Switchable selectivity in multicomponent heterocyclizations of acetoacetamides, aldehydes, and 3-amino-1,2,4-triazoles/5-aminopyrazoles

DOI: 10.1016/j.tet.2011.09.138

Source and publish data:

Tetrahedron p. 9389 - 9400 (2011)

Update date:2022-08-06

Topics:

Authors:

Muravyova, Elena A.

Desenko, Sergey M.

Rudenko, Roman V.

Shishkina, Svetlana V.

Shishkin, Oleg V.

Sen'ko, Yulia V.

Vashchenko, Elena V.

Chebanov, Valentin A.

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Article abstract of DOI:10.1016/j.tet.2011.09.138

Multicomponent heterocyclizations of 3-amino-1,2,4-triazoles/5- aminopyrazoles with acetoacetamides and aromatic aldehydes were studied in detail using conventional thermal heating, ultrasonication, and microwave irradiation. Several different synthetic p

Full text of DOI:10.1016/j.tet.2011.09.138

Tetrahedron 67 (20 1 1 ) 9389e9400

Contents lists available at SciVerse ScienceDirect

Tetrahedron

journal homepage: w ww.elsevier.com/locate/tet

Switchable selectivity in multicomponent heterocyclizations of acetoacetamides,

aldehydes, and 3-amino-1,2,4-triazoles/5-aminopyrazoles

Elena A. Muravyova ^a, Sergey M. Desenko ^{a b}, Roman V. Rudenko ^a, Svetlana V. Shishkina ^a,

Oleg V. Shishkin ^{a b}, Yulia V. Sen’ko ^a, Elena V. Vashchenko ^a, Valentin A. Chebanov^a

^aState Scientiﬁc Institution ‘Institute for Single Crystals’ of National Academy of Sciences of Ukraine, Lenin Ave. 60, 61001 Kharkiv, Ukraine

^bKarazin Kharkiv National University, Svobody sq., 4, 61077 Kharkiv, Ukraine

a r t i c l e i n f o

a b s t r a c t

Article history:

Received 7 June 2011

Received in revised form 7 September 2011

Accepted 26 September 2011

Available online 5 October 2011

Multicomponent heterocyclizations of 3-amino-1,2,4-triazoles/5-aminopyrazoles with acetoacetamides

and aromatic aldehydes were studied in detail using conventional thermal heating, ultrasonication, and

microwave irradiation. Several different synthetic pathways for these cyclocondensations occurring

under either kinetic or thermodynamic control were established depending on the temperature regime

and building block selection. The experimental data obtained and the procedures developed allow tuning

selectivity of the multicomponent reactions studied.

Keywords:

Multicomponent heterocyclization

Switchable selectivity

Aminoazole

Acetoacetamide

Ultrasonic-assisted reaction

1. Introduction

often appears⁴and, therefore, one of the interesting challenges is

increasing selectivity for such treatments by development of the

Polyfunctionalized heterocyclic compounds play an important

role in the drug discovery processdan analysis of drugs on the

market shows that about 70% of them are heterocycles.¹Therefore

it is not surprising that research concerning their synthesis has

received special attention. For example, fused heterocycles con-

taining pyrimidine or pyridine ring as a core unit are known to

exhibit various biological and pharmaceutical activities,²and syn-

thesis of these complex heterocyclic scaffolds is assigned as one of

the most fertile areas for both organic and medicinal chemistry.

One of the main tasks of modern synthetic chemistry is to de-

velop efﬁcient approaches allowing in a minimum synthetic steps

to give an opportunity of obtaining target compound in high yields

from available starting reagents. Due to the simplicity, convenience,

great diversity, and combinatorial potential multicomponent re-

actions attract an attention of chemists working in the ﬁeld of both

classical organic synthesis and drug discovery.³It leads to their

widespread application for solving problems of medicinal chem-

istry and, in particular, for producing libraries of compounds for

high-throughput biological screening. However, the problem con-

cerning the ambiguity of direction of multicomponent reaction

methods of tuning their direction.

