Mol Divers (2012) 16:81–90
DOI 10.1007/s11030-012-9357-2
FULL-LENGTH PAPER
Parallel synthesis of 1,2,4-triazole derivatives using microwave
and continuous-flow techniques
Tamás Szommer · András Lukács · József Kovács ·
Miklós J. Szabó · Michael G. Hoffmann ·
Monika H. Schmitt · János Gerencsér
Received: 21 September 2011 / Accepted: 9 January 2012 / Published online: 26 January 2012
© Springer Science+Business Media B.V. 2012
Abstract An efficient and convenient solution-phase
synthesis of a 1H -1,2,4-triazole library with potential agro-
chemical activity is reported employing microwave-assisted
organic synthesis (MAOS) and continuous-flow microfluidic
synthetic methods starting from commercially available 3,5-
dibromo-1H -1,2,4-triazole (1). MAOS was used for the syn-
thesis of 5-amino-3-bromo-1,2,4-triazole analogs 3 and for
their 3-aryl derivatives 4 via Suzuki–Miyaura coupling with
polymer-supported catalyst. A microfluidic hydrogenation
reactor integrated into an automated parallel synthesis plat-
form was built and utilized for the reductive dehalogenation
reactions providing 5-aminotriazoles (5).
Keywords Microwave-assisted organic synthesis ·
Continuous-flow hydrogenation · 1H -1,2,4-triazole
Introduction
Chemical pest control is essential for worldwide food pro-
duction and public health. Although the usage of biopesti-
cides is continuously growing, it covers only approximately
2% of the global pesticide market as of today [1]. Thus, it is
expected that chemical pesticides will continue to dominate
This manuscript is dedicated to Professor Árpád Furka on the
occasion of his 80th birthday.
T. Szommer · A. Lukács · J. Kovács · M. J. Szabó · J. Gerencsér (B)
AMRI Hungary Zrt., Záhony u. 7., Budapest, 1035, Hungary
e-mail: janos.gerencser@amriglobal.com
M. G. Hoffmann · M. H. Schmitt
Bayer CropScience AG, Industriepark Höchst, G 836,
65926 Frankfurt am Main, Germany
the market in the foreseeable future. Concerns about environ-
mental pollution, resistance of pests to chemical control, and
toxic residual effects of chemical pesticides, however, are
the driving force for the research and development of novel,
more potent and less toxic agrochemicals with environmental
sustainability.
1H -1,2,4-Triazole derivatives have widely been investi-
gated for anticonvulsant and plant growth regulatory activ-
ities, and in particular, disubstituted 1,2,4-triazole derivatives
showed antifungal, insecticidal, and herbicidal properties
[2–7]. 1,2,4-Triazole derivatives play an important role in
agrochemistry, and there have been several triazole herbi-
cides (e.g., amitrole, cafenstrole, epronaz, flupoxam) and
fungicides (e.g., difenoconazole, fenbuconazole, myclobu-
tanil, propiconazole, tebuconazole, tetraconazole, triadime-
fon, and triticonazole) introduced to the market. The triazole
core, hence, can be considered as a privileged substructure.
Inspired by the above observations, we devised the synthe-
sis of di- and trisubstituted 5-amino-1H -1,2,4-triazole
libraries with potential herbicide and fungicide activities.
Herein we report the convenient and efficient synthesis of
di- and trisubstituted aminotriazole libraries utilizing micro-
wave-assisted organic synthesis (MAOS) and continuous-
flow synthesis techniques (Scheme 1).
Zarguil et al. [8] described the synthesis of a series of 3-
substituted-5-amino-1H -1,2,4-triazoles (4) from imidates 6
and 7 (Scheme 2). Incorporation of R1 and R4 diversity ele-
ments was well documented; however, only aniline or amino
groups were reported for the substitution at the 5th position
of the 1,2,4-triazole ring system.
While this reported method appeared to be amenable to
parallel chemistry, it would not give rise to the wide range
of ring substitution that we wanted to prepare. We there-
fore devised a linear and sequential synthetic method for
the introduction of variable residues onto the triazole ring
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82 Mol Divers (2012) 16:81–90

