Multicomponent cyclocondensation reactions of aminoazoles, arylpyruvic acids and aldehydes with controlled chemoselectivity

Article abstract of DOI:10.1016/j.tet.2008.09.089

The multicomponent reactions of 3-amino-1,2,4-triazoles/5-aminotetrazole with phenylpyruvic acids and aromatic aldehydes were studied using conventional thermal heating, ultrasonification and microwave dielectric heating. Two different reaction pathways for these cyclocondensations occurring under either kinetic or thermodynamic control were established depending on the temperature regime and building block selection. In case of aminotriazoles, an unprecedented reaction pathway leading to 5-aryl-7-hydroxy-6-phenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimi dine-7-carboxylic acids was found and discussed.

Full text of DOI:10.1016/j.tet.2008.09.089

Tetrahedron 64 (2008) 11041–11049
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Multicomponent cyclocondensation reactions of aminoazoles, arylpyruvic acids
and aldehydes with controlled chemoselectivity
,
Yana I. Sakhno a c, Sergey M. Desenko a, Svetlana V. Shishkina a, Oleg. V. Shishkin a, Dmytro O. Sysoyev c,
,b,
Ulrich Groth c, C. Oliver Kappe b, Valentin A. Chebanov a
*
a State Scientific Institution ‘Institute for Single Crystals’ of National Academy of Sciences of Ukraine, Lenin Ave, 60, Kharkiv 61001, Ukraine
b Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
c University of Konstanz, Fachbereich Chemie, Fach M-720, Universitaetsstrasse 10, 78457 Konstanz, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2008
Received in revised form 9 September 2008
Accepted 25 September 2008
Available online 8 October 2008
The multicomponent reactions of 3-amino-1,2,4-triazoles/5-aminotetrazole with phenylpyruvic acids
and aromatic aldehydes were studied using conventional thermal heating, ultrasonification and micro-
wave dielectric heating. Two different reaction pathways for these cyclocondensations occurring under
either kinetic or thermodynamic control were established depending on the temperature regime and
building block selection. In case of aminotriazoles, an unprecedented reaction pathway leading to 5-aryl-
7-hydroxy-6-phenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acids was found and
discussed.
Keywords:
Heterocycles
Cyclocondensations
Ó 2008 Elsevier Ltd. All rights reserved.
Selective multicomponent reactions
Microwave-assisted organic synthesis
Ultrasonic-promoted reactions
Phenylpyruvic acid
Aminoazoles
1. Introduction
R2 (Scheme 1).4a,b In this case no clear relationships between the
electronic character of the substituents and the reaction products
Multicomponent reactions of pyruvic acids with nitrogen con-
taining nucleophiles play an important role in the synthesis of
heterocyclic compounds possessing diverse types of physiological
activities including antitumour,1a antimalarial,1b,c antimicrobial,1d
antifungal,1e and analgesic1f–h activities. The Do¨bner reaction, i.e.,
the three-component condensation of pyruvic acid, aldehydes and
aniline derivatives leading to quinoline carboxylic acids, was dis-
covered in the late 19th century2a,b and has since been investigated
in detail in numerous publications.1a,3 Initially, it was considered
that the Do¨bner reaction proceeds via arylidenepyruvic acid for-
mation3a but later this pathway was refuted and an alternative
mechanistic pathway involving the formation of a Schiff base
followed by cyclization was proposed.3c,f,g,
was established.
A Biginelli-like reaction of arylpyruvic acids with urea and
aldehydes in the presence of catalytic amounts of acid to yield
dihydropyrimidine carboxylic acids III has also been reported in the
literature.4c Similar pyrimidines were synthesized using a polymer-
supported solid-phase procedure.4d
Numerous publications deal with arylpyruvic acids as a-keto-
acids and describe their transformations with 1,2-diamines yielding
quinoxalines or analogous heterocyclic systems.5 There also is an
interesting example of four-component Ugi reactions involving
arylpyruvic acids as building-blocks.5e
The chemo- and regioselectivity of multicomponent condensa-
tions is among the key problems of synthetic organic chemistry.6
Our previous publications7 concerning reactions of pyruvic acids
with aminoazoles highlighted some of the selectivity issues in this
field. The structure of the binucleophile, the electron character of
the substituents as well as the reaction conditions significantly in-
fluence these multicomponent condensations and several different
reaction products can be obtained from similar starting materi-
als.7a,b On the other hand, application of non-classical activation
methods like microwave and ultrasonic irradiation have appeared
as powerful tools for tuning multicomponent condensations.8
Multicomponent reactions of arylpyruvic acids leading to
heterocyclic compounds have been rarely investigated. It was pre-
viously shown that the three-component reaction of phenylpyruvic
acid with aldehydes and anilines yields either pyrrolidine-2,3-dione
I or quinoline-4-carboxylic acid II depending on substituents R1 and
* Corresponding author. Tel.: þ38 057 341 01 91; fax: þ38 057 340 93 43.
E-mail address: chebanov@isc.kharkov.com (V.A. Chebanov).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.089

11042
Y.I. Sakhno et al. / Tetrahedron 64 (2008) 11041–11049
O
O
HO
Ph
O
Ph
R1
H
R1
O
O
NH2
N
+
R1
N
Ph
OH
R2
OH
R2
R2
II
I
O
O
H
R1
R2
HN
OH R2
Scheme 1.
NH
HO
+
H2N
O
O
R1
HO
NH2
O
III
For example, with the help of low-temperature ultrasonic-
promoted and high-temperature microwave-assisted procedures
starting from the same building-blocks three different classes of
heterocyclic compounds were obtained with good selectivity.8f,g
In this article we disclose our results on the tuning of multi-
component condensation reactions of phenylpyruvic acid, aromatic
aldehydes and aminoazoles (3-aminotriazoles and 5-amino-
tetrazole) using both traditional heating and non-classical activa-
tion methodsdmicrowave and ultrasonic irradiation.
controlled reaction products while pyrrolones 5 may be viewed as
the thermodynamically preferred products. In the present study,
ultrasonic and microwave irradiations were additionally applied
to investigate the formation of 5-aryl-7-hydroxy-6-phenyl-4,5,6,7-
tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acids
4
and 5-aryl-3-hydroxy-4-phenyl-1-(1,2,4-triazol-5-yl)-1,5-dihydro-
2H-pyrrol-2-ones 5. It was found that treatment of 3-amino-1,2,4-
triazoles 1a,b, phenylpyruvic acid and p-tolualdehyde 3c in acetic
acid under sonication at room temperature for 30 min yielded
exclusively fused triazolopyrimidinecarboxylic acids 4c,g. Longer
action of ultrasonic irradiation (up to 3 h) did not change the
outcome of the reaction. Using the same procedure for amino-
azoles 1c,d was not successful and the starting compounds were
isolated unchanged after sonication.
High-temperature experiments were carried out in a sealed
vessel in a monomode microwave reactor, which allowed a precise
temperature control. Using microwave heating in acetic acid we
observed a significant influence of the reaction temperature and
time on the multicomponent process using 1a, 2 and 3c as building-
blocks. Increasing the reaction temperature from 120 ꢀC to 170 ꢀC
2. Results and discussion
2.1. Multicomponent reactions of phenylpyruvic acid,
aminoazoles and aldehydes
After a series of experiments it was established that the con-
densation of aminotriazoles 1a–d with phenylpyruvic acid 2 and
aromatic aldehydes 3a–d in boiling acetic acid can lead to different
products depending on the reaction conditions. 5-Aryl-7-hydroxy-
6-phenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-7-carb-
oxylic acids 4a–h (63–79%) were isolated from the reaction mixture
after refluxing (w120 ꢀC) equimolar amounts of aminotriazoles
1a,b, aldehydes 3a–d and phenylpyruvic acid 2 in HOAc for 2–3 min
while reaction for 180 min provided 5-aryl-3-hydroxy-4-phenyl-1-
(1,2,4-triazol-5-yl)-1,5-dihydro-2H-pyrrol-2-ones 5a–h in 56–75%
yields (Table 1). Reaction times in between those extremes in most
cases led to the formation of both triazolopyrimidines 4 and
pyrrolones 5. It was additionally established that triazolopyr-
imidinecarboxylic acids 4a–h after refluxing in acetic acid for
approximately 3 h were completely converted into pyrrolones 5a–h
while heating 4 in NMR tubes in DMSO-d6 (1 min,100 ꢀC) led totheir
decomposition with formation of the starting materials 1–3; after
cooling the reverse process occurred, which produced again tri-
azolopyrimidines 4.
Multicomponent condensations of phenylpyruvic acid 2, alde-
hydes 3a–d with 5-aminotetrazole 1c and 3,5-diamino-1-(4-
chlorophenyl)-1,2,4-triazole 1d in boiling acetic acid did not furnish
fused pyrimidines of type 4 but only provided pyrrolones 5i–p.
