Controlled switching of multicomponent heterocyclizations of 5-amino-N-arylpyrazole-4-carboxamides, 1,3-cyclohexanediones, and aldehydes

Article abstract of DOI:10.1002/ejoc.201200669

Multicomponent heterocyclization of 5-amino-N-arylpyrazole-4-carboxamides, 1,3-cyclohexanediones, and aromatic aldehydes was studied, and reaction conditions allowing selective switching between two directions were found. When the reaction was carried out under thermal heating or ultrasonication at room temperature, formation of linear pyrazoloquinoline-3-carboxamides was observed. Isomeric angular heterocycles were obtained by ultrasonic-assisted synthesis at ambient temperature in the presence of HCl catalyst. Treatment with 2 equiv. of 1,3-diketone in boiling N,N-dimethylformamide/HCl gave a mixture of pyrazoloquinoline-3-carboxamides and unusual acridin-10-yl-pyrazole-4- carboxamides, which showed hindered rotation of the pyrazole fragment around the C-N bond.

Full text of DOI:10.1002/ejoc.201200669

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FULL PAPER
DOI: 10.1002/ejoc.201200669
Controlled Switching of Multicomponent Heterocyclizations of 5-Amino-N-
arylpyrazole-4-carboxamides, 1,3-Cyclohexanediones, and Aldehydes
Valentin A. Chebanov,*[a,b] Vyacheslav E. Saraev,[a] Svetlana V. Shishkina,[a]
Oleg V. Shishkin,[a,b] Vladimir I. Musatov,[a] and Sergey M. Desenko[a,b]
Keywords: Multicomponent reactions / Heterocycles / Chemoselectivity / Combinatorial chemistry / Synthetic methods
Multicomponent heterocyclization of 5-amino-N-arylpyraz-
ole-4-carboxamides, 1,3-cyclohexanediones, and aromatic
aldehydes was studied, and reaction conditions allowing se-
lective switching between two directions were found. When
the reaction was carried out under thermal heating or ultra-
heterocycles were obtained by ultrasonic-assisted synthesis
at ambient temperature in the presence of HCl catalyst.
Treatment with 2 equiv. of 1,3-diketone in boiling N,N-di-
methylformamide/HCl gave a mixture of pyrazoloquinoline-
3-carboxamides and unusual acridin-10-yl-pyrazole-4-carb-
sonication at room temperature, formation of linear pyrazolo- oxamides, which showed hindered rotation of the pyrazole
quinoline-3-carboxamides was observed. Isomeric angular
fragment around the C–N bond.
Introduction
Heterocycles containing a pyrazole ring are important
targets in synthetic and medicinal chemistry, because this
fragment is a key moiety in numerous biologically active
compounds such as Allopurinol (I), Viagra (II), Zaleplon
(III), Celebrex (IV) (Figure 1), and others.[1] Therefore, the
chemistry of a range of aminopyrazoles, as promising build-
ing blocks in preparative organic chemistry for the synthesis
of fused heterocycles containing the pyrazole core, has been
extensively investigated for a long time. The scope and
limitations of this chemistry has been reported in several
reviews[2] covering, in detail, the general pattern of reactiv-
ity of 3(5)-aminopyrazoles, 4-aminopyrazoles, 1-aminopyr-
azoles, and some diaminopyrazoles in two- and multicom-
ponent reactions.
Figure 1. Some examples of pyrazole-containing biologically active
compounds.
3(5)-Aminopyrazoles are the most attractive starting
points for the study of multicomponent heterocyclizations
from several viewpoints. First, there are a number of pos-
sible ways to introduce different substituents in the pyrazole
ring,[2a] which allows the combinatorial potential of such
building blocks to be increased. Secondly, the presence of
several non-equivalent nucleophilic reaction centers in these
compounds can cause additional variability of the direc-
tions of their multicomponent reactions, which gives an op-
portunity to enlarge molecular diversity of the final hetero-
cycles. However, this second feature only becomes an ad-
vantage when suitable methodologies are available that al-
low selective switching of the reaction from one direction
to another, otherwise, two or more pathways may proceed
simultaneously to generate complex mixtures of final com-
pounds.[3]
The development of methods for tuning the selectivity of
multicomponent reactions involving 3(5)-aminopyrazoles
was illustrated in several resent publications by their hetero-
cyclizations with triethyl orthoesters and p-substituted
benzoylacetonitriles,[4] or with aldehydes and cyclopentan-
one,[5] acetoacetamides,[6a] pyruvic acids,[6b–6d] 1,3-cyclo-
hexanediones,[6e–6g] or barbituric acids.[6h] In most of these
articles, nonclassical activation methods such as microwave
and ultrasonic irradiation together with different types of
catalysts and reaction media were required.
[a] Division of Functional Materials Chemistry, SSI “Institute for
Single Crystals” NAS of Ukraine,
Lenin Ave. 60, Kharkiv 61001, Ukraine
Fax: +38-057-341-02-73
E-mail: chebanov@isc.kharkov.com
Homepage: http://chem.isc.kharkov.com/
[b] Faculty of Chemistry, V.N. Karazin Kharkiv National
University,
Multicomponent heterocyclizations of 5-aminopyrazole-
4-carboxamides may also proceed in several alternative di-
rections; the formation of the new heterocycle ring can in-
Svobody sq. 4, Kharkiv 61077, Ukraine
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FULL PAPER
volve the participation of pyrazole NH2 and endocyclic NH Table 1. Synthesis of compounds 4, 5, and 7.
(structure V, Figure 2),[6a–6c,7] pyrazole NH2 and carbox-
Aminopyrazole
R
Aldehyde
R1
Diketone
Product
Yield [%]
amide NH2 (structure VI),[8] or only pyrazole NH2 (struc-
ture VII).[6b]
R2
1a
1a
1a
1a
Ph
Ph
Ph
Ph
2c
4-CH3C6H4
3a
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
79[a]
85[a]
2b 4-CH3OC6H4 3a
2d 4-ClC6H4 3a
2e 4-CO2HC6H4 3a
71[a]
71[a]
1b 4-MeC6H4 2a
1b 4-MeC6H4 2c
1b 4-MeC6H4 2b
1b 4-MeC6H4 2d
Ph
3a
3a
3a
3a
86[a]
4-MeC6H4
4-MeOC6H4
4-ClC6H4
87[a]
78[a]
92[a]
Figure 2. Possible reaction products of heterocyclizations of 5-ami-
nopyrazole-4-carboxamides.
1b 4-MeC6H4 2e 4-CO2HC6H4 3a
65[a]
1c 4-ClC6H4
1c 4-ClC6H4
1c 4-ClC6H4
1c 4-ClC6H4
1c 4-ClC6H4
2a
2c
2b
2d
Ph
3a
3a
3a
3a
4j
4k
4l
89[a]
4-MeC6H4
4-MeOC6H4
4-ClC6H4
90[a]
There is also an additional possibility of the formation
of position isomers for each of these structures, which in-
creases the challenge of generating 5-aminopyrazole-4-
carboxamides selectively in multicomponent reactions. In
the present article we disclose our efforts to selectively
switch the course of multicomponent reactions with 5-
59[a]
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
5a
5b
5c
5d
5e
5f
64[a]
2e 4-CO2HC6H4 3a
78[a]
1a
1a
1a
Ph
Ph
Ph
2a
2c
2d
Ph
3b
3b
3b
3b
3b
3b
3b
3b
3b
3a
3a
3a
3a
3a
3a
3a
3a
69[a]
4-MeC6H4
4-ClC6H4
Ph
4-MeC6H4
4-ClC6H4
Ph
4-MeC6H4
4-ClC6H4
Ph
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
H
H
H
H
79[a]
89[a]
1b 4-MeC6H4 2a
1b 4-MeC6H4 2c
1b 4-MeC6H4 2d
1c 4-ClC6H4
1c 4-ClC6H4
1c 4-ClC6H4
79[a]
91[a]
amino-N-arylpyrazole-4-carboxamides,
1,3-cyclohexane-
H
H
H
H
90[a]
diones, and aromatic aldehydes by means of variation of
the reaction conditions through the application of ultra-
sonication.
2a
2c
2d
70[a]
75[a]
63[a]
1b 4-MeC6H4 2a
Me
Me
Me
Me
Me
Me
Me
Me
68[b],[c]
71[b],[c]
63[b],[c]
65[b],[c]
78[b],[c]
75[b],[c]
35[c]
1a
1a
Ph
Ph
2c
2d
Results and Discussion
As anticipated, on the basis of earlier results with other
aminoazoles,[3a,3b] the three-component reaction of 5-
amino-N-arylpyrazole-4-carboxamides 1a–c, aromatic alde-
hydes 2a–e, and 1,3-cyclohexanediones 3a and 3b in boiling
N,N-dimethylformamide (DMF) for 15 min led to the isola-
tion of pyrazoloquinoline-3-carboxamides 4a–w in 59–92%
1b 4-MeC6H4 2d
1b 4-MeC6H4 2f
1b 4-MeC6H4 2c
1b 4-MeC6H4 2d
1b 4-MeC6H4 2b
7a
7b
30[c]
[a] Reaction in boiling DMF. [b] Reaction in DMF/HCl under
yields (Scheme 1, Table 1). The same results were found ultrasonication. [c] 2 equiv. of dimedone were used.
Scheme 1. Three-component reaction of 5-amino-N-arylpyrazole-4-carboxamides, 1,3-cyclohexanediones, and aromatic aldehydes.
