Features of switchable multicomponent heterocyclizations of salicylic aldehydes and 5-aminopyrazoles with pyruvic acids and antimicrobial activity of the reaction products

Article abstract of DOI:10.1016/j.tet.2013.08.055

Three-component reactions of 5-aminopyrazoles and salicylic aldehydes with pyruvic acids were studied. The method of tuning of the selectivity of the heterocyclizations allowing to change its direction by variation of the reaction parameters was worked out. The treatment involving pyruvic acid can be selectively directed to the formation to either 3-aryl-10,11-dihydro-4,10- methano-pyrazolo[4,3-c][1,5]benzoxazocine-4-carboxylic acids or 3,6-diarylpyrazolo[3,4-b]pyridine-4-carboxylic acids, while the reaction involving arylpyruvic acid leads only to 7-hydroxy-2,5,6-triaryl-4,5,6,7- tetrahydro-pyrazolo[1,5-a]pyrimidine-7-carboxylic acids. Antimicrobial activity of the compounds obtained was also studied: Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) were found sensitive to the substances tested, however, only in the highest concentration.

Full text of DOI:10.1016/j.tet.2013.08.055

Tetrahedron xxx (2013) 1e9
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Features of switchable multicomponent heterocyclizations of
salicylic aldehydes and 5-aminopyrazoles with pyruvic acids and
antimicrobial activity of the reaction products
,
Maryna V. Murlykina a, Yana I. Sakhno a, Sergey M. Desenko a b, Iryna S. Konovalova a,
,b,
Oleg V. Shishkin a, Dmytro A. Sysoiev c, Maryna N. Kornet d, Valentin A. Chebanova
*
a Division of Chemistry of Functional Materials, State Scientific Institution “Institute for Single Crystals” of National Academy of Sciences of Ukraine,
Lenin Ave. 60, 61001 Kharkiv, Ukraine
b Faculty of Chemistry, V.N. Karazin Kharkiv National University, Svobody Sq. 4, 61077 Kharkiv, Ukraine
c Fachbereich Chemie, University of Konstanz, Fach M-720, Universitaetsstrasse 10, 78457 Konstanz, Germany
d Laboratory of Biotechnology of Physiologically Active Substances, Zaporizhzhya National University, Zhukovsky Str. 66, Zaporizhzhya 69600, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Three-component reactions of 5-aminopyrazoles and salicylic aldehydes with pyruvic acids were stud-
ied. The method of tuning of the selectivity of the heterocyclizations allowing to change its direction by
variation of the reaction parameters was worked out. The treatment involving pyruvic acid can be se-
lectively directed to the formation to either 3-aryl-10,11-dihydro-4,10-methano-pyrazolo[4,3-c][1,5]
benzoxazocine-4-carboxylic acids or 3,6-diarylpyrazolo[3,4-b]pyridine-4-carboxylic acids, while the re-
action involving arylpyruvic acid leads only to 7-hydroxy-2,5,6-triaryl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]
pyrimidine-7-carboxylic acids. Antimicrobial activity of the compounds obtained was also studied:
Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) were found sensitive to the sub-
stances tested, however, only in the highest concentration.
Received 29 May 2013
Received in revised form 6 August 2013
Accepted 19 August 2013
Available online xxx
Keywords:
Aminoazole
Salicylaldehyde
Pyruvic acids
Ultrasound
Ó 2013 Elsevier Ltd. All rights reserved.
Multicomponent reaction
1. Introduction
Multicomponent synthesis of oxygen-bridged pyrimidine sys-
tems has been described in several publications.3e6 In most cases it
The intense interest in multicomponent reactions observed in
recent decades has been related to the development of combina-
torial and medicinal-orientated chemistry as well as to their high
efficiency and convenience in comparison with multistage pro-
cedures. Herewith, scientific efforts are focused on multicompo-
nent procedures for generation of heterocyclic compound libraries
and, in last years, on Diversity Oriented Synthesis.1
Studying the multicomponent cyclizations involving carbonyl
compounds and aminoazoles containing several alternative re-
action centers is an important task due to the possibility of several
different reaction pathways depending on the structure of reagents,
type of solvent, and catalyst.2 Moreover, the introduction of an OH-
group in the ortho-position of an aromatic ring of the aldehyde
additionally allows oxygen-bridged and several other types of final
structure.3,4
was realized as three-component condensation of a nitrogen-
containing binucleophile (urea and its derivatives, aminoazoles),
ortho-salicylaldehyde, and CH-acid (ketones, 1,3-dicarbonyl com-
pounds,
b-ketoacids, and their derivatives etc.). Such hetero-
cyclizations were carried out both under the classical conventional
conditions and with the use of microwave irradiation,3 as well as
with application of different catalysts.5,6 Application of sequential
reactions of nitrogen-containing binucleophiles with preliminary
obtained a,b-unsaturated ketones was also described for the syn-
thesis of oxygen-bridged pyrimidine systems.7
However, multicomponent heterocyclizations based on amino-
azoles and ortho-salicylaldehydes is sometimes ambiguous.
For instance, in the Biginelli-like heterocyclization of salicy-
laldehyde I and 3-amino-1,2,4-triazole II with acetone III, Gorobets
et al.3 obtained either benzoxadiazocine IV (pathway A, Scheme 1)
or tetrahydropyrimidine V (pathway B) depending on the reaction
conditions. In the same reaction in the presence of a double excess
of salicylaldehyde I, instead of the expected bridged structure,
spiroheterocyclic compound VII (Scheme 1) was isolated by Svetlik
et al.8
* Corresponding author. Tel.: þ380 57 341 01 91; fax: þ380 57 341 02 73; e-mail
address: chebanov@isc.kharkov.com (V.A. Chebanov).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.055
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2
M.V. Murlykina et al. / Tetrahedron xxx (2013) 1e9
Scheme 1.
Scheme 3.
Oxygen-bridged pyridines were also obtained in the three-
component reaction of ammonium acetate, 4-(2-hydroxyphenyl)
but-3-en-2-one, and different CH-acids (methyl acetoacetate,9
pentane-2,4-dione,9 dimedone,9 Meldrum acid10), in condensa-
tion of urea, salicylaldehyde, and Meldrum acid,10 as well as by
sequential reaction of enaminonitriles with 4-(2-hydroxyphenyl)
but-3-en-2-one.9,11
Another reaction was described by Svetlik et al.7dit was found
that the reaction of salicylaldehyde I, methylacetoacetate VI, and 5-
amino-3-methylpyrazole VIII led to lactonization and formation of
tetracyclic pyrazolopyridine IX (Scheme 2).
Scheme 4.
Scheme 2.
20 min), which allows a four-fold reduction in the time of the
process due to the higher reaction temperature.
Dihydropyridopyrazoles XIII were obtained when furan-2,4-
dione XI was used as CH-acid in the reaction with salicylalde-
hydes X and 5-aminopyrazole XII in ethanol with catalytic amounts
of Et3N.12 In this case the hydroxyl group of the salicylaldehyde was
not involved in the reaction (Scheme 2).
Thus, multicomponent reactions based on the treatment of CH-
acids, aminoazoles, and ortho-salicylaldehydes can proceed by
several alternative pathways and, therefore, are challenging objects
for study. In continuation of our recent research13 devoted to the
tuning of the selectivity of heterocyclizations involving amino-
azoles, aromatic aldehydes, and pyruvic acids usually resulting in
formation of different types of heterocyclic compounds (Scheme 3),
we studied similar MCRs with the participation of ortho-
salicylaldehydes.
Treatment of the same starting materials 1, 2, and 3 in acetic acid
at room temperature under ultrasonic irradiation yielded 3-aryl-
10,11-dihydro-4,10-methanopyrazolo[4,3-c][1,5]benzoxazocine-4-
carboxylic acids 4aep (Scheme 4). These oxygen-bridged hetero-
cycles were stable upon boiling in a series of solvents (acetic acid,
methanol, ethanol, and butanol). However, stirring in ethanol with
addition of sodium hydroxide led to cleavage of the bridged frag-
ment, oxidation, and formation of compounds 5 with 90% yield
(Scheme 4). After MW irradiating compounds 4 in HOAc (150 ꢀC,
15 min) or heating them in DMSO for 48 h the formation of het-
eroaromatic carboxylic acids 5 was also observed. On the other
hand, refluxing benzoxazocines 4 in DMF for 2 h led to their de-
composition with formation of a resinous mixture in which the
components were not identified.
Synthesis of the benzoxazocines 4 was also possible without
using ultrasonic irradiation just by mechanical stirring. However, in
this case the reaction time increased from 90 min to 20 h, and there
were impurities of azomethines 6 in the final products. The same
impurities as well as some amount of the starting materials were in
the precipitate, and in the mother liquor when synthesizing com-
pounds 4 in methanol with catalytic amount of HCl.
2. Results and discussion
It was established that the three-component reaction of an
equimolar mixture of 5-amino-3-arylpyrazole 1aee, salicylalde-
hyde 2aed, and pyruvic acid (3) under conventional refluxing in
acetic acid led to 3-aryl-6-(2-hydroxyphenyl)-pyrazolo[3,4-b]pyri-
dine-4-carboxylic acids 5aeg (Scheme 4, Table 1). These substances
could also be obtained under microwave irradiation (AcOH, 150 ꢀC,
It seems that azomethines can be intermediates of both heter-
ocyclizations mentioned above. Indeed, treatment of preliminary
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M.V. Murlykina et al. / Tetrahedron xxx (2013) 1e9
3
Table 1
to the tetrahydro derivatives 9bed as in the case of pyruvic acid
(Scheme 5, Table 2).