This problem is also urgent for multicomponent heterocycliza-

tions involving aminoazoles as key building-blocks.^4aEspecially it

is an actual matter when aminoazole molecule contains alternative

nucleophilic reaction centers making their cyclocondensations

with carbonyl and active methylene compounds ambiguous from

the viewpoint of chemo- and regioselectivity.^4,5Moreover, the

formation of several ﬁnal compounds is caused not only by com-

petition of the reaction centers, but also by position isomerism

(different location of substituents in the heterocyclic skeleton). For

example, there are literature data on the multicomponent treat-

ment of 3-amino-1,2,4-triazole with aromatic aldehydes and ace-

tophenone yielding sole dihydrotriazolopyrimidine as the reaction

product.⁶On the other hand, a similar heterocyclization involving

benzocycloalkanones instead of acetophenone led to the formation

of two position isomers I and II (Scheme 1), which differed by lo-

cation of cycloalkane and aldehyde fragments.⁶

The formation of mixtures of isomeric 4,5- and 4,7-dihydrotri-

azolopyrimidines was also observed in the reaction of 3-amino-

1,2,4-triazole with methylarylketones in the presence of ZnCl₂

while under acidic catalysis (acetic or mineral acids) the same

treatment yielded only 4,5-dihydroderivatives.^7b

There are publications concerning multicomponent hetero-

cyclizations of aminoazoles with wide sets of aldehydes and

* Corresponding author. Tel.: þ380 57 341 0191; fax: þ380 57 341 0273; e-mail

address: chebanov@isc.kharkov.com (V.A. Chebanov).

doi:10.1016/j.tet.2011.09.138

9390

E.A. Muravyova et al. / Tetrahedron 67 (2011) 9389e9400

(CH₂)n

N NH

NH₂

(CH₂)n

COR¹

R¹

H₂O, rt

X = H

COR¹

N NH

-H₂O

NH₂

III

R¹

p-TsOH / H₂O

X = SCH₃

H C

Scheme 1.

Scheme 2.

derivatives of acetoacetic acid giving diverse types of azolopyr-

ymidines.⁸In several cases such treatments led to the unusual re-

sults from the viewpoint of selectivity. For instance, reaction of 3-

2. Results and discussion

amino-1,2,4-triazole with aldehydes and b-dicarbonyl CH-acids in

water at room temperature without any catalyst gave tetrahydro-

triazolopyrimidines III (Scheme 1), which further were not able to

eliminate water.^8fFormation of similar compounds was also de-

scribed by Rusinov and colleagues^8cfor heterocyclizations in-

volving ﬂuoroalkyl derivatives of acetoacetic ester. It should be

noted that in both of these articles the structure of ﬁnal compounds

was established only with help of ¹H and ¹³C NMR data that, in our

opinion, was not enough due to possibility of formation of position

isomers.^8h,9

2.1. Three-component reaction of aminoazoles, aldehydes,

and acetoacetamides

The comprehensive study of three-component reactions of

aminoazoles 1aem, acetoacetamides 2aed, and aromatic alde-

hydes 3aeo allowed us to establish a dependence of direction of

the treatments on the temperature regime and structure of the

starting building-blocks.

For example, proceeding the reaction involving 5-alkylthio-3-

amino-1,2,4-triazoles (1a,b), anilides of acetoacetic acid 2aec, and

aldehydes 3aee was successfully tuned by variation of the tem-

perature with help of ultrasonication, conventional thermal heat-

ing or microwave irradiation.

It was established, that a three-component treatment of the

starting materials in EtOH at 25 ^ꢀC under ultrasonication, similar to

the analogous reactions involving pyruvic acids,⁹gave only 7-

hydroxy-7-methyl-2-(alkylthio)-N,5-diaryl-4,5,6,7-tetrahydro-

[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamides (4aeg, Scheme 3)

in 55e86% yields (Table 1). This procedure opens the way to high

selective synthesis of heterocycles like V (Scheme 1), described as

side products by Yang et al.^8hOn the other hand, as it had been

already shown in our earlier publication,^8dreaction of the same

building-blocks under microwave irradiation (EtOH, 120 ^ꢀC, 5 min)

or under conventional reﬂuxing in DMF yielded 5-methyl-2-

(alkylthio)-N,7-diaryl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-

6-carboxamides (5aeg). Additionally it was found that smooth

heating (w50 ^ꢀC) of tetrahydropyrimidines 4aeg in DMF led to

their reversible decomposition into the starting compounds (NMR

control), while heating at reﬂux for 3 h converted them into het-

erocycles 5aeg (80e90%, Table 1).