Scheme 1 Retrosynthetic plan R4

N
for chemsets 4 and 5 N R2
R2 N N
N N N
N R3
R3 R1
R1
4 5

Br Br Br
N N N
R2
N N N N
N Br N Br N
R3 R1 H
R1
3 2 1

S presence of DBU at elevated temperatures yielding

N
R 1 NHNH 2
R4 NHR 2
OEt
N Under conventional heating at 120 ◦ C, the reaction times
6 R2
N N
H N
R1
N CN 4
R4 R 1 NHNH 2
OEt
R2 = Ph or H
7
Scheme 2 Synthesis of 3-substituted-5-amino-1H -1,2,4-triazoles (4)
from imidates 6 and 7
starting from the commercially available 3,5-dibromo-1,2,4-
triazole (1). The method that we developed further utilizes the
common intermediate 3 for the synthesis of both chemsets 4
and 5. Dibromo-triazole 1 offers valuable synthetic potential
due to the different reactivities of the two halogens in nucle-
ophilic substitution reactions [9]. Furthermore, in contrast
to the synthesis strategy involving the imidate synthesis, our
synthetic plan allowed the introduction of both primary and
secondary amines onto position 5 of the 1,2,4-triazole ring
system.
Results and discussion
3,5-Dibromo-1H -1,2,4-triazole (1) was alkylated with an
array of 8{1–7} benzyl bromide derivatives using a stan-
dard literature method [10] furnishing 1-substituted triazoles
2{1–7} with no visible traces of the 4-substituted adducts
(Scheme 3). The regioselective nucleophilic substitution of
the 5-bromine of chemset 2 with primary and secondary
amines 9{1–11} was successfully performed in anisole in the
1-benzylic-5-amino-3-bromo-1H -1,2,4-triazole derivatives
R4
3 {1–7, 1–11} (Scheme 3).
varied between 12 and 20 h, but the time could significantly
be reduced by application of heating by microwave irradia-
tion at 160 ◦ C for 2 × 1 h (Scheme 4; Table 1). The reactions
were carried out in a Milestone microwave instrument using
an HPR 10/1000 high-pressure rotor. The developed condi-
tions were applicable to both primary and secondary amines
with relatively good nucleophilicity and there was no need
for the use of palladium catalyst.
The regioselectivity of the alkylation reaction was estab-
lished by NMR measurements (Fig. 1). The nucleophilic dis-
placement of the bromine exclusively took place in position
5 as proven for two samples by NOE measurements apply-
ing selective irradiation of the benzylic methylene protons.
The measured enhancements are shown on the correspond-
ing arrows which connect protons having nuclear Overhauser
effects (Fig. 1).
Out of the 77 possible R1 and R2 –R3 combinations, 56
reactions were launched, from which forty seven compounds
were synthesized successfully. The synthesized 47 deriva-
tives of 3 were sufficient for the synthesis of the desired
approximately 500-member library. The library generation
step was the Suzuki–Miyaura coupling reaction of chemset
3 with boronic acids 10{1–20} (Scheme 5).
Boronic acids were arbitrarily chosen and used to syn-
thesize chemset 4. Only small groups were applied as sub-
stituents on the aromatic ring, in order to obtain drug-like
products. First, we tested reaction conditions that were
applicable for a multimode cavity instrument (Milestone
microwave reactor equipped with a CombiCHEM rotor, irra-
diation at 120 ◦ C for 1 h) in order to gain higher throughput.
However, in most reactions we observed the formation of
significant amount of the dehalogenated by-product 5. The

123
Mol Divers (2012) 16:81–90 83

Scheme 3 Synthesis of chemset 3; variations at two diversity points

NH2
N N
Br Br H N
N Br
9{5}
N N N N N
Conditions

2{1} 3{1,5}

Scheme 4 Optimization scheme of chemset 3

123
84 Mol Divers (2012) 16:81–90

Table 1 Optimization conditions for nucleophilic substitution of chem- Br Br

CH3 CH3
set 2 N N
3.20 3.14
Entry Base Solvent Temp. (◦ C) Time (h) Yieldc N N
2.88 N N F 2.83 N N
H3C 5.22 H3C 5.12 7.24
1a K2 CO3 DEF 25 12 No reaction
2a K2 CO3 DEF 90 12 67% 0.6% 0.8%
3b K2 CO3 DEF 160 1 Low conversion 0.8% F 1.1% 1.3% F
4a DBU Anisole 120 12 Low conversion
5a DBU Anisole 120 20 67% 3 {5,11} 3 {2,11}
6b DBU Anisole 160 1 Low conversion
Fig. 1 Establishment of the position of the nucleophilic substitution
7b DBU Anisole 160 2×1 73% using NMR selective NOE measurements
a Conventional heating, b The reactions were carried out in a multimode

