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12
Microwave-Assisted Combinatorial Chemistry
C. Oliver Kappe and Alexander Stadler
12.1
Introduction
Combinatorial chemistry, the art and science of synthesizing and testing compounds
for bioactivity en masse, has emerged as one of the most promising approaches to drug
discovery [15]. Because of the enormous progress made in genomic sciences, molecu-
lar biology, and biochemistry, a large number of biologically important target proteins
has now become available for screening purposes. This has led to an ever-growing de-
mand for large libraries of novel compounds that are being evaluated for their biological
properties by use of appropriate screening procedures. The discovery of novel biological
targets was paralleled by the development of novel assays and high-throughput screen-
ing (HTS) technologies including miniaturized formats, enabling the testing of thou-
sands of individual compounds per day. Traditional methods of organic synthesis are or-
ders of magnitude too slow to satisfy the increasing demand for these compounds.
Combinatorial chemistry officially dates back to the mid-1980s and since then has
experienced enormous growth and has steadily attracted the interest of researchers
from a variety of different fields. The essence of combinatorial synthesis is the ability
to generate large numbers of chemical compounds very quickly [15]. Chemistry in
the past has been characterized by slow, steady, and painstaking work; combinatorial
chemistry has broken many of the preconceptions and resulted in a level of chemical
productivity thought impossible a few years ago. In the past chemists made one com-
pound at a time, in one reaction at a time. For example, compound A would have
been reacted with compound B to give product AB, which would have been isolated
after reaction, workup, and purification by chromatography. In contrast with this ap-
proach combinatorial chemistry offers the potential to make every combination of
compound A1 to An with compound B1 to Bn (Fig. 12.1). The range of combinatorial
techniques is highly diverse and the products could be made individually in a parallel
fashion or in mixtures, by use of either solution or solid-phase techniques [16].
Parallel to these developments in combinatorial chemistry, microwave-enhanced
organic synthesis has attracted a substantial amount of attention in recent years. As
evidenced from the other chapters in this book and the large number of review arti-
cles available on this subject [714], high-speed microwave-assisted synthesis has
A1 B1
A2 B2
A3 B3
A4 B4 A1-nB1-n
A+B AB
. .
. .
An Bn
(A) (B)
Fig. 12.1 (A) In a conventional synth- ferent building blocks of type A1 An are
esis, one starting material A reacts with treated with different building blocks of
one reagent B resulting in one product type B1n according to combinatorial
AB. (B). In a combinatorial synthesis, dif- principles.
been applied successfully in many fields of synthetic organic chemistry. It is, in fact,
becoming evident that microwave approaches can probably be developed for most
chemical transformations requiring heat, and/or for processes in which small polar
molecules are removed from a chemical equilibrium. Although different hypotheses
have been proposed to account for the rate-enhancements observed under micro-
wave irradiation, a generally accepted rationalization remains elusive (Chapt. 3) [13,
14]. Irrespective of the origin and/or existence of a special microwave effect, rapid
microwave dielectric heating (microwave flash heating) is extremely efficient and ap-
plicable to a broad range of practical synthesis [712].
The main benefits of performing reactions under microwave irradiation condi-
tions are the significant rate-enhancements and the higher product yields that can
frequently be observed. Not surprisingly, these features have recently also attracted
interest from the combinatorial and/or medicinal chemistry community, for whom
reaction speed is of great importance [1518]. Combination of microwave heating
technology and combinatorial chemistry applications is, therefore, a logical conse-
quence of the increased speed and effectiveness afforded by microwave heating. In
that respect, all chemical transformations that can be speeded up by microwave irra-
diation should, by definition, be of interest to practitioners in the field of combinator-
ial and medicinal chemistry [1518].