2
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Controlled Switching of Multicomponent Heterocyclizations
when the heterocyclization was carried out in acetic acid or homogenization of the reaction mixture under ultra-
DMF at room temperature under ultrasonication, although sonication in comparison with mechanical stirring.
some previously published articles[6a,6b,6e,6h] had given
Switching the direction of this multicomponent heterocy-
grounds to expect, in this case, the formation of another clization may arise as a result of the influence of acid cata-
type of final product. lyst and temperature regime on the stability of azomethines
Nevertheless, the direction of this multicomponent reac- 6, which are anticipated to be intermediates in the reaction
tion was changed by additional application of acid catalysis; leading to compounds 5.[6a–6c] Indeed, it was established
the treatment of aminopyrazoles 1a,b, aldehydes 2a,c,d,f, that treatment of compounds 6a–d with 1,3-diketone 3a at
and dimedone 3a in either EtOH or DMF containing cata- room temperature under ultrasonic irradiation in the pres-
lytic amounts of HCl under ultrasonic irradiation at ambi- ence of HCl yielded heterocycles 5a–d, whereas boiling the
ent temperature, gave exclusively the position isomeric pyr- same starting materials in pure DMF or ultrasonicating
azoloquinoline-3-carboxamide 5a–f (63–78%). The yields them in pure DMF or AcOH always led to decomposition
of the heterocyclizations were slightly higher in ethanol, of the azomethines and isolation of pyrazoloquinolines
whereas the purity of the final compounds (TLC, HPLC 4a,c,e,h. The latter compounds were also obtained, in all
and NMR analysis) was higher in DMF. In both cases, after cases, in the presence of triethylamine.
isolation of pyrazoloquinolines 5, which was further char-
Another unusual result was found when aminopyrazole
acterized by chromatography without additional purifica- 1b, aldehyde 2b,d, and dimedone 3a were treated in a 1:1:2
tion, insignificant amounts of compounds 4, 6, and 9 were ratio in boiling DMF containing a catalytic amount of HCl
found in the mother liquor.
(Scheme 2). In this case, a precipitate was isolated that con-
It is worth noting that there are only a few publications tained two visually different types of crystals, which were
concerning multicomponent reactions of aminoazoles, alde- separated mechanically with the help of an optical micro-
hydes, and cyclic active methylene compounds in which the scope. The first type of compound was identified without
aldehyde component reacts with the exocyclic NH2 instead additional purification as pyrazoloquinoline-3-carboxamide
of the endocyclic nucleophilic centers. For example, such a 4g,h (40–50%), whereas the second was first crystallized
cyclization of 3-amino-1,2,4-triazole and cyclohexanone from EtOH/H2O (2:3), which allowed the structure of
was previously described[9a] and, recently, was also reported 5-(1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10-yl)-pyr-
the condensation of aminopyrazoles, aldehydes, and some azole-4-carboxamides 7a,b to be assigned. The yields of
cyclic ketones.[9b,9c] However, in most cases, the formation these reaction products were in the 30–35% range.
of angular-type azoloazines such as 5 was observed as side
Thus, 5-amino-N-arylpyrazole-4-carboxamide, being a
reactions in low yields[10] or the reaction involved triethyl typical 1,3-binucleophile with high reactivity of both pyr-
orthoesters,[4] DMF,[11] or DMF/DMA[12] instead of alde- azole NH2 and endocyclic NH reaction centers, in this case
hyde.
plays the role of a primary amine. Unfortunately, attempts
All the heterocyclization reactions mentioned above were to elaborate a preparative multicomponent procedure for
also carried out under standard magnetic stirring instead of the selective synthesis of 7 were unsuccessful; conventional
in an ultrasonic bath. However, under these conditions the thermal or microwave heating at a wide range of tempera-
reaction proceeded with a significant decrease in both the tures or ultrasonication carried out in numerous solvents
yield and the purity of the final compounds, and required (primary alcohols, DMF, HOAc) led to mixtures of several
an increase in the reaction time (up to 24 h). This result is products including heterocycles 4, 7, and 9. A sequential
connected, in our opinion, with better mass transfer and approach involving preliminary production of Michael ad-
Scheme 2. Third direction of the multicomponent heterocyclization.
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duct 8[13] and its further treatment with aminopyrazole 1a C3–C8–C9-C13 and C8–C9–C13–C18 torsion angles are
also yielded pyrazoloquinoline 4 as the main product and –92.4(2)° and 32.9(3)°, respectively]. The formation of the
xanthenedione 9 as a minor product.
N4-H···O1Ј (0.5 + x, 0.5 – y, –0.5 + z) intermolecular hy-
All the compounds synthesized were identified with the drogen bond leads to an elongation of the N4–C19
help of elemental analysis, mass spectrometry, NMR spec- [1.364(3) Å] and O1–C7 [1.234(2) Å] bonds compared to
troscopy and X-ray diffraction analysis.
their mean values[15] (1.334 and 1.210 Å, respectively).
1
The H NMR spectra of heterocycles 4 showed the fol-
The 1H NMR spectra of acridinediones 7 exhibited sing-
lowing signals: singlets for cyclohexanone methyl groups at lets for four CH3 groups (δ = 0.7 and 0.8 ppm), multiplets
δ = 0.9 and 1.0 ppm (compounds 4a–n), four doublet sig- for the CH2 groups of the cyclohexanone rings (δ = 1.7–
nals (J ≈ 16 Hz) for two CH2 groups (compounds 4a–n), or 2.4 ppm), singlets for 9-CH (δ ≈ 4.9 ppm), pyrazole CH (δ
several multiplet signals for three CH2 groups (compounds ≈ 8.6 ppm), pyrazole NH (δ ≈ 10.0 ppm), and carboxamide
4o–w), singlets for CH of the pyrimidine ring (δ = 6.1– NH (δ ≈ 13.5 ppm). Signals arising from the aromatic rings
6.2 ppm) and of the pyrazole ring (δ = 8.0–8.1 ppm), a (δ = 6.5–7.7 ppm) and other substituents were also found
broad signal at δ = 9.7–9.8 ppm for both pyrimidine and at the appropriate positions.
carboxamide NH, signals of aromatic fragments within
range of δ = 6.6–7.9 ppm as well as all necessary signals of heterocycles 7 measured at 20 °C revealed a doubling of all
However, detailed analysis of the 1H NMR spectra of
the other terminal substituents.
the signals and further complication of the multiplets from
The 1H NMR spectra of angular quinozalines 5, in com- the aromatic rings. Such spectral characteristics may indi-
parison with the spectra of linear heterocycles 4, showed cate the occurrence of hindered rotation of one of the sub-
shifts of some signals. In particular, downfield shifts of the stituents and the appearance of axial chirality. This assump-
1
signals of all protons of the cyclohexanone moiety (by 0.1– tion was confirmed by temperature-dependence H NMR
0.2 ppm) and upfield shifts of the signals of the pyrimidine experiments that showed that increasing the temperature
CH and NH protons (by 0.6 and 1.5 ppm, respectively), from 20 to 150 °C led to averaging of the doubled signals
1
were found. A clear dependence of the H NMR chemical right up to their complete convergence (Figure 4).
shift of this NH proton on the structure of the azoloazine
skeleton was previously described in several publications.[13]
Additionally, it is worth noting that the pyrimidine CH and
NH moieties appeared in the spectra as doublets (J = 2.3–
2.5 Hz) and showed cross-peaks in COSY and NOESY ex-
periments.
The structure of heterocycles 5 was unequivocally estab-
lished by X-ray diffraction analysis of a single crystal of
compound 5c (Figure 3). It was found that the dihydropyr-
imidine and cyclohexenone rings of the tricyclic fragment
adopt a distorted sofa conformation. The puckering param-
eters[14] are S = 0.46, Θ = 54.6°, Ψ = 11.7° for the dihy-
Figure 4. Dependence of the 1H NMR spectra of compound 7a on
the temperature.
dropyrimidine ring and S = 0.71, Θ = 41.9°, Ψ = 9.5° for
the cyclohexenone ring. The chlorophenyl substituent is al-
most orthogonal to the plane of the partially saturated het-
erocycle and is turned relatively to the C8–C9 bond [the
In our opinion, such rotamerism is due to restricted rota-
tion of the whole pyrazole fragment around the C–N bond
(Figure 5), as previously described for N-aryl-substituted
acridinediones.[16]
Figure 5. Hindered rotation of the pyrazolyl substituent around the
C–N bond.
Conclusions
The direction of multicomponent heterocyclization of 5-
Figure 3. Molecular structure of compound 5c according to X-ray
diffraction data.
amino-N-arylpyrazole-4-carboxamides,
1,3-cyclohexane-
4
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Controlled Switching of Multicomponent Heterocyclizations
cated from electron density difference maps and refined by the “ri-
ding” model with Uiso = nUeq of the carrier atom (n = 1.5 for
methyl groups and n = 1.2 for other hydrogen atoms). Full-matrix
least-squares refinement against F2 in anisotropic approximation
for non-hydrogen atoms using 3763 reflections converged to wR2
= 0.096 [R1 = 0.040 for 1917 reflections with F Ͼ 4σ(F), S = 0.856].
CCDC-871752 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
diones, and aromatic aldehydes can be efficiently controlled
by changing the reaction parameters. Treatment of the
starting materials under neutral conditions or in the pres-
ence of Et3N in boiling DMF or with the help of ultra-
sonication in AcOH at room temperature yields N,9-diaryl-
8-oxo-4,5,6,7,8,9-hexahydropyrazolo[5,1-b]quinazoline-3-
carboxamides 4. In the case of ultrasonic-assisted reactions
at room temperature, addition of HCl switches the direction
towards formation of the position-isomeric N,5-diaryl-6-
oxo-4,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinazoline-3-
carboxamide 5. Change of selectivity of the heterocycli-
zation depends on the stability of azomethines 6 as the in-
termediates of the last reaction.
The third direction of the multicomponent cyclization
with formation of 5-(1,8-dioxo-1,2,3,4,5,6,7,8-octahydro-
acridin-10-yl)pyrazole-4-carboxamides 7 is observed as a
side process when 2 equiv. of dimedone react with 1 equiv.
of 5-amino-N-arylpyrazole-4-carboxamides and 1 equiv. of
aromatic aldehyde in boiling DMF in the presence of cata-
lytic amounts of HCl. The acridinediones obtained display
hindered rotation of the pyrazole moiety around the C–N
bond and exhibit axial chirality.