cavity microwave instrument, c Isolated yield after chromatographic

purification

Scheme 5 Synthesis of chemset R2 R4-B(OH)2 R2

4 via Suzuki–Miyaura N Br 10{1–20} N R4
N N
cross-coupling reaction R3 R3
N N N N
PS-Pd[P(Ph)3]4
R1 R1
aq. K2CO3
3{1–7,1–11} DME-EtOH 4{1–7,1–11,1–20}
MW, 170 °C, 15min
R4-B(OH)2 Building Blocks Employed:
OH OH OH OH
B B Me B F3C B
OH OH OH OH

Me
10{1} 10{2} 10{3} 10{4}
OH OH OH OH
NC B B MeO B MeO B
OH OH OH OH

MeO MeO
10{5} 10{6} 10{7} 10{8}

OH OH OH OH
Cl B Me B F B F B
OH OH OH OH

Me Me OMe
Cl
10{9} 10{10} 10{11} 10{12}
OH OH OH OH
Cl B F3CO B B B
OH OH OH OH

OMe Me2N N
H
10{13} 10{14} 10{15} 10{16}

OH OH OH OH
B B O B B
N OH OH OH OH
O MeO N

10{17} 10{18} 10{19} 10{20}

123
Mol Divers (2012) 16:81–90 85

Scheme 6 Optimization scheme B(OH)2

of chemset 4 MeN MeN
N N Br 10{1} N N

N N N N
Conditions

3{2,9} F 4{2,9,1} F

Table 2 Optimization conditions for Suzuki–Miyaura coupling

Entry Base Ligand Cat.c Temp. Time Yieldf 140
120
1a Cs2 CO3 t Bu P A Refluxd 5h 18% 120

Number of compounds
3
2a Cs2 CO3 t Bu P
3 A 120 ◦ Ce 40 min 21% 100
88
94

3a Na2 CO3 Ph3 P B 160 ◦ Ce 40 min Low conversion 80 70

4b K2 CO3 – C 140 ◦ Ce 60 min 14%
60
5a K2 CO3 – C 120 ◦ Ce 60 min 25% 41

6a KB – C 120 ◦ Ce 60 min 22% 40

22
7a Cs2 CO3 – C 120 ◦ Ce 60 min 23% 20
6 8 8
120 ◦ Ce 60 min 30%
1
8a K2 CO3 – D 0
9a K2 CO3 – E 170 ◦ Ce 15 min 65%
.5

.0

.5

.0

.5

.0

.5

.0

.5

.0
-2

-3

-3

-4

-4

-5

-5

-6

-7
-6
0

5
5
2.

2.

6.

6.
3.

3.

4.

4.

5.

5.
a DME/EtOH/water; b Toluene/EtOH/water; c A: 5 mol% Pd2 (dba)3 , B: cLogP
5 mol% Pd(OAc)2 , C: 5 mol% PdCl2 (Ph3 P)2 , D: 5 mol% Pd(Ph3 P)4 ,
E: 10 mol% PS–Pd–Ph3 P; d Conventional heating; e The reactions were 250
carried out in a monomode cavity microwave instrument; f Isolated yield
after HPLC purification 197
Number of compounds

200

150
127
formation of the unwanted by products was observed across
93
the reactor plate and found to be independent from the posi- 100
tion of the reaction vials. Thus, we had to modify the condi-
50 40
tions to suppress the rate of the—this time unwanted—side
reaction. Since the room for improvement was very narrow 1 0
0
in the multimode instrument due to temperature and pressure
00