Three-component reactions of 5-amino-3-arylpyrazoles, salicylaldehydes, and pyr-
uvic acid via Scheme 4
Building blocks
Aminopyrazole
Product
Table 2
Salicylaldehyde
Reactions of 5-aminopyrazoles, salicylaldehydes, and pyruvic acid derivatives via
Scheme 5
Compound
R1
Compound
R2
Compound
Yield (%)
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
1b
1a
1b
1c
1d
1e
1a
1d
C6H5
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2c
2c
2c
2c
2c
2d
2a
2a
2a
2a
2a
2c
2b
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
72
88
82
80
74
75
76
78
85
80
70
73
81
72
79
67
Building blocks
Aminopyrazole
Compound R1
Product
4-CH3OC6H4
4-BrC6H4
4-ClC6H4
4-C2H5C6H4
C6H5
4-CH3OC6H4
4-BrC6H4
4-ClC6H4
4-C2H5C6H4
C6H5
4-CH3OC6H4
4-BrC6H4
4-ClC6H4
4-C2H5C6H4
4-CH3OC6H4
C6H5
4-CH3OC6H4
4-BrC6H4
4-ClC6H4
4-C2H5C6H4
C6H5
Pyruvic acid derivative
Compound R3
Compound Yield (%)
H
7
d
3
H
9a
9b
65
75
52
70
70
56
59
79
68
74
69
58
64
3-CH3O
3-CH3O
3-CH3O
3-CH3O
3-CH3O
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-NO2
H
7
d
8a
8b
8c
8a
8b
8c
8a
8b
8c
C6H5
7
d
4-CH3OC6H4 9c
7
d
4-ClC6H4
C6H5
9d
10a
1a
1a
1a
1d
1d
1d
1e
1e
1e
C6H5
C6H5
C6H5
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-C2H5C6H4 8a
4-C2H5C6H4 8b
4-C2H5C6H4 8c
4j
4k
4l
4-CH3OC6H4 10b
4-ClC6H4
C6H5
10c
10d
4m
4n
4o
4p
5a
5b
5c
5d
5e
5f
4-CH3OC6H4 10e
4-ClC6H4
C6H5
10f
10g
30a
45a
42a
40a
39a
35a
28a
4-CH3OC6H4 10h
4-ClC6H4 10i
H
H
H
H
5-Cl
3-CH3O
On the other hand, heterocyclization of pyrazoles 1a,d,e and
salicylaldehyde 2 with arylpyruvic acids 8aec under ultrasonic ir-
radiation, in contrast to multicomponent reactions involving pyr-
uvic acid, proceeded with the formation of a pyrimidine ring
instead of a pyridine one (carboxylic acids 10aei, Scheme 5).
Compounds 9 and 10 were also obtained in the reaction of the
corresponding azomethines 6 with arylpyruvic acids 8.
It should be noted that tetrahydropyrimidines 9 and 10 are
unstable and they decompose gradually in HOAc and rapidly in
DMSO to the mixture of starting materials. All our attempts to carry
out dehydration in order to obtain dihydropyrimidine or oxygen-
bridged azoloazines from compounds 9 and 10 employing differ-
ent conditions were unsuccessful, as was described in our earlier
publications for similar heterocycles.13c,14c
Three-component reactions of pyrazoles 1 and 7 with salicy-
laldehyde 2 and arylpyruvic acids 8 carried out in the different
solvents (also by adding of alkali or protic acids) both under the
conventional refluxing and microwave irradiation led to the mix-
tures of starting materials, sometimes with the impurities con-
sisting of azomethines or other difficult to identify compounds.
4-ClC6H4
5g
a
MW irradiation in HOAc.
obtained imines 6aep with pyruvic acid 3 in acetic acid under
ultrasonication led to the formation of benzoxazocines 4aep
(Scheme 4). The possibility of the transformation of azomethines
into pyrazolopyridines like 5 by refluxing with pyruvic acid was
described in our earlier publications.13c,d,14c
5-Aminopyrazoles containing a substituent in the fourth posi-
tion in order to promote only one possible reaction pathway
sometimes possessed specific properties and exhibited unusual
behavior in multicomponent reactions.14 In our case, hetero-
cyclization of 5-amino-4-ethyl-3-(4-fluorophenyl)-pyrazole 7 with
salicylaldehyde 2 and pyruvic acid 3 led to tetrahydropyrimidine
carboxylic acid 9a while the expected formation of an oxygen-
bridged compound was not observed (Scheme 5).
3. Structure elucidation
The structures of the synthesized heterocyclic compounds were
established by means of elemental analysis, mass-spectrometry,
NMR spectroscopy, and X-ray diffraction study.
The 1H NMR spectra of benzoxazocines 4 exhibit a broad singlet
for the pyrazole NH and COOH groups at 12.00e12.50 ppm, a broad
singlet for the pyridine NH near 6.40e6.57 ppm, a multiplet for the
CH2-group at 2.19e2.22 ppm, a multiplet for the CH-group at
4.39e4.42 ppm, peaks for aromatic protons around 6.70e7.70 ppm
as well as signals for other terminal substituents. The 1H NMR
spectra of carboxylic acids 5 also contain a broad peak for both
pyrazole NH and COOH functionalities ca. at 14.00 ppm, a broad
singlet for the OH-group at 12.50 ppm, and signals for the aromatic
protons including a sharp singlet for the pyridine CH near
7.00e8.00 ppm.
Scheme 5.
On the other hand, modifying the pyruvic acid with an aryl
substituent considerably influences the reaction behavior, and
sometimes can cause the formation of other types of heterocyclic
compound in comparison with heterocyclizations involving pyr-
uvic acid.13c,14c However, it was found that the three-component
reaction of pyrazole 7, salicylaldehyde 2, and arylpyruvic acids
8aec in acetic acid under ultrasonication at room temperature led
The presence of a resonance signal for the pyrazole NH (for
compound 4 and 5) and the absence of a singlet for the pyrazole CH
group confirmed the formation of the pyridine but not pyrimidine
ring.
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4
M.V. Murlykina et al. / Tetrahedron xxx (2013) 1e9
However, the spectral data obtained for benzoxazocines 4 may
correspond to at least two possible isomers A and B (Fig. 1).
Final assignment of the structure A for these heterocycles was
made with help of 2D NMR experiments (Fig. 4).
A
B
Fig. 1. Alternative structures A and B for benzoxazocines 4.
Fig. 4. Selected data of HMBC and NOESY experiments and relative stereochemistry of
stereogenic centers at positions 10 and 11.
COSY and NOESY experiments showed correlations between the
protons of NH and CH groups in the pyridine ring, and no in-
teraction between the aryl and R-substituent was observed, which
should be expected in a structure like B. All the data obtained from
HMBC spectra also corresponded to structure A but not to B.
Ultimately, the structure of compounds 4aep was proven by an
X-ray analysis of compound 4e (Fig. 2).
Relative stereochemistry of stereogenic centers at positions 10
and 11 for compounds 9 and 10 was established by analysis of 1D
and 2D NMR spectra. Thus, the spinespin interaction constants (3J)
for these protons are about 11e12 Hz, which corresponds to their
trans-orientation, which earlier was found for similar compounds
by NMR and X-ray analysis.13c The trans-orientation of the sub-
stituents in the pyrimidine moiety is also understandable from the
general steric reasoning.
4. Antimicrobial activity
Antimicrobial activity of compounds 4b,g,h, 5f,g and 9a was
studied (see Experimental part for details) against reference strains
of following test cultures: Bacillus subtilis, Staphylococcus aureus,
Escherichia coli (strain 1257) and Pseudomonas aeroginosa. It was
found that Gram-negative bacteria (E. coli and P. aeroginosa) had
showed resistance to all the compounds tested in the concentration
range 250.000e15.625 mg/ml. Strains of Gram-positive bacteria (B.
subtilis and S. aureus) were found more sensitive, however, bacte-
riostatic activity was fixed only in the highest concentration
250 mg/ml during the first day of the experiment. Thus, the com-
pounds tested inferior in action to nitroxoline being reference
substance.
It should be additionally noted that for compounds 4b,g,h and
5g after 48 h sufficient increase in biomass of culture E. coli com-
pared with control was found. For compound 4b the same situation
was also observed in the case of P. aeroginosa. After detailed study
this effect may be used, for instance, to stimulate the growth of
producers of biologically active compounds.
Fig. 2. Molecular structure of 10,11-dihydro-3-(4-ethylphenyl)-4,10-methanopyrazolo
[4,3-c][1,5]benzoxazocine-4-carboxylic acid 4e according to X-ray diffraction data.
The structure of compounds 5aeg was established with the help
of NMR spectra by their comparison with literature data for similar
compounds.13d
The 1H NMR spectra of carboxylic acids 9bed exhibit doublets for
the CH-protons at positions 10 and 11 near 5.38e5.43 and
3.92e3.99 ppm, correspondingly, with 2J w11.2e11.8 Hz. In the case
of compound 9a, a multiplet for the CH-proton at position 11 at ca.
4.9 ppm and a multiplet for the CH2-group at ca. 2.2 ppm are ob-
served. The spectra also contain broad singlets for the COOH-group at
12.95e13.06 ppm, pyrimidine NH-group at 6.26e6.33 ppm, and
phenol OH-group at 9.39e9.45 ppm as well as a multiplet of aromatic
protons including broad singlet of OH-group at 6.58e7.59 ppm.