Thus, the experimental data indicates that this three-

component reaction can proceed both under kinetic and under

thermodynamic control that gives an opportunity to direct it into

two different ways reaching true chemoselectivity.

5-Aminopyrazoles 1cee, containing in the fourth position

electron-withdrawing substituents (R¼CN, CO₂CH₃, CONH₂)

showed in the three-component reactions with aldehydes and

acetoacetamides similar behavior: kinetically controlled treatment

(ultrasonication in EtOH at 25 ^ꢀC) yielded tetrahydropyrazolopyr-

imidines 6aee, while under thermodynamic control (reﬂuxing in

DMF) reaction switched to formation of dihydroderivatives 7aee

Yang et al.^8hdeclared the ﬁrst example of regioselective

Biginelli-like heterocyclization based on reaction of 3-alkylthio-5-

amino-1,2,4-triazole, aldehydes, and acetoacetic esters in water

medium. However, the heterocyclization described in this article in

the most cases gave mixtures of two different compounds (IV and

V, Scheme 1). Selective procedure for the synthesis of tetrahydro-

triazolopyrimidine V were not developed at all, while highly ef-

fective method for obtaining heterocycles IV had already been

elaborated in our earlier publication.^8d

On the other hand, a possibility of tuning the chemo- and

regioselectivity of heterocyclizations allowing their switching from

one direction to another by variation of the reaction parameters

was shown in several publications of our laboratory^9,10and other

authors.¹¹

For example, heterocyclizations of some aminoazoles and al-

dehydes with derivatives of pyruvic acid proceeding under kinetic

or thermodynamic control can be directed by variation of the

temperature regime to the formation of four types of ﬁnal com-

pounds (VIeIX, Scheme 2).^9,10a,c,hCombination of different acti-

vation methods (microwave or ultrasonic irradiation) and

changing catalytic systems allows tuning selectivity of three-

component reaction between 3-aryl-5-aminopyrazoles, alde-

hydes, and 1,3-cyclohexanediones, which gives a possibility to

obtain three classes of heterocycles (XeXII, Scheme 2).^10b,dSim-

ilar principles were applied to switch directions of hetero-

cyclizations involving 5-aminopyrazoles, aldehydes and

barbituric acids,^10e3-amino-1,2,4-triazole, o-salicylic aldehyde,

and carbonyl-containing CH-acids.^10f

In this article we disclose our recent results in tuning selectivity

of multicomponent heterocyclization involving aromatic alde-

hydes, 3-amino-1,2,4-triazoles or 5-aminopyrazoles, and acetoa-

cetamides being earlier less studied in similar treatments.

E.A. Muravyova et al. / Tetrahedron 67 (2011) 9389e9400

9391

Scheme 3.

Table 1

Three-component synthesis of compounds 4aeg, 5aeg, 6aee, 7aee, 8aei, 13aee, 14aee, 15ael