This attractive linking of combinatorial processing with microwave heating was re-
cognized in a 1995 summary of microwave-assisted organic reactions [8]. This review
is limited to microwave-assisted processes and techniques that are of direct relevance
to combinatorial chemistry applications, including solid-phase organic synthesis, the
use of polymer-bound scavengers or reagents, synthesis on soluble polymer sup-
ports, fluorous phase techniques, parallel synthesis, and the construction of libraries
in automated format by use of microwave technology. Because some of these applica-
tions require specialized equipment, a section will be devoted to microwave reactor
technology for high-throughput synthesis. In many of the examples of microwave
chemistry presented in this review we mention reported rate-enhancements in the
microwave-heated reactions compared with conventional heating. The reader should
be aware that such comparisons are inherently troublesome (Chapt. 3) [13, 14] and
do not a priori imply the existence of nonthermal or specific microwave effects.
12.2 Solid-phase Organic Synthesis 407
12.2
Solid-Phase Organic Synthesis
One of the cornerstones of combinatorial synthesis has been the development of so-
lid-phase organic synthesis (SPOS) based on the original Merrifield method for pep-
tide preparation [19]. Because transformations on insoluble polymer supports should
enable chemical reactions to be driven to completion and enable simple product pur-
ification by filtration, combinatorial chemistry has been primarily performed by
SPOS [1923]. Nonetheless, solid-phase synthesis has several shortcomings, because
of the nature of heterogeneous reaction conditions. Nonlinear kinetic behavior, slow
reaction, solvation problems, and degradation of the polymer support, because of the
long reactions, are some of the problems typically experienced in SPOS. It is, there-
fore, not surprising that the first applications of microwave-assisted solid-phase
synthesis were reported as early 1992 [24].
The earliest published example of microwave-assisted SPOS involved diisopropyl-
carbodiimide (DIC)-mediated solid-phase peptide couplings [24]. Numerous Fmoc-
protected amino acids and peptide fragments were coupled with glycine-preloaded
polystyrene Wang resin (PS-Wang) in DMF, using either the symmetric anhydride or
preformed N-hydroxybenzotriazole active esters (HOBt) as precursors (Scheme 12.1).
Reactions were performed in an unmodified domestic microwave oven employing
a custom-made solid-phase reaction vessel under atmospheric pressure. Efficiencies
were significantly improved by use of microwave irradiation for all the peptide cou-
plings tested, the rate enhancement being at least 23-fold compared with conven-
tional couplings at room temperature. In general, peptide bond formations were
completed within 26 min, compared to 30 min for reactions without microwave ir-
radiation at room temperature. As with so many of the early publications in micro-
wave-assisted chemistry, the exact reaction temperature during the irradiation period
was not determined, presumably because of lack of suitable instrumentation
(although the temperature at the end of the reaction could have been measured).
The reasons for the observed rate-enhancements, and the possible involvement of
so-called nonthermal microwave effects (Chapt. 3) [13, 14] therefore remain unclear.
In a more recent study using dedicated multimode microwave reactors for chemical
synthesis, which enable temperature and power control, it was demonstrated that mi-
crowave irradiation could be effectively employed to couple aromatic carboxylic acids
to polystyrene Wang resin [25], if the symmetrical anhydride procedure was used, and
not the three-component O-acylisourea activation method [19]. Almost quantitative
loading was achieved in 1-methyl-2-pyrrolidone (NMP) at 200 8C within 10 min under
(PhCO)2O, O
a) OH MW, 10 min
O Ph
PS-Wang NMP, 200 C
RCO2 H, Cs2CO3 O
b) Cl MW, 5-15 min
O R
PS-Merrifield/Wang NMP, 200 C
33 examples
Scheme 12.2 Attachment of carboxylic acids to Wang and Merrifield resins.