50

00

50

00

50
restrictions (maximum 160 ◦ C and maximum 4 bar, respec-
-3

-5
-3

-4

-4

-5
0

0
0

0
0
25

50
30

35

40

45

tively), we switched to a monomode cavity instrument (CEM

Molecular Weight
Explorer 24) and were able to identify the conditions which
were well applicable for the library generation step. Inter- 160
estingly, in the monomode instrument the previously iden- 140
138
127
Number of compounds

tified reductive dehalogenation reaction was not observed 120

anymore. Finally, the library synthesis was carried out with
100
an array of twenty arylboronic acids using PS-supported pal-
80
ladium catalyst and aqueous potassium carbonate as base in
a DME–EtOH solvent system at 170 ◦ C furnishing 1-alkyl-
57
60 51
41
5-amino-3-aryl-1H -1,2,4-triazole derivatives 4 (Scheme 5). 40 27
As our optimization efforts (Scheme 6; Table 2) were inde- 20 13
4
pendently and successfully completed, we discovered that 0
similar conditions were reported in the literature for a simi-
0

0
0

0
0

-6

-7

-8
-4

-5
-2

-3
-1

30

40
5

10

20

50

60

70

lar core structure [11].

Produced Quantity (mg)
Due to the variable amounts of the bromide intermedi-
ates 3 altogether 650 reactions could be launched instead of Fig. 2 cLogP, molecular weight, and produced quantity distributions
the theoretically possible 47 × 20 = 940 combinations. The of chemset 4

123
86
Fig. 3 Alkyl bromides 8 for the
synthesis of chemset 5 8 {1}– 8{7}
Br F 3CO
F3CO
8{11}
MeO
Br
MeO
OMe
8{15}
library synthesis and subsequent HPLC purification efforts
resulted in 458 compounds fulfilling both the purity and the
weight criteria providing the samples in at least 5 mg and
in >85% purity as assessed by HPLC-MS analysis. The
cLogP (octanol/water partition coefficients (cLogP) were
calculated using Chemaxon JChem software version 5.3.8),
molecular weight and produced quantity distributions are
shown in Fig. 2.
In addition to the above described trisubstituted triazole
chemset 4, we developed a method for the synthesis of a 1,5-
disubstituted triazole library (5). For this purpose, the syn-
thesized chemset 3 looked to be a good starting point because
having developed methodology to prepare chemset 3, this key
intermediate could be used as a branch-point to initiate the
synthesis of this new library by the reductive dehalogenation
of 3. Thus, an additional ten benzyl halides were introduced,
extending the list of electrophiles to 17 (Fig. 3).
However, the applied method for the synthesis of chemset
3 was not amenable to high-throughput parallel chemistry on
small scale, as the high-pressure vessels were too large in vol-
ume for milligram scale synthesis. Thus, for the synthesis of
the disubstituted triazole series 5 it was necessary to develop
a method that was amenable to a larger set including less
nucleophilic amines than previously used (Fig. 4). Library
design was done using the Chemaxon Reactor module inte-
grated with AMRI’s in-house developed chemoinformatic
system.
The reactants were adsorbed onto basic alumina and the
obtained solid mixture was irradiated in a Milestone micro-
wave instrument equipped with a CombiCHEM rotor at
160 ◦ C for 4 × 30 min. By applying basic alumina as reaction
media, we were able to replace the otherwise very inconve-
123
Mol Divers (2012) 16:81–90
F CF3
Br Br
Br
F 3C
F
8{8} 8{9} 8{10}
Me
Br
Br Br
tBu
Me
8{12} 8{13} 8{14}
F
F
Me Br
Br
MeO
8{16} 8{17}
nient anisole/DBU system, which allowed an easier work-
up procedure and thus more amenable to parallel synthesis.
Under these conditions, even the less nucleophilic amines
reacted with bromide 3 giving the corresponding product.
Using this more general method, we launched 322 reactions
between dibromo derivatives 2{1–17} and the
extended list of amines 8{1–34} from which after HPLC
purification a total of 256 5-amino-1H -1,2,4-triazoles 3{1–
17, 1–34} were successfully isolated in at least 15 mg quan-
tity and in higher than 85% purity as assessed by LCMS
analysis (Scheme 7). The purified samples of 3 were then
subjected to reductive dehalogenation.
The use of automated flow-through hydrogenation sys-
tems was reported in the literature [12,13]. We applied the
set-up successfully implemented previously in our laboratory
[12]. The hydrogenation system for the dehalogenation pro-
cess was made up of an H-CubeTM , a Tecan CAVRO two-arm
injector–collector, a Knauer HPLC pump, and a VICI Val-
co 6-port valve (Fig. 5) [12]. Starting in position A of the
Valco 6-way valve, the HPLC pump controlled a continu-
ous stream of solvent through the injector and then into the
reactor. Meanwhile the CAVRO system injected a solution
of the substrate into the valve’s injection loop. The injector
valve (Fig. 5) switched to position B which altered the flow
of solvent from the reactor to the injection loop, pushing the
injected substrate out of the loop and into the reactor. In the
reactor, hydrogen was mixed with the substrate and passed
through a stainless steel column packed with 10% palladium
on charcoal. The hydrogenated product continuously flowed
out of the hydrogenation column into a collection vial which
was controlled by the second arm of the CAVRO robotic
station. The fraction collector arm positioned itself over a
Mol Divers (2012) 16:81–90 87