Similar spectra were observed for compounds 10aei,
which however, may correspond to four possible isomers AeD
(Fig. 3).
5. Conclusions
In summary, the direction of the multicomponent reactions
between 5-aminopyrazoles, salicylic aldehydes, and pyruvic acids
depends on the temperature regime and structure of the starting
materials, which allows controlling chemoselectivity. Thus, three-
component treatment of 5-amino-3-arylpyrazole, pyruvic acid,
and salicylic aldehyde can proceed under kinetic control (ultra-
sonication at room temperature) yielding 10,11-dihydro-4,10-
methanopyrazolo[4,3-c][1,5]benzoxazocine-4-carboxylic acids. On
the other hand, under thermodynamic control (refluxing or MW
heating), reaction of the same starting materials gives pyrazolo[3,4-
b]pyridines containing free carboxylic and hydroxyl-groups, which
are potentially able to form complexes with different metals. In the
case of arylpyruvic acids the multicomponent reaction studied
changes direction yielding 4,5,6,7-tetrahydropyrazolo[1,5-a]py-
rimidine-7-carboxylic acids instead of expected fused pyridine
derivatives. The same heterocyclic system was obtained when
pyruvic acids and salicylic aldehydes react with 5-amino-4-
ethylpyrazole. Most likely all the treatments studied pass via
Fig. 3. Alternative structures AeD for compounds 10.
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M.V. Murlykina et al. / Tetrahedron xxx (2013) 1e9
5
formation of azomethines between aminopyrazole and salicylic
aldehyde on the first stage of the multicomponent reaction.
159.96, 172.37. MS (EI, 70 eV): m/z (%)¼363 (64.5, Mþ), 318 (99.9),
270 (14.4), 246 (4.5), 226 (11.2), 189 (15.5), 170 (5.8), 131 (19.7), 102
(5.0), 77 (13.1), 51 (2.9).
6. Experimental section
6.1. General
6.3.3. 3-(4-Bromophenyl)-10,11-dihydro-4,10-methanopyrazolo[4,3-
c][1,5]benzoxazocine-4-carboxylic acid (4c). Colorless solid, mp
180e181 ꢀC. [Found: C, 55.41; H, 3.38; N, 10.15. C19H14BrN3O3 re-
quires C, 55.36; H, 3.42; N, 10.19%]; nmax (KBr) 3292, 2930, 1721,
The starting arylpyruvic acids 8aec were synthesized according
to the known literature procedure15 and were subsequently used
directly without additional purification. 3-Substituted 5-
aminopyrazoles 1aee and 5-amino-4-ethyl-3-(4-fluorophenil)-
pyrazole 7 were commercially available. Azomethine 6 was ob-
tained as reported.16
1609, 1482, 1457, 1240, 1012, 830, 759 cmꢁ1
; dH (200 MHz, DMSO-
d6) 12.21 (s, 2H, OHþNH), 6.84e7.67 (m, 8H, Ar), 6.56 (s, 1H, NH),
4.37e4.46 (m,1H, CH), 2.15e2.23 (m, 2H, CH2); dC (100 MHz, DMSO-
d6) 34.00, 46.38, 72.82, 99.50, 117.19, 121.05, 121.73, 125.58, 127.52,
129.36, 129.70, 130.79, 131.83, 142.67, 152.09, 153.21, 172.31. LS/MS:
411 (Mþ).
Melting points of all the compounds synthesized were de-
termined with a Kofler melting point apparatus and are un-
corrected. The NMR spectra were recorded in DMSO-d6 at 200 MHz
with a Varian Mercury VX-200 spectrometer, at 400 MHz (100 MHz
for 13C) with a Jeol ECP-Eclipse 400 and at 600 MHz (150 MHz for
13C) with a Bruker Avance DRX600. The MS spectra were measured
on a GS-MS Varian 1200L (ionizing voltage 70 eV), on Finnigan MAT
8200 with the use of FAB-method and on LC/MS Agilent 1100. El-
emental analysis was realized on Euro Vector EA-3000. IR-spectra
were recorded on a PerkineElmer 100 Series FT-IR spectrometer
and on a PerkineElmer Spectrum One FTIR spectrometer.
US-experiments were performed using the standard US-bath
(SELDI, Ukraine) with working frequency of 44.2 kHz. Microwave
experiments were carried out using the EmrysÔ Creator EXP syn-
thesizer from Biotage AB (Uppsala, Sweden) possessing a single-
mode microwave cavity producing controlled irradiation at
2.45 MHz. Experiments were carried out in sealed microwave
process vials utilizing the high absorbance level. Reaction time
reflects irradiation times at the set reaction temperature (fixed hold
times).
6.3.4. 3-(4-Chlorophenyl)-10,11-dihydro-4,10-methanopyrazolo[4,3-
c][1,5]benzoxazocine-4-carboxylic acid (4d). Colorless solid, mp
203e204 ꢀC. [Found: C, 62.11; H, 3.89; N, 11.40. C19H14ClN3O3 re-
quires C, 62.05; H, 3.84; N, 11.43%]; nmax (KBr) 3388, 2924, 2853,
1734, 1607, 1482, 1457, 1239, 760 cmꢁ1
; dH (200 MHz, DMSO-d6)
12.55 (s, 2H, OHþNH), 6.84e7.64 (m, 8H, Ar), 6.57 (s, 1H, NH),
4.38e4.46 (m, 1H, CH), 2.15e2.24 (m, 2H, CH2); dC (100 MHz,
DMSO-d6) 34.33, 46.72, 73.20, 99.78, 117.36, 121.19, 125.80, 128.96,
129.48, 129.68, 130.87, 131.26, 133.25, 143.09, 152.09, 153.49, 172.32.
MS (Mass-FAB): 368 (MHþ).
6.3.5. 3-(4-Ethylphenyl)-10,11-dihydro-4,10-methanopyrazolo[4,3-c]
[1,5]benzoxazocine-4-carboxylic acid (4e). Colorless solid, mp
206e207 ꢀC. [Found: C, 69.82; H, 5.37; N, 11.60. C21H19N3O3 re-
quires C, 69.79; H, 5.30; N, 11.63%]; nmax (KBr) 3377, 2931, 2874,
1727, 1647, 1541, 1481, 1240, 1122, 758 cmꢁ1
; dH (200 MHz, DMSO-
d6) 12.42 (s, 2H, OHþNH), 6.83e7.56 (m, 8H, Ar), 6.43 (s, 1H, NH),
4.34e4.43 (m, 1H, CH), 2.61 (q, 2H, J 7.5 Hz, CH2CH3), 2.15e2.23 (m,
2H, CH2), 1.19 (t, 3H, J 7.5 Hz, CH2CH3); dC (100 MHz, DMSO-d6)
15.84, 21.52, 34.28, 46.43, 72.93, 99.59, 117.17, 120.97, 125.80, 127.68,
128.27, 128.65, 129.29, 130.75, 142.52, 144.11, 153.05, 153.29, 172.40.
LS/MS: 362 (MHþ).
6.2. General procedure for the synthesis of 3-aryl-10,11-
dihydro-4,10-methanopyrazolo[4,3-c][1,5]benzoxazocine-4-
carboxylic acids 4aee
The appropriate 5-aminopyrazole 1 (0.9 mmol) was dissolved in
HOAc (2.5 ml) then the salicylaldehyde 2a (0.9 mmol) and pyruvic
acid 3 (0.9 mmol) were added. The mixture was put into the US-
bath for 1.5 h. The precipitate was filtered and dried under vacuum.
6.4. General procedure for the synthesis of 3-aryl-10,11-
dihydro-4,10-methanopyrazolo[4,3-c][1,5]benzoxazocine-4-
carboxylic acids 4fep
The appropriate 5-aminopyrazole 1 (0.9 mmol) was dissolved in
HOAc (2.5 ml), then the appropriate salicylaldehyde 2 (0.9 mmol)
and 1.5 excess of pyruvic acid 3 (1.35 mmol) were added. The
mixture was put into the US-bath for 1.5 h. The precipitate was
filtered and dried under vacuum.
6.3. Characterization data for compounds 4aee
6.3.1. 3-Phenyl-10,11-dihydro-4,10-methanopyrazolo[4,3-c][1,5]ben-
zoxazocine-4-carboxylic acid (4a). Colorless solid, mp 191e192 ꢀC.
[Found: C, 68.51; H, 4.60; N, 12.58. C19H15N3O3 requires C, 68.46; H,
4.54; N, 12.61%]; nmax (KBr) 3306, 2927, 1727, 1634, 1588, 1482, 1456,
6.5. Characterization data for compounds 4fep
1121, 900, 757, 697 cmꢁ1
; dH (200 MHz, DMSO-d6) 12.47 (s, 2H,
OHþNH), 6.78e7.70 (m, 9H, Ar), 6.45 (s, 1H, NH), 4.35e4.44 (m, 1H,
CH), 2.13e2.26 (m, 2H, CH2); dC (100 MHz, DMSO-d6) 34.24, 46.41,
72.91, 99.65, 117.18, 120.98, 125.75, 127.68, 128.44, 128.88, 129.30,
130.77, 131.42, 142.85, 152.82, 153.28, 172.35; MS (EI, 70 eV): m/z
(%)¼333 (64.5, Mþ), 246 (8.5), 210 (8.0), 127 (19.4), 88 (21.0), 65
(49.5), 63 (99.9).