Work up procedures for compounds 4 and 5 typically consisted
of a simple filtration of the crystalline materials after cooling of the
reaction mixtures. In the case of pyrrolones 5, cold ethanol was
added before the filtration step for more complete precipitation. No
additional purification such as crystallization or column chroma-
tography was required for triazolopyrimidines 4, while pyrrolones
5 sometimes had to be recrystallized from ethanol.
Table 1
Reactions of aminoazoles 1a–d with arylpyruvic acids 2a–c and aldehydes 3a–d
(Scheme 2)
Building-blocks
Aminoazole
Product
Aldehyde
Compound
X
R2
Compound R1
Compound Yielda (%)
1a
1a
1a
1a
1b
1b
1b
1b
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
CH
CH
CH
CH
CSCH3
CSCH3
CSCH3
CSCH3
CH
CH
CH
CH
CSCH3
CSCH3
CSCH3
CSCH3
N
N
N
N
CNH2
CNH2
CNH2
CNH2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3a
3b
3c
3d
3a
3b
3c
3d
3a
3b
3c
3d
3a
3b
3c
3d
H
Cl
4a
4b
4c
79
76
68
65
63
71
76
66
56
72
60
68
70
75
72
71
60
67
52
64
59
68
63
62
CH3
CH3O 4d
H
Cl
CH3
CH3O 4h
H
Cl
CH3
CH3O 5d
H
Cl
CH3
CH3O 5h
H
Cl
4e
4f
4g
5a
5b
5c
5e
5f
5g
5i
5j
5k
CH3
CH3O 5l
H
Cl
CH3
CH3O 5p
4-Cl–C6H4 3a
4-Cl–C6H4 3b
4-Cl–C6H4 3c
4-Cl–C6H4 3d
5m
5n
5o
Our experimental data indicate that in the three-component
condensation of phenylpyruvic acid 2, aminoazoles 1a,b and aro-
matic aldehydes 3a–d the fused pyrimidines 4 are the kinetically
a
Isolated yield of pure product (after recrystallization in case of 5e–h,m–p).

Y.I. Sakhno et al. / Tetrahedron 64 (2008) 11041–11049
11043
as well as the reaction time led to an increased amount of pyrrolone
5c at the expense of triazolopyrimidinecarboxylic acid 4c in the
reaction mixture. Specifically, compound 4c was isolated in 78%
yield by three-component condensation of starting materials 1a, 2
and 3c in acetic acid applying microwave irradiation at 120 ꢀC for
2 min while after 20 min at the same temperature a mixture con-
taining 70% of 4c and 30% of 5c was isolated. The same ratio of two
reaction products was observed at 170 ꢀC after 2 min of irradiation.
Extending the reaction time to 20 min at 170 ꢀC gave only pyrro-
lone 5c in 60% yield. The full rearrangement (NMR control) of
triazolopyrimidine 4c into pyrrolone 5c at 170 ꢀC in a microwave
reactor was achieved in 40 min.
The results presented above confirm our hypothesis about
kinetic and thermodynamic control in the three-component pro-
cesses shown in Scheme 2 and hence allow a simple tuning of
chemoselectivity by changing the reaction temperature. Sonication
of the starting materials for 30 min at room temperature or heating
in acetic acid for 2 min at w120 ꢀC provides the kinetic tri-
azolopyrimidine products 4a–h, while high-temperature treatment
(HOAc, MW, 150 ꢀC, 40 min or refluxing at w120 ꢀC for 180 min)
yielded the thermodynamically preferred pyrrolones 5a–h.
It was additionally established that treatment of Schiff bases 6a–
c with phenylpyruvic acid 2 in HOAc under ultrasonic irradiation
(room temperature, 30 min) or by thermal heating (2–5 min) also
furnished triazolopyrimidines 4 (Scheme 3).
protons. In addition a singlet for the CH-group of the triazole ring
(compounds 4a–d) at 7.4–7.5 ppm as well as multiplets for the
aromatic rings (6.5–7.4 ppm), signals for the NH-group of the
pyrimidine ring at ca. 7.8 ppm and signals for the other terminal
substituents were observed. For the minor stereoisomers, observed
in amounts up to w5%, practically all signals down-field shifted for
0.2–0.4 ppm while spin–spin coupling constants of tetrahydropyr-
imidine ring protons are the same (11.7–12.0 Hz) and correspond-
ing to trans-configuration of these stereogenic centres.
The spectral data obtained for the triazolopyrimidines may
correspond to several possible regioisomers 4, 7–9 (Fig. 1). Addi-
tional NOE experiments, confirming the spatial closeness of the CH-
proton at the aryl substituent with the pyrimidine NH-group,
allowed us to exclude structures 7 and 9. Ultimately, the structures
and stereochemistry of triazolopyrimidines 4 were unequivocally
established by X-ray diffraction analysis carried out for a single
crystal of one diastereomer of compound 4d, which allowed
assignment of the structure as 7-hydroxy-5-(4-methoxyphenyl)-6-
phenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-7-car-
boxylic acid (Fig. 2).
The analysis of the bond lengths in the molecule 4d demon-
strates that this compound exists in the crystal phase in zwitter-
ionic form. The C–O bond lengths in the carboxyl group are rather
close to each other (C(19)–O(2) 1.233(2) Å, C(19)–O(3) 1.262(2) Å)
and are comparable with the mean value9 of the bond length in the
carboxylate anion. This also agrees well with location of hydrogen
atoms at the N(1) and N(2) atoms instead of the carboxyl fragment.
It can thus be assumed that the negative charge is located within
the carboxyl substituent.
The C(1)–N(4) 1.326(2) Å, C(1)–N(2) 1.324(2) Å and C(1)–N(1)
1.328(2) Å bonds of the triazolopyrimidine fragment are equalized
and their values are slightly longer than the mean value for
a Csp2]N (1.313 Å) bond and are shorter as compared with the
mean value for the Csp2–N (1.339 Å) bond. Such redistribution of
the electron density suggests a description of the structure of the
triazolopyrimidine cycle as superposition of the three resonance
structures (Fig. 3).
2.2. Structure determination
The structures of the heterocyclic compounds synthesized were
established by MS-spectrometry, NMR spectral data and an X-ray
diffraction study and additionally supported by elemental analysis
(for details, see Section 4).
The NMR spectra of heterocycles 4a–h showed duplication of
some signals due to the presence of two diastereomeric pairs. 1H
NMR spectra of the main stereoisomers of 4a–h contain two dou-
blets for the CH-proton of the pyrimidine ring at 3.67–5.02 ppm
with Jw11.7–11.9 Hz corresponding to trans-orientation of these
O
OH
H
HO
N
R1
N
N
HOAc, Δ, 2-3 min
X
or sonication, r.t., 30 min
3a-d
N
H
H
R1
O
4a-h
N
NH
+
R1
X
NH2
N
HO
HO
X = CH, CSCH3
1a,b
2
HOAc, Δ, ~180 min
O
H
N
N
OH
5a-h
or MW, 170 °C, 20 min
N
N
X
O
R1
R2
N
N
HOAc, Δ, ~180 min
N
R2
X
+
2 + 3a-d
N
NH2
HO
N
N
or MW, 170 °C, 20 min
N
X
O
1c,d
X = N, CNH2
5i-p
Scheme 2.

11044
Y.I. Sakhno et al. / Tetrahedron 64 (2008) 11041–11049
O
OH
O
HO
N
H
N
N
N
NH
HOAc, Δ
OH
X
+
X
N
R1
O
N
H
N
H
R1
4a-c,e-g
2
6a-c
6a-c: a R1 = H, X = CH; b R1 = Cl, X = CH; c R1 = CH3, X = CH
Scheme 3.
In the crystal phase the zwitter-ionic form is stabilized, proba-
Waals radii sum is 2.87 Å)). This causes also considerable twisting of
the C]C double bond in the partially hydrogenated cycle (the C(1)–
C(2)–C(3)–C(4) torsion angle is 9.5(4)ꢀ). The tolyl substituent has
the pseudoaxial orientation (the C(7)–C(1)–C(2)–C(3) torsion angle
is 111.6(4)ꢀ) and it is turned relatively the C(1)–C(2) bond (the C(2)–
C(1)–C(7)–C(8) torsion angle is 128.4(4)ꢀ). The phenyl substituent is
coplanar to the endocyclic double bond of the dihydropyrrole ring
(the C(3)–C(2)–C(14)–C(19) torsion angle is 1.2(7)ꢀ), which is sup-
ported partially by the formation of a weak intramolecular hydro-
gen bond C(19)–H(19)/O(1) H/O 2.31 Å C–H/O 128ꢀ.
bly, by two intermolecular hydrogen bonds: N(1)–H(1N)/O(2)0
(0.5þx, 0.5ꢁy, 0.5þz) H/O 1.97 Å N–H/O 164ꢀ and N(2)–H(2N)/
O(3)0 (0.5þx, 0.5ꢁy, 0.5þz) H/O 1.68 Å N–H/O 173ꢀ.