Typical Procedure for the Thermal Synthesis of 6,6-Dimethyl-8-oxo-
N-phenyl-9-p-tolyl-4,5,6,7,8,9-hexahydropyrazolo[5,1-b]quinazol-
ine-3-carboxamide (4a): A mixture containing 5-amino-N-phenyl-
1H-pyrazolo-4-carboxamide (1a; 0.3 g, 1.5 mmol), 4-methylbenz-
aldehyde (2c; 0.18 g, 1.5 mmol), and 5,5-dimethylcyclohexane-1,3-
dione (3a; 0.21 g, 1.5 mmol) in DMF (2 mL) was heated to reflux
for 15 min. After cooling to ca. 50 °C, an EtOH/H2O (1:1, 4 mL)
mixture was added, and the precipitate formed was filtered, washed
with ethanol, and air-dried. Yield: 0.51 g (79%); m.p. 259–261 °C.
1H NMR ([D6]DMSO, 200 MHz): δ = 0.91 (s, 3 H, CH3), 1.02 (s,
3 H, CH3), 2.06 (d, J = 16.2 Hz, 1 H, CH2), 2.20 (s, 3 H, CH3),
2.21 (d, J = 16.2 Hz, 1 H, CH2), 2.64 (d, J = 17.2 Hz, 1 H, CH2),
2.76 (d, J = 17.2 Hz, 1 H, CH2), 6.12 (s, 1 H, 9-CH), 6.92–7.78 (m,
9 H, ArH), 8.05 (s, 1 H, pyrazole CH), 9.77 (br. s, 1 H, NH), 9.79
(br. s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ = 21.12,
27.21, 29.25, 32.67, 50.34, 57.74, 100.26, 106.67, 120.48, 123.76,
127.20, 129.1, 129.24, 137.26, 138.65, 139.49, 139.81, 139.86,
149.63, 161.59, 193.52 ppm. MS (EI, 70 eV): m/z (%) = 427 (32)
[M+], 426 (37), 425 (19), 336 (13), 335 (36), 334 (59), 333 (87), 332
(78), 306 (81), 305 (79), 304 (19), 250 (34), 249 (43), 248 (18), 243
(16), 242 (100), 241 (59), 186 (20), 185 (23), 157 (16), 149 (25), 148
(24), 115 (15). C26H26N4O2 (426.52): calcd. C 73.22, H 6.14, N
13.14; found C 73.01, H 6.12, N 13.09.
Experimental Section
General: The melting points of all compounds synthesized were
determined with a Gallenkamp melting point apparatus. NMR
spectra were recorded in [D6]DMSO at 500 MHz (125 MHz for
13C) or at 200 MHz (50 MHz for 13C) with Bruker Avance and
Varian Mercury VX-200 spectrometers. Chemical shifts (δ) are
given in ppm relative to TMS as internal standard. Mass spectra
were measured with a GC–MS Varian 1200L (ionizing voltage
70 eV) instrument using direct input of compounds. Elemental
analyses were determined with a EuroVector EA-3000. Analytical
HPLC analysis was carried out with a Bischoff module chromato-
graph on a C18 reversed-phase analytical column (119ϫ3 mm,
particle size 5 mm) or a reversed-phase column (150ϫ4.6 mm, par-
ticle size 5 mm) at 25 °C using a mobile phase A [water/acetonitrile,
90:10 (v/v) + 0.1% TFA] and B (MeCN + 0.1% TFA) at a flow
rate of 1.0 mL/min. The following gradient was applied: linear in-
crease from solution 30% B to 100% B in 8 min, hold at 100%
solution B for 7 min. TLC analyses were performed on pre-coated
(silica gel 60 HF254) plates. Ultrasonication was carried out with a
standard ultrasonic bath operating at 44.2 kHz. Microwave experi-
ments were performed with an Emrys Creator EXP from Biotage
Typical Procedure for the Ultrasonic-Assisted Synthesis of 6,6-Di-
methyl-8-oxo-N-phenyl-9-p-tolyl-4,5,6,7,8,9-hexahydropyrazolo-
[5,1-b]quinazoline-3-carboxamide (4a): A mixture containing 5-
amino-N-phenyl-1H-pyrazolo-4-carboxamide (1a; 0.3 g,
1.5 mmol), 4-methylbenzaldehyde (2c; 0.18 g, 1.5 mmol) and 5,5-
dimethylcyclohexane-1,3-dione (3a; 0.21 g, 1.5 mmol) was ultra-
sonicated in AcOH (2 mL) for 45 min. After cooling, an EtOH/
H2O (1:1, 4 mL) mixture was added, and the precipitate formed
was filtered, washed with ethanol, and air-dried.
9-(p-Methoxyphenyl)-6,6-dimethyl-8-oxo-N-phenyl-4,5,6,7,8,9-hexa-
hydropyrazolo[5,1-b]quinazoline-3-carboxamide (4b): Yield: 85%;
1
m.p. 165–167 °C. H NMR ([D6]DMSO, 200 MHz): δ = 0.93 (s, 3
H, CH3), 1.02 (s, 3 H, CH3), 2.05 (d, J = 16.3 Hz, 1 H, CH2), 2.21
(d, J = 16.3 Hz, 1 H, CH2), 2.63 (d, J = 17.4 Hz, 1 H, CH2), 2.77
(d, J = 17.4 Hz, 1 H, CH2), 3.67 (s, 3 H, OCH3), 6.12 (s, 1 H, CH-
9), 6.63–7.86 (m, 9 H, ArH), 8.06 (s, 1 H, CH), 9.75 (s, 1 H, NH),
9.78 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ =
27.25, 29.25, 32.61, 50.35, 55.53, 57.44, 100.23, 106.71, 114.06,
120.48, 123.76, 128.48, 129.09, 134.95, 138.62, 139.49, 139.76,
149.57, 159.11, 161.61, 193.56 ppm. MS (EI, 70 eV): m/z (%) = 442
(10) [M], 350 (22), 349 (66), 348 (39), 322 (34), 321 (56), 320 (21),
266 (17), 242 (46), 241 (43), 186 (14), 148 (220), 122 (15), 111 (27),
96 (46), 94 (20), 92 (19), 91 (24), 83 (100), 79 (40), 77 (40), 65 (19),
64 (29), 60 (14), 57 (49). C26H26N4O3 (442.52): calcd. C 70.57, H
5.92, N 12.66; found C 70.31, H 5.90, N 12.61.
AB (Uppsala, Sweden) in
a single-mode microwave cavity
(2.45 GHz). Solvents, 1,3-cyclohexanediones and aromatic alde-
hydes were commercially available and used without additional pu-
rification. Aminopyrazoles 1a–c were obtained by a known meth-
od,[6b] azomethines 6a–d were obtained from the corresponding
aminoazoles and aldehydes.[17]
X-ray Diffraction Data: Colorless crystals of 5c (C25H23N4O2Cl);
monoclinic; 293 K; a = 8.926(5), b = 21.999(5), c = 11.413(5) Å, β
= 100.629(5)°; V = 2203(2) Å3; M = 446.92; Z = 4; space group
P21/n; dcalcd. = 1.348 g/cm3; μ(Mo-Kα) = 0.204 mm–1; F(000) = 936.
Intensities of 11649 reflections (3800 independent, Rint = 0.041)
were measured with an Xcalibur-3 diffractometer (graphite-mono-
9-(p-Chlorophenyl)-6,6-dimethyl-8-oxo-N-phenyl-4,5,6,7,8,9-hexa-
hydropyrazolo[5,1-b]quinazoline-3-carboxamide (4c): Yield: 71%;
chromated Mo-Kα radiation, CCD detector, ω-scaning, 2θmax
=
1
50°). The structure was solved by direct methods using the
m.p. 251–253 °C. H NMR ([D6]DMSO, 200 MHz): δ = 0.91 (s, 3
SHELXTL package.[18] Positions of the hydrogen atoms were lo-
H, CH3), 1.02 (s, 3 H, CH3), 2.07 (d, J = 16.2 Hz, 1 H, CH2), 2.21
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20669
/KAP1
Date: 14-08-12 16:29:36
Pages: 11
V. A. Chebanov et al.
FULL PAPER
(d, J = 16.2 Hz, 1 H, CH2), 2.64 (d, J = 17.2 Hz, 1 H, CH2), 2.76
(d, J = 17.2 Hz, 1 H, CH2), 6.18 (s, 1 H, CH-9), 6.95–7.83 (m, 9
H, ArH), 8.09 (s, 1 H, CH), 9.81 (s, 1 H, NH), 9.85 (s, 1 H,
NH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ = 27.31, 29.11,
32.65, 50.28, 57.44, 100.40, 106.10, 120.5, 123.82, 128.75, 129.11,
(s, 3 H, CH3), 2.61 (d, J = 17.6 Hz, 1 H, CH2), 2.75 (d, J = 17.6 Hz,
1 H, CH2), 3.67 (s, 3 H, OCH3), 6.11 (s, 1 H, CH-9), 6.94–7.22 (m,
4 H, ArH), 6.75 (d, J = 8.4 Hz, 2 H, ArH), 7.52 (d, J = 8.4 Hz, 2
H, ArH), 8.03 (s, 1 H, CH), 9.70 (br. s, 2 H, HNH) ppm. 13C NMR
([D6]DMSO, 125 MHz): δ = 20.95, 27.27, 29.24, 32.62, 50.36,
129.18, 132.63, 138.92, 139.43, 139.77, 141.60, 149.97, 161.48, 55.54, 57.41, 100.26, 106.66, 114.06, 120.53, 128.45, 129.49, 132.69,
193.60 ppm. MS (EI, 70 eV): m/z (%) = 446 (9) [M], 355 (22), 354 134.96, 136.91, 138.55, 139.68, 149.59, 159.10, 161.44, 193.54 ppm.