6.5.1. 5-Methoxy-3-phenyl-10,11-dihydro-4,10-methanopyrazolo
[4,3-c][1,5]benzoxazocine-4-carboxylic acid (4f). Colorless solid, mp
>300 ꢀC. [Found: C, 66.22; H, 4.82; N, 11.52. C20H17N3O4 requires C,
66.11; H, 4.72; N, 11.56%]; nmax (KBr) 3377, 3314, 1716, 1576, 1534,
1476, 1264, 1229, 1082, 1025, 754 cmꢁ1
; dH (200 MHz, DMSO-d6)
12.33 (s, 2H, OHþNH), 6.68e7.80 (m, 8H, Ar), 6.43 (s, 1H, NH),
4.33e4.43 (m, 1H, CH), 3.73 (s, 3H, CH3O), 2.16e2.24 (m, 2H, CH2);
dC (100 MHz, DMSO-d6) 34.20, 46.57, 56.26, 72.89, 99.79, 111.97,
120.58, 122.26, 126.29, 127.79, 128.41, 128.84, 131.44, 142.77, 142.97,
148.94, 152.99, 172.37. LS/MS: 364 (MHþ).
6.3.2. 3-(4-Methoxyphenyl)-10,11-dihydro-4,10-methano-pyrazolo
[4,3-c][1,5]benzoxazocine-4-carboxylic acid (4b). Colorless solid, mp
197e198 ꢀC. [Found: C, 66.16; H, 4.81; N, 11.53. C20H17N3O4 requires
C, 66.11; H, 4.72; N, 11.56%]; nmax (KBr) 3376, 2925, 2853, 1728, 1614,
1483, 1456, 1253, 840, 761 cmꢁ1
;
dH (200 MHz, DMSO-d6) 12.33 (s,
6.5.2. 5-Methoxy-3-(4-methoxyphenyl)-10,11-dihydro-4,10-methano
pyrazolo[4,3-c][1,5]benzoxazocine-4-carboxylic acid (4g). Colorless
solid, mp 225e226 ꢀC. [Found: C, 64.18; H, 4.91; N, 10.62.
2H, OHþNH), 6.80e7.60 (m, 8H, Ar), 6.40 (s, 1H, 1NH), 4.35e4.42
(m, 1H, CH), 3.77 (s, 3H, CH3O), 2.15e2.23 (m, 2H, CH2); dC
(100 MHz, DMSO-d6) 34.58, 46.79, 55.93, 73.35, 99.62, 114.55,
117.32, 121.07, 124.34, 126.07, 129.37, 130.84, 142.84, 152.92, 153.58,
C
21H19N3O5 requires C, 64.12; H, 4.87; N, 10.68, %]; nmax (KBr) 3338,
2931, 1733, 1615, 1585, 1483, 1260, 1180, 1027, 839 cmꢁ1
;
dH
Please cite this article in press as: Murlykina, M. V.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.08.055

6
M.V. Murlykina et al. / Tetrahedron xxx (2013) 1e9
(200 MHz, DMSO-d6) 12.16 (s, 2H, OHþNH), 6.70e7.64 (m, 7H, Ar),
6.34 (s, 1H, NH), 4.32e4.40 (m, 1H, CH), 3.73 (s, 3H, CH3O), 3.77 (s,
3H, CH3O), 2.13e2.21 (m, 2H, CH2) ppm; dC (100 MHz, DMSO-d6)
34.20, 46.59, 55.64, 56.21, 72.93, 99.53, 111.89, 114.29, 120.59,
122.22, 123.70, 126.36, 129.22, 142.28, 142.95, 148.94, 153.20,
159.69, 172.44. LS/MS: 394 (MHþ).
2925, 1716, 1641, 1476, 1243, 1174, 1013, 823 cmꢁ1
; dH (200 MHz,
DMSO-d6) 12.44 (s, 2H, OHþNH), 6.86e7.71 (m, 7H, Ar), 6.60 (s, 1H,
NH), 4.40e4.49 (m, 1H, CH), 2.15e2.23 (m, 2H, CH2); dC (100 MHz,
DMSO-d6)
d 33.59, 46.18, 73.16, 99.22, 119.11, 121.83, 124.57, 127.67,
129.13, 129.72, 130.21, 130.97, 131.85, 142.69, 152.08, 152.15, 171.96.
MS (Mass-FAB): 446 (MHþ).
6.5.3. 3-(4-Bromophenyl)-5-methoxy-10,11-dihydro-4,10-methano
pyrazolo[4,3-c][1,5]benzoxazocine-4-carboxylic acid (4h). Colorless
solid, mp >300 ꢀC. [Found: C, 54.35; H, 3.70; N, 9.48. C20H16BrN3O4
requires C, 54.31; H, 3.65; N, 9.50%]; nmax (KBr) 3336, 2932, 2852,
6.5.9. 7-Chloro-3-(4-chlorophenyl)-10,11-dihydro-4,10-methano
pyrazolo[4,3-c][1,5]benzoxazocine-4-carboxylic acid (4n). Colorless
solid, mp 204e205 ꢀC. [Found: C, 56.77; H, 3.33; N, 10.42.
C
19H13Cl2N3O3 requires C, 56.73; H, 3.26; N, 10.45%]; nmax (KBr)
1716, 1639, 1585, 1482, 1460, 1263, 1025, 838 cmꢁ1
;
dH (200 MHz,
3338, 2925, 1724, 1607, 1532, 1476, 1173, 1093, 835 cmꢁ1
;
dH
DMSO-d6) 12.46 (s, 2H, OHþNH), 6.73e7.72 (m, 7H, Ar), 6.52 (s, 1H,
NH), 4.36e4.43 (m, 1H, CH), 3.73 (s, 3H, CH3O), 2.15e2.22 (m, 2H,
CH2); dC (100 MHz, DMSO-d6) 33.98, 46.55, 56.25, 72.79, 99.67,
111.98, 120.68, 121.71, 122.23, 126.12, 129.79, 131.22, 131.77, 142.69,
142.90, 148.94, 152.24, 172.33. MS (Mass-FAB): 442 (MHþ).
(200 MHz, DMSO-d6) 12.55 (s, 2H, OHþNH), 6.83e7.71 (m, 7H, Ar),
6.58 (s, 1H, NH), 4.40e4.49 (m, 1H, CH), 2.14e2.26 (m, 2H, CH2); dC
(100 MHz, DMSO-d6) 33.60, 46.18, 73.16, 99.24, 119.11, 124.57,
127.68, 128.94, 129.12, 129.43, 130.21, 130.62, 133.19, 142.63, 152.02,
152.15, 171.96. LS/MS: 402.0 (MHþ).
6.5.4. 3-(4-Chlorophenyl)-5-methoxy-10,11-dihydro-4,10-methano
pyrazolo[4,3-c][1,5]benzoxazocine-4-carboxylic acid (4i). Colorless
solid, mp >300 ꢀC. [Found: C, 60.41; H, 4.09; N, 10.54. C20H16ClN3O4
requires C, 60.38; H, 4.05; N, 10.56%]; nmax (KBr) 3362, 2931, 2852,
6.5.10. 7-Chloro-3-(4-ethylphenyl)-10,11-dihydro-4,10-methano
pyrazolo[4,3-c][1,5]benzoxazocine-4-carboxylic acid (4o). Colorless
solid, mp 198e199 ꢀC. [Found: C, 63.79; H, 4.65; N, 10.61.
C
21H18ClN3O3 requires C, 63.72; H, 4.58; N, 10.62%]; nmax (KBr) 3311,
1710, 1646, 1585, 1480, 1265, 1090, 842, 735 cmꢁ1
;
dH (200 MHz,
2964, 2873, 1733, 1635, 1593, 1476, 1244, 1173, 819 cmꢁ1
;
dH
DMSO-d6) 12.38 (s, 2H, OHþNH), 6.70e7.76 (m, 7H, Ar), 6.50 (s, 1H,
NH), 4.35e4.44 (m, 1H, CH), 3.73 (s, 3H, CH3O), 2.14e2.23 (m, 2H,
CH2); dC (100 MHz, DMSO-d6) 34.00, 46.56, 56.27, 72.80, 99.67,
112.00, 120.67, 122.24, 126.14, 128.85, 129.50, 130.89, 133.07, 142.57,
142.92, 148.95, 152.25, 172.32. LS/MS: 398.1 (MHþ).
(200 MHz, DMSO-d6) 12.25 (s, 2H, OHþNH), 6.78e7.60 (m, 7H, Ar),
6.49 (s, 1H, NH), 4.37e4.46 (m, 1H, CH), 2.60 (q, 2H, J 7.5 Hz,
CH2CH3), 2.14e2.25 (m, 2H, CH2), 1.18 (t, 3H, J 7.5 Hz, CH2CH3); dC
(100 MHz, DMSO-d6) 15.83, 28.39, 33.89, 46.25, 73.29, 99.26, 119.07,
124.49, 127.68, 127.92, 128.28, 128.49, 129.03, 130.18, 142.47, 144.16,
152.25, 152.94, 172.00. LS/MS: 396 (MHþ).
6.5.5. 3-(4-Ethylphenyl)-5-methoxy-10,11-dihydro-4,10-methano
pyrazolo[4,3-c][1,5]benzoxazocine-4-carboxylic acid (4j). Colorless
solid, mp 177e178 ꢀC. [Found: C, 67.56; H, 5.49; N, 10.71.