The tetrahydropyrimidine ring adopts an asymmetric half-chair
conformation (the puckering parameters10 are S¼0.79,
Q
¼37.3ꢀ,
J
¼20.3ꢀ). Deviations of the C(4) and C(5) atoms from the mean
plane of the remaining atoms of the ring are 0.54 Å and ꢁ0.27 Å,
respectively. This ring conformation leads to an apparent shortened
intramolecular contact H(4)/C(1) 2.74 Å (the van der Waals radii
sum11 is 2.87 Å). The hydroxyl group is located in the pseudoaxial
position and the carboxyl group is situated in the pseudoequatorial
position and it is turned relatively the N(4)–C(3) bond (the C(1)–
N(4)–C(3)–O(1), C(1)–N(4)–C(3)–C(19) and N(4)–C(3)–C(19)–O(3)
torsion angles are ꢁ100.6(2)ꢀ, 138.3(2)ꢀ and 119.6(2)ꢀ, re-
spectively). The geminal substituents form the O(1)–H(1O)/O(3)
H/O 1.98 Å O–H/O 131ꢀ intramolecular hydrogen bond. The
phenyl and methoxyphenyl substituents have an equatorial orien-
tation (the N(4)–C(3)–C(4)–C(13) and C(1)–N(1)–C(5)–C(6) torsion
angles are 179.0(2)ꢀ and ꢁ166.0(2)ꢀ, respectively).
2.3. Mechanistic aspects
In this study, we have disclosed a new direction for the multi-
component condensation of aminotriazoles 1a,b, phenylpyruvic
acid 2 and aldehydes 3a–d leading to triazolopyrimidines 4a–h. In
general, the three-component reactions have different path-
waysdthe aldehyde can react with the endocyclic NH while the
carbonyl group of the CH-acid reacts with the exocyclic NH2-group
(structure 7, Fig. 1).7a,8h,12 The formation of triazolopyrimidines
with such ‘classical’ orientation of substituents was described in
several publications,13 however, the authors provided no strong
arguments for the proposed structures. It should be noted that the
direction observed in our case is characteristic for multicomponent
processes involving 5-aminopyrazoles.7b
The three-component reaction of the starting materials 1–3 at
low temperatures giving triazolopyrimidines 4 most probably
proceeds via the initial formation of azomethines 6 and its sub-
sequent reaction with phenylpyruvic acid and heterocyclization,
which is not a synchronous process (pathway ‘a’, Scheme 4). This
pathway was indirectly proven by the treatment of Schiff base 6
with phenylpyruvic acid 2 yielding triazolopyrimidines 4 and by
observation of compounds of type 6 in trace amounts in the mother
liquor of the multicomponent reaction.
1
The H NMR spectra of pyrrolones 5 exhibit, apart from signals
for the terminal substituents in appropriate areas and aromatic
rings (6.7–8 ppm), sharp singlets for the CH-groups of the pyrrole
ring at 6–7 ppm, broad CH (for heterocycles 5a–d) and NH singlets
for the triazole ring and signals for hydroxyl group protons at 10.3–
11.5 ppm. Broad singlets for the NH2-group for compounds 5m–o
are found at ca. 6.6 ppm. Additionally, for compounds 5m–o a NOE
between the NH2-group and the ortho-protons of the aryl sub-
stituent is observed that confirms the participation of the amino-
group in position 3 of aminoazole 1d in the reaction. The 1H NMR
data observed may correspond to several structures, the most
probable are 5, 10–12 (Fig. 4).
The structure of heterocycles of type 5 wasassigned on the basis of
an X-ray diffraction analysis made for 3-hydroxy-4-phenyl-5-(4-
methylphenyl)-1-(1,2,4-triazol-3-yl)-1H-pyrrol-2(5H)-on 5c (Fig. 5).
The triazole and dihydropyrrole cycles are turned slightly rela-
tive to each other (the C(4)–N(1)–C(5)–N(2) torsion angle is
20.8(6)ꢀ), which probably causes the interruption of the conjuga-
tion between them. The presence of the bulky substituents at the
neighbouring atoms in the dihydropyrrole ring leads to the no-
ticeable repulsion between them (the shortening contacts H(12)/
C(2) 2.84 Å, H(15)/C(1) 2.64 Å, H(15)/C(7) 2.77 Å (the van der
5-Aminotetrazole does not form azomethines with aldehydes
and therefore the appropriate tetrazolopyrimidines were not
isolated.
The high-temperature reaction pathway leading to pyrrolones 5
is also unusual for aminoazoles acting in this reaction as mono-
nucleophiles like anilines.14 The pathway leading to pyrrolones is
not completely clear. The related three-component reaction of ani-
lines, pyruvic acids and aldehydes proceeds through the formation
R1
R1
O
O
HO
HO
OH
Ph
OH
Ph
Ph
Ph
X
N
X
N
N
N
N
N
N
N
N
N
N
N
X
X
OH
OH
OH
OH
N
H
N
H
N
H
N
H
R1
R1
O
O
8
9
4
7
Figure 1. Possible regioisomers for compounds 4.

Y.I. Sakhno et al. / Tetrahedron 64 (2008) 11041–11049
11045
recorded in DMSO-d6 at 400 MHz (100 for 13C), 360 MHz (90.5 MHz
for 13C) and at 200 MHz (50 MHz for 13C) with a Varian Unity Plus-
400, Bruker AMX-360 and Varian Mercury VX-200 spectrometers.
The MS spectra were measured on a GC–MS Varian 1200L (ionizing
voltage 70 eV) instrument. IR spectra were recorded in KBr pellets
with Perkin Elmer Spectrum One FTIR Spectrometer. Elemental
analysis was realized on EuroVector EA-3000.
All microwave experiments were performed using the EmrysÔ
Creator EXP and EmrysÔ Initiator synthesizers from Biotage AB
(Uppsala, Sweden) possessing a single-mode microwave cavity
producing controlled irradiation at 2.45 GHz. Experiments were
carried out in sealed microwave process vials using high absor-
bance level settings and IR temperature monitoring. Reaction time
reflect irradiation times at the set reaction temperature (fixed hold
times).
Sonication was carried out with help of standard ultrasonic bath
producing irradiation at 44.2 kHz in round-bottom flasks equipped
with a condenser.
Figure 2. Molecular structure of 7-hydroxy-5-(4-methoxyphenyl)-6-phenyl-4,5,6,7-
tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acid 4d according to X-ray
diffraction data.
Solvents, aminoazoles 1a,c and aromatic aldehydes were com-
mercially available. Phenylpyruvic acid 2 was synthesized according to
the literature procedure.18 Azomethines 6 were obtained from corre-
sponding aminoazoles and aldehydes.19 3-Amino-5-methylthio-1,2,4-
triazol 1b and 3,5-diamino-1-(4-chlorophenyl)-1,2,4-triazole 1d
were synthesized by known methods.20 3-Hydroxy-4,5-diphenyl-
furan-2(5H)-one 14 was obtained from phenylpyruvic acid and
benzaldehyde.16
of furanone derivatives like 13 (pathway ‘b’).15 However, it was
established that compounds 13, synthesized by reaction of phenyl-
pyruvic acid and aldehydes,16 did not react with aminoazoles 1 and
therefore cannot be intermediates in this multicomponent process.
The probable sequence may include formation of aldols 14 at the
first stage of the high-temperature three-component reaction,
subsequent nucleophilic substitution of the hydroxyl group with
aminoazole (intermediate 15) and ultimately an intramolecular
condensation (pathway ‘c’). We cannot exclude other mechanisms,
for example, via arylidenephenylpyruvic acids 16 formed by water
elimination from aldols 15. However, our attempts to synthesize
compound 17 by direct reaction of phenylpyruvic acid and alde-
hydes under different condition were unsuccessful, which is in
good agreement with literature data for the synthesis of similar
unsaturated acids.17
4.2. General procedure for the synthesis of 5-aryl-7-hydroxy-
6-phenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-
7-carboxylic acids 4a–h
Method A. A mixture of 3-amino-1,2,4-triazole 1a,b (2.3 mmol),
phenylpyruvic acid 2 (2.3 mmol) and the appropriate aldehyde 3
(2.3 mmol) in 2 mL of acetic acid was refluxed for 2 min in a round-
bottom flask equipped with a condenser. After cooling, the pre-
cipitate formed was isolated by filtration, washed with ethanol and
air dried.
The reaction can be also carried out at room temperature under
sonication for 30 min or under microwave irradiation in sealed
vessel at 120 ꢀC for 2 min.