Building-blocks

Reaction products

Compound Yield, %

Aminoazole

Compound

Acetoacetamide

Compound

Aldehyde

R/R³

R¹

Compound

R²

CH₃

C₆H₅

CH₃

C₆H₅

CONH₂

C₆H₅

2-CH₃OC₆H₄

4-CH₃OC₆H₄

C₆H₅

4-(CH₃CH₂)C₆H₄

4-ClC₆H₄

4-CH₃C₆H₄

4-(CH₃CH₂)C₆H₄

4-BrC₆H₄

13a

13b

13c

13d

13e

14a

14b

14c

14d

14e

15a

15b

15c

15d

15e

15f

15g

15h

15i

15j

15k

15l

C₆H₅

4-(CH₃CH₂)C₆H₄

4-ClC₆H₄

4-CH₃C₆H₄

4-(CH₃CH₂)C₆H₄

4-BrC₆H₄

90, 80^a

80, 80^a

85, 82^a

85, 85^a

85, 87^a

90, 85^a

90, 90^a

C₆H₅

2-CH₃OC₆H₄

4-CH₃OC₆H₄

C₆H₅

2,4-(CH₃)₂C₆H₃

2-CH₃OC₆H₄

C₆H₅

2,4-(CH₃)₂C₆H₃

2-CH₃OC₆H₄

4-CH₃OC₆H₄

2-CH₃OC₆H₄

C₆H₅

4-ClC₆H₄

C₆H₅

4-(CH₃CH₂)C₆H₄

4-OHe3-CH₃OC₆H₄

3,4- (CH₃O)₂C₆H₃

4-BrC₆H₄

C₆H₅

4-ClC₆H₄

4-OHe3-CH₃OC₆H₃

3,4-(CH₃O)₂C₆H₃

4-BrC₆H₄

C₆H₅

4-ClC₆H₄

4-CH₃C₆H₄

4-BrC₆H₄

C₆H₅

4-ClC₆H₄

4-BrC₆H₄

C₆H₅

4-CH₃C₆H₄

4-BrC₆H₄

4-OHe3-CH₃OC₆H₃

4-CNC₆H₄

4-BrC₆H₄

4-NO₂eC₆H₄

4-CO₂HC₆H₄

4-NO₂C₆H₄

4-OHe3-(CH₃CH₂O)C₆H₃

3,4-(OH)₂C₆H₃

3,4-(CH₃O)₂C₆H₃

4-OHC₆H₄

4-N(CH₃)₂C₆H₄

4-OHe3-CH₃OC₆H₃

4-CO₂HC₆H₄

4-CNC₆H₄

CO₂CH₃

CONH₂

55, 82^a

65, 90^a

65, 85^a

60, 85^a

50, 82^a

CO₂CH₃

CH₃/4-ClC₆H₄

C₆H₅/H

4-ClC₆H₄/H

4-FC₆H₄/H

CH₃

C₆H₅

4-ClC₆H₄

4-CH₃OC₆H₄

4-NO₂C₆H₄

C₆H₅

b-C₅H₄N

2-CH₃OC₆H₄

2,4-(CH₃)₂C₆H₃

C₆H₅

4-BrC₆H₄

4-OHe3-CH₃OC₆H₃

4-ClC₆H₄

4-OHe3-CH₃OC₆H₃

4-BrC₆H₄

2-CH₃OC₆H₄

2,4-(CH₃)₂C₆H₃

4-BrC₆H₄

Yields of the transformations of compounds 4 and 6.

9392

E.A. Muravyova et al. / Tetrahedron 67 (2011) 9389e9400

R²

having opposite location of two substituents in pyrimidine ring

(Scheme 3). Compounds 6aee at reﬂux in DMF for 3 h can be easily

transformed into heterocycles 7aee in 82e90% yields (Table 1).

The presence of a methyl or aryl substituent in the fourth po-

sition of 5-aminopyrazole changes its behavior in the multicom-

ponent reaction with acetoacetamides and aldehydes. It was

established that treatment of the starting materials 1fei, 2b,c, and

3bef in EtOH at room temperature gave the expected tetrahy-

dropyrazolopyrimidines 8aei (Scheme 4, Table 1), whereas ther-

modynamic controlled reactions (reﬂuxing in EtOH or DMF) of the

same compounds never yielded heterocycles 9 being ‘classical’

products of such treatments. Instead of them the mixtures of

compounds 10, 11, and 12 were isolated. In order to carry out their

identiﬁcation analytical samples of representatives of compounds

11 (R¼CH₃, R³¼4-ClC₆H₄) and 12 (R¼4-FC₆H₄, R¹¼C₆H₅, R²¼4-

OHe3-CH₃OC₆H₃, R³¼H) were obtained.

R¹

13a-e

R¹

R = CH₃

R²

DMF,

+2a,b,d + 3b,d,f-o

NH₂

-2H₂O

14a-e

1j-m

R²

R¹

R = Ar

15a-l

DMF, 25 ^oC, )))

-H₂O

R²

Scheme 5.

component. Application of aldehydes 3d,hej containing electron-

withdrawing groups in para-position led to the formation of py-

rimidine ring (compounds 13aee) while a presence of

p-electron-

donating substituents (aldehydes 3g,ken) switched the direction

toward 3,6-dimethyl-N,4-diaryl-4,7-dihydropyrazolo-[3,4-b]pyri-

dine-5-carboxamides (14aee).