6.5.11. 3-(4-Methoxyphenyl)-7-nitro-10,11-dihydro-4,10-methano
pyrazolo[4,3-c][1,5]benzoxazocine-4-carboxylic acid (4p). Colorless
solid, mp 203e204 ꢀC. [Found: C, 58.89; H, 3.99; N,13.75. C20H16N4O6
requires C, 58.82; H, 3.95; N, 13.72%]; nmax (KBr) 3334, 2928, 1760,
C
22H21N3O4 requires C, 67.51; H, 5.41; N, 10.74%]; nmax (KBr) 3369,
2930, 1733, 1645, 1586, 1483, 1263, 1023, 765 cmꢁ1
;
dH (200 MHz,
DMSO-d6) 12.34 (s, 2H, OHþNH), 6.70e7.67 (m, 7H, Ar), 6.37 (s, 1H,
NH), 4.32e4.42 (m, 1H, CH), 3.73 (s, 3H, CH3O), 2.60 (q, 2H, J 7.5 Hz,
CH2CH3), 2.09e2.25 (m, 2H, CH2), 1.19 (t, 3H, J 7.5 Hz, CH2CH3); dC
(100 MHz, DMSO-d6) 15.76, 28.54, 34.58, 46.97, 56.97, 73.33, 99.94,
113.12, 120.71, 122.67, 126.73, 128.12, 128.21, 129.26, 143.17, 143.67,
144.13, 149.32, 153.02, 172.35. LS/MS: 392.0 (MHþ).
1706, 1650, 1520, 1477, 1340, 1255, 1027, 836 cmꢁ1
; dH (200 MHz,
DMSO-d6) 12.08 (s, 2H, OHþNH), 6.82e8.46 (m, 7H, Ar), 6.64 (s, 1H,
NH), 4.54e4.62 (m, 1H, CH), 3.77 (s, 3H, CH3O), 2.24e2.31 (m, 2H,
CH2); dC (50 MHz, DMSO-d6) 33.90, 46.46, 55.90, 74.81, 98.99, 114.61,
118.48, 123.83, 125.21, 127.23, 127.28, 129.43, 141.70, 143.07, 152.61,
159.47, 160.13, 171.47. MS (Mass-FAB): 409 (MHþ).
6.5.6. 7-Chloro-3-phenyl-10,11-dihydro-4,10-methanopyrazolo[4,3-
c][1,5]benzoxazocine-4-carboxylic acid (4k). Colorless solid, mp
205e206 ꢀC. [Found: C, 62.10; H, 3.91; N,11.47. C19H14ClN3O3 requires
C, 62.05; H, 3.84; N, 11.43%]; nmax (KBr) 3336, 2931, 1718, 1635, 1458,
6.6. General procedure for the synthesis of 3-aryl-6-(2-
hydroxyphenyl)-pyrazolo[3,4-b]pyridine-4-carboxylic acids
5aeg
1026, 837 cmꢁ1
;
dH (200 MHz, DMSO-d6) 12.17 (s, 2H, OHþNH),
The appropriate 5-aminopyrazole 1 (0.9 mmol) was dissolved in
HOAc (2.5 ml), then the appropriate salicylaldehyde 2 (0.9 mmol)
and pyruvic acid 3 (0.9 mmol) were added. The mixture was
refluxed for 1 h or MW irradiated (15 min, 150 ꢀC). The precipitate
was filtered and dried under vacuum.
6.84e7.70 (m, 8H, Ar), 6.51 (s, 1H, NH), 4.37e4.46 (m, 1H, CH),
2.13e2.27 (m, 2H, CH2); dC (100 MHz, DMSO-d6) 33.83, 46.22, 73.26,
99.33, 119.09, 124.50, 127.69, 127.85, 128.52, 128.90, 129.05, 130.19,
131.23, 142.38, 152.23, 152.71, 171.98. MS (Mass-FAB): 368 (MHþ).
6.5.7. 7-Chloro-3-(4-methoxyphenyl)-10,11-dihydro-4,10-methano
pyrazolo[4,3-c][1,5]benzoxazocine-4-carboxylic acid (4l). Colorless
solid, mp 193e194 ꢀC. [Found: C, 60.43; H, 4.11; N, 10.51.
6.7. Characterization data for compounds 5aeg
6.7.1. 6-(2-Hydroxyphenyl)-3-phenylpyrazolo[3,4-b]pyridine-4-
carboxylic acid (5a). Yellowish solid, mp >300 ꢀC. [Found: C, 68.93;
H, 3.99; N, 12.64. C19H13N3O3 requires C, 68.88; H, 3.95; N, 12.68%];
nmax (KBr) 3236, 2924, 2853, 1712, 1599, 1496, 1456, 1274, 1233, 989,
C
20H16ClN3O4 requires C, 60.38; H, 4.05; N,10.56%]; nmax (KBr) 3334,
2933, 1705, 1614, 1476, 1252, 1173, 1029, 837 cmꢁ1
;
dH (200 MHz,
DMSO-d6) 12.13 (s, 2H, OHþNH), 6.80e7.65 (m, 7H, Ar), 6.44 (s, 1H,
NH), 4.36e4.45 (m, 1H, CH), 3.76 (s, 3H, CH3O), 2.15e2.22 (m, 2H,
CH2); dC (100 MHz, DMSO-d6) 33.86, 46.26, 55.67, 73.33, 99.06,
114.36, 119.06, 123.53, 124.48, 127.96, 129.02, 129.09, 130.18, 142.25,
152.24, 152.95, 159.73, 172.02. LS/MS: 398 (MHþ).
753 cmꢁ1
;
dH (200 MHz, DMSO-d6) 14.18 (s, 2H, OHþNH), 12.47 (s,
1H, OH), 8.14 (s, 1H, CH), 6.92e8.12 (m, 9H, Ar); dC (100 MHz,
DMSO-d6) 107.37, 114.04, 118.24, 119.94, 120.98, 128.32, 128.45,
128.97, 129.05, 129.38, 132.30, 137.88, 144.92, 151.94, 156.74, 158.71,
167.76. MS (Mass-FAB): 332 (MHþ).
6.5.8. 3-(4-Bromophenyl)-7-chloro-10,11-dihydro-4,10-methano
pyrazolo[4,3-c][1,5]benzoxazocine-4-carboxylic acid (4m). Colorless
solid, mp 203e204 ꢀC. [Found: C, 51.16; H, 2.99; N, 9.37.
6.7.2. 6-(2-Hydroxyphenyl)-3-(4-methoxyphenyl)-pyrazolo[3,4-b]
pyridine-4-carboxylic acid (5b). Yellowish solid, mp >300 ꢀC.
[Found: C, 66.53; H, 4.23; N, 11.60. C20H15N3O4 requires C, 66.48; H,
C
19H13BrN3O3 requires C, 51.09; H, 2.93; N, 9.41%]; nmax (KBr) 3306,
Please cite this article in press as: Murlykina, M. V.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.08.055

M.V. Murlykina et al. / Tetrahedron xxx (2013) 1e9
7
4.18; N,11.63%]; nmax (KBr) 3235, 2924, 2852,1732, 1602, 1459,1239,
987, 841, 749, 642 cmꢁ1
dH (200 MHz, DMSO-d6) 14.08 (s, 2H,
OHþNH), 12.54 (s, 1H, OH), 8.11 (s, 1H, CH), 6.93e8.11 (m, 8H, Ar),
3.80 (s, 3H); dC (100 MHz, DMSO-d6) 55.69, 107.28, 113.77, 114.00,
118.22, 119.91, 120.96, 126.48, 129.38, 130.25, 132.29, 137.88, 143.66,
151.74, 156.60, 158.70, 159.69, 167.89. LS/MS: 362 (MHþ).
mixture was put into the US-bath for 60 min. The precipitate was
filtered and dried under vacuum. Colorless solid, mp 177e178 ꢀC.
[Found: C, 63.53; H, 5.04; N, 10.60. C21H20FN3O4 requires C, 63.47;
H, 5.07; N, 10.57%]; nmax (KBr) 3365, 2960, 2843, 1707, 1576, 1458,
;
1221, 843 cmꢁ1
; dH (200 MHz, DMSO-d6) 12.96 (s, 1H, OH), 9.59 (s,
1H, OH), 6.82e7.58 (m, 8H, Ar), 6.25 (s, 1H, NH), 4.86e5.06 (m, 1H,
CH), 2.40 (q, 2H, J 7.5 Hz, CH2CH3), 2.02e2.32 (m, 2H, CH2), 1.01 (t,
3H, J 7.5 Hz, CH2CH3); dC (150 MHz, DMSO-d6) 15.41, 15.71, 40.42,
44.89, 82.29, 98.68, 115.56, 115.70, 119.62, 127.57, 128.58, 128.61,
129.40, 129.46, 131.88 (d, 3J 4 Hz), 145.28, 148.00, 155.03, 161.41 (d,
2J 250 Hz), 171.68. MS (Mass-FAB): 398.4 (MHþ).
6.7.3. 3-(4-Bromophenyl)-6-(2-hydroxyphenyl)-pyrazolo[3,4-b]pyri-
dine-4-carboxylic acid (5c). Yellowish solid, mp >300 ꢀC. [Found: C,
55.71; H, 2.98; N, 10.21. C19H12BrN3O3 requires C, 55.63; H, 2.95; N,
10.24%]; nmax (KBr) 3228, 2924, 2853, 1692, 1600, 1497, 1288, 1238,
987, 841, 753 cmꢁ1
;
dH (200 MHz, DMSO-d6) 14.23 (s, 2H, OHþNH),
12.35 (s, 1H, OH), 8.16 (s, 1H, CH), 6.84e8.13 (m, 8H, Ar); dC
(100 MHz, DMSO-d6) 107.44, 114.71, 118.19, 119.98, 121.14, 121.89,
129.52, 131.19, 131.38, 132.35, 133.54, 137.21, 143.91, 151.94, 156.83,
158.55, 167.54. LS/MS: 410 (MHþ).