(47), 327 (20), 326 (37), 270 (14), 242 (60), 241 (55), 149 (35), 112
MS (EI, 70 eV): m/z (%) = 456 (9) [M], 350 (22), 349 (28), 348 (11),
(22), 111 (26), 110 (15), 94 (42), 93 (95), 92 (45), 90 (14), 83 (24), 322 (12), 321 (20), 320 (13), 242 (23), 108 (24), 107 (80), 106 (100),
77 (34), 74 (16), 71 (14), 67 (29), 66 (45), 65 (28), 57 (58), 56 (34), 105 (64), 92 (14), 91 (14), 83 (32), 82 (26), 79 (15), 78 (20), 77 (31).
55 (53), 54 (100). C25H23ClN4O2 (446.94): calcd. C 67.18, H 5.19, C27H28N4O3 (456.54): calcd. C 71.03, H 6.18, N 12.27; found C
Cl 7.93, N 12.54; found C 66.89, H 5.17, Cl 7.95, N 12.49.
70.73, H 6.16, N 12.22.
9-(4-Chlorophenyl)-6,6-dimethyl-8-oxo-N-(p-tolyl)-4,5,6,7,8,9-
hexahydropyrazolo[5,1-b]quinazoline-3-carboxamide (4h): Yield:
92%; m.p. 284–286 °C. 1H NMR ([D6]DMSO, 200 MHz): δ = 0.90
(s, 3 H, CH3), 1.01 (s, 3 H, CH3), 1.92–2.36 (m, 2 H, CH2), 2.24
(s, 3 H, CH3), 2.63 (d, J = 17.6 Hz, 1 H, CH2), 2.75 (d, J = 17.6 Hz,
1 H, CH2), 6.17 (s, 1 H, CH-9), 6.96–7.75 (m, 8 H, ArH), 8.06 (s,
1 H, CH), 9.74 (s, 1 H, NH), 9.84 (s, 1 H, NH) ppm. 13C NMR ([D6]-
DMSO, 125 MHz): δ = 20.95, 27.31, 29.11, 32.65, 50.28, 57.42,
100.44, 106.07, 120.56, 128.74, 129.16, 129.50, 132.61, 132.75,
136.86, 138.84, 139.70, 141.62, 149.97, 161.32, 193.58 ppm. MS
(EI, 70 eV): m/z (%) = 461 (6) [M+], 461 (19) [M], 356 (14), 355
(27), 354 (41), 353 (67), 327 (17), 326 (39), 325 (17), 270 (26), 243
(16), 242 (100), 186 (14), 107 (19), 106 (42). C26H25N4O2 (425.51):
calcd. C 67.75, H 5.47, Cl 7.69, N 12.15; found C 67.49, H 5.45,
Cl 7.71, N 12.11.
9-(p-Carboxyphenyl)-6,6-dimethyl-8-oxo-N-phenyl-4,5,6,7,8,9-
hexahydropyrazolo[5,1-b]quinazoline-3-carboxamide (4d): Yield:
71%; m.p. 305–307 °C. 1H NMR ([D6]DMSO, 200 MHz): δ = 0.89
(s, 3 H, CH3), 1.01 (s, 3 H, CH3), 2.05 (d, J = 16.1 Hz, 1 H, CH2),
2.21 (d, J = 16.1 Hz, 1 H, CH2), 2.64 (d, J = 17.3 Hz, 1 H, CH2),
2.76 (d, J = 17.3 Hz, 1 H, CH2), 6.24 (s, 1 H, CH-9), 6.91–7.90 (m,
9 H, ArH), 8.08 (s, 1 H, CH), 9.83 (s, 1 H, NH), 9.89 (br. s, 1
H, NH), 12.93 (br. s, 1 H, COOH) ppm. 13C NMR ([D6]DMSO,
125 MHz): δ = 27.22, 29.13, 32.64, 50.27, 57.83, 100.45, 106.07,
120.51, 123.82, 127.53, 129.10, 129.86, 130.60, 138.96, 139.43,
139.85, 147.15, 150.06, 161.50, 167.45, 193.58 ppm. MS (EI,
70 eV): m/z (%) = 456 (10) [M], 364 (27), 363 (34), 336 (22), 335
(19), 243 (16), 242 (100), 186 (23), 158 (16), 149 (14), 129 (29), 128
(12), 127 (19), 115 (27), 111 (17), 110 (43), 107 (34), 106 (19), 105
(14), 104 (13), 103 (13), 101 (13), 98 (16), 97 (28), 96 (17), 95 (16),
94 (26), 93 (88), 91 (22). C26H24N4O4 (456.50): calcd. C 68.41, H
5.30, N 12.27; found C 67.18, H 5.28, N 12.23.
9-(4-Carboxyphenyl)-6,6-dimethyl-8-oxo-N-(p-tolyl)-4,5,6,7,8,9-hexa-
hydropyrazolo[5,1-b]quinazoline-3-carboxamide (4i): Yield: 65%;
1
m.p. Ͼ310 °C. H NMR ([D6]DMSO, 200 MHz): δ = 0.89 (s, 3 H,
6,6-Dimethyl-8-oxo-9-phenyl-N-p-tolyl-4,5,6,7,8,9-hexahydropyr-
azolo[5,1-b]quinazoline-3-carboxamide (4e): Yield: 86%; m.p. 245–
CH3), 1.01 (s, 3 H, CH3), 1.95–2.33 (m, 2 H, CH2), 2.24 (s, 3 H,
CH3), 2.63 (d, J = 17.5 Hz, 1 H, CH2), 2.75 (d, J = 17.5 Hz, 1 H,
CH2), 6.23 (s, 1 H, CH-9), 7.11 (d, J = 8.3 Hz, 2 H, ArH), 7.25 (d,
J = 8.1 Hz, 2 H, ArH), 7.57 (d, J = 8.3 Hz, 2 H, ArH), 7.83 (d, J
= 8.1 Hz, 2 H, ArH), 8.06 (s, 1 H, CH), 9.76 (s, 1 H, NH), 9.87
(br. s, 1 H, NH), 12.87 (br. s, 1 H, COOH) ppm. 13C NMR ([D6]-
DMSO, 125 MHz): δ = 20.95, 27.22, 29.13, 32.64, 50.27, 57.81,
100.49, 106.03, 120.55, 127.50, 129.51, 129.85, 130.65, 132.76,
136.87, 138.89, 139.79, 147.17, 150.08, 161.34, 167.46, 193.55 ppm.
MS (EI, 70 eV): m/z (%) = 471 (20) [M+], 470 (22) [M], 365 (22),
364 (62), 363 (100), 362 (57), 337 (27), 336 (50), 335 (47), 334 (16),
242 (43), 241 (34), 149 (20),148 (17), 129 (17), 128 (15), 108 (23),
107 (44), 106 (92), 105 (32), 97 (24), 84 (24), 83 (42), 82 (39), 77
(24), 76 (25), 73 (26), 72 (30), 70 (27), 69 (33), 68 (25), 57 (40), 56
(60), 55 (79), 54 (36). C27H26N4O4 (470.53): calcd. C 68.92, H 5.57,
N 11.91; found C 68.65, H 5.55, N 11.87.
1
247 °C. H NMR ([D6]DMSO, 200 MHz): δ = 0.90 (s, 3 H, CH3),
1.02 (s, 3 H, CH3), 1.94–2.33 (m, 2 H, CH2), 2.25 (s, 3 H, CH3),
2.62 (d, J = 17.1 Hz, 1 H, CH2), 2.74 (d, J = 17.1 Hz, 1 H, CH2),
6.16 (s, 1 H, CH-9), 7.01–7.65 (m, 9 H, ArH), 8.05 (s, 1 H, CH),
9.73 (br. s, 1 H, NH), 9.78 (br. s, 1 H, NH) ppm. 13C NMR ([D6]-
DMSO, 125 MHz): δ = 20.95, 27.23, 29.21, 32.64, 50.32, 57.98,
100.36, 106.50, 120.54, 127.25, 128.03, 128.71, 129.50, 132.72,
136.90, 138.67, 139.78, 142.69, 149.81, 161.40, 193.54 ppm. MS
(EI, 70 eV): m/z (%) = 427 (18) [M+], 426 (55) [M], 349 (156), 321
(16), 320 (80), 319 (90), 239 (14), 292 (72), 291 (43), 243 (19), 242
(100), 236 (38), 186 (16), 107 (34), 106 (21) ppm. C26H26N4O2
(426.52): calcd. C 73.22, H 6.14, N 13.14; found C 72.91, H 6.12,
N 13.09.
6,6-Dimethyl-8-oxo-N,9-bis(p-tolyl)-4,5,6,7,8,9-hexahydropyr-
azolo[5,1-b]quinazoline-3-carboxamide (4f): Yield: 87%; m.p. 260–
N-(4-Chlorophenyl)-6,6-dimethyl-8-oxo-9-phenyl-4,5,6,7,8,9-hexa-
hydropyrazolo[5,1-b]quinazoline-3-carboxamide (4j): Yield: 89%;
1
262 °C. H NMR ([D6]DMSO, 200 MHz): δ = 0.90 (s, 3 H, CH3),
1
1.02 (s, 3 H, CH3), 1.94–2.33 (m, 2 H, CH2), 2.20 (s, 3 H, CH3),
2.25 (s, 3 H, CH3), 2.62 (d, J = 17.1 Hz, 1 H, CH2), 2.74 (d, J =
17.1 Hz, 1 H, CH2), 6.12 (s, 1 H, CH-9), 7.01–7.70 (m, 8 H, ArH),
8.03 (s, 1 H, CH), 9.70 (br. s, 2 H, HNH) ppm. 13C NMR ([D6]-
DMSO, 125 MHz): δ = 20.95, 21.11, 27.22, 29.25, 32.62, 50.34,
57.72, 100.29, 106.63, 120.53, 127.18, 129.23, 129.49, 132.70,
136.91, 137.25, 138.57, 139.74, 139.87, 149.64, 161.43, 193.50. ppm.