EtOH, 25 ^oC

)))

-H₂O

R¹

R³

R²

8a-i

N NH

NH₂

+ 2b,c + 3b-f

R³

Realization of the different directions in the three-component

reactions involving 3-methyl- or 3-aryl-substituted 5-

aminopyrazoles concerned, in our opinion, with sterical inﬂuence

of the substituent: in the case of methyl-derivative both 4-CH and

1-NH centers are accessible for other reagents while 3-aryl ring due

to its size prevents participation of 4-CH center in the treatment

that leads to the formation of dihydropyrimidine nucleus only. A

similar inﬂuence of the character of the substituents in 5-

aminopyrazoles on the direction of multicomponent reactions

was observed and discussed in our earlier publications.^10c,d

EtOH or DMF

R₂

R¹

1f-i

R³

9a-i

R²

N NH

R³

R²

R¹

Scheme 4.

In the case of kinetic controlled reactions after isolation of the

main products and evaporation of the mother liquor in the rest

formed with help of ¹H NMR a presence of target compounds (up to

7%), corresponding azomethines of aldehydes and aminozoles,

starting acetoacetamides, and several undeﬁned products in minor

amounts were found. Very similar situation, excepting azomethine,

was observed for the thermodynamic controlled reactions.

Our attempts to carry out dehydration of tetrahydroazolopyr-

imidines 4, 6, and 8 were unsuccessful: heating in ethanol in the

presence of HCl or p-TsOH led to their recyclization or de-

composition (in the case of 8) while at room temperature only the

starting heterocycles were quantitatively isolated from the reaction

mixture.

Another situation was observed for the multicomponent re-

actions between aldehydes, acetoacetamides, and 3-substituted 5-

aminopyrazoles. In this case direction of the treatment was

strongly depended on the character of substituents in pyrazole and

aldehyde while changing temperature regime did not give the ex-

pected results. It was found that three-component reaction of

aminopyrazoles 1jem, amides 2a,b,d, and aldehydes 3b,d,feo in

DMF at room temperature yielded only corresponding imines 16

(Scheme 5) in 50e70% yields. On the other hand, increasing the

temperature led to the formation of heterocyclized compounds,

though, their structures were different.

2.2. Structure determination

Identiﬁcation of all the compounds synthesized was made with

help of elemental analysis, MS spectrometry, NMR spectroscopy,

and X-ray study.

Physicochemical characteristics and spectra of dihydro-

triazolopyrimidines 5 were in good accordance with the data de-

scribed for these types of compounds in earlier publications.^8d,hTo

determine structures of heterocycles 7, 13e15 the algorithm used

before for similar compounds^8d,9,10awas applied. Spectra of azo-

methines 16 were in a good accordance with known data.¹²

The ¹H NMR spectra ofheterocycles 4, 6, and 8 showed duplication

of some signals due to the presence of two diastereomeric pairs. ¹H

NMR spectra of the main stereoisomers of these compounds contain

two doublets for the CH-protons of the pyrimidine ring at

3.08e4.97 ppm with J w11.2e11.7 Hz corresponding to their trans-

orientation. In addition a singlet for the CH-group of the pyrazole ring

(compounds 6aee, 8aei) at 7.6e7.8 ppm as well as multiplets for the

aromatic rings (6.4e7.7 ppm), signals for the NH-group of the py-

rimidineringatca. 6.3e7.0 ppm, amideNHat8.8e9.7 ppm, OHgroup

at 6.5e7.77 ppm, and signals for the other terminal substituents at

appropriate positions were found. For the minor stereoisomers, ob-

served in amounts up to w5%, practically all signals were down-ﬁeld

shifted for 0.2e0.4 ppm while spinespin coupling constants of CH

protons of tetrahydropyrimidine ring were the same (11.4e12.0 Hz)

and corresponded to trans-conﬁguration of these stereogenic centers

as well. It means that for minor stereoisomer relative orientation of

OHeCeCH₃moiety changes in comparison with major one.