6.9. General procedure for the synthesis of 6-aryl-3-ethyl-2-
(4-fluorophenyl)-7-hydroxy-5-(2-hydroxyphenyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylic acids 9bed
6.7.4. 3-(4-Chlorophenyl)-6-(2-hydroxyphenyl)-pyrazolo[3,4-b]pyri-
dine-4-carboxylic acid (5d). Yellowish solid, mp >300 ꢀC. [Found: C,
62.42; H, 3.37; N, 11.47. C19H12ClN3O3 requires C, 62.39; H, 3.31; N
11.49%]; nmax (KBr) 3229, 2924, 2853, 1709, 1601, 1497, 1289, 1267,
5-Amino-4-ethyl-3-(4-fluorophenyl)-pyrazole 7 (0.73 mmol)
was dissolved in HOAc (2.5 ml), then the salicylaldehyde 2
(0.73 mmol) and appropriate arylpyruvic acid 8 (0.73 mmol) were
added. The mixture was put into the US-bath for 60 min. The
precipitate was filtered and dried under vacuum.
989, 841, 754 cmꢁ1
;
dH (200 MHz, DMSO-d6) 14.24 (s, 2H, OHþNH),
12.33 (s, 1H, OH), 8.17 (s, 1H, CH), 6.89e8.15 (m, 8H, Ar); dC
(100 MHz, DMSO-d6) 107.47, 114.60, 118.19, 119.98, 121.11, 128.47,
129.49, 130.88, 132.34, 133.17, 133.25, 137.48, 143.90, 151.93, 156.81,
158.57, 167.63. MS (Mass-FAB): 366 (MHþ).
6.10. Characterization data for compounds 9bed
6.10.1. 3-Ethyl-2-(4-fluorophenyl)-7-hydroxy-5-(2-hydroxyphenyl)-
6-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylic
acid (9b). Colorless solid, mp 146e147 ꢀC. [Found: C, 68.54; H, 5.15;
N, 8.89. C27H24FN3O4 requires C, 68.49; H, 5.11; N, 8.87%]; nmax (KBr)
6.7.5. 3-(4-Ethylphenyl)-6-(2-hydroxyphenyl)-pyrazolo[3,4-b]pyri-
dine-4-carboxylic acid (5e). Yellowish solid, mp >300 ꢀC. [Found: C,
70.25; H, 4.85; N, 11.68. C21H17N3O3 requires C, 70.18; H, 4.77; N,
11.69%]; nmax (KBr) 3247, 2924, 2854, 1715, 1601, 1460, 1277, 1237,
3410, 1712, 1635, 1591, 1457, 1352, 1231, 1146, 822, 750 cmꢁ1
; dH
992, 840, 746 cmꢁ1
;
dH (200 MHz, DMSO-d6) 14.12 (s, 2H, OHþNH),
(200 MHz, DMSO-d6) 13.06 (s, 1H, OH), 9.42 (s, 1H, OH), 6.59e7.54
(m, 13H, Ar), 6.26 (s, 1H, NH), 5.38 (d, J 11.8 Hz, 1H, CH), 2.34 (q, 2H, J
7.5 Hz, CH2CH3), 3.92 (d, J 11.8 Hz, 1H, CH), 0.96 (t, 3H, J 7.5 Hz,
CH2CH3); dC (150 MHz, DMSO-d6) 15.48, 15.69, 48.02, 51.81, 85.53,
98.01, 115.53, 115.66, 119.26, 126.97, 127.14, 127.55, 128.46, 129.32,
129.40, 130.76, 131.96 (d, 3J 3 Hz), 136.89, 144.55, 148.17, 155.84,
161.86 (d, 2J 240 Hz), 170.49. MS (Mass-FAB): 474.5 (MHþ).
12.51 (s,1H, OH), 8.12 (s,1H, CH), 6.91e8.11 (m, 8H, Ar), 2.66 (q, 2H, J
7.5 Hz, CH2CH3), 1.22 (t, 3H, J 7.5 Hz, CH2CH3); dC (100 MHz, DMSO-
d6) 15.94, 28.47,107.26,113.84,118.22,119.94,120.94,127.90,128.94,
129.40, 131.45, 132.32, 137.90, 144.06, 144.91, 151.81, 156.65, 158.70,
167.88. LS/MS: 360 (MHþ).
6.7.6. 7-Chloro-3-phenyl-6-(2-hydroxyphenyl)-pyrazolo[3,4-b]pyri-
dine-4-carboxylic acid (5f). Yellowish solid, mp >300 ꢀC. [Found: C,
62.42; H, 3.35; N, 11.51. C19H12ClN3O3 requires C, 62.39; H, 3.31; N,
11.49%]; nmax (KBr) 3308, 2922, 2853, 1715, 1595, 1475, 1275, 987,
6.10.2. 3-Ethyl-2-(4-fluorophenyl)-7-hydroxy-5-(2-hydroxyphenyl)-
6-(4-methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-
7-carboxylic acid (9c). Colorless solid, mp 143e144 ꢀC. [Found: C,
66.85; H, 5.29; N, 8.30. C28H26FN3O5 requires C, 66.79; H, 5.20; N,
8.35%]; nmax (KBr) 3391, 2933, 2717, 1599, 1515, 1460, 1349, 1250,
698 cmꢁ1
;
dH (200 MHz, DMSO-d6) 14.21 (s, 2H, OHþNH), 12.16 (s,
1H, OH), 8.21 (s, 1H, CH), 6.99e8.15 (m, 8H, Ar); dC (100 MHz,
DMSO-d6) 107.57, 114.97, 119.85, 123.39, 123.68, 128.49, 128.52,
128.97, 129.02, 131.60, 134.06, 137.56, 144.94, 152.17, 155.03, 156.99,
167.79. MS (Mass-FAB): 366 (MHþ).
1034, 845, 753 cmꢁ1
; dH (200 MHz, DMSO-d6) 12.95 (s, 1H, OH),
9.39 (s, 1H, OH), 6.59e7.54 (m, 12H, Ar), 6.26 (s, 1H, NH), 5.38 (d, J
11.8 Hz, 1H, CH), 2.34 (q, 2H, J 7.0 Hz, CH2CH3), 3.92 (d, J 11.8 Hz, 1H,
CH), 3.60 (s, 3H, CH3O), 0.96 (t, 3H, J 7.0 Hz, CH2CH3); dC (150 MHz,
DMSO-d6) 15.51, 15.61, 48.19, 51.89, 55.19, 85.53, 98.03, 113.01,
115.54, 115.68, 119.30, 126.98, 128.08, 128.42, 129.34, 129.39, 131.71,
131.99 (d, 3J 4 Hz), 144.57, 148.16, 155.86, 158.36, 161.88 (d, 2J
250 Hz), 170.57. MS (Mass-FAB): 504.5 (MHþ).
6.7.7. 3-(4-Chlorophenyl)-5-methoxy-6-(2-hydroxyphenyl)-pyrazolo
[3,4-b]pyridine-4-carboxylic acid (5g). Yellowish solid, mp >300 ꢀC.
[Found: C, 60.71; H, 3.59; N, 10.60. C20H14N3ClO4 requires C, 60.69;
H, 3.57; N, 10.62%]; nmax (KBr) 3302, 2924, 2852, 1706, 1601, 1454,
1245, 1050, 989, 853, 726 cmꢁ1
; dH (200 MHz, DMSO-d6) 14.27 (s,
2H, OHþNH), 12.05 (s, 1H, OH), 8.15 (s, 1H, CH), 6.85e7.70 (m, 7H,
Ar), 3.83 (s, 3H, CH3O); dC (100 MHz, DMSO-d6) 55.42, 107.36,
107.46, 114.35, 115.10, 119.32, 120.96, 121.33, 128.46, 130.90, 133.25,
137.04, 143.87, 148.50, 149.19, 158.93, 156.91, 167.54. MS (Mass-
FAB): 396 (MHþ).
6.10.3. 6-(4-Chlorophenyl)-3-ethyl-2-(4-fluorophenyl)-7-hydroxy-5-
(2-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-
carboxylic acid (9d). Colorless solid, mp 141e142 ꢀC. [Found: C,
63.89; H, 4.61; N, 8.23. C27H23FClN3O4 requires C, 63.84; H, 4.56; N,
8.27%]; nmax (KBr) 3393, 2931, 1643, 1598, 1459, 1346, 1238, 1160,
1092, 842, 754 cmꢁ1
; dH (200 MHz, DMSO-d6) 13.00 (s, 1H, OH),
6.8. General procedure for the synthesis of 3-ethyl-2-(4-
fluorophenyl)-7-hydroxy-5-(2-hydroxyphenyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylic acid 9a
9.45 (s, 1H, OH), 6.64e7.53 (m, 12H, Ar), 6.33 (s, 1H, NH), 5.38 (d, J
11.2 Hz, 1H, CH), 2.39 (q, 2H, J 7.1 Hz, CH2CH3), 3.94 (d, J 11.2 Hz, 1H,
CH), 0.96 (t, 3H, J 7.1 Hz, CH2CH3); dC (150 MHz, DMSO-d6) 15.50,
15.61, 46.77, 52.64, 85.30, 98.13, 115.57, 115.71, 119.40, 126.57,
127.59, 128.86, 129.36, 129.41, 131.91 (d, 3J 4 Hz), 131.98, 132.55,
135.24, 144.55, 148.26, 155.78, 161.91 (d, 2J 245 Hz), 170.38. MS
(Mass-FAB): 509 (MHþ).