I Ph
H Bu3SnPh, [Pd] H
N MW, 3.8 min N
a)
O NMP
O
TentaGel-Rink
X Ar
H ArB(OH)2, Na2CO3, [Pd] H
N MW, 3.8 min
N
b)
O X = Br, I DME, EtOH, H2O
O 14 examples
TentaGel-Rink
1. Zn(CN)2, [Pd] N
N
MW, 2 min N
I
H 2. NaN3, NH4Cl H N
MW, 20 min H
N N
c)
NMP
O O
TentaGel-Rink
p-Tol
H
H N H N
N p-TolB(OH)2, Cu(OAc)2, [Pd] N
N MW, 0.5 min N
d)
pyridine-NMP
O O
TentaGel-PAL
proved by use of microwave irradiation (e. g. Scheme 12.3 d) [29]. These experiments
were performed with a domestic microwave oven and use of several intermittent ir-
radiation cycles and multiple additions of excess reagent. Compared with the con-
ventional thermal procedure (80 8C) the reaction time was effectively reduced from
48 h (overall) to less than 5 min and afforded a variety of N-arylated heterocycles in
high yield and purity after cleavage from the solid support.
Another metal-catalyzed microwave-assisted transformation performed on a poly-
mer support involves the asymmetric allylic malonate alkylation reaction shown in
Scheme 12.4. The rapid molybdenum(0)-catalyzed process involving thermostable
chiral ligands proceeded with 99 % ee on a solid support. When TentaGel was used
as as support, however, the yields after cleavage were low (834 %) compared with
the corresponding solution phase microwave-assisted process (monomode cavity)
which generally proceeded in high yields (>85 %) [30].
Multicomponent reactions (MCR), in which three or more reactions combine to
give a single product, have lately received much attention. The Ugi four-component
condensation in which an amine, an aldehyde or ketone, a carboxylic acid, and an iso-
cyanide combine to yield an a-acylamino amide, is particularly interesting, because
410 12 Microwave-assisted Combinatorial Chemistry
O
O O O O
Ph O OMe
O OMe Mo(CO)6, ligand O OMe
MW, 10 min
TentaGel-OH Ph
THF
Scheme 12.4 Solid-phase molybdenum(0)-catalyzed allylic alkylation.
of the wide range of products obtainable by variation of the starting materials [31].
Although conventional solid-phase Ugi reactions require several days for completion,
it has been demonstrated that by use of microwave irradiation (monomode instru-
ment, sealed Pyrex vessel), products of high purity were obtained in moderate to ex-
cellent yields (2496% yield) within 5 min irradiation time (Scheme 12.5) [32].
A polymer-bound amino component was used and a mixture of dichloromethane
and methanol (DCMMeOH 2 : 1) as solvent which both absorbed microwave energy
and solvated the resin. A library comprising 18 members was obtained after cleavage
of the resin-bound material from the support with TFA : DCM 19 : 1.
Another condensation process that has been performed by microwave heating is
the Knoevenagel reaction (Scheme 12.6). Resin-bound nitroalkenes, for example,
R1CHO,
R2CO2H, R 3NC R1 H
MW, 5 min N
NH2 N R3
DCM/MeOH Scheme 12.5 Ugi 4-component
O
TentaGel-RAM O R2 reactions on a solid support.
O
NO2
HO
ArCHO, NH4OAc
DIC, HOBt, rt, 17 h O O
MW, 20 min
NO 2 NO2
THF O THF O
Ar
5 examples
OH
PS-Wang
O O
ArCHO
R1O R
O O piperidinium acetate O O
MW, 170 C, 1-10 min MW, 125 C, 60 min
O R O R
1,2-Dichlorobenzene 1,2-Dichlorobenzene
7 examples Ar
21 examples
Scheme 12.6 Knoevenagel condensations on solid support.
12.2 Solid-phase Organic Synthesis 411
R R2XH (X = O, NR) R
N N Cl MW, 6 min N N X
L L R2
N N NMP or DMSO N N
PP or cellulose
membrane X X
R1 R1
Scheme 12.7 High-speed nucleophilic substitution reactions on polypropylene
or cellulose membranes.