3-Aryl-5-aminopyrazoles 1kem in their three-component re-

action with aldehydes and acetoacetamides in boiling DMF gave

exclusively 5-methyl-N,2,7-triaryl-4,7-dihydropyrazolo[1,5-a]py-

rimidine-6-carboxamides (15ael). In the case of 5-amino-3-

methylpyrazole (1j) proceeding the similar treatments was am-

biguous and depended on the substituent in the aldehyde

The spectral data obtained for the compounds 4, 6, and 8 may

correspond to several possible regioisomers. For example, for the

E.A. Muravyova et al. / Tetrahedron 67 (2011) 9389e9400

9393

products of three-component reaction involving 5-alkylthio-3-

amino-1,2,4-triazoles according to ¹H and ¹³C NMR may be

assigned several different structures AeD (Fig. 1).

C2eC15eN5eC16 torsion angle is ꢁ171.2(2)^ꢀ) and is turned with

respect to the amide fragment (the C17eC16eN5eC15 torsion angle

is ꢁ62.3(3)^ꢀ).

3. Conclusions

R²

R₁

In summary, the direction of the multicomponent reactions be-

tween aminoazoles, aldehydes, and acetoacetamides depends on the

temperature regime and structure of the starting materials, which

allows controlling chemoselectivity. Thus, three-component hetero-

cyclizations involving 3-amino-1,2,4-triazoles or 4-substututed 5-

aminopyrazoles can proceed under kinetic control (ultrasonication

at room temperature) yielding 4,5,6,7-tetrahydrozolo[1,5-a]pyrimi-

dine-6-carboxamides. Under thermodynamic control (at reﬂux in an

appropriate solvent) 5-aminopyrazole having in the fourth position

electron-withdrawing substituents (CN, CO₂CH₃, CONH₂) gives 4,7-

dihydropyrazolo[1,5-a]pyrimidine-6-carboxamides while in the

case of methyl or aryl substituents heterocycles of this type are not

formed. Direction of the treatments involving 3-substituted 5-

aminopyrazoles under reﬂux depends on the structure both of ami-

noazoles and aldehydes, which allows to synthesize either pyr-

azolopyridine or pyrazolopyrimidine heterocyclic systems. The same

treatments under ultrasonication at room temperature yields no

heterocyclic compound but only corresponding azomethines.

R²

R¹

R²

Fig. 1. Possible isomers (AeD), stereochemistry of main diastereomers, and some

ROESY (1) and HMBC (2, 3) correlations for compounds 4.

ROESYand HMBC experiments allowed conﬁrming the structure

of type B for the compounds synthesized and establishing their

stereochemistry were carried out (Fig. 1). The same approach was

applied for the compounds 6 and 8. Additionally, the structures of

pyrazolopyrimidines 6 were unequivocally established by X-ray

diffraction analysis of a single crystal of one diastereomer of com-

pound 6d, which allowed assignment of the structure as 3-cyano-7-

hydroxy-N-(2-methoxyphenyl)-7-methyl-5-phenyl-4,5,6,7-

tetrahydropyrazolo-[1,5-a]pyrimidine-6-carboxamide (Fig. 2).

The tetrahydropyrimidine ring of the compound 6d adopts an

asymmetric half-chair conformation where the deviations of the C1

and C2 atoms from the mean plane of the remaining atoms of the

ring are 0.19 A and ꢁ0.60 A, respectively. The hydroxyl substituent

has an axial orientation while other substituents in tetrahydropyr-

imidine ring have an equatorial orientation (the O1eC3eN2eC4,

C8eC3eN2eC4, C15eC2eC3eN2, and C9eC1eN1eC4 torsion an-

gles are ꢁ86.2(3)^ꢀ, 150.8(3)^ꢀ, 176.4(2)^ꢀ, and ꢁ166.9(2)^ꢀ, re-

spectively). The phenyl substituent and the amide fragment are

turned almost orthogonal to the C1eC2 endocyclic bond (the

C1eC2eC15eO2 and C2eC1eC9eC10 torsion angles are 94.4(2)^ꢀ

and 97.8(3)^ꢀ, respectively). The orientation of the amide fragment is

stabilized additionally by the N5eH/O1 intramolecular hydrogen

4. Experimental part

4.1. General

The melting points of all compounds synthesized were de-

termined with a Gallenkamp melting point apparatus. The NMR

spectra were recorded in DMSO-d₆at 400 MHz (100 MHz for ¹³C)

and at 200 MHz (50 MHz for ¹³C) with a Varian Unity Plus-400 and

Varian Mercury VX-200 spectrometers. The MS spectra were

measured on a GCeMS Varian 1200L (ionizing voltage 70 eV) in-

strument. Elemental analysis was realized on EuroVector EA-3000.