5-Amino-4-ethyl-3-(4-fluorophenyl)-pyrazole 7 (0.73 mmol)
was dissolved in HOAc (2.5 ml), then the salicylaldehyde 2
(0.73 mmol) and pyruvic acid 3 (0.73 mmol) were added. The
Please cite this article in press as: Murlykina, M. V.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.08.055

8
M.V. Murlykina et al. / Tetrahedron xxx (2013) 1e9
6.11. General procedure for the synthesis of 2,6-diaryl-7-
hydroxy-5-(2-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-7-carboxylic acid derivatives 10aei
1094, 752 cmꢁ1
; dH (200 MHz, DMSO-d6) 13.06 (s, 1H, OH), 9.46 (s,
1H, OH), 6.60e7.69 (m, 12H, Ar), 6.72 (s, 1H, NH), 5.57 (s, 1H, CH),
5.38 (d, J 11.1 Hz, 1H, CH), 3.60 (s, 3H, CH3O), 3.94 (d, J 11.1 Hz, 1H,
CH); dC (150 MHz, DMSO-d6) 46.55, 51.82, 55.19, 82.19, 85.71, 113.14,
115.74, 119.44, 126.68, 127.21, 128.00, 128.66, 128.95, 129.52, 131.71,
132.26, 133.35, 147.93, 149.31, 155.87, 158.45, 170.57. MS (Mass-
FAB): 493 (MHþ).
5-Amino-3-arylpyrazole 1 (0.6 mmol) was dissolved in HOAc
(2.5 ml), then the salicylaldehyde 2 (0.6 mmol) and appropriate
arylpyruvic acid 8 (0.73 mmol) were added. The mixture was put
into the US-bath for 60 min. The precipitate was filtered and dried
under vacuum.
6.12.6. 2,6-Bis(4-chlorophenyl)-7-hydroxy-5-(2-hydroxyphenyl)-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylic
acid
6.12. Characterization data for compounds 10aei
(10f). Colorless solid, mp 154e155 ꢀC. [Found: C, 60.53; H, 3.88; N,
8.45. C25H19Cl2N3O4 requires C, 60.50; H, 3.86; N, 8.47%]; nmax (KBr)
6.12.1. 7-Hydroxy-5-(2-hydroxyphenyl)-2,6-diphenyl-4,5,6,7-
3373, 2924, 1608, 1459, 1340, 1093, 750 cmꢁ1
; dH (200 MHz, DMSO-
tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylic
acid
d6) 13.34 (s, 1H, OH), 9.52 (s, 1H, OH), 6.60e7.69 (m, 12H, Ar), 6.78
(s, 1H, NH), 5.59 (s, 1H, CH), 5.39 (d, J 11.0 Hz, 1H, CH), 3.97 (d, J
11.0 Hz, 1H, CH); dC (150 MHz, DMSO-d6) 46.20, 52.39, 82.20, 85.38,
115.64, 119.45, 126.22, 127.19, 127.67, 128.83, 128.92, 132.03, 132.20,
132.49, 133.26, 135.13, 147.83, 149.27, 155.72, 170.25. MS (Mass-
FAB): 497 (MHþ).
(10a). Colorless solid, mp 165e166 ꢀC. [Found: C, 70.29; H, 5.01; N,
9.81. C25H21N3O4 requires C, 70.25; H, 4.95; N, 9.83%]; nmax (KBr)
3357, 2924, 2704, 1602, 1458, 1339, 1258, 1141, 757, 696 cmꢁ1
; dH
(200 MHz, DMSO-d6) 13.37 (s, 1H, OH), 9.48 (s, 1H, OH), 6.60e7.66
(m, 14H, Ar), 6.68 (s, 1H, NH), 5.57 (s, 1H, CH), 5.43 (d, J 11.2 Hz, 1H,
CH), 4.02 (d, J 11.2 Hz, 1H, CH); dC (150 MHz, DMSO-d6) 46.72, 52.64,
82.12, 85.63, 115.70, 119.41, 125.55, 126.53, 127.27, 127.71, 127.88,
128.68, 128.93, 129.53, 130.77, 134.45, 136.22, 147.79, 150.45, 155.87,
170.58. MS (Mass-FAB): 428.5 (MHþ).
6.12.7. 2-(4-Ethylphenyl)-7-hydroxy-5-(2-hydroxyphenyl)-6-phenyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylic
acid
(10g). Colorless solid, mp 150e151 ꢀC. [Found: C, 71.25; H, 5.50; N,
9.25. C27H25N3O4 requires C, 71.19; H, 5.53; N, 9.22%]; nmax (KBr)
6.12.2. 7-Hydroxy-5-(2-hydroxyphenyl)-6-(4-methoxyphenyl)-2-
phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylic
acid (10b). Colorless solid, mp 155e156 ꢀC. [Found: C, 68.31; H,
5.11; N, 9.14. C26H23N3O5 requires C, 68.26; H, 5.07; N, 9.19%]; nmax
3371, 2926, 1624, 1491, 1458, 1325, 1237, 1140, 742, 698 cmꢁ1
; dH
(200 MHz, DMSO-d6) 13.37 (s, 1H, OH), 9.50 (s, 1H, OH), 6.62e7.59
(m, 13H, Ar), 6.68 (s, 1H, NH), 5.54 (s, 1H, CH), 5.45 (d, J 11.4 Hz, 1H,
CH), 4.02 (d, J 11.4 Hz, 1H, CH), 2.59 (q, 2H, J 7.5 Hz, CH2CH3), 1.17 (t,
3H, J 7.5 Hz, CH2CH3); dC (150 MHz, DMSO-d6) 16.03, 28.44, 46.53,
52.59, 81.92, 85.53, 115.65, 119.34, 125.54, 126.57, 127.19, 127.66,
128.24, 128.61, 128.82, 130.74, 131.97, 136.23, 143.29, 147.67, 150.43,
155.83, 170.55. MS (Mass-FAB): 456.5 (MHþ).
(KBr) 3389, 2932,1615,1515,1457,1348,1248,1178,1029, 754 cmꢁ1
;
dH (200 MHz, DMSO-d6) 12.75 (s, 1H, OH), 9.46 (s, 1H, OH),
6.61e7.81 (m, 13H, Ar), 6.68 (s, 1H, NH), 5.56 (s, 1H, CH), 5.39 (d, J
11.0 Hz, 1H, CH), 3.61 (s, 3H, CH3O), 3.99 (d, J 11.0 Hz, 1H, CH); dC
(150 MHz, DMSO-d6) 46.88, 51.84, 55.17, 82.02, 85.61, 113.10, 115.67,
119.37, 125.50, 126.73, 127.80, 128.06, 128.59, 128.88, 131.28, 131.67,
134.46, 147.76, 150.35, 155.84, 158.39, 170.59. MS (Mass-FAB): 458.5
(MHþ).
6.12.8. 2-(4-Ethylphenyl)-7-hydroxy-5-(2-hydroxyphenyl)-6-(4-
methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-
carboxylic acid (10h). Colorless solid, mp 138e139 ꢀC. [Found: C,
69.30; H, 5.66; N, 8.68. C28H27N3O5 requires C, 69.26; H, 5.61; N,
8.65%]; nmax (KBr) 3377, 2928, 1615, 1514, 1458, 1248, 1036, 843,
6.12.3. 6-(4-Chlorophenyl)-7-hydroxy-5-(2-hydroxyphenyl)-2-
phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylic
acid (10c). Colorless solid, mp 179e180 ꢀC. [Found: C, 65.10; H,
4.39; N, 9.12. C25H20ClN3O4 requires C, 65.01; H, 4.36; N, 9.10%];
nmax (KBr) 3372, 2925, 2707, 1607, 1493, 1459, 1345, 1145, 1092,
749 cmꢁ1
; dH (200 MHz, DMSO-d6) 12.82 (s, 1H, OH), 9.44 (s, 1H,
OH), 6.60e7.57 (m, 12H, Ar), 6.64 (s, 1H, NH), 5.51 (s, 1H, CH), 5.38
(d, J 11.4 Hz, 1H, CH), 3.60 (s, 3H, CH3O), 3.94 (d, J 11.4 Hz, 1H, CH),
2.59 (q, 2H, J 7.6 Hz, CH2CH3), 1.16 (t, 3H, J 7.6 Hz, CH2CH3); dC
(150 MHz, DMSO-d6) 16.03, 28.42, 46.75, 51.93, 55.19, 81.87, 85.57,
113.08, 115.64, 119.35, 125.51, 125.56, 126.77, 128.08, 128.23, 128.55,
131.66, 131.99, 143.26, 147.67, 150.38, 155.83, 158.37, 170.61. MS
(Mass-FAB): 486.5 (MHþ).
750 cmꢁ1
; dH (200 MHz, DMSO-d6) 13.20 (s, 1H, OH), 9.50 (s, 1H,
OH), 6.61e7.65 (m, 13H, Ar), 6.75 (s, 1H, NH), 5.57 (s, 1H, CH), 5.40
(d, J 11.9 Hz, 1H, CH), 4.01 (d, J 11.9 Hz, 1H, CH); dC (150 MHz, DMSO-
d6) 46.49, 52.67, 82.18, 85.39, 115.71, 119.49, 125.54, 126.27, 127.70,
127.88, 128.91, 129.50, 131.33, 132.07, 132.53, 134.39, 135.23, 147.74,
150.48, 155.78, 172.40. MS (Mass-FAB): 463 (MHþ).