Method B. A mixture of phenylpyruvic acid 2 (1.2 mmol) and the
appropriate azomethine 6 (1.2 mmol) in 2 mL of acetic acid was
refluxed for 2 min in a round-bottom flask equipped with a con-
denser. After cooling, the precipitate formed was isolated by fil-
tration, washed with ethanol and air dried.
The reaction can be also carried out at room temperature under
sonication for 30 min or under microwave irradiation in sealed
vessel at 120 ꢀC for 2 min.
3. Conclusions
The three-component condensation of 3-amino-1,2,4-triazoles/
5-aminotetrazole with phenylpyruvic acid and aromatic aldehydes
leads to two distinct and unusual reaction pathways. The kinetically
controlled reaction of the starting materials at room temperature
proceeds via formation of an azomethine intermediate ultimately
providing triazolopyrimidinecarboxylic acids of type 4. At high
temperatures the thermodynamically controlled multicomponent
cyclocondensation of the same building-blocks proceeds via a dif-
ferent pathway yielding pyrrolones of type 5. The use of controlled
microwave heating allows the tuning of reaction conditions to ac-
cess either one of the two isomers in high selectivity.
4.2.1. 5,6-Diphenyl-7-hydroxy-4,5,6,7-tetrahydro[1,2,4]triazolo-
[1,5-a]pyrimidine-7-carboxylic acid (4a)
4. Experimental
4.1. General
Yield 610 mg (79%) of colourless crystals, mp 188–190 ꢀC. IR
(KBr): 3114, 2918, 1672. 1H NMR (DMSO-d6)
d
3.74 (d, J¼11.7 Hz, 1H,
6-H), 4.99 (d, J¼11.7 Hz, 1H, 5-H), 6.92–7.38 (m, 10H, ArH), 7.43 (s,
1H, 2-H), 7.76 (br s, 1H, NH). 13C NMR (DMSO-d6)
53.4, 55.8, 84.1,
d
Melting points of all compounds synthesized were determined
with a Gallenkamp melting point apparatus. The NMR spectra were
127.1, 127.4, 127.6, 127.9, 128.3, 130.5, 134.6, 139.7, 149.1, 153.3, 169.1.
MS (EI, 70 eV): m/z (%)¼318 (13) [Mþꢁ18], 171 (87), 119 (36), 118
-OOC
-OOC
-OOC
OH
OH
OH
Ph
Ph
Ph
N
N
N
N
N
N
N
H
N
H
N
N
N
N
H
H
H
H
OMe
OMe
OMe
Figure 3. Resonance structures for compound 4d.

11046
Y.I. Sakhno et al. / Tetrahedron 64 (2008) 11041–11049
R1
R1
O
N
OH
R1
N
N
H
N
N
N
X
N
N
X
N
X
HN
N
N
H
O
O
N
HN
N
N
H
OH
R1
O
O
OH
X
5
10
11
12
Figure 4. Possible isomers for compounds 5.
(69). Anal. Calcd for C18H16N4O3: C, 64.28; H, 4.79; N, 16.66. Found:
C, 64.33; H, 4.73; N, 16.62.
CH3O), 3.70 (d, J¼11.9 Hz, 1H, 6-H), 4.97 (d, J¼11.9 Hz, 1H, 5-H),
6.57–7.29 (m, 9H, ArH), 7.44 (s, 1H, 2-H), 7.73 (br s, 1H, NH), 13.35
(br s, 1H, COOH). 13C NMR (DMSO-d6)
d 53.3, 54.8, 55.1, 84.1, 113.2,
4.2.2. 5-(4-Chlorophenyl)-7-hydroxy-6-phenyl-4,5,6,7-tetrahydro-
[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acid (4b)
126.9, 127.4, 129.4, 130.5, 131.5, 134.7, 149.1, 153.3, 158.4, 169.1. MS
(EI, 70 eV): m/z (%)¼348 (7) [Mþꢁ18], 238 (25), 202 (42), 201 (100).
Anal. Calcd for C19H18N4O4: C, 62.29; H, 4.95; N, 15.29. Found: C,
62.31; H, 4.92; N, 15.26.
Yield 650 mg (76%) of colourless crystals, mp 193–195 ꢀC. IR
(KBr): 3423, 3147, 2921, 1672, 1649. 1H NMR (DMSO-d6)
d 3.70 (d,
J¼11.7 Hz, 1H, 6-H), 5.02 (d, J¼11.7 Hz, 1H, 5-H), 6.96–7.37 (m, 9H,
ArH), 7.45 (s, 1H, 2-H), 7.85 (br s, 1H, NH). 13C NMR (DMSO-d6)
4.2.5. 7-Hydroxy-2-(methylthio)-5,6-diphenyl-4,5,6,7-tetrahydro-
[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acid (4e)
d
53.3, 55.1, 83.9, 127.2, 127.5, 127.8, 130.2, 130.5, 131.9, 134.3, 138.8,
149.2, 153.2, 168.8. MS (EI, 70 eV): m/z (%)¼352 (8%) [Mþꢁ18], 205
(58), 178 (11), 119 (31), 118 (31). Anal. Calcd for C18H15ClN4O3: C,
58.31; H, 4.08; N, 15.11. Found: C, 58.38; H, 4.06; N, 15.08.
Yield 550 mg (63%) of colourless crystals, mp 178–180 ꢀC. IR
(KBr): 3423, 3033, 2928, 1692. 1H NMR (DMSO-d6)
d 2.42 (s, 3H,
CH3), 3.71 (d, J¼11.7 Hz, 1H, 6-H), 5.01 (d, J¼11.7 Hz, 1H, 5-H), 6.92–
7.38 (m, 10H, ArH), 7.94 (br s, 1H, NH), 13.01 (br s, 1H, COOH). 13C
4.2.3. 7-Hydroxy-6-phenyl-5-p-tolyl-4,5,6,7-tetrahydro-
[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acid (4c)
Yield 550 mg (68%) of colourless crystals, mp 263–265 ꢀC. IR
NMR (DMSO-d6) d 13.4, 21.0, 53.3, 55.5, 83.9, 127.0, 127.4, 127.5,
127.8, 128.2, 130.4, 134.3, 139.4, 154.2, 157.9, 168.8, 172.0. MS (EI,
70 eV): m/z (%)¼364 (11) [Mþꢁ18], 218 (66), 217 (100), 179 (37).
Anal. Calcd for C19H18N4O3S: C, 59.67; H, 4.74; N, 14.65. Found: C,
59.73; H, 4.71; N, 14.62.
(KBr): 3379, 3114, 2923,1672,1651. 1H NMR (DMSO-d6)
d 2.13 (s, 3H,
CH3), 3.72 (d, J¼11.7 Hz, 1H, 6-H), 4.96 (d, J¼11.7 Hz, 1H, 5-H), 6.84–
7.25 (m, 9H, ArH), 7.44 (s, 1H, 2-H), 7.73 (br s, 1H, NH). 13C NMR
(DMSO-d6)
d
20.5, 53.2, 55.3, 83.9, 127.0, 127.4, 128.1, 128.4, 130.5,
4.2.6. 5-(4-Chlorophenyl)-7-hydroxy-2-(methylthio)-6-phenyl-
4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic
acid (4f)
134.6, 136.4, 136.6, 149.2, 153.3, 169.0. MS (EI, 70 eV): m/z (%)¼332
(11) [Mþꢁ18], 185 (47), 119 (56), 118 (100). Anal. Calcd for
C19H18N4O3: C, 65.13; H, 5.18; N, 15.99. Found: C, 65.08; H, 5.14; N,
15.96.
Yield 680 mg (71%) of colourless crystals, mp 191–193 ꢀC. IR
(KBr): 3420, 3029, 2931, 1688. 1H NMR (DMSO-d6)
d 2.42 (s, 3H,
CH3), 3.70 (d, J¼11.7 Hz, 1H, 6-H), 5.02 (d, J¼11.7 Hz, 1H, 5-H), 6.96–
4.2.4. 7-Hydroxy-5-(4-methoxyphenyl)-6-phenyl-4,5,6,7-
tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acid (4d)
Yield 550 mg (65%) of colourless crystals, mp 215–216 ꢀC. IR
7.39 (m, 9H, ArH), 7.96 (br s, 1H, NH), 12.78 (br s, 1H, COOH). 13C
NMR (DMSO-d6)
d 13.4, 53.2, 54.8, 83.9, 127.2, 127.5, 127.8, 130.1,
130.4, 131.9, 134.1, 138.6, 154.0, 157.9, 168.7. MS (EI, 70 eV): m/z
(%)¼398 (10) [Mþꢁ18], 157 (27). Anal. Calcd for C19H17ClN4O3S: C,
54.74; H, 4.11; N, 13.44. Found: C, 54.79; H, 4.07; N, 13.39.