Analytical samples of the compounds were obtained by their re-

crystallization from ethanol and further drying in vacuum at room

temperature.

ꢀ

Sonication was carried out with the help of standard ultrasonic

bath producing irradiation at 44.2 kHz. Microwave experiments

were performed using the EmrysÔ Creator EXP from Biotage AB

(Uppsala, Sweden) possessing a single-mode microwave cavity

producing controlled irradiation at 2.45 GHz.

ꢀ

bond (H/O 2.16 A NeH/O 131 ). The methoxyphenyl substituent is

located in ap-conformation relatively to the C2eC15 bond (the

The syntheses of 3-amino-5-alkylthio-1,2,4-triazoles 1a,b,^13a,bof

5-aminopyrazoles 1c,d,^13c,d1jen,^13eand of acetoacetamides 2aed^13f

were carried out according to known methods. Solvents, other

aminoazoles, and aromatic aldehydes were commercially available

and used without additional puriﬁcation.

4.2. X-ray diffraction data

The colorless crystals of 6d (C₂₂H₂₁N₅O₃) are monoclinic. At

¼91.75(1)^ꢀ,

ꢀ

293 K a¼11.805(1), b¼8.380(1), c¼19.578(3) A,

ꢀ

V¼1935.9(5) A , M_r¼403.44, Z¼4, space group P2₁/n,

d_calcd¼1.384 g/cm³,

(Mo

)¼0.095 mm^ꢁ1

F(000)¼848. In-

tensities of 12,636 reﬂections (3392 independent, R_int¼0.110)

were measured on the ‘Xcalibur-3’ diffractometer (graphite

monochromated Mo K

a radiation, CCD detector, u-scanning,

q_max¼50^ꢀ). The structure was solved by direct method using

SHELXTL package.¹⁴Positions of the hydrogen atoms were located

from electron density difference maps and reﬁned by ‘riding’

model with U_iso¼nU_eqof the carrier atom (n¼1.5 for methyl and

hydroxy group and n¼1.2 for other hydrogen atoms). Full-matrix

least-squares reﬁnement against F²in anisotropic approximation

for non-hydrogen atoms using 3364 reﬂections was converged to

Fig. 2. Molecular structure of compound 6d according to X-ray diffraction data.

9394

E.A. Muravyova et al. / Tetrahedron 67 (2011) 9389e9400

wR2¼0.037 (R1¼0.033 for 1108 reﬂections with F>4

(F),

pyrimidine-6-carboxamide (4d). Yield 450 mg (85%) of colorless

prisms, mp 163e165 ^ꢀC. [Found: C, 65.8; H, 5.9; N, 13.2.

C₂₉H₃₁N₅O₃S requires C, 65.76; H, 5.90; N, 13.22%]; d_H(200 MHz,

DMSO-d₆) 1.12 (3H, t, J 7.1 Hz, CH₃), 1.79 (3H, s, CH₃), 2.54 (2H, q, J

7.1 Hz, CH₂), 3.25 (1H, d, J 11.4 Hz, 6-CH), 3.75 (3H, s, CH₃O), 4.20

(1H, d, J 13.0 Hz, CH), 4.25 (1H, d, J 13.0 Hz, CH), 4.85 (1H, d, J

11.4 Hz, 5-CH), 6.98 (1H, s, 4-NH), 6.79e7.52 (13H, m, ArH), 7.76 (1H,

s, OH), 9.28 (1H, s, CONH); d_C(50 MHz, DMSO-d₆) 15.4, 24.4, 27.7,

34.6, 53.5, 55.7, 57.6, 81.1, 111.1, 120.0, 121.6, 122.3, 124.4, 126.5,

126.9, 127.3, 128.2, 128.7, 136.3, 138.1, 143.3, 149.4, 153.3, 155.9,

166.1; MS (EI, 70 eV): m/z (%)¼529 (1.1) [M^þ], 322 (99.9), 323 (56.2),

294 (26.6), 289 (31.6), 207 (37.0), 149 (27.2),123 (97.1),108 (87.4), 91

(71.9).