MS (EI, 70 eV): m/z (%) = 441 (26) [M+], 440 (80) [M], 349 (14),
335 (20), 334 (92), 333 (99), 307 (20), 306 (59), 250 (38), 243 (20),
242 (100), 186 (16), 107 (44), 106 (29). C27H28N4O2: C 73.61, H
6.41, N 12.72; found C 73.32, H 6.39, N 12.67.
m.p. 295–298 °C. H NMR ([D6]DMSO, 200 MHz): δ = 0.91 (s, 3
H, CH3), 1.02 (s, 3 H, CH3), 2.06 (d, J = 16.3 Hz, 1 H, CH2), 2.22
(d, J = 16.3 Hz, 1 H, CH2), 2.64 (d, J = 16.9 Hz, 1 H, CH2), 2.76
(d, J = 16.9 Hz, 1 H, CH2), 6.17 (s, 1 H, CH-9), 7.03–7.51 (m, 6
H, ArH), 7.52–7.85 (m, 3 H, ArH), 8.04 (s, 1 H, CH), 9.80 (s, 1 H,
NH), 9.90 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ
= 27.22, 29.21, 32.63, 50.31, 58.01, 100.14, 106.59, 121.97, 127.27,
127.38, 128.06, 128.72, 129.01, 138.46, 138.75, 139.92, 142.62,
149.78, 161.58, 193.56 ppm. MS (EI, 70 eV): m/z (%) = 447 (7)
[M+], 446 (14) [M], 321 (15), 320 (80), 319 (100), 292 (53), 291
(30), 243 (15), 242 (98), 236 (38), 186 (17), 127 (32). C25H23ClN4O2
(446.94): calcd. C 67.18, H 5.19, Cl 7.93, N 12.54; found C 66.90,
H 5.17, Cl 7.97, N 12.49.
9-(4-Methoxyphenyl)-6,6-dimethyl-8-oxo-N-(p-tolyl)-4,5,6,7,8,9-
hexahydropyrazolo[5,1-b]quinazoline-3-carboxamide (4g): Yield:
78%; m.p. 257–259 °C. 1H NMR ([D6]DMSO, 200 MHz): δ = 0.92 N-(4-Chlorophenyl)-6,6-dimethyl-8-oxo-9-(p-tolyl)-4,5,6,7,8,9-
(s, 3 H, CH3), 1.02 (s, 3 H, CH3), 1.90–2.33 (m, 2 H, CH2), 2.25 hexahydropyrazolo[5,1-b]quinazoline-3-carboxamide (4k): Yield:
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20669
/KAP1
Date: 14-08-12 16:29:36
Pages: 11
Controlled Switching of Multicomponent Heterocyclizations
90%; m.p. 302–304 °C. 1H NMR ([D6]DMSO, 200 MHz): δ = 0.91
(s, 3 H, CH3), 1.02 (s, 3 H, CH3), 2.03 (d, J = 16.3 Hz, 1 H, CH2),
101 (15), 99 (27), 93 (19), 91 (19). C26H23ClN4O4 (490.95): calcd.
C 63.61, H 4.72, Cl 7.22, N 11.41; found C 63.34, H 4.70, Cl 7.25,
2.20 (s, 3 H, CH3), 2.24 (d, J = 16.3 Hz, 1 H, CH2), 2.62 (d, J = N 11.37.
17.7 Hz, 1 H, CH2), 2.74 (d, J = 17.7 Hz, 1 H, CH2), 6.12 (s, 1 H,
N,9-Diphenyl-8-oxo-4,5,6,7,8,9-hexahydropyrazolo[5,1-b]quinazol-
ine-3-carboxamide (4o): Yield: 69%; m.p. 208–210 °C. H NMR
CH-9), 6.92–7.83 (m, 8 H, ArH), 8.03 (s, 1 H, CH), 9.76 (s, 1 H,
NH), 9.90 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ
= 21.11, 27.22, 29.24, 32.62, 50.33, 57.75, 75.98, 100.08, 106.72,
121.95, 127.20, 127.36, 129.00, 129.24, 137.28, 138.48, 138.64,
138.65, 139.81, 139.89, 149.60, 161.60, 193.54 ppm. MS (EI,
70 eV): m/z (%) = 461 (5) [M+], 460 (17) [M], 335 (15), 334 (84),
333 (96), 307 (14), 306 (66), 305 (40), 250 (42), 243 (14), 242 (100),
186 (15), 129 (13), 127 (26). C26H25ClN4O2 (460.96): calcd. C 67.75,
H 5.47, Cl 7.69, N 12.15; found C 67.48, H 5.45, Cl 7.73, N 12.10.
1
([D6]DMSO, 200 MHz): δ = 1.65–2.08 (m, 2 H, CH2), 2.12–2.36
(m, 2 H, CH2), 2.55–2.80 (m, 1 H, CH2), 2.82–3.06 (m, 1 H, CH2),
6.19 (s, 1 H, CH-9), 6.94–7.44 (m, 8 H, ArH), 7.60–7.83 (m, 2 H,
ArH), 8.07 (s, 1 H, CH), 9.79 (br. s, 1 H, NH), 9.89 (br. s, 1 H,
NH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ = 21.15, 26.78,
36.81, 57.71, 100.27, 107.55, 120.49, 123.78, 127.78, 128.03, 128.75,
129.09, 138.71, 139.47, 139.74, 142.59, 151.88, 161.55, 193.87 ppm.
MS (EI, 70 eV): m/z (%) = 385 (5) [M+], 384 (18), 292 (43), 291
(61), 264 (40), 263 (25), 236 (13), 214 (100), 93 (14). C23H20N4O2
(384.44): calcd. C 71.86, H 5.24, N 14.57; found C 71.68, H 5.22,
N 14.52.
N-(4-Chlorophenyl)-9-(4-methoxyphenyl)-6,6-dimethyl-8-oxo-
4,5,6,7,8,9-hexahydropyrazolo[5,1-b]quinazoline-3-carboxamide (4l):
1
Yield: 59%; m.p. 303–306 °C. H NMR ([D6]DMSO, 200 MHz): δ
= 0.93 (s, 3 H, CH3), 1.02 (s, 3 H, CH3), 2.05 (d, J = 16.3 Hz, 1
H, CH2), 2.21 (d, J = 16.3 Hz, 1 H, CH2), 2.61 (d, J = 17.1 Hz, 1
H, CH2), 2.77 (d, J = 17.1 Hz, 1 H, CH2), 3.67 (s, 3 H, OCH3),
6.11 (s, 1 H, CH-9), 6.81 (d, J = 8.7 Hz, 2 H, ArH), 7.07 (d, J =
8.7 Hz, 2 H, ArH), 7.38 (d, J = 8.9 Hz, 2 H, ArH), 7.73 (d, J =
8.9 Hz, 2 H, ArH), 8.03 (s, 1 H, CH), 9.75 (s, 1 H, NH), 9.90 (s, 1
H, NH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ = 27.27, 29.24,
32.62, 50.34, 55.55, 57.43, 100.04, 106.74, 114.07, 121.95, 127.35,
128.47, 129.01, 134.89, 138.48, 138.63, 139.82, 149.57, 159.12,
161.60, 193.56, 194.59 ppm. MS (EI, 70 eV): m/z (%) = 476 (8) [M],
350 (47), 349 (100), 348 (58), 322 (54), 321 (43), 266 (28), 265 (22),
242 (46), 241 (23), 186 (14), 185 (17), 129 (16), 127 (26), 126 (186),
83 (19), 57 (21), 56 (24). C26H25ClN4O3 (476.96): calcd. C 65.47,
H 5.28, Cl 7.43, N 11.75; found C 65.21, H 5.26, Cl 7.47, N 11.71.
N-Phenyl-8-oxo-9-(p-tolyl)-4,5,6,7,8,9-hexahydropyrazolo[5,1-b]-
quinazoline-3-carboxamide (4p): Yield: 79%; m.p. 180–183 °C. 1H
NMR ([D6]DMSO, 200 MHz): δ = 1.49–2.10 (m, 2 H, CH2), 2.08–
2.42 (m, 2 H, CH2), 2.20 (s, 3 H, CH3), 2.53–3.09 (m, 2 H, CH2),
6.15 (s, 1 H, CH), 6.80–7.21 (m, 5 H, ArH), 7.18–7.51 (m, 2 H,
ArH), 7.56–7.84 (m, 2 H, ArH), 8.06 (s, 1 H, CH), 9.79 (br. s, 1 H,
NH), 9.85 (br. s, 1 H, NH) ppm. 13C NMR ([D6 ]DMSO,
125 MHz): δ = 21.11, 21.18, 26.77, 36.83, 57.44, 100.20, 107.69,
120.48, 123.76, 127.18, 129.09, 129.26, 137.26, 138.62, 139.48,
139.72, 139.77, 151.70, 161.57, 193.88 ppm. MS (EI, 70 eV): m/z
(%) = 399 (9) [M+], 398 (30) [M], 306 (54), 305 (86), 278 (61), 277
(33), 250 (14), 215 (13), 214 (100), 93 (16). C24H22N4O2 (398.46):
calcd. C 72.34, H 5.57, N 14.06; found C 72.16, H 5.55, N 14.00.
9-(4-Chlorophenyl)-8-oxo-N-phenyl-4,5,6,7,8,9-hexahydropyrazolo-
[5,1-b]quinazoline-3-carboxamide (4q): Yield: 89 %; m.p. 217–
N,9-Bis(4-chlorophenyl)-6,6-dimethyl-8-oxo-4,5,6,7,8,9-hexahydro-
pyrazolo[5,1-b]quinazoline-3-carboxamide (4m): Yield: 64%; m.p.