(KBr): 3416, 3034, 2930, 1671. 1H NMR (DMSO-d6)
d 3.60 (s, 3H,
4.2.7. 7-Hydroxy-2-(methylthio)-6-phenyl-5-p-tolyl-4,5,6,7-
tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acid (4g)
Yield 690 mg (76%) of colourless crystals, mp 195–197 ꢀC. IR
(KBr): 3370, 3029, 2926, 1678. 1H NMR (DMSO-d6)
d 2.13 (s, 3H,
CH3), 2.41 (s, 3H, CH3), 3.69 (d, J¼11.7 Hz, 1H, 6-H), 4.96 (d,
J¼11.7 Hz, 1H, 5-H), 6.79–7.36 (m, 9H, ArH), 7.86 (br s, 1H, NH),
13.48 (br s, 1H, COOH). 13C NMR (DMSO-d6)
d 13.4, 20.5, 53.2, 55.1,
83.9, 127.0, 127.4, 128.1, 128.4, 130.4, 134.5, 136.4, 136.5, 154.1, 157.9,
168.8. MS (EI, 70 eV): m/z (%)¼378 (5) [Mþꢁ18], 164 (30), 119 (98),
118 (100). Anal. Calcd for C20H20N4O3S: C, 60.59; H, 5.08; N, 14.13.
Found: C, 60.63; H, 5.06; N, 14.11.
4.2.8. 7-Hydroxy-5-(4-methoxyphenyl)-2-(methylthio)-6-phenyl-
4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic
acid (4h)
Yield 630 mg (66%) of colourless crystals, mp 185–187 ꢀC. IR
(KBr): 3410, 2923, 1675. 1H NMR (DMSO-d6)
d 2.41 (s, 3H, CH3), 3.61
(s, 3H, CH3O), 3.69 (d, J¼11.9 Hz, 1H, 6-H), 4.94 (d, J¼11.9 Hz, 1H, 5-
H), 6.59–7.27 (m, 9H, ArH), 7.82 (br s, 1H, NH), 13.46 (br s, 1H,
COOH). 13C NMR (DMSO-d6)
113.75, 127.51, 127.93, 129.86, 130.99, 131.89, 135.13, 154.72, 158.37,
d
13.97, 53.85, 55.38, 55.41, 84.50,
Figure 5. Molecular structure of 3-hydroxy-4-phenyl-5-(4-methylphenyl)-1-(1,2,4-
triazol-3-yl)-1H-pyrrol-2(5H)-on 5c according to X-ray diffraction data.

Y.I. Sakhno et al. / Tetrahedron 64 (2008) 11041–11049
11047
HO
O
OH
O
HO
N
OH
N
N
X
NH
"a"
X
N
R1
N
- H2O
N
N
H
R1
6
4
R1
R1
3
O
O
"b"
HO
HO
N
X
NH
O
R1
+
N
X
NH
NH2
N
NH2
HO
N
O
1
13
2
//
H
N
N
X
N
O
- H2O
N
OH
R1
5
N
X
NH
NH2
X
N
NH
OH
O
N
O
"c"
N
O
O
NH
OH
- H2O
- H2O
OH
R1
OH
R1
O
O
15
16
14
Scheme 4.
158.96, 169.35. MS (EI, 70 eV): m/z (%)¼394 (19) [Mþꢁ18], 248 (60),
247 (36), 164 (42), 118 (100). Anal. Calcd for C20H20N4O4S: C, 58.24;
H, 4.89; N, 13.58. Found: C, 58.28; H, 4.92; N, 13.61.
C18H14N4O2: C, 67.91; H, 4.43; N, 17.6. Found: C, 67.95; H, 4.41; N,
17.56.
4.3.2. 5-(4-Chlorophenyl)-3-hydroxy-4-phenyl-1-(2H-1,2,4-triazol-
3-yl)-1H-pyrrol-2(5H)-one (5b)
4.3. General procedure for the synthesis of 5-aryl-3-hydroxy-
4-phenyl-1-azolyl-1,5-dihydro-2H-pyrrol-2-ones 5a–p
Yield 580 mg (72%) of colourless crystals, mp 269–272 ꢀC. IR
(KBr): 3203, 2923, 1702. 1H NMR (DMSO-d6)
d
6.28 (s, 1H, 5-H),
6.76–7.85 (m, 9H, ArH), 8.21 (s, 1H, CHtriaz), 10.88 (br s, 1H, OH),
13.79 (br s, 1H, NH). 13C NMR (DMSO-d6)
55.5, 60.5, 123.4, 126.9,
Method A. A mixture of 3-amino-1,2,4-triazole 1a,b (2.3 mmol),
phenylpyruvic acid 2 (2.3 mmol) and the appropriate aldehyde 3
(2.3 mmol) in 3 mL of acetic acid was refluxed for 3 h in a round-
bottom flask equipped with a condenser. After cooling, the reaction
mixture was allowed to stand overnight, then 6 mL of ethanol was
added and the formed precipitate was isolated by filtration, washed
with ethanol and air dried. In case of compounds 5e–h,m–p, the
crude reaction products were recrystallized from ethanol.
Method B. A mixture of 3-amino-1,2,4-triazole 1a,b (2.3 mmol),
phenylpyruvic acid 2 (2.3 mmol) and the appropriate aldehyde 3
(2.3 mmol) in 2 mL of acetic acid was microwave irradiated in
10 mL sealed vial with vigorous stirring at 170 ꢀC for 20 min. After
cooling the reaction mixture was allowed to stand overnight, then
6 mL of ethanol was added and the formed precipitate isolated by
filtration, washed with ethanol and air dried. In case of compounds
5e–h,m–p the crude reaction products were recrystallized from
ethanol.
d
127.5, 127.6, 128.8, 129.2, 130.8, 132.1, 135.9, 142.2, 144.9, 164.2. MS
(EI, 70 eV): m/z (%)¼352 (28) [Mþ], 178 (48), 111 (100). Anal. Calcd
for C18H13ClN4O2: C, 61.28; H, 3.71; N, 15.88. Found: C, 61.28; H,
3.67; N, 15.85.
4.3.3. 3-Hydroxy-4-phenyl-5-p-tolyl-1-(2H-1,2,4-triazol-3-yl)-1H-
pyrrol-2(5H)-one (5c)
Yield 460 mg (60%) of colourless crystals, mp 292–294 ꢀC. IR
(KBr): 3209, 2923, 1700. 1H NMR (DMSO-d6)
d
2.13 (s, 3H, CH3), 6.20
(s, 1H, 5-H), 6.72–7.93 (m, 9H, ArH), 8.35 (s, 1H, CHtriaz), 10.72 (br s,
1H, OH), 13.73 (br s, 1H, NH). 13C NMR (DMSO-d6)
19.8, 61.1, 122.9,
d
124.0, 126.9, 127.1, 127.3, 127.6, 128.3, 131.1, 133.7, 136.8, 141.9, 164.4.
MS (EI, 70 eV): m/z (%)¼332 (32) [Mþ], 222 (100). Anal. Calcd for
C19H16N4O2: C, 68.66; H, 4.85; N, 16.86. Found: C, 68.69; H, 4.82; N,
16.84.
4.3.1. 3-Hydroxy-4,5-diphenyl-1-(2H-1,2,4-triazol-3-yl)-1H-pyrrol-
2(5H)-one (5a)
4.3.4. 3-Hydroxy-5-(4-methoxyphenyl)-4-phenyl-1-(2H-1,2,4-
triazol-3-yl)-1H-pyrrol-2(5H)-one (5d)
Yield 420 mg (56%) of colourless crystals, mp 274–276 ꢀC. IR
Yield 550 mg (68%) of colourless crystals, mp 259–264 ꢀC. IR
(KBr): 3231, 2925, 1698. 1H NMR (DMSO-d6)
d
6.23 (s, 1H, 5-H),
6.64–7.95 (m, 10H, ArH), 8.09 (s, 1H, CHtriaz), 10.71 (br s, 1H, OH),
13.79 (br s, 1H, NH). 13C NMR (DMSO-d6)
61.4, 126.9, 127.1, 127.3,
(KBr): 3209, 2931, 1694. 1H NMR (DMSO-d6)
d
3.61 (s, 3H, CH3O),
6.19 (s, 1H, 5-H), 6.61–7.79 (m, 9H, ArH), 8.32 (s, 1H, CHtriaz), 10.72
(br s, 1H, OH), 13.77 (br s, 1H, NH). 13C NMR (DMSO-d6)
54.8, 56.0,
d
d
127.4, 127.5, 127.6, 130.9, 136.7, 141.9, 164.3. MS (EI, 70 eV): m/z
(%)¼318 (35) [Mþ], 208 (23), 178 (35), 111 (100). Anal. Calcd for
109.2, 114.2,126.5, 126.9, 127.6, 128.7, 128.8, 130.6, 131.1,134.4, 141.4,
158.4, 163.1. MS (EI, 70 eV): m/z (%)¼348 (44) [Mþ], 238 (84), 165