412 12 Microwave-assisted Combinatorial Chemistry
O ArNCO O O
a) MW, 12 min
H Ar
O N O N N
DCM
R R H
PS-Wang
5 examples
O O O
e.g.
O
O SiO2 /TaCl5 O
b) MW, 5-7 min
NH2 N
O O
no solvent
PS-Merrifield O
6 examples
O O O OH
MW, 4-6 min
c) O
O R
R DMF
PS-Merrifield
8 examples
Scheme 12.8 Miscellaneous solid-phase reactions performed under
the action of microwave irradiation.
12.2 Solid-phase Organic Synthesis 413
O TFA/DCM 1:1 O
MW, 120 C (7 bar), 30 min
Scheme 12.9 Microwave- O Ph
assisted cleavage of benzoic HO Ph
acid from Merrifield resin. PS-Merrifield
O2 O2 O R1R2NH O
H H
a) S S N Ph MW ,~140 C, 15 min R1 N Ph
NH2 N N
O DMSO R2 O
Me Me
PS NC
1) p-NO2C6H4OCOCl
S DCM, 0C S
2) RNH2, DMF O
R
PS OH O N
H
R1R2NH O
MW, 1-20 min R2 R1
N N
NMP H
R1
Scheme 12.11 Microwave-assisted aminolysis (Marshall linker).
12.3
Polymer-supported Reagents, Scavengers, and Catalysts
Apart from traditional solid-phase organic synthesis (SPOS), the use of polymer-sup-
ported reagents (PSR) has gained increasing attention from practitioners in the field of
combinatorial chemistry [4952]. The use of PSR combines the benefits of SPOS with
the advantages of solution-phase synthesis. The most important advantages of these re-
agents are simplification of reaction workup and product isolation, the workup being
reduced to simple filtration. PSR can also be used in excess without affecting the purifi-
cation step. By using this technique, reactions can be driven to completion more easily
than in conventional solution-phase chemistry. So far only a few applications of micro-
wave-assisted PSR strategies have been reported in the literature.
One recent process involves the use of a polymer-supported Burgess reagent for
the synthesis of 1,3,4-oxadiazoles from 1,2-diacylhydrazines (Scheme 12.12). Irradia-
tion of a variety of 1,2-diacylhydrazines with a polyethylene glycol (PEG 750)-sup-
ported Burgess reagent in THF provided the corresponding 1,3,4-oxadiazoles in
7596 % yield and high purity after only 28 min irradiation [53]. Under conventional
reflux conditions a 40 % conversion was obtained after 3 h. Apart from filtration
through silica gel to remove the soluble polymer-supported reagent, and evaporation
of the solvent, no purification was necessary. Reactions were performed in dedicated
monomode instruments under sealed vessel conditions (no temperatures given). In
a variation of this procedure the same authors also described the cyclodehydration of
diacylhydrazines to oxadiazoles by use of the insoluble polystyrene-supported re-
agents A and B (Scheme 12.12) [54]. Similar reduced reaction times as with the solu-
ble polymer support (510 min) were also achieved by use of either of the two poly-
styrene-supported reagents in THF with microwave irradiation in sealed vessels.
Another example of microwave-assisted PSR chemistry involves the rapid conver-
sion of amides to thioamides by use of a polystyrene-supported Lawesson-type thio-
nating reagent. By use of microwave irradiation at 200 8C in sealed vessels (mono-
mode reactor), a range of secondary and tertiary amides was converted within
O2 O
S
Et3N N O
PEG R1 O R2
O O
R2 MW, 2-8 min
R1
N N N N
THF
H H 16 examples
O2 O Et2N NtBu
S Me P
N N O N N
Me2N PS PS
A B
Scheme 12.12 Synthesis of 1,3,4-oxadiazoles by use of polymer-supported
reagents.