O NH2
NH 2 NH2 NH2
9{1} – 9{11}

9{12} 9{13} 9{14} 9{15}

Me H
OMe NH F NH MeO N
Me NH
NH2 N N
MeO Me

9{16} 9{17} 9{18} 9{19} 9{20}

NH2 N NH2 MeO NH2 Me 2N

N MeO NH2
NH2

9{21} 9{22} 9{23} 9{24} 9{25}

Me
NH
Me NH 2 F 3C NH2 N NH 2
N N NH 2
Me

9{26} 9{27} 9{28} 9{29} 9{30}

O NH NH 2
NH 2 NH2
Me2N

9{31} 9{32} 9{33} 9{34}

Fig. 4 Extended list of amines 8 used for the synthesis of chemset 5

Scheme 7 Synthesis of chemset H

5 using a sequential R 1-Br N
R2 R3
continuous-flow hydrogenation N
method (H-CubeTM ) N 8{1-17} Br Br 9{1-34}
Br Br
N N
HN N DIPEA, MeCN basic alumina
reflux, 3-8h R1
MW, 160 °C, 4×30 min
1 2 {1-7}
17 samples
synthesized

R2 R2
N N N
N Br H 2, Pd/C
R3 R3
N N N N
R1 H-Cube: R1
60 bar, rt, 1.5 mL/min
3{1-17,1-34} 5{1-17,1-34}

256 samples 192 samples

synthesized synthesized

123
88
Fig. 5 Flow of solvent through
valve in positions A and B
collection vial and collected all the eluted product and sol-
vent washing into the vial. While this process took place, the
valve positions were reset back to position A, the injection
needle proceeded into a washing program and the system was
ready for the next sample-injection.
Evaporation of the solvent followed by HPLC purifica-
tion yielded 192 compounds meeting the pre-set quality and
quantity criteria, providing the samples in at least 5 mg and in
higher than 85% purity. The cLogP, molecular weight and
produced quantity distributions of chemset 5 are shown in
Fig. 6.
Conclusion
Herein, we report an efficient and convenient synthesis of
a library of nearly 500 1-alkyl-3-aryl-5-amino-1H -1,2,4-tri-
azoles (4) using microwave-assisted synthetic methods by
sequential introduction of the variable substituents starting
from 3,5,dibromo-1H -1,2,4-triazole (1). Nearly 200 1-
alkyl-5-amino-1H -1,2,4-triazoles (5) were successfully syn-
thesized from bromide intermediate 3 using continuous-flow
hydrogenation technique integrated into the parallel synthe-
sis platform.
Experimental
General methods and instruments
All reagents and solvents were used without further puri-
fication. Thin-layer chromatography (TLC) was performed
using silica gel 60 F254 (Merck) and visualized by UV light
(254 nm). Column chromatography was carried out using
silica gel 60 unless otherwise specified. Proton nuclear mag-
netic resonance spectra were recorded on a Bruker Avance
II instrument at 400 MHz or on a Bruker DRX instrument at
300 MHz. The 13 C NMR spectra were recorded on a Bruker
123
Mol Divers (2012) 16:81–90
Avance II instrument at 100 MHz. The measurements were
done at room temperature and chemical shifts (δ) are given
in ppm with coupling constants and J values reported in
Hertz. For the calibration of the spectra solvent signal and
TMS signal were used in case of chloroform-d and solvent
signal was used in case of DMSO-d6 . The HPLC-MS mea-
surements were carried out using a Waters Acquity UPLC
instrument with BEH C18, 2.1 × 50 mm, 1.7 µm column
using a gradient program which was adjusted according to
the compound properties; Eluent I: acetonitrile/water = 5/95
with 20 mM ammonium formate buffer, pH 7.4, Eluent II:
acetonitrile/water = 80/20 with 20 mM ammonium formate
buffer, pH 7.4. The preparative HPLC purifications were per-
formed on a LaChrom HPLC system (Merck–Hitachi) and
a Waters HPLC-MS mass directed instrument with a C18
reverse phase column using a solvent gradient program which
was adjusted according to the logP; Method A: eluent I:
water, eluent II: acetonitrile; Method B: eluent I: water, elu-
ent II: acetonitrile/trifluoroacetic acid, 99.9/0.1; in both cases
eluent III: acetonitrile/2-propanol/formic acid 70/30/0.1 was
used for washing the column. The high resolution mass spec-
trometric data were obtained using Waters Q-TOF Premier
LCMS system by electrospray ionization. Microwave-
irradiated nucleophilic substitution reactions were performed
using a Milestone MicroSYNTH instrument equipped either
with an HPR 10/1000 for intermediate synthesis, or a
CombiCHEM rotor for small scale parallel synthesis. The
reaction vessels were standard Milestone HPR vessels and
4-mL Milestone microwave vials with silicone/TEF cover.
A CEM Explorer-24 instrument was used for the Suzuki–
Miyaura coupling library synthesis step. The reaction vessels
were 10-mL CEM microwave vials with silicone/TEF cover.
An H-CubeTM instrument integrated with a PC-controlled
Cavro RSP 9000 liquid handler was used for the automatic
sequential hydrogenation reactions. The liquid-liquid extrac-
tions for the libraries were carried out in screw-threaded 5-
mL tare weighed standard glass vials with polypropylene
Mol Divers (2012) 16:81–90 89