Ͼ310 °C. 1H NMR ([D6]DMSO, 200 MHz): δ = 0.91 (s, 3 H, CH3),
1.02 (s, 3 H, CH3), 2.07 (d, J = 16.3 Hz, 1 H, CH2), 2.21 (d, J =
16.3 Hz, 1 H, CH2), 2.61 (d, J = 17.0 Hz, 1 H, CH2), 2.77 (d, J =
17.0 Hz, 1 H, CH2), 6.18 (s, 1 H, CH-9), 7.16 (d, J = 8.8 Hz, 2 H,
ArH), 7.32 (d, J = 9.8 Hz, 2 H, ArH), 7.37 (d, J = 9.8 Hz, 2 H,
ArH), 7.72 (d, J = 8.8 Hz, 2 H, ArH), 8.06 (s, 1 H, CH), 9.86 (br.
s, 1 H, NH), 9.93 (br. s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
125 MHz): δ = 27.32, 29.11, 32.65, 50.28, 57.44, 100.22, 106.15,
121.98, 127.40, 128.75, 129.02, 129.18, 132.64, 138.43, 138.93,
139.85, 141.55, 149.95, 161.50, 193.60 ppm. MS (EI, 70 eV): m/z
(%) = 480 (10) [M], 356 (18), 355 (30), 354 (55), 353 (74), 326 (37),
325 (23), 270 (34), 243 (15), 242 (100), 186 (18), 129 (12), 127 (40),
99 (12). C25H22Cl2N4O2 (481.38): calcd. C 62.38, H 4.61, Cl 17.73,
N 11.64; found C 62.13, H 4.60, Cl 17.81, N 11.60.
1
220 °C. H NMR ([D6]DMSO, 200 MHz): δ = 1.68–2.08 (m, 2 H,
CH2), 2.09–2.36 (m, 2 H, CH2), 2.54–2.79 (m, 1 H, CH2), 2.86–
3.06 (m, 1 H, CH2), 6.20 (s, 1 H, CH-9), 6.92–7.48 (m, 7 H, ArH),
7.53–7.84 (m, 2 H, ArH), 8.09 (s, 1 H, CH), 9.81 (s, 1 H, NH), 9.95
(s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ = 21.14,
26.79, 36.78, 57.18, 100.34, 107.11, 120.50, 123.81, 128.75, 129.10,
129.21, 132.65, 138.88, 139.43, 139.66, 141.51, 152.05, 161.47,
193.90 ppm. MS (EI, 70 eV): m/z (%) = 418 (16) [M], 327 (24), 326
(34), 325 (55), 299 (12), 298 (32), 297 (16), 270 (12), 215 (13), 214
(100), 93 (22). C23H19ClN4O2 (418.88): calcd. C 65.95, H 4.57, Cl
8.46, N 13.38; found C 65.79, H 4.56, Cl 8.50, N 13.34.
9-Phenyl-8-oxo-N-(p-tolyl)-4,5,6,7,8,9-hexahydropyrazolo[5,1-b]-
quinazoline-3-carboxamide (4r): Yield: 79%; m.p. 283–285 °C. 1H
NMR ([D6]DMSO, 200 MHz): δ = 1.68–2.05 (m, 2 H, CH2), 2.11–
2.36 (m, 2 H, CH2), 2.24 (s, 3 H, CH3), 2.56–2.79 (m, 1 H, CH2),
2.80–3.07 (m, 1 H, CH2), 6.19 (s, 1 H, CH-9), 7.00–7.39 (m, 7 H,
ArH), 7.41–7.71 (m, 2 H, ArH), 8.05 (s, 1 H, CH), 9.73 (s, 1 H,
NH), 9.87 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ
= 20.95, 21.15, 26.78, 36.81, 57.70, 100.31, 107.53, 120.54, 127.27,
128.01, 128.74, 129.49, 132.71, 136.90, 138.64, 139.68, 142.62,
151.86, 161.40, 193.84 ppm. MS (EI, 70 eV): m/z (%) = 399 (7)
[M+], 398 (25) [M], 292 (49), 291 (60), 264 (41), 263 (26), 236 (13),
215 (14), 214 (100), 107 (22), 106 (14). C24H22N4O2 (398.46): calcd.
C 72.34, H 5.57, N 14.06; found C 72.17, H 5.55, N 14.01.
9-(4-Carboxyphenyl)-N-(4-chlorophenyl)-6,6-dimethyl-8-oxo-
4,5,6,7,8,9-hexahydropyrazolo[5,1-b]quinazoline-3-carboxamide
(4n): Yield: 78%; m.p.Ͼ 310 °C. 1H NMR ([D6]DMSO, 200 MHz):
δ = 0.89 (s, 3 H, CH3), 1.02 (s, 3 H, CH3), 2.05 (d, J = 16.1 Hz, 1
H, CH2), 2.21 (s, J = 16.1 Hz, 1 H, CH2), 2.64 (d, J = 17.4 Hz, 1
H, CH2), 2.76 (d, J = 17.4 Hz, 1 H, CH2), 6.24 (s, 1 H, CH-9), 7.26
(d, J = 8.4 Hz, 2 H, ArH), 7.38 (d, J = 9.0 Hz, 2 H, ArH), 7.72 (d,
J = 9.0 Hz, 2 H, ArH), 7.83 (d, J = 8.4 Hz, 2 H, ArH), 8.06 (s, 1
H, CH), 9.89 (br. s, 1 H, NH), 9.94 (br. s, 1 H, NH), 12.97 (br. s,
1 H, COOH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ = 27.22,
8-Oxo-9,N-bis(4-tolyl)-4,5,6,7,8,9-hexahydropyrazolo[5,1-b]quin-
29.13, 32.64, 50.26, 57.83, 100.27, 106.11, 121.89, 127.53, 129.02, azoline-3-carboxamide (4s): Yield: 91%; m.p. 209–212 °C. 1H NMR
129.86, 130.60, 138.44, 138.96, 139.92, 147.11, 150.04, 161.51, ([D6]DMSO, 200 MHz): δ = 1.71–2.07 (m, 2 H, CH2), 2.09–2.35
167.44, 193.58 ppm. MS (EI, 70 eV): m/z (%) = 492 (4) [M + 2],
(m, 2 H, CH2), 2.20 (s, 3 H, CH3), 2.24 (s, 3 H, CH3), 2.55–3.07
491 (5) [M+], 490 (12) [M], 365 (19), 364 (98), 363 (84), 337 (12), (m, 2 H, CH2), 6.14 (s, 1 H, CH), 6.90–7.25 (m, 6 H, ArH), 7.47–
336 (48), 335 (32), 280 (22), 243 (13), 242 (100), 186 (18), 149 (23),
129 (33), 128 (16), 127 (66), 115 (14), 11 (18), 110 (43), 107 (17),
7.72 (m, 2 H, ArH), 8.03 (s, 1 H, CH.), 9.72 (br. s, 2 H, 2NH) ppm.
13C NMR ([D6]DMSO, 125 MHz): δ = 20.94, 21.11, 21.17, 26.77,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 14-08-12 16:29:36
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V. A. Chebanov et al.
FULL PAPER
36.82, 57.42, 100.23, 107.65, 120.52, 127.17, 129.25, 129.49, 132.69,
136.91, 137.24, 138.54, 139.64, 139.80, 151.70, 161.41, 193.80 ppm.
MS (EI, 70 eV): m/z (%) = 413 (5) [M+], 412 (20) [M], 306 (53),
305 (100), 304 (43), 278 (54), 277 (67), 246 (16), 215 (12), 214 (89),
213 (77), 107 (14), 106 (20), 77 (11), 55 (22), 24 (17). C25H24N4O2
(412.49): calcd. C 72.80, H 5.86, N 13.58; found C 72.60, H 5.84,
N 13.53.
128 (20), 127 (25), 126 (30), 55 (32), 54 (28). C23H18Cl2N4O2
(453.33): calcd. C 60.94, H 4.00, Cl 15.64, N 12.36; found C 60.70,
H 3.99, Cl 15.72, N 12.32.
Typical Procedure for the Ultrasonic-Assisted Synthesis of 8,8-Di-
methyl-6-oxo-5-phenyl-N-(p-tolyl)-4,5,6,7,8,9-hexahydropyrazolo-
[1,5-a]quinazoline-3-carboxamide (5a): A mixture of 5-amino-N-(p-
tolyl)-1H-pyrazole-4-carboxamide (1b; 0.22 g, 1 mmol), dimedone
(3a; 0.28 g, 2 mmol), benzaldehyde (2a; 0.11 g, 1 mmol) and DMF
(1.5 mL) containing a catalytic amount of HCl in a round-bottom
flask, was irradiated in an ultrasonic bath (44.2 kHz) for 45 min.
9-(4-Chlorophenyl)-8-oxo-N-(p-tolyl)-4,5,6,7,8,9-hexahydropyr-
azolo[5,1-b]quinazoline-3-carboxamide (4t): Yield: 90%; m.p. 270–
1
273 °C. H NMR ([D6]DMSO, 200 MHz): δ = 1.66–2.07 (m, 2 H,
CH2), 2.10–2.36 (m, 2 H, CH2), 2.24 (s, 3 H, CH3), 2.57–2.80 (m, The reaction mixture was cooled to room temperature and an
1 H, CH2), 2.81–3.05 (m, 1 H, CH2), 6.19 (s, 1 H, CH-9), 7.01– EtOH/H2O (1:1, 4 mL) mixture was added. After cooling, the crys-
7.43 (m, 6 H, ArH), 7.45–7.71 (m, 2 H, ArH), 8.06 (s, 1 H, CH), tals formed were removed by filtration, washed with EtOH/H2O
9.75 (s, 1 H, NH), 9.93 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
(1:1) and dried in air. Yield: 0.29 g (68%); m.p. 235–238 °C. 1H
125 MHz): δ = 20.94, 21.14, 26.80, 36.78, 57.17, 100.39, 107.09, NMR ([D6]DMSO, 200 MHz): δ = 0.98 (s, 3 H, CH3), 1.08 (s, 3
120.55, 128.74, 129.20, 129.49, 132.63, 132.74, 136.87, 138.81, H, CH3), 2.24 (d, J = 16.0 Hz, 1 H, CH2), 2.26 (s, 3 H, ArCH3),
139.60, 141.54, 152.03, 161.32, 193.87 ppm. MS (EI, 70 eV): m/z
(%) = 434 (9) [M + 2], 432 (27) [M], 327 (31), 326 (49), 325 (69),
298 (43), 2697 (19), 214 (100), 107 (60), 106 (21). C24H21ClN4O2
(432.91): calcd. C 66.59, H 4.89, Cl 8.19, N 12.94; found C 66.42,
H 4.88, Cl 8.23, N 12.89.