416 12 Microwave-assisted Combinatorial Chemistry
O S
MW, 200 C, 15 min
R NR1R2 R NR1R2
toluene, ionic liquid
9 examples
15 min to the corresponding thioamides, in high yield and purity (Scheme 12.13)
[55]. Compared with classical reflux conditions, these thionation reactions were
much faster and reaction times were reduced from 30 h to 1015 min. Interestingly,
even heating at these elevated temperatures caused no damage to the polymeric sup-
port. Because toluene is not an optimum solvent for absorption and dissipation of
microwave energy [48], a small amount of ionic liquid (1-ethyl-3-methyl-1H-imidazo-
lium hexafluorophosphate) was added to the reaction mixture to ensure even and ef-
ficient distribution of heat.
In a related example, the catalytic transfer hydrogenation of olefinic substrates
using a polymer-supported hydrogen donor has been reported. By use of microwave
irradiation (monomode reactor) high yields of products (8095 %) could be obtained
by irradiation of a mixture of an Amberlite-derived supported formate, Wilkinson's
catalyst (RhCl(PPh3)3), and the olefinic substrate in the minimum quantity of
DMSO (Scheme 12.14) [56]. After separation of the Amberlite at the end of the reac-
tion the polymer-supported formate salt could easily be regenerated and used in
further hydrogenation reactions. In total, five reactionregeneration cycles were pos-
sible before an appreciable decrease in the reaction yield was noted.
Very recently a novel one-pot three-step Wittig reaction using microwave irradia-
tion and polymer-supported triphenylphosphine has been reported [57]. By use of
PS
N HCOO
RhCl(PPh 3)3
E MW, 30 s E Scheme 12.14 Microwave-medi-
R R ated hydrogenation using a polymer-
DMSO
supported hydrogen
8 examples donor.
PS Ph
P
Ph
O MW, 150 C, 5 min R2
R1 + Br R2 R1
H MeOH, K2CO3
15 examples
12.4
Soluble Polymer-supported Synthesis
ArB(OH)2
Pd(OAc)2, K2CO3 O
O
MW, 2 min S
S Ar
O Br O
H2O
PEG
5 examples
ArB(OH)2
Pd(OAc)2, K2CO3 O
O
MW, 2-4 min
O O
H2O
PEG
X Ar
X = I, OTf, ONf 12 examples
O RX, Cs2CO3 O
MW, 30-60 min
N Ph N Ph
O no solvent O
PEG Ph R Ph
8 examples
Scheme 12.17 Microwave-assisted alkylations on PEG support.
O O
AlkO R
O O
MW, 10 min
O R Scheme 12.18 Derivatization of
OH no solvent
poly(styrene-co-allyl alcohol) with
R = Me, Ph, OEt b-dicarbonyl compounds.
12.5 Fluorous-phase Synthesis 419
O E2 E1
E2 E1
NaOMe, rt, 18 h
H
MeOH MeO
O
O
5 examples
12.5
Fluorous-phase Synthesis
[Pd], LiCl
MW, 1.5-2 min
Ara X + (C6F13CH2CH2)3Sn-Arb Ara Arb
DMF
X = Br, I, OTf (14 examples)
Scheme 12.20 Fluorous Stille couplings under the action of microwave irradiation.
12.6.
Parallel Synthesis
Parallel processing of synthetic operations has been one of the cornerstones in com-
binatorial chemistry for years [16]. In the parallel synthesis of combinatorial li-
braries, compounds are synthesized using ordered arrays of spatially separated reac-
tion vessels adhering to the traditional one vessel-one compound philosophy. The
defined location of the compound in the array provides the structure of the com-
pound. A commonly used format for parallel synthesis is the 96-well microtiter plate,
and today combinatorial libraries comprising hundreds to thousands of compounds
can be synthesized by parallel synthesis, often in an automated fashion [6].