60 uired benzyl bromide derivative (306 mmol, 1.02 equiv) in

53

50 acetonitrile (250 mL) was stirred at reflux temperature for

Number of compounds

45
3–8 h. The solvent was evaporated under reduced pressure,
40 38 38
the residue was dissolved in ethyl acetate (250 mL), washed
30 with water (100 mL), 3% aq. HCl (60 mL) and 5% aq.
22 NaHCO3 solution (60 mL), respectively. The organic phase
20 18
13
was dried over Na2 SO4 , filtered, and evaporated under
10
reduced pressure. The crude product was purified either by
1
3 3 crystallization from n-hexane or by flash chromatography
0 (silica gel, chloroform).
.5

.0

.5

.0

.0

.5
.5

.0

.0
.5
-2

-3

-4

-5
-1

-2

-3

-4

-5

-6
5

0
0

5
0

0
1.

2.

4.
1.

2.

3.

3.

4.

5.

5.
clogP General procedure for the synthesis of chemset 3

100 92 Procedure A (intermediate synthesis): The amine compo-

88
90 nent (45 mmol) was dissolved in anisole (50 mL) then DBU
Number of compounds

80 (9.4 mL, 9.6 g, 63 mmol, 1.4 equiv) was dispensed into the
70
solution. The mixture was stirred at room temperature for
60
15 min and triazole 2 (15 mmol) was added in one portion.
50
41 The resulting reaction mixture was transferred to a Milestone
40
HPR vial and microwave irradiated at 160 ◦ C for 2 × 60 min.
30
20
The solvent was removed in vacuo, the residue was dis-
10 7 6 solved in chloroform (50 mL), washed with water (70 mL),
0 3% aq. citric acid (50 mL) and water (50 mL), respectively.
The organic phase was dried over Na2 SO4 or MgSO4 , fil-
0

0
25

30

35

40

45

Molecular Weight tered, and evaporated under reduced pressure. The crude
product was purified by flash chromatography (silica gel,
100 chloroform).
90
90 Procedure B (library synthesis): Basic aluminum oxide
81
Number of compounds