2.36 (d, J = 16.0 Hz, 1 H, CH2), 2.75 (d, J = 18.5 Hz, 1 H, CH2),
3.03 (d, J = 18.5 Hz, 1 H, CH2), 5.59 (d, J = 2.6 Hz, 1 H, CH),
6.96–7.65 (m, 9 H, ArH), 8.09 (d, J = 2.6 Hz, 1 H, NH), 8.23 (s, 1
H, CH), 9.53 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 125 MHz):
δ = 20.91, 27.39, 29.23, 32.53, 37.00, 50.21, 50.35, 97.35, 112.22,
120.27, 126.37, 128.01, 129.01, 129.45, 132.36, 137.10, 142.75,
143.82, 147.45, 148.53, 161.53, 195.26 ppm. MS (EI, 70 eV): m/z
(%) = 426 (15) [M], 349 (16), 320 (33), 319 (71), 318 (57), 242 (100),
241 (80), 186 (53), 185 (47), 149 (71), 148 (75), 107 (59), 106 (54),
82 (40), 57 (54), 56 (68), 55 (74), 44 (29), 41 (42). C26H26N4O2
(426.52): calcd. C 73.22, H 6.14, N 13.14; found C 72.91, H 6.12,
N 13.10.
N-(4-Chlorophenyl)-8-oxo-9-phenyl-4,5,6,7,8,9-hexahydropyrazolo-
[5,1-b]quinazoline-3-carboxamide (4u): Yield: 70%; m.p.Ͼ 310 °C.
1H NMR ([D6]DMSO, 200 MHz): δ = 1.67–2.07 (m, 2 H, CH2),
2.11–2.37 (m, 2 H, CH2), 2.56–2.79 (m, 1 H, CH2), 2.80–3.06 (m,
1 H, CH2), 6.19 (s, 1 H, C9-H), 7.05–7.31 (m, 5 H, ArH), 7.37 (d,
J = 8.8 Hz, 2 H, ArH), 7.72 (d, J = 8.8 Hz, 2 H, ArH), 8.04 (s, 1
H, CH), 9.89 (br. s, 1 H, NH), 9.91 (br. s, 1 H, NH) ppm. 13C
NMR ([D6]DMSO, 125 MHz): δ = 21.15, 26.77, 36.81, 57.72, 8,8-Dimethyl-6-oxo-N-phenyl-5-(p-tolyl)-4,5,6,7,8,9-hexahydropyr-
100.08, 107.59, 121.97, 127.28, 127.36, 128.04, 128.74, 129.00, azolo[1,5-a]quinazoline-3-carboxamide (5b): Yield: 71%; m.p. 225–
1
138.46, 138.71, 139.82, 142.54, 151.85, 161.56, 193.86 ppm. MS 227 °C. H NMR ([D6]DMSO, 200 MHz): δ = 0.98 (s, 3 H, CH3),
(EI, 70 eV): m/z (%) = 418 (11) [M], 292 (79), 291 (82), 264 (43), 1.08 (s, 3 H, CH3), 2.20 (s, 3 H, ArCH3), 2.24 (d, J = 16.6 Hz, 1
263 (27), 236 (15), 214 (100), 127 (25). C23H19ClN4O2 (418.88): H, CH2), 2.36 (d, J = 16.6 Hz, 1 H, CH2), 2.75 (d, J = 18.3 Hz, 1
calcd. C 65.95, H 4.57, Cl 8.46, N 13.38; found C 65.70, H 4.57,
Cl 8.48, N 13.35.
H, CH2), 3.03 (d, J = 18.3 Hz, 1 H, CH2), 5.54 (d, J = 2.4 Hz, 1
H, CH), 6.85–7.19 (m, 5 H, ArH), 7.18–7.38 (m, 2 H, ArH), 7.53–
7.74 (m, 2 H, ArH), 8.08 (d, J = 2.4 Hz, 1 H, NH), 8.25 (s, 1 H,
CH), 9.59 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,125 MHz): δ
= 21.11, 27.40, 29.24, 32.53, 36.99, 49.97, 50.37, 97.30, 112.34,
120.19, 123.45, 126.32, 129.05, 129.53, 137.24, 139.68, 140.90,
142.69, 147.30, 148.59, 161.68, 195.22 ppm. MS (EI, 70 eV): m/z
(%) = 426 (7) [M+], 334 (27), 333 (56), 332 (35), 305 (25), 242 (97),
241 (100), 185 (21), 149 (19), 92 (26). C26H26N4O2 (426.52): calcd.
C 73.22, H 6.14, N 13.14; found C 72.91, H 6.12, N 13.11.
N-(4-Chlorophenyl)-8-oxo-9-(p-tolyl)-4,5,6,7,8,9-hexahydropyr-
azolo[5,1-b]quinazoline-3-carboxamide (4v): Yield: 75%; m.p. 290–
1
292 °C. H NMR ([D6]DMSO, 200 MHz): δ = 1.70–2.05 (m, 2 H,
CH2), 2.09–2.33 (m, 2 H, CH2), 2.20 (s, 3 H, CH3), 2.55–2.77 (m,
1 H, CH2), 2.80–3.03 (m, 1 H, CH2), 6.14 (s, 1 H, CH-9), 6.92–
7.14 (m, 4 H, ArH), 7.36 (d, J = 8.8 Hz, 2 H, ArH), 7.72 (d, J =
8.8 Hz, 2 H, ArH), 8.03 (s, 1 H, CH), 9.86 (br. s, 1 H, NH), 9.90
(br. s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ = 21.10,
21.16, 26.77, 36.82, 57.45, 100.02, 107.73, 121.95, 127.19, 127.35,
5-(4-Chlorophenyl)-8,8-dimethyl-6-oxo-N-phenyl-4,5,6,7,8,9-hexahy-
128.99, 129.26, 137.27, 138.48, 138.62, 139.74, 139.80, 151.66, dropyrazolo[1,5-a]quinazoline-3-carboxamide (5c): Yield: 63%; m.p.
161.59, 193.82 ppm. MS (EI, 70 eV): m/z (%) = 434 (7) [M + 2],
154–156 °C. 1H NMR ([D6]DMSO, 200 MHz): δ = 0.97 (s, 3 H,
432 (24) [M], 431 (21) [M–], 306 (80), 305 (100), 304 (55), 279 (37), CH3), 1.08 (s, 3 H, CH3), 2.22 (d, J = 16.1 Hz, 1 H, CH2), 2.38 (d,
277 (54), 249 (20), 248 (16), 214 (80), 213 (76), 128 (19), 127 (28),
126 (19). C24H21ClN4O2 (432.91): calcd. C 66.59, H 4.89, Cl 8.19,
N 12.94; found C 66.32, H 4.89, Cl 8.23, N 12.90.
J = 16.1 Hz, 1 H, CH2), 2.75 (d, J = 18.4 Hz, 1 H, CH2), 3.04 (d,
J = 18.4 Hz, 1 H, CH2), 5.58 (d, J = 3.0 Hz, 1 H, CH), 6.90–7.10
(m, 1 H, ArH), 7.18–7.45 (m, 6 H, ArH), 7.54–7.74 (m, 2 H, ArH),
8.20 (d, J = 3.0 Hz, 1 H, NH), 8.27 (s, 1 H, CH), 9.63 (s, 1 H,
NH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ = 27.41, 29.18,
32.52, 37.00, 49.75, 50.30, 97.38, 111.86, 120.20, 123.49, 128.32,
129.03, 132.62, 139.65, 142.77, 142.86, 147.64, 148.40, 161.64,
195.27 ppm. MS (EI, 70 eV): m/z (%) = 448 (21) [M + 2], 447 (20)
[M+], 446 (55) [M], 445 (20) [M–], 242 (86), 186 (67), 158 (22), 94
(20), 93 (100), 65 (19). C25H23ClN4O2 (446.94): calcd. C 67.18, H
5.19, Cl 7.93, N 12.54; found C 66.96, H 5.17, Cl 7.96, N 12.50.
N,9-Bis(4-chlorophenyl)-8-oxo-4,5,6,7,8,9-hexahydropyrazolo[5,1-b]-
quinazoline-3-carboxamide (4w): Yield: 63%; m.p. 298–302 °C. 1H
NMR ([D6]DMSO, 200 MHz): δ = 1.71–2.06 (m, 2 H, CH2), 2.11–
2.38 (m, 2 H, CH2), 2.57–2.79 (m, 1 H, CH2), 2.79–3.04 (m, 1 H,
CH2), 6.19 (s, 1 H, CH-9), 7.17 (d, J = 8.6 Hz, 2 H, ArH), 7.32 (d,
J = 8.6 Hz, 2 H, ArH), 7.37 (d, J = 8.8 Hz, 2 H, ArH), 7.72 (d, J
= 8.8 Hz, 2 H, ArH), 8.06 (s, 1 H, CH), 9.99 (br. s, 2 H, NH) ppm.
13C NMR ([D6]DMSO, 125 MHz): δ = 21.14, 26.79, 36.78, 57.21,
100.17, 107.17, 121.97, 127.40, 128.74, 128.99, 129.22, 132.67, 5-(4-Chlorophenyl)-8,8-dimethyl-6-oxo-N-(p-tolyl)-4,5,6,7,8,9-
138.44, 138.87, 139.74, 141.47, 151.98, 161.51, 193.88 ppm. MS hexahydropyrazolo[1,5-a]quinazoline-3-carboxamide (5d): Yield:
(EI, 70 eV): m/z (%) = 453 (8) [M+], 452 (8) [M], 328 (21), 327 (50), 65%; m.p. 218–220 °C. 1H NMR ([D6]DMSO, 200 MHz): δ = 0.97
326 (87), 325 (89), 299 (24), 298 (44), 270 (16), 215 (13), 214 (100),
(s, 3 H, CH3), 1.08 (s, 3 H, CH3), 2.23 (s, 3 H, ArCH3), 2.17 (d, J
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20669
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Date: 14-08-12 16:29:36
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Controlled Switching of Multicomponent Heterocyclizations
= 15.7 Hz, 1 H, CH2), 2.43 (d, J = 15.7 Hz, 1 H, CH2), 2.73 (d, J
= 18.5 Hz, 1 H, CH2), 3.02 (d, J = 18.5 Hz, 1 H, CH2), 5.57 (d, J
[M + 2], 583 (12) [M+], 582 (26) [M+], 473 (30), 472 (89), 471 (100),
110 (17), 109 (14), 108 (36), 107 (64), 106 (87), 105 (49), 83 (27).