As demonstrated in the previous sections of this review, microwave-assisted reac-
tions allow rapid product generation in high yield under uniform conditions. There-
fore, they should be ideally suited for parallel synthesis and/or combinatorial chem-
istry applications. The first example of parallel reactions performed under micro-
wave irradiation conditions involved the nucleophilic substitution of an alkyl iodide
with 60 diverse piperidine or piperazine derivatives (Scheme 12.22) [71]. Reactions
were performed in a multimode microwave reactor in individual sealed polypropy-
12.6. Parallel Synthesis 421
X
I X NH
N
N MW, 4 h
NH2 N
S MeCN X = NR, CR1R2 NH2
S
60 examples
Scheme 12.22 Nucleophilic substitution reactions performed in parallel.
O O Ar O
Ar bentonite clay
R2 MW, 5 min R2 R2
+ + NH4NO3
O H no solvent
R1 O R1 N R1
> 96 examples
Scheme 12.23 Microwave-assisted Hantzsch pyridine synthesis.
lene vials using acetonitrile as solvent (no further details given). Screening of the re-
sulting 2-aminothiazole library in a herpes simplex virus-1 (HSV-1) assay led to three
confirmed hits, demonstrating the potential of this method for rapid lead optimiza-
tion.
In a key 1998 publication, the concept of microwave-assisted combinatorial chem-
istry was introduced for the first time. Using the three-component Hantzsch pyri-
dine synthesis as a model reaction, libraries of substituted pyridines were prepared
in a high-throughput parallel fashion. In this variation of the Hantzsch multicompo-
nent reaction, ammonium nitrate was used as the ammonium source as well as oxi-
dizing agent, employing bentonite clay as inorganic support (Scheme 12.23) [72]. Mi-
crowave irradiation was performed in 96-well filter-bottom polypropylene plates, in
which the corresponding eight 1,3-dicarbonyl compounds and twelve aldehyde build-
ing blocks were dispensed using a robotic liquid handler. Microwave irradiation of
the 96-well plate containing aldehydes, 1,3-dicarbonyl compounds, and ammonium
nitrateclay in a domestic microwave oven for 5 min produced the expected pyridine
library directly, after the desired products were extracted from the solid support by
organic solvent and collected in a receiving plate. HPLCMS analysis showed that
the reactions were uniformly successful across the 96-well reactor plate, without any
starting material being present. The diversity of this method was further extended
when mixtures of two different 1,3-dicarbonyl compounds were used in the same
Hantzsch synthesis, potentially leading to three distinct pyridine derivatives (not
shown).
Using a similar format, dihydropyrimidines were obtained in a microwave-expe-
dited version of the classical Biginelli three-component condensation (Scheme 12.24)
[73]. Neat mixtures of b-ketoesters, aryl aldehydes and (thio)ureas with polyphosphate
ester (PPE) as reaction mediator were irradiated in a domestic microwave oven for
1.5 min. The desired dihydropyrimidines were obtained in 6195 % yield after aqu-
422 12 Microwave-assisted Combinatorial Chemistry
Ar O Ar
O
PPE H
O H R1O N
R1O NH2 MW, 1.5 min
+
R2 O HN X no solvent R2 N X
R3 R3
15 examples
Scheme 12.24 Microwave-assisted Biginelli dihydropyrimidine
synthesis.
R1
R1
O
H NH 2 Montmorillonite K-10 clay N
a) + MW, 4 min R2
R2 NC N X N X
no solvent
Y Y
X = Y = CH 14 examples
X = CH, Y = N
X = N, Y = CH
R2
R2
R1 O H2N NH4OAc, Al2O3 R1 N
b) MW, 20 min
+ O R3
R1 O no solvent R1 N
R3
H
4 examples
O Lawesson's reagent S
R1 MW, 8 min R1
Ar N Ar N
c) R2 no solvent R2
25 examples
Ar O Ar
O
R H O CN R CN
MW,15-20 min N
d) N
+ Me
Me no solvent X N N Ph
X N NH2 O Ph H
X = O, S; R = H, Me 9 examples
sualization procedures for the results of the reaction. In this particular example, the
synthesis of an arylpiperazine library (Scheme 12.26) was described, but the simpli-
city and general utility of the approach for the rapid screening of solvent-free micro-
wave reactions may make this a powerful screening and reaction optimization tool.