6.12.9. 6-(4-Chlorophenyl)-2-(4-ethylphenyl)-7-hydroxy-5-(2-
hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-car-
boxylic acid (10i). Colorless solid, mp 162e163 ꢀC. [Found: C, 66.23;
H, 4.99; N, 8.57. C27H24ClN3O4 requires C, 66.19; H, 4.94; N, 8.58%];
6.12.4. 2-(4-Chlorophenyl)-7-hydroxy-5-(2-hydroxyphenyl)-6-
phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-carboxylic
acid (10d). Colorless solid, mp 137e138 ꢀC. [Found: C, 65.09; H,
4.41; N, 9.06. C25H20ClN3O4 requires C, 65.01; H, 4.36; N, 9.10%];
nmax (KBr) 3374, 2925, 2718, 1607, 1457, 1339, 1244, 1095, 836, 751,
nmax (KBr) 3372, 2926, 1623, 159, 1239, 745 cmꢁ1
; dH (200 MHz,
DMSO-d6) 12.94 (s,1H, OH), 9.49 (s,1H, OH), 6.60e7.58 (m,12H, Ar),
6.72 (s, 1H, NH), 5.53 (s, 1H, CH), 5.39 (d, J 10.6 Hz, 1H, CH), 4.00 (d, J
10.6 Hz, 1H, CH), 2.48 (q, 2H, J 7.5 Hz, CH2CH3), 0.97 (t, 3H, J 7.5 Hz,
CH2CH3); dC (150 MHz, DMSO-d6) 16.03, 28.42, 46.24, 52.44, 81.99,
85.32, 115.66, 119.44, 125.53, 126.31, 127.67, 128.24, 128.79, 131.32,
131.90, 132.02, 132.51, 135.24, 143.32, 147.63, 150.48, 155.74, 170.39.
MS (Mass-FAB): 491 (MHþ).
698 cmꢁ1
; dH (200 MHz, DMSO-d6) 12.99 (s, 1H, OH), 9.49 (s, 1H,
OH), 6.64e7.71 (m, 13H, Ar), 6.77 (s, 1H, NH), 5.62 (s, 1H, CH), 5.48
(d, J 11.4 Hz, 1H, CH), 4.05 (d, J 11.4 Hz, 1H, CH); dC (150 MHz, DMSO-
d6) 46.54, 52.51, 82.12, 85.60, 115.64, 119.34, 126.46, 127.18, 127.21,
127.67, 128.64, 128.91, 129.74, 130.71, 132.17, 133.31, 136.12, 147.86,
149.21, 155.81, 170.40. MS (Mass-FAB): 463 (MHþ).
6.13. Methodology of antimicrobial study
6.12.5. 2-(4-Chlorophenyl)-7-hydroxy-5-(2-hydroxyphenyl)-6-(4-
methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-7-
carboxylic acid (10e). Colorless solid, mp 142e143 ꢀC. [Found: C,
63.55; H, 4.59; N, 8.51. C26H22ClN3O5 requires C, 63.48; H, 4.51; N,
8.54%]; nmax (KBr) 3368, 2929, 2853, 1609, 1514, 1458, 1247, 1180,
Study of antimicrobial activity of the compounds was performed
in vitro by the method of two-fold serial dilutions in a liquid culture
medium (Hottinger Broth, at pH 7.2e7.4).17 For this purpose the
initial solution of the compound being studied with concentration
Please cite this article in press as: Murlykina, M. V.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.08.055

M.V. Murlykina et al. / Tetrahedron xxx (2013) 1e9
9
of 250
a serial two-fold dilution the compound concentrations of 125,
62.5, 31.25 etc. g/ml of the culture medium were obtained. Col-
m
g/ml of the culture medium was prepared. By means of
Dr. Elena Vashchenko for measuring some MS spectra, Dr. D.
Sofronov for recording IR spectra. Dr. D. Sysoiev thanks A. Friemel
(University of Konstanz, NMR Facility) for help with NMR
measurements.
m
lectable reference strains of bacteria were used as test cultures: B.
subtilis, S. aureus (Gram-positive cultures), E. coli (strain 1257) and
P. aeroginosa (Gram-negative cultures). Microbial load was pre-
pared according to optical turbidity standard and was 500,000
microbial cells in 1 ml of the daily culture of bacteria (0.5 according
to McFarland standard). Each experiment was performed in tripli-
cate. The tubes with a mixture were placed in a thermostat at 37 ꢀC
for 24 h, the tube with the ‘negative control’ containing no sub-
stance was placed in a refrigerator at 4 ꢀC. Accounting was per-
formed twice (in 24 h and in 48 h); the presence or absence of
growth was assessed visually. The minimum bacteriostatic con-
centration was defined as the lowest concentration of the com-
References and notes
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sence of any signs of growth on meat-extract agar in Petri plates.
Nitroxoline, the quinoline based drug, was used as a comparison
standard.
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6.14. X-ray diffraction data
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The colorless crystals of 4e C21H19N3O3$0.5C2H3N$0.5H2O are
ꢀ
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orthorhombic. At 100 K a¼13.840(1), b¼19.652(2), c¼28.254(4) A,
ꢁ
3
ꢀ
9. Svetlik, J.; Turecek, F.; Hanus, V. J. Chem. Soc., Perkin Trans. 1 1988, 2053.
V¼7685(2) A , Mr¼390.93, Z¼8, space group Pbca, dcalcd¼1.352 g/
10. Svetlik, J.; Veizerova, L. Helv. Chim. Acta 2011, 94, 199.
cm3,
m
(MoKa)¼0.093 mmꢁ1, F(000)¼3296. Intensities of 26,588
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2011, 54, 4234.
13. (a) Chebanov, V. A.; Sakhno, Y. I.; Desenko, S. M. Ultrason. Sonochem. 2012, 19,
707; (b) Sakhno, Y. I.; Desenko, S. M.; Shishkina, S. V.; Shishkin, O. V.; Mu-
satov, V. I.; Chebanov, V. A. Synthesis 2011, 1120; (c) Sakhno, Y. I.; Desenko, S.
M.; Shishkina, S. V.; Shishkin, O. V.; Sysoyev, D. O.; Croth, U.; Kappe, C. O.;
Chebanov, V. A. Tetrahedron 2008, 64, 11041; (d) Cebanov, V. A.; Sakhno, Y. I.;
Desenko, S. M.; Chernenko, V. N.; Musatov, V. I.; Shishkina, S. V.; Shishkin, O.
V.; Kappe, C. O. Tetrahedron 2007, 63, 1229; (e) Chebanov, V. A.; Sakhno, Y. I.;
Desenko, S. M.; Shishkina, S. V.; Musatov, V. I.; Shishkin, O. V.; Knyazeva, I. V.
Synthesis 2005, 15, 2597.
reflections (6761 independent, Rint¼0.1) were measured on the
‘Xcalibur-3’ diffractometer (graphite monochromated MoKa radia-
tion, CCD detector,
u
-scanning, 2Qmax¼50ꢀ). The structure was
solved by direct method using SHELXTL package.18 Positions of the
hydrogen atoms were located from electron density difference maps
and refined by ‘riding’ model with Uiso¼nUeq (n¼1.5 for methyl and
hydroxyl groups and n¼1.2 for other hydrogen atoms) of the carrier
atom. Full-matrix least-squares refinement against F2 in anisotropic
approximation for non-hydrogen atoms using 6709 reflections was
converged to wR2¼0.054 (R1¼0.043 for 3258 reflections with
F>4s
(F), S¼0.726). The final atomic coordinates and crystallo-
14. (a) Chebanov, V. A.; Saraev, V. E.; Shishkina, S. V.; Shishkin, O. V.; Musatov, V. I.;
Desenko, S. M. Eur. J. Org. Chem. 2012, 5515; (b) Muravyova, E. A.; Desenko, S. M.;
Rudenko, R. V.; Shishkina, S. V.; Shishkin, O. V.; Sen’ko, Y. V.; Vashchenko, E. V.;
Chebanov, V. A. Tetrahedron 2011, 67, 9389; (c) Sakhno, Y. I.; Shishkina, S. V.;
Shishkin, O. V.; Musatov, V. I.; Vashchenko, E. V.; Desenko, S. M.; Chebanov, V. A.
Mol. Diversity 2010, 14, 523.
graphic data for molecule 4e have been deposited to the Cambridge
Crystallographic Data Centre,12 Union Road, CB21EZ, UK (fax: þ44-
1223-336033; e-mail: deposit@ccdc.cam.ac.uk) and are available on
request quoting the deposition numbers CCDC 930676.
15. Busca, P.; Paradisi, F.; Moynihan, E.; Maguire, A. R.; Engel, P. V. Org. Biomol.
Chem. 2004, 15, 2684.
Acknowledgements
16. Henry, R. A.; Finnegan, W. G. J. Am. Chem. Soc. 1954, 76, 923.
17. Briger, M. O. Dictionary of Microbiological and Virological Methods; Medicine:
Moscow, 1982.
Prof. V. Chebanov was supported by DAAD scholarship. We
thank Dr. Vladimir Musatov for recording some 1H NMR spectra,
18. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
Please cite this article in press as: Murlykina, M. V.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.08.055