= 2.4 Hz, 1 H, CH), 7.08 (d, J = 8.1 Hz, 2 H, ArH), 7.21 (d, J = C34H35ClN4O3 (583.13): calcd. C 70.03, H 6.05, Cl 6.08, N 9.61;
8.4 Hz, 2 H, ArH), 7.34 (d, J = 8.4 Hz, 2 H, ArH), 7.52 (d, J =
8.1 Hz, 2 H, ArH), 8.15 (d, J = 2.4 Hz, 1 H, NH), 8.24 (s, 1 H,
CH), 9.56 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ
= 20.92, 27.41, 29.18, 32.53, 36.99, 49.73, 50.30, 97.42, 111.86,
120.27, 128.31, 129.03, 129.46, 132.40, 132.60, 137.08, 142.79,
142.83, 147.65, 148.33, 161.48, 195.27 ppm. MS (EI, 70 eV): m/z
(%) = 460 (3) [M], 353 (15), 243 (15), 242 (44), 241 (29), 186 (19),
108 (14), 107 (70), 106 (100), 78 (19). C26H25ClN4O2 (460.96):
calcd. C 67.75, H 5.47, Cl 7.69, N 12.15; found C 67.61, H 5.46,
Cl 7.72, N 12.11.
found C 69.75, H 6.03, Cl 6.11, N 9.58.
5-[9-(4-Methoxyphenyl)-3,3,6,6-tetramethyl-1,8-dioxo-
1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl]-N-(p-tolyl)-1H-pyr-
azole-4-carboxamide (7b): Yield: 30 %; m.p. Ͼ300 °C. 1H NMR
([D6]DMSO, 200 MHz): δ = 0.69 (0.72) (s, 3 H, CH3), 0.84 (0.86)
(s, 3 H, CH3), 1.70–2.30 (m, 8 H, 4CH2), 2.24 (2.25) (s, 3 H,
ArCH3), 3.64 (3.66) (s, 3 H, ArOCH3), 4.83 (4.89) (s, 1 H, CH),
6.52–7.68 (m, 8 H, ArH), 8.53 (8.64) (s, 1 H, CH), 9.90 (10.00) (s,
1 H, NH), 13.52 (br. s, 1 H, NH) ppm. MS (EI, 70 eV): m/z (%) =
578 (6) [M], 471 (14), 108 (66), 107 (100), 106 (87), 92 (48), 82 (28),
78 (29), 77 (64). C35H38N4O4 (578.71): calcd. C 72.64, H 6.62, N
9.68; found C 72.35, H 6.03, Cl 6.61, N 9.65.
5-(4-Fluorophenyl)-8,8-dimethyl-6-oxo-N-(p-tolyl)-4,5,6,7,8,9-
hexahydropyrazolo[1,5-a]quinazoline-3-carboxamide (5e): Yield:
78%; m.p. 146–149 °C. 1H NMR ([D6]DMSO, 200 MHz): δ = 0.98
(s, 3 H, CH3), 1.07 (s, 3 H, CH3), 2.23 (s, 3 H, ArCH3), 2.24 (d, J
= 16.2 Hz, 1 H, CH2), 2.36 (d, J = 16.2 Hz, 1 H, CH2), 2.73 (d, J
= 18.5 Hz, 1 H, CH2), 3.02 (d, J = 18.5 Hz, 1 H, CH2), 5.57 (d, J
= 2.3 Hz, 1 H, CH), 6.98–7.37 (m, 6 H, ArH), 7.38–7.62 (m, 2 H,
ArH), 8.12 (d, J = 2.3 Hz, 1 H, NH), 8.24 (s, 1 H, CH), 9.55 (s, 1
H, NH) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ = 20.91, 27.43,
29.18, 32.53, 36.98, 49.65, 50.31, 97.39, 112.09, 115.70, 115.87,
120.27, 128.47, 129.45, 132.39, 137.08, 140.14, 142.79, 147.52,
148.35, 160.97, 161.51, 195.26 ppm. MS (EI, 70 eV): m/z (%) = 444
(6) [M], 338 (11), 242 (25), 108 (15), 107 (71), 106 (100), 78 (15).
C26H25FN4O2 (444.51): calcd. C 70.25, H 5.67, F 4.27, N 12.60;
found C 69.95, H 5.66, F 4.29, N 12.56.
Acknowledgments
The authors thank Dr. Vataliy Polovinko (Enamine Ltd., Ukraine)
and Dr. Dmytro Sysoev (Konstanz University, Germany) for meas-
uring some NMR spectra.
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5-(4-Methoxyphenyl)-8,8-dimethyl-6-oxo-N-(p-tolyl)-4,5,6,7,8,9-
hexahydropyrazolo[1,5-a]quinazoline-3-carboxamide (5f): Yield:
75%; m.p. 168–171 °C. 1H NMR ([D6]DMSO, 200 MHz): δ = 0.99
(s, 3 H, CH3), 1.08 (s, 3 H, CH3), 2.22 (s, 3 H, ArCH3), 2.23 (d, J
= 14.2 Hz, 1 H, CH2), 2.34 (d, J = 14.2 Hz, 1 H, CH2), 2.75 (d, J
= 14.2 Hz, 1 H, CH2), 3.04 (d, J = 14.2 Hz, 1 H, CH2), 3.66 (s, 3
H, ArOCH3), 5.50 (d, J = 2.3 Hz, 1 H, CH), 6.73–6.99 (m, 2 H,
ArH), 7.00–7.33 (m, 4 H, ArH), 7.40–7.69 (m, 2 H, ArH), 8.02 (d,
J = 2.3 Hz, 1 H, NH), 8.22 (s, 1 H, CH), 9.53 (s, 1 H, NH) ppm.
13C NMR ([D6]DMSO,125 MHz): δ = 20.91, 27.45, 29.24, 32.53,
36.97, 49.69, 50.37, 55.54, 97.34, 112.43, 114.06, 114.35, 120.25,
120.54, 127.63, 128.45, 129.45, 132.35, 136.00, 137.11, 142.64,
147.19, 148.46, 159.14, 161.54, 195.21 ppm. MS (EI, 70 eV): m/z
(%) = 457 (14) [M+], 456 (45) [M], 350 (26), 349 (62), 348 (46), 322
(27), 321 (40), 242 (53), 243 (34), 186 (24), 149 (23), 108 (22), 107
(80), 106 (100), 83 (39), 77 (52). C27H28N4O3 (456.54): calcd. C
71.03, H 6.18, N 12.27; found C 70.88, H 6.16, N 12.23.
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Typical Procedure for the Synthesis of 5-[9-(4-Chlorophenyl)-3,3,6,6-
tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl]-
N-(p-tolyl)-1H-pyrazole-4-carboxamide (7a): A mixture of 5-amino-
N-(p-tolyl)-1H-pyrazole-4-carboxamide (1b; 0.32 g, 1.5 mmol), di-
medone 3a (0.42 g, 3 mmol), 4-chlorobenzaldehyde (2d; 0.21 g,
1.5 mmol) and DMF (2 mL) with a catalytic amount of HCl was
heated to reflux for 15 min. The reaction mixture was cooled to
50–60 °C, and EtOH/H2O (1:1, 4 mL) was added. The precipitate
formed was removed by filtration, washed with EtOH/H2O (1:1),
and dried in air. To obtain an analytical sample of compound 7a
it was mechanically separated from compound 4h and recrystallized
from EtOH/H2O (2:3). Yield: 0.3 g (35%); m.p. Ͼ300 °C. 1H NMR
([D6]DMSO, 200 MHz): δ = 0.68 (0.71) (s, 3 H, CH3), 0.84 (0.86)
(s, 3 H, CH3), 1.69–2.41 (m, 8 H, 4CH2), 2.24 (2.26) (s, 3 H,
ArCH3), 4.87 (4.94) (s, 1 H, CH), 6.93–7.38 (m, 5 H, ArH), 7.41–
7.82 (m, 3 H, ArH), 8.57 (8.65) (s, 1 H, CH), 9.92 (10.00) (s, 1 H,
NH), 13.20 (s, 1 H, NH) ppm. MS (EI, 70 eV): m/z (%) = 584 (7)
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V. A. Chebanov et al.
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Received: May 17, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20669
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Date: 14-08-12 16:29:36
Pages: 11
Controlled Switching of Multicomponent Heterocyclizations
Chemoselective Cyclization
V. A. Chebanov,* V. E. Saraev,
S. V. Shishkina, O. V. Shishkin,
V. I. Musatov, S. M. Desenko .......... 1–11
Controlled Switching of Multicomponent
Heterocyclizations of 5-Amino-N-arylpyr-
azole-4-carboxamides,
diones, and Aldehydes
1,3-Cyclohexane-
Keywords: Multicomponent reactions
/
Heterocycles / Chemoselectivity / Combi-
natorial chemistry / Synthetic methods
The multicomponent heterocyclization of
5-amino-N-arylpyrazole-4-carboxamides,
1,3-cyclohexanediones, and aldehydes was
switched between pyrazolo[5,1-b]- and pyr-
azolo[1,5-a]-quinazolines by changing the
reaction parameters. An unusual third
pathway leading to the formation of 5-
acridin-10-yl-pyrazole-4-carboxamides
with hindered rotation of the pyrazole moi-
ety around the C–N bond was also found.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11