Other microwave-assisted parallel processes, for example, involving solid-phase or-
ganic synthesis (SPOS) have already been discussed in Sect. 12.2. (Schs. 12.6, 12.7,
and 12.10). In the majority of cases described so far, however, domestic multimode
microwave ovens have been used as heating devices, without utilizing specialized re-
actor equipment. Since reactions in household multimode ovens are notoriously dif-
ficult to reproduce due to the lack of temperature and pressure control, pulsed irra-
424 12 Microwave-assisted Combinatorial Chemistry
12.7
Equipment for High-throughput Microwave-assisted Synthesis
only one mode is present and the electromagnetic irradiation is focused directly
through an accurately designed wave guide on to the reaction vessel mounted in a
fixed distance from the radiation source. For combinatorial chemistry applications,
the key difference between the two types of reactor systems is that in multimode cav-
ities several reaction vessels can be irradiated simultaneously, whereas in monomode
systems, only one vessel can be irradiated at a time. One instrument designed for
high-throughput organic synthesis is the Ethos SYNTH microwave labstation (Mile-
stone Inc.) [80, 83]. This multimode instrument features a built-in magnetic stirrer,
direct temperature control of the reaction mixture with the aid of fiber-optic probes
and software that enables online temperature and/or pressure control by regulation
of microwave power output (1000 W maximum). The flexible modular platform al-
lows the use of standard glassware for reactions performed at atmospheric pressure,
sealed reaction vessels for performing synthetic transformations at elevated tempera-
ture and pressure, and the application of various parallel reactors [80, 83]. For all con-
figurations, the operator has full on-line access to all control parameters such as tem-
perature, pressure, microwave power, and irradiation time. For this reactor so-called
multiPREP rotors have been developed that house 36, 50, or 80 reaction vessels that
fit into the large multimode cavity. These continuously moving rotors operate at at-
mospheric pressure with ca. 20 mL glass, TFM, or PFA vessels. For applications re-
quiring sealed vessel conditions a rotor system with 36 glass vessels (Ethos multi-
PREP-36/P, Fig. 12.3) with a maximum operating temperature and pressure of
200 8C and 15 bar, respectively, has also been developed. In general, the temperature
in a parallel reaction is measured in one reference vessel either by fiber-optic sensor
or with the aid of a shielded thermocouple. During the reaction the temperature can
additionally be controlled by an external IR sensor in the wall of the instrument,
monitoring the surface temperature of the individual vessels as they move by the
sensor. Magnetic stirring of each vessel ensures homogeneous mixing of the sample
and even temperature distribution. Published applications of the multiPREP 50-ro-
tor system (open vessels) have included the generation of a 21-member library by
parallel solid-phase Knoevenagel condensations (Scheme 12.6) [34]. Here the tem-
perature was monitored with the aid of a shielded thermocouple inserted into one of
the reaction containers. It has been confirmed by standard temperature measure-
ments performed immediately after the irradiation period that the resulting end
temperature in each vessel was the same within 2 8C [34]. In a different study invol-
ving the multiPREP 36/P rotor (Fig. 12.3) utilizing sealed glass vessels, the unifor-
mity of the reaction conditions in such a parallel set-up was investigated. For that
426 12 Microwave-assisted Combinatorial Chemistry
100 b
80 b Aldehydes a-f
c
Yield (%)
60 a c a f
e f d e
40 d
20
0
1 6 11 16 21 26 31 36
Reaction Vessel
Fig. 12.6 Monomode microwave reactor with and reaction vials (bottom right) are also dis-
integrated robotics interface for automated use played (Emrys Synthesizer, Personal Chemistry
(left). Details of the cavity/gripper (top right) AB) [86].
the outside of the reaction vessel. The instrument processes up to 120 reactions per
run with a typical throughput of 1215 reactions h1. Magnetic stirring of each indi-
vidual process vial (250 8C, 20 bar maximum temperature and pressure, respectively)
and unattended operation are some of the features of this microwave reactor. In con-
trast to the parallel synthesis application in multimode cavities this, approach allows
the user to perform a series of optimization reactions with each reaction separately
programmed.
