed
À1
placed in a Harvard 22 syringe pump that was set to deliver 20 mLmin
and the single mode microwave (Biotage Smith Creator Synthesizer
TM
)
was programmed to heat constantly at 170 W. The syringe pump and
MW were turned on and the output from the reactor was fed into collec-
1
1
through the reactor. All products are known and the H NMR spectra
tion tubes and was analyzed directly by H NMR spectroscopy immedi-
[
26]
[27]
[28]
1
obtained for compounds 7, 8, and 9; 10; and 11 were consistent
with the literature data for these compounds. All compounds in this
study were isolated by silica gel chromatography for the purpose of spec-
troscopic identification.
ately after reaction. Product 26 is known and the H NMR spectrum ob-
[31]
tained was consistent with the literature. Compounds 27, 28, and 29
1
gave H NMR data consistent with samples prepared previously in our
laboratories. All compounds in this study were isolated by silica gel chro-
matography for the purpose of spectroscopic identification.
Preparation of an array of compounds by nucleophilic aromatic substitu-
tion via two-stream infusion into the microreactor of the MACOS system
Preparation of libraries of compounds by sequential, parallel, capillary ir-
(
(
(
Table 2): Stock solutions containing the aryl amines 13 (stream B1), 14
stream B2), 15 (stream B3), 16 (stream B4) and 17 (stream B5),
1.5 mmol, 2 equiv) were prepared and loaded into Hamilton gas-tight sy-
radiation using the multi-inlet reactor (Table 4): Two separate stock solu-
tions containing aryl halides
6 (bromide A1) and 2 (bromide A2)
(6 mmol, 1 equiv) and each containing Pd(PPh3)4 (34 mg, 0.003 mmol,
5 mol%) in DMF (2.9 mL) were prepared and loaded into Hamilton gas-
tight syringes A1 and A2, respectively. Similarly, four separate stock solu-
tions containing boronic acids 1 (boronic acid B1), 29 (boronic acid B2),
ringes B1 to B5, respectively. A stock solution containing 2-fluoronitro-
benzene (12; stream A; 104 mg, 0.74 mmol, 1 equiv) and diisopropyla-
mine (0.26 mL, 0.74 mmol) in DMF (0.74 mL) was prepared and loaded
7226
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Chem. Eur. J. 2005, 11, 7223 – 7227

Microwave-Assisted Synthesis
FULL PAPER
3
0 (boronic acid B3) and 31 (boronic acid B4) (7.8 mmol, 1.3 equiv), each
[14] P. Watts, S. J. Haswell, Curr. Opin. Chem. Biol. 2003, 7, 380.
containing 2m KOH (0.9 mL, 3.0 equiv, 1.8 mmol) in DMF (2 mL), were
prepared and loaded into Hamilton gas-tight syringes B1 to B4, respec-
tively. The continuous flow multi-inlet microwave system was primed
with DMF and syringes A1, A2, B1 and B2 were connected to the reactor
[15] P. Watts, S. J. Haswell, Chem. Soc. Rev. 2005, 34, 235.
[16] H. Pennemann, P. Watts, S. J. Haswell, V. Hessel, H. Loewe, Org.
Process Res. Dev. 2004, 8, 422.
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[18] This work was first presented at the Cutting Edge Technologies in
Combinatorial Chemistry Conference, September 29, 2004.
[19] a) M. G. Organ, E. Comer, U. S. Provisional Patent 60/605505,
2004; b) E. Comer, M. G. Organ, J. Am. Chem. Soc. 2005, 127, 8160.
[20] There exists one example in which a variety of aminothiazoles were
prepared where the authors heated the base of a glass microreactor
with a Peltier heater, see: E. Garcia-Egido, S. Y. F. Wong, B. H. War-
rington, Lab Chip 2002, 2, 31.
system as shown in Figures 1B, 1C, and 3 and Table 4 with the aid of Mi-
TM
crotight
fittings. The syringes were placed in a Harvard 22 syringe
À1
pump that was set to deliver 20 mLmin and the single mode microwave
Biotage Smith Creator Synthesizer ) was programmed to heat con-
TM
(
stantly at 170 W. The syringe pump and MW were turned on and the
output from the reactor was fed into collection tubes and was analyzed
1
directly by H NMR spectroscopy immediately after reaction. When
0
.15 mL of the four streams had been fed into the reactor, the syringe
was switched to one containing just DMF that was ran for 30 s to clean
the lines. The syringes were then switched to B3 and B4 and the process
repeated until all stock solutions had passed through the reactor. Prod-
[21] For a report on room-temperature Swern Oxidation reactions per-
formed in a microscale flow reactor, see: T. Kawaguchi, H. Miyata,
K. Ataka, Angew. Chem. 2005, 117, 16, 2465; Angew. Chem. Int. Ed.
2005, 44, 2413.
[
26]
[26]
[32]
[33]
[34]
[35]
[36]
[36]
ucts 7, 3, 32, 33, 34, 35, 36, and 37 are known and the
1
H NMR spectra obtained were consistent with the literature. All com-
pounds in this study were isolated by silica gel chromatography for the
purpose of spectroscopic identification
[22] For examples of the use of microwave-assisted microfluidic devices
to prepare individual compounds at a time, see: a) P. He, S. J. Has-
well, P. D. I. Fletcher, Lab Chip 2004, 4, 38; b) P. He, S. J. Haswell,
P. D. I. Fletcher, Appl. Catal. 2004, A274, 111; c) P. He, S J. Haswell,
P. D. I. Fletcher, Sens. Actuators B 2005, 105, 516; d) P. Watts, S. J.
Haswell, Chem. Eng. Technol. 2005, 28, 290.
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TM
otage Inc. for the donation of a Smith Creator Synthesizer to develop
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Published online: September 15, 2005
Chem. Eur. J. 2005, 11, 7223 – 7227
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7227