11048
Y.I. Sakhno et al. / Tetrahedron 64 (2008) 11041–11049
(34), 111 (100). Anal. Calcd for C19H16N4O3: C, 65.51; H, 4.63; N,
16.08. Found: C, 65.49; H, 4.62; N, 16.05.
4.3.11. 3-Hydroxy-4-phenyl-1-(1H-tetrazol-5-yl)-5-p-tolyl-1H-
pyrrol-2(5H)-one (5k)
Yield 400 mg (52%) of colourless crystals, mp 233–235 ꢀC. IR
4.3.5. 3-Hydroxy-1-(5-(methylthio)-2H-1,2,4-triazol-3-yl)-4,5-
diphenyl-1H-pyrrol-2(5H)-one (5e)
(KBr): 3480, 2923, 2532, 1959, 1713, 1602. 1H NMR (DMSO-d6)
d
2.19
(s, 3H, CH3), 6.76 (s, 1H, 5-H), 6.84–7.51 (m, 9H, ArH), 10.63 (br s, 1H,
OH), 13.35 (br s, 1H, NH). 13C NMR (DMSO-d6)
20.6, 62.3, 114.7,
Yield 590 mg (70%) of colourless crystals, mp 209–210 ꢀC. IR
d
(KBr): 3303, 2929, 1698, 1569. 1H NMR (DMSO-d6)
d
2.45 (s, 3H,
CH3), 6.25 (s, 1H, 5-H), 7.02–7.82 (m, 10H, ArH), 11.04 (br s, 1H, OH),
13.64 (br s, 1H, NH). 13C NMR (DMSO-d6)
13.6, 60.7, 127.3, 127.5,
126.1,127.4,127.5,127.9,128.8, 129.3, 135.7, 135.8,138.1, 149.3, 163.8.
MS (EI, 70 eV): m/z (%)¼333 (29) [Mþ], 304 (51), 260 (65), 242 (100).
Anal. Calcd for C18H15N5O2: C, 64.86; H, 4.54; N, 21.01. Found: C,
64.89; H, 4.51; N, 21.03.
d
127.8, 128.0, 128.1, 128.2, 128.3, 128.4, 128.9, 129.2, 131.2, 136.9,
171.9. MS (EI, 70 eV): m/z (%)¼364 (48) [Mþ], 178 (33), 157 (100).
Anal. Calcd for C19H16N4O2S: C, 62.62; H, 4.43; N, 15.37. Found: C,
62.66; H, 4.41; N, 15.34.
4.3.12. 3-Hydroxy-5-(4-methoxyphenyl)-4-phenyl-1-(1H-tetrazol-
5-yl)-1H-pyrrol-2(5H)-one (5l)
Yield 510 mg (64%) of colourless crystals, mp 232–234 ꢀC. IR
4.3.6. 5-(4-Chlorophenyl)-3-hydroxy-1-(5-(methylthio)-2H-1,2,4-
triazol-3-yl)-4-phenyl-1H-pyrrol-2(5H)-one (5f)
(KBr): 3276, 2839, 2517, 1885, 1693. 1H NMR (DMSO-d6)
d
3.66 (s,
3H, CH3O), 6.75 (s, 1H, 5-H), 6.78–7.31 (m, 9H, ArH), 10.64 (br s, 1H,
OH), 13.62 (br s, 1H, NH). 13C NMR (DMSO-d6)
55.1, 62.1, 114.1,
Yield 690 mg (75%) of colourless crystals, mp 214–217 ꢀC. IR
d
(KBr): 3370, 2923, 1698, 1577. 1H NMR (DMSO-d6)
d
2.46 (s, 3H,
CH3), 6.28 (s, 1H, 5-H), 7.01–7.90 (m, 9H, ArH), 11.20 (br s, 1H, OH),
13.40 (br s, 1H, NH). 13C NMR (DMSO-d6)
13.6, 59.8, 127.5, 127.9,
114.9, 126.1, 127.4, 127.9, 128.8, 128.9, 130.7, 135.9, 149.3, 159.3,
163.8. MS (EI, 70 eV): m/z (%)¼349 (47) [Mþ], 320 (41), 288 (54), 276
(100). Anal. Calcd for C18H15N5O3: C, 61.89; H, 4.33; N, 20.05. Found:
C, 61.86; H, 4.31; N, 20.01.
d
128.3, 128.4, 130.0, 130.8, 132.6, 136.0, 141.9, 147.2, 157.5, 164.8,
172.0. MS (EI, 70 eV): m/z (%)¼398 (59) [Mþ], 213 (17), 178 (19), 157
(100). Anal. Calcd for C19H16ClN4O2S: C, 57.21; H, 3.79; N, 14.05.
Found: C, 57.25; H, 3.75; N, 14.03.
4.3.13. 1-(5-Amino-1-(4-chlorophenyl)-1H-1,2,4-triazol-3-yl)-3-
hydroxy-4,5-diphenyl-1H-pyrrol-2(5H)-one (5m)
Yield 600 mg (59%) of yellowish crystals, mp 274–276 ꢀC. IR
4.3.7. 3-Hydroxy-1-(5-(methylthio)-2H-1,2,4-triazol-3-yl)-4-
phenyl-5-p-tolyl-1H-pyrrol-2(5H)-one (5g)
(KBr): 3197, 1698, 1619. 1H NMR (DMSO-d6)
d
6.12 (s, 1H, 5-H), 6.63
(br s, 2H, NH2), 7.03–7.77 (m, 14H, ArH), 10.36 (br s, 1H, OH). 13C
NMR (DMSO-d6) 61.0, 122.7, 124.0, 127.3, 127.4, 128.0, 128.1, 128.2,
Yield 630 mg (72%) of colourless crystals, mp 194–196 ꢀC. IR
d
(KBr): 3313, 2925, 1683, 1572. 1H NMR (DMSO-d6)
d
2.15 (s, 3H,
CH3), 2.46 (s, 3H, CH3), 6.19 (s, 1H, 5-H), 6.92–7.74 (m, 9H, ArH),
11.51 (br s, 1H, OH), 12.62 (br s, 1H, NH). 13C NMR (DMSO-d6)
13.4,
128.3, 129.3, 130.9, 131.4, 135.7, 137.6, 142.8, 152.6, 154.1, 164.2. MS
(EI, 70 eV): m/z (%)¼443 (52) [Mþ], 238 (41), 236 (100). Anal. Calcd
for C24H18ClN5O2: C, 64.94; H, 4.09; N, 15.78. Found: C, 64.99; H,
4.05; N, 15.74.
d
19.8, 60.8, 126.8, 126.9, 127.0, 127.3, 127.4, 127.6, 128.1, 128.7, 130.8,
133.3, 136.8, 141.5, 164.2. MS (EI, 70 eV): m/z (%)¼378 (27) [Mþ], 157
(100). Anal. Calcd for C20H18N4O2S: C, 63.47; H, 4.79; N, 14.80.
Found: C, 63.49; H, 4.75; N, 14.79.
4.3.14. 1-(5-Amino-1-(4-chlorophenyl)-1H-1,2,4-triazol-3-yl)-5-
(4-chlorophenyl)-3-hydroxy-4-phenyl-1H-pyrrol-2(5H)-one (5n)
Yield 750 mg (68%) of yellowish crystals, mp 294–296 ꢀC. IR
4.3.8. 3-Hydroxy-5-(4-methoxyphenyl)-1-(5-(methylthio)-2H-
1,2,4-triazol-3-yl)-4-phenyl-1H-pyrrol-2(5H)-one (5h)
(KBr): 3183, 2923,1715, 1639. 1H NMR (DMSO-d6)
d
6.16 (s, 1H, 5-H),
6.64 (br s, 2H, NH2), 7.09–7.74 (m, 13H, ArH), 11.16 (br s, 1H, OH). 13
NMR (DMSO-d6) 60.1, 122.4, 124.1, 127.3, 127.4, 128.2, 128.3, 129.3,
C
Yield 640 mg (71%) of colourless crystals, mp 247–249 ꢀC. IR
d
(KBr): 3225, 2923, 1687, 1563. 1H NMR (DMSO-d6)
d
2.47 (s, 3H,
CH3), 3.63 (s, 3H, CH3O), 6.20 (s, 1H, 5-H), 6.69–7.79 (m, 9H, ArH),
10.79 (br s, 1H, OH), 13.65 (br s, 1H, NH). 13C NMR (DMSO-d6)
13.6,
129.9, 131.0, 131.2, 132.4, 135.7, 136.7, 142.9, 152.5, 154.1, 164.1. MS
(EI, 70 eV): m/z (%)¼477 (39) [Mþ], 236 (100). Anal. Calcd for
C24H17Cl2N5O2: C, 60.26; H, 3.58; N, 14.64. Found: C, 60.29; H, 3.55;
N, 14.61.
d
54.9, 60.2, 113.6, 125.2, 127.6, 128.2, 128.7, 128.9, 129.3, 131.1, 141.7,
147.2, 157.5, 158.9, 164.9. MS (EI, 70 eV): m/z (%)¼394 (48) [Mþ], 157
(100). Anal. Calcd for C20H18N4O3S: C, 60.90; H, 4.60; N, 14.20.