80
(250 mg/vial) was weighed into Milestone CombiCHEM
70
microwave vials to which a solution of 2 (1 mL/vial; 0.5 M
60
solution in EtOH) was dispensed. The resulting suspension
50 44
40
was shaken for 10 min and the reactant amines (9 equiv) were
30
added to the mixtures. The solvent was removed in vacuo and
20
18 the resulting solid reaction mixtures were microwave irra-
10 diated in a Milestone microwave instrument at 160 ◦ C for
1
0 4 × 30 min. The reaction mixtures were diluted with DCE
(2.5 mL/vial) and filtered into 5-mL glass vials. The alumi-
0

0
-1

-3

-4
-2

-5
5

10

20

30

40

num oxide pads were washed with DCE (1 mL/vial). The

Produced quantity (mg)
organic solutions were extracted with water (2 × 1 mL/vial),
Fig. 6 cLogP, molecular weight, and produced quantity distributions evaporated and the resulting crude products were analyzed by
of chemset 5 LCMS, and further purified by preparative HPLC (Method
B).

coated plastic caps and NR/TEF septa. Edmund Bühler shak- General procedure for the synthesis of chemset 4
ers were used for the proper mixing of phases during extrac-
tion and mixing of reactants. A TECAN Genesis 150 robotic To PS–Pd[P(Ph)3 ]4 (1 mol%) in a 10-mL CEM microwave
system was used for liquid handling, for phase separation vial was dispensed 3 (300 µL of a 0.5 M DME solution,
during extraction, and for analytical sampling. 0.15 mmol), followed by the appropriate boronic acid 9 (840
µL, 0.25 M EtOH solution, 0.21 mmol, 1.4 equiv) and then
General procedure for the synthesis of chemset 2 aq. potassium carbonate (500 µL, 0.45 M, 0.23 mmol, 1.5
equiv). The reaction mixture was microwave irradiated in
A mixture of 3,5-dibromo-1H -1,2,4-triazole (1, 300 mmol), a CEM Explorer microwave instrument at 170 ◦ C for 15 min.
DIPEA (45 mL, 33.0 g, 306 mmol, 1.02 equiv) and the req- The catalyst resin was removed by filtration, the filtrate

123
90
collected in a 5-mL standard glass vial and then evaporated
under reduced pressure. The resulting residue was dissolved
in 1, 2-dichloroethane (2.5 mL/vial) and washed with water
(2 × 1 mL/vial). The organic phase was evaporated under
reduced pressure and the resulting crude 4 was purified by
preparative HPLC (Method A).
General procedure for the synthesis of chemset 5
A 50 mm 10% Pd/C CatCartTM catalyst cartridge (Thales
Nanotech) was placed in the H-CubeTM , the hydrogen pres-
sure was set to 60 bar, the temperature was set to room tem-
perature and EtOH was pumped through the system for
10 min at a flow rate of 1.5 mL/min. Compound 3 (0.05–
0.2 mmol/vial) was dissolved in EtOH (2.5 mL/vial) and the
solution was injected by a program controlled Cavro liq-
uid handler into the H-CubeTM device. EtOH was pumped
through the system for 8 min, followed by a mixture 20%
sat. ammonium hydroxide in 1,4-dioxane for 5 min and col-
lected in a scintillation vial. After this, the process restarted
automatically with a new sample of 3. The transformations
were monitored by TLC (silica gel, n-hexanes–EtOAc 3:2).
The collected fractions were evaporated, the residues were
dissolved in 1,2-dichloroethane (2.5 mL/vial) and transferred
into 5-mL glass vials. The solvent was removed and the
resulting crude chemset 5 was purified by preparative HPLC
(Method B) and then analyzed by LCMS analysis.
Supporting information available
The collection of HPLC-MS, 1 H NMR, 13 C NMR data, and
spectra and HRMS data is available as Supporting Informa-
tion. This material is available free of charge via the Internet
at http://www.springerlink.com.
Acknowledgment The authors are grateful to Drs. Richárd Lágner
and Tamás Karancsi, AMRI, for performing the HPLC-MS and HRMS
analyses. Special thanks are due to Mr. Lajos Németh and Ms. Barbara
Herczeg, AMRI, for the HPLC purifications of the synthesized libraries,
and to Ms. Judit Szernicsek, AMRI, for helping in compilation of the
manuscript and the supporting information. The authors highly appreci-
ate the valuable comments, advices and technical support of Drs. Brian
T. Gregg and Gergely M. Makara, AMRI.
123
Mol Divers (2012) 16:81–90
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