The use of this setup for automated sequential microwave-assisted library synth-
esis was first reported in the context of preparing a series of dihydropyrimidines by
the Biginelli reaction (see Scheme 12.24). A diverse set of 17 CH-acidic carbonyl
compounds, 25 aldehydes, and 8 urea and/or thioureas was used in the preparation
of a dihydropyrimidine library [88]. Of the 3400 theoretically possible dihydropyrimi-
dine derivatives, a representative subset of 48 analogs was prepared using automated
addition of building blocks and subsequent sequential microwave irradiation of each
process vial. For most building block combinations, 10 min of microwave flash heat-
ing at 120 8C using AcOHEtOH, 3 : 1, and 10 mol % Yb(OTf)3 as solventcatalyst
system proved to be successful, leading to an average isolated yield of 52 % of
DHPM with > 90 % purity. For some building block combinations the general condi-
tions were modified, by changing the solvent, catalyst, reaction temperature, or irra-
diation time. The unattended automation capabilities of the microwave synthesizer
enables a library of this size to be prepared within 12 h.
In a related example involving the use of the same instrument (Fig. 12.6) in the
Hantzsch multicomponent condensation, the serial synthesis of 24 dihydropyridine
12.7 Equipment for High-throughput Microwave-assisted Synthesis 429
R O R O
O O
O H MW, 140-150 C, 10-15 min R1 R1
R1 R1
+
R2 O O R2 aqueous NH3 (25%) R2 N R2
H
24 examples
Scheme 12.27 Generation of a dihydropyridine library using automated sequential
microwave processing.
derivatives was reported, involving the microwave assisted reaction of 6 different al-
dehydes with 4 different b-ketoesters or 1,3-dicarbonyl compounds and aqueous am-
monia (Scheme 12.27) [89]. Reactions were run in sealed vessels (see above) at
140150 8C for 1015 min, providing the desired products in 3989 % yield and low
to excellent purities (5399 %).
Additional applications of this technology for rapid lead discovery and lead optimi-
zation have been reported [87, 9093]. It should also be noted that a variety of chemi-
cal transformations, in particular in the area of transition-metal catalyzed reactions,
have been performed with this or related equipment (Chapt. 11) [25]. Other mono-
mode microwave reactors using related concepts to introduce high-throughput were
recently introduced by CEM Corp. (Discover or Explorer line of products, Fig. 12.7.)
[81]. At the time of writing this review no published synthetic applications using this
microwave reactor were available.
The issue of parallel versus sequential synthesis using multimode or monomode
cavities, respectively deserves special comment. While the parallel setup allows for
considerable throughput that can be achieved in the relatively short timeframe of a
microwave-enhanced chemical reaction, the individual control over each reaction
vessel in terms of reaction temperature and/or pressure is limited. In the parallel
mode, all reaction vessels are exposed to the same irradiation conditions. In order to
ensure similar temperatures in each vessel, the same amount of the identical solvent
should be used in each reaction vessel because of the dielectric properties involved
[48]. An alternative to parallel processing the automated sequential synthesis of li-
braries can be a viable strategy. Irradiating each individual reaction vessel separately
gives better control over the reaction parameters, and allows for the rapid optimiza-
tion of reaction conditions. For the preparation of relatively small libraries, where de-
licate chemistries are to be performed, the sequential format may be preferable.
12.8
Conclusion
References