Found: C, 60.94; H, 4.57; N, 14.16.
4.3.15. 1-(5-Amino-1-(4-chlorophenyl)-1H-1,2,4-triazol-3-yl)-3-
hydroxy-4-phenyl-5-p-tolyl-1H-pyrrol-2(5H)-one (5o)
Yield 660 mg (63%) of yellowish crystals, mp 279–281 ꢀC. IR
4.3.9. 3-Hydroxy-4,5-diphenyl-1-(1H-tetrazol-5-yl)-1H-pyrrol-
2(5H)-one (5i)
(KBr): 3208, 2923, 1697. 1H NMR (DMSO-d6)
d
2.16 (s, 3H, CH3), 6.08
(s,1H, 5-H), 6.62 (br s, 2H, NH2), 6.93–7.74 (m,13H, ArH),10.60 (br s,
1H, OH). 13C NMR (DMSO-d6)
20.6, 60.7, 122.7, 124.0, 127.2, 127.4,
Yield 440 mg (60%) of colourless crystals, mp 224–226 ꢀC. IR
d
(KBr): 3315, 2918, 1709, 1609. 1H NMR (DMSO-d6)
d
6.82 (s, 1H, 5-H),
127.9, 128.1,128.9,129.3, 130.9, 131.5,134.5,135.7,137.2,142.7, 152.6,
154.1, 164.2. MS (EI, 70 eV): m/z (%)¼457 (48) [Mþ], 238 (27), 236
(100). Anal. Calcd for C25H20ClN5O2: C, 65.57; H, 4.40; N, 15.29.
Found: C, 65.59; H, 4.37; N, 15.26.
6.92–7.48 (m, 10H, ArH), 10.68 (br s, 1H, OH), 13.69 (br s, 1H, NH). 13C
NMR (DMSO-d6)
d 62.6, 114.4, 125.8, 126.7, 126.8, 127.1, 127.7, 128.1,
128.5,135.1,137.9,149.1,162.8. MS (EI, 70 eV): m/z (%)¼319 (27) [Mþ],
246 (100), 242 (80), 220 (81), 208 (49). Anal. Calcd for C17H13N5O2: C,
63.94; H, 4.10; N, 21.93. Found: C, 63.97; H, 4.12; N, 21.91.
4.3.16. 1-(5-Amino-1-(4-chlorophenyl)-1H-1,2,4-triazol-3-yl)-3-
hydroxy-5-(4-methoxyphenyl)-4-phenyl-1H-pyrrol-2(5H)-one (5p)
Yield 670 mg (62%) of yellowish crystals, mp 272–273 ꢀC. IR
4.3.10. 5-(4-Chlorophenyl)-3-hydroxy-4-phenyl-1-(1H-tetrazol-5-
yl)-1H-pyrrol-2(5H)-one (5j)
(KBr): 3290, 2925, 1705. 1H NMR (DMSO-d6)
d
3.63 (s, 3H,
CH3O), 6.05 (s, 1H, 5-H), 6.62 (br s, 2H, NH2), 6.71–7.73 (m, 13H,
ArH), 10.20 (br s, 1H, OH). 13C NMR (DMSO-d6)
54.8, 60.5,
Yield540 mg(67%) of colourless crystals, mp 217–219 ꢀC. IR (KBr):
3309, 2923, 2851, 1741, 1606. 1H NMR (DMSO-d6)
d
6.88 (s, 1H, 5-H),
d
6.96–7.42 (m, 9H, ArH), 10.72 (br s, 1H, OH), 13.49 (br s, 1H, NH). 13C
113.6, 122.6, 124.0, 127.2, 127.4, 128.1, 129.1, 129.2, 129.3, 130.9,
131.5, 135.7, 142.7, 152.4, 154.1, 158.7, 164.1 MS (EI, 70 eV): m/z
(%)¼473 (100) [Mþ], 443 (36), 236 (63). Anal. Calcd for
C25H20ClN5O3: C, 63.36; H, 4.25; N, 14.78. Found: C, 63.39; H,
4.22; N, 14.76.
NMR (DMSO-d6)
d 61.9, 113.8, 126.1, 126.9, 127.2, 128.1, 128.5, 128.7,
133.0,135.1,136.9,149.1,162.7. MS (EI, 70 eV): m/z (%)¼353 (38) [Mþ],
324 (50), 281 (57), 280 (84), 242 (45). Anal. Calcd for C17H12ClN5O2: C,
57.72; H, 3.42; N, 19.80. Found: C, 57.68; H, 3.45; N, 19.77.

Y.I. Sakhno et al. / Tetrahedron 64 (2008) 11041–11049
11049
J. Indian Chem. Soc. 1984, 61, 816; (e)Bergman, J.;Brynolf, A. Tetrahedron1990, 46,
1295; (f) Milyutin, A. V.; Amirova, L. R.; Kolla, V. E.; Nazmetdinov, F. Ya.; Dro-
vosekova, L. P.; Andreichikov, Yu. S. Khim.-Farm. Zh. 1998, 32, 24; (Pharm. Chem.
J. 1998, 32, 422); (g) Nekrasov, D. D.; Chizh, V. G.; AndreichikovYu, S.; Tul’bo-
vich, G. A.; Aleksandrova, G. A. Khim.-Pharm. Zh. 1997, 31, 34; (Pharm. Chem. J.
1997, 31, 140); (h) Milyutin, A. V.; Makhmudov, R. R.; AndreichikovYu, S.; Gole-
neva, A. F.; Tul’bovich, G. A.; Kovina, T. I. Khim.-Farm. Zh. 1996, 30, 20; (Pharm.
Chem. J. 1996, 30, 374).
4.4. X-ray diffraction data
The colourless crystals of 4d (C19H18N4O4) are monoclinic. At
293 K a¼13.243(1), b¼10.953(5), c¼13.447(1) Å,
b
¼116.54(1)ꢀ, V¼
1745.1(9) Å3, Mr¼366.37, Z¼4, space group P21/n, dcalcd¼1.395 g/cm3,
m
(Mo
K
a
)¼0.100 mmꢁ1
F(000)¼768. Intensities of 9437 re-
,
2. (a) Do¨bner, O. Ber. Dtsch. Chem. Ges. 1887, 20, 277; (b) Do¨bner, O. Justus Liebigs
Ann. Chem. 1887, 242, 256.
flections (3033 independent, Rint¼0.050) were measured on the
‘Xcalibur-3’ diffractometer (graphite monochromated Mo
Ka
3. See, for example: (a) Borsche, W. Chem. Ber. 1908, 41, 3884; (b) Toma, M. Gazz.
Chim. Ital. 1952, 82, 40; (c) Nitidandhaprabhas, O. Nature 1966, 212, 5061; (d)
Saggiomo, A. J.; Kato, K.; Kaiya, T. J. Med. Chem. 1968, 11, 277; (e) Herbert, R. B.;
Kattah, A. E.; Knagg, E. Tetrahedron 1990, 46, 7119; (f) Mitra, A. K.; De, A.;
Karchaudhuri, N. Synth. Commun. 1999, 29, 573; (g) Um, S.-J.; Park, S.-H.; Park,
C.-H.; Chang, B.-H.; Yoon, J.-H.; Sin, H.-S. Bull. Korean Chem. Soc. 2003, 24, 677.
4. (a) Borsche, W. Chem. Ber. 1910, 42, 4072; (b) Borsche, W.; Wagner-Roem-
mich, M. Lieb. Ann. 1940, 544, 280; (c) Abelman, M. M.; Smith, S. C.; James,
D. R. Tetrahedron Lett. 2003, 44, 4559; (d) Li, W.; Lam, Y. J. Comb. Chem.
2005, 7, 721.
5. (a) Vinot, N.; Maitte, P. J. Heterocycl. Chem. 1982, 19, 349; (b) Wiedermannova, I.;
Slouka, J. J. Heterocycl. Chem. 2001, 38, 1465; (c) Colombo, A.; Frigola, J.; Pares, J.;
Andaluz, B. J. Heterocycl. Chem. 1989, 26, 949; (d) Holla, B. S.; Sarojini, B. K.; Rao,
B. S.; Poojary, B. Indian J. Chem., Sect. B 2003, 42B, 2054; (e) Nixey, T.; Tempest, P.;
Hulme, C. Tetrahedron Lett. 2002, 43, 1637.
6. (a) Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Wein-
heim, Germany, 2005; (b) Bagley, M. C.; Lubinu, M. C. Top. Heterocycl. Chem.
2006, 31; (c) Do¨mling, A.; Ugi, I. Andew. Chem., Int. Ed. 2000, 39, 3168; (d) Si-
mon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957.
7. (a) Chebanov, V. A.; Sakhno, Y. I.; Desenko, S. M.; Shishkina, S. V.; Musatov, V. I.;
Shishkin, O. V.; Knyazeva, I. V. Synthesis 2005, 2597; (b) Chebanov, V. A.;
Sakhno, Ya. I.; Desenko, S. M.; Chernenko, V. N.; Musatov, V. I.; Shishkina, S. V.;
Shishkin, O. V.; Kappe, C. O. Tetrahedron 2007, 63, 1229.
8. See, for example: (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250; (b)
Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38, 653; (c) De La Hoz, A.;
Diaz-Ortiz, A.; Moreno, A. Chem. Soc. Rev. 2005, 34, 164; (d) Bonrath, W.; Paz
Schmidt, R. A. In Advances in Organic Synthesis; Atta-ur-Rahman, Ed.; Bentham
Science: Oak Park, IL, 2005; Chapter 3, pp 81–117; (e) Mason, T. J.; Luche, J.-L. In
Chemistry Under Extreme or Non-classical Conditions; van Eldick, R., Hubbard, C.
D., Eds.; John Wiley: Stony Brook, NY, 1997; (f) Chebanov, V. A.; Saraev, V. E.;
Desenko, S. M.; Chernenko, V. N.; Shishkina, S. V.; Shishkin, O. V.; Kobzar, K. M.;
Kappe, C. O. Org. Lett. 2007, 9, 1691; (g) Chebanov, V. A.; Saraev, V. E.; Desenko, S. M.;
Chernenko, V. N.; Knyazeva, I. V.; Groth, U.; Glasnov, T. N.; Kappe, C. O. J. Org. Chem.
2008, 73, 5110; (h) Muravyova, E. A.; Desenko, S. M.; Musatov, V. I.; Knyazeva, I. V.;
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P. Tetrahedron 2008, 64, 8169.
radiation, CCD detector,
u
-scanning, 2Qmax¼50ꢀ). The structure
was solved by direct method using SHELXTL package.21 Position
of the hydrogen atoms were located from electron density dif-
ference maps and refined by ‘riding’ model with Uiso¼nUeq of
the carrier atom (n¼1.5 for methyl group and n¼1.2 for other
hydrogen atoms). The hydrogen atoms participating in the for-
mation of the hydrogen bonds were refined in isotropic ap-
proximation. Full-matrix least-squares refinement against F2 in
anisotropic approximation for non-hydrogen atoms using 2996
reflections was converged to wR2¼0.060 (R1¼0.035 for 1323
reflections with F>4
s
(F), S¼0.679). The final atomic coordinates,
and crystallographic data for molecule 6 have been deposited to
with the Cambridge Crystallographic Data Centre, 12 Union
Road, CB2 1EZ, UK (fax: þ44 1223 336033; e-mail: deposit@
ccdc.cam.ac.uk) and are available on request quoting the de-
position numbers CCDC 695198.
The colourless crystals of 5c (C19H16N4O2) are monoclinic. At
293 K a¼16.493(1), b¼7.212(1), c¼16.497(1) Å,
b
¼119.37(1)ꢀ, V¼
1710.0(2) Å3, Mr¼332.36, Z¼4, space group P21/c, dcalcd¼1.291 g/cm3,
m
(Mo
K
a
)¼0.087 mmꢁ1
,
F(000)¼696. Intensities of 4979
reflections (2952 independent, Rint¼0.070) were measured on
the ‘Xcalibur-3’ diffractometer (graphite monochromated Mo K
a
radiation, CCD detector,
u
-scanning, 2Qmax¼50ꢀ). The structure
was solved by direct method using SHELXTL package.21 Position
of the hydrogen atoms were located from electron density dif-
ference maps and refined by ‘riding’ model with Uiso¼nUeq of
the carrier atom (n¼1.5 for methyl group and n¼1.2 for other
hydrogen atoms). Full-matrix least-squares refinement against F2
in anisotropic approximation using 2910 reflections was con-
verged to wR2¼0.195 (R1¼0.085 for 1995 reflections with
9. Burgi, H.-B.; Dunitz, J. D. Structure Correlation; VCH: Weinheim, Germany, 1994;
Vol. 2, pp 741–784.
10. Zefirov, N. S.; Palyulin, V. A.; Dashevskaya, E. E. J. Phys. Org. Chem. 1990, 3, 147.
11. Zefirov Yu, V. Kristallografiya 1997, 42, 936.
12. (a) Gladkov, E. S.; Chebanov, V. A.; Desenko, S. M.; Shishkin, O. V.; Shishkina,
S. V.; Dallinger, D.; Kappe, C. O. Heterocycles 2007, 73, 469; (b) Lipson, V. V.;
Desenko, S. M.; Shishkina, S. V.; Shirobokova, M. G.; Shishkin, O. V.; Orlov, V. D.
Khim. Geterotsikl. Soedin. 2003, 1194; (c) Lipson, V. V.; Desenko, S. M.; Borodina,
V. V.; Shirobokova, M. G.; Musatov, V. I. Zh. Org. Khim. 2005, 115; (d)Lipson, V.V.;
Desenko, S. M.; Shirobokova, M. G.; Borodina, V. V. Khim. Geterotsikl. Soedin. 2003,
1383.
F>4
s
(F), S¼1.072). The final atomic coordinates, and crystallo-
graphic data for molecule 6 have been deposited to with the
Cambridge Crystallographic Data Centre, 12 Union Road, CB2
1EZ, UK (fax: þ44 1223 336033; e-mail: deposit@ccdc.
cam.ac.uk) and are available on request quoting the deposition
numbers CCDC 695199.
13. (a) Shaabani, A.; Rahmati, A.; Rezayan, A. H.; Darvishi, M.; Badri, Z.; Sarvari, A.
QSAR Comb. Sci. 2007, 36, 973; (b) Shaabani, A.; Farhangi, E.; Rahmati, A.
Comb. Chem. High Throughput Screening 2006, 9, 771; (c) Pryadeina, M. V.;
BurgartYa, V.; Saloutin, V. I.; Kodess, M. I.; Ulomskii, E. N.; Rusinov, V. L. Zh.
Org. Khim. 2004, 40, 938.
14. (a) Vaughan, W. R.; Covey, I. S. J. Am. Chem. Soc. 1958, 80, 2197; (b) Merchant,
J. R.; Hakim, M. A.; Pillay, K. S.; Patell, J. R. J. Med. Chem. 1971, 14, 1239.
15. Vaughan, W. R.; Tripp, R. C. J. Am. Chem. Soc. 1960, 82, 4370.
16. Dieckmann, W. Chem. Ber. 1910, 43, 1024.
Acknowledgements
The present work was supported by an INTAS grant (V.A.C., Nr.
04-83-2844) and DAAD Euler scholarship (Y.I.S.). We thank Biotage
AG for the use of the Emrys Creator and Emrys Initiator microwave
reactors. We also thank Dr. Vladimir Musatov for recording some 1H
NMR spectra, Dr. Dmytro S. Sofronov for recording IR spectra and
Ms. Irina Knyazeva for measuring MS spectra.
17. Al-Najjar, A.; Bowden, K. J. Chem. Soc., Perkin Trans. 2 1997, 993.
18. Busca, P.; Paradisi, F.; Moynihan, E.; Maguire, A. R.; Engel, P. Org. Biomol. Chem.
2004, 2, 2684.
19. (a) Henry, R. A.; Finnegan, W. G. J. Am. Chem. Soc. 1954, 76, 923; (b) Hennig, L.;
Hofmann, J.; Alva-Astudillo, M.; Mann, G. J. Prakt. Chem. 1990, 332, 351.
20. Steck, E. A.; Brundage, R. P.; Fletcher, L. T. J. Am. Chem. Soc. 1958, 80, 3929.
21. Sheldrick, G. M. SHELXTL PLUS. PC Version. A System of Computer Programs
for the Determination of Crystal Structure from X-ray Diffraction Data. Rev.5.1;
1998.
References and notes
1. (a) Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1989, 32, 396; (b)
Epling, G. A.; Lin, K. Y. J. Heterocycl. Chem. 1987, 24, 853; (c) Andrew, J.; Kato, K.;
Kaiya, T. J. Med. Chem. 1968, 11, 277; (d) Bhatt, D. J.; Kamdar, G. C.; Parikh, A. R.