S¼0.515). The ﬁnal atomic coordinates, and crystallographic data

for molecule 6d have been deposited to with the Cambridge

Crystallographic Data Centre, 12 Union Road, CB2 1EZ, UK (fax:

þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk) and are

available on request quoting the deposition numbers CCDC

818957.

4.3. General procedure for the ultrasonic promoted synthesis

of 2-alkylthio-N,5-diaryl-7-hydroxy-7-methyl-4,5,6,7-

tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamides

4aeg

A mixture of aminoazole 1a,b (1 mmol), acetoacetamide 2aec

(1 mmol), and aromatic aldehyde 3aee (1 mmol) in 10 mL of eth-

anol was ultrasonicated at room temperature for 90 min in a round-

bottom ﬂask equipped with a condenser. The reaction mixture was

allowed to stand up to 12 h at room temperature and then was

ﬁltered out to give the solid compounds 4aeg, which were then

washed with ethanol and air dried. Reaction products were ob-

tained in high purity and did not require further puriﬁcation by

recrystallization.

4.3.5. 2-(Benzylthio)-5-(4-bromophenyl)-7-hydroxy-N-(2-

methoxyphenyl)-7-methyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]py-

rimidine-6-carboxamide (4e). Yield 406 mg (70%) of colorless

prisms, mp 177e178 ^ꢀC. [Found: C, 55.8; H, 4.5; N, 12.0.

C₂₇H₂₆BrN₅O₃S requires C, 55.87; H, 4.51; N, 12.06%]; d_H(200 MHz,

DMSO-d₆) 1.79 (3H, s, CH₃), 3.26 (1H, d, J 11.7 Hz, 6-CH), 3.75 (3H, s,

OCH₃), 4.23 (1H, d, J 13.0 Hz, CH), 4.29 (1H, d, J 13.0 Hz, CH), 4.88

(1H, d, J 11.7 Hz, 5-CH), 6.99 (1H, s, 4-NH), 6.81e7.52 (13H, m, ArH),

7.84 (1H, s, OH), 9.31 (1H, s, CONH); MS (EI, 70 eV): m/z (%)¼580

(1.0) [M^þ], 561 (2.4), 376 (11.8), 375 (42.8), 374 (99.9), 254 (10.5),

253 (55.4), 252 (13.5), 251 (55.4), 196 (16.4), 195 (10.0), 194 (29.5),

191 (12.2), 190 (78.8), 134 (16.5), 131 (31.3), 102 (35.6), 91 (58.2), 65

(42.4), 43 (43.4).

4.3.1. 5-(4-Ethylphenyl)-2-(ethylthio)-7-hydroxy-7-methyl-N-phe-

nyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide

(4a). Yield 371 mg (85%) of colorless prisms, mp 177e178 ^ꢀC.

[Found: C, 63.2; H, 6.2; N, 16.0. C₂₃H₂₇N₅O₂S requires C, 63.13; H,

6.22; N, 16.01%]; d_H(200 MHz, DMSO-d₆) 1.09 (3H, t, J 7.1 Hz, CH₃),

1.28 (3H, t, J 7.3 Hz, CH₃), 1.75 (3H, s, CH₃), 2.54 (2H, q, J 7.1 Hz, CH₂),

2.97 (2H, q, J 7.3 Hz, SCH₂), 3.08 (1H, d, J 11.4 Hz, 6-CH), 4.98 (1H, d, J

11.4 Hz, 5-CH), 6.69 (1H, s, 4-NH), 6.99e7.46 (9H, m, ArH), 7.68 (1H,

s, OH), 9.69 (1H, s, CONH); d_C(50 MHz, DMSO-d₆) 15.1, 15.3, 26.3,

28.0, 30.7, 59.8, 113.6, 113.8, 115.6, 119.0, 119.4, 123.7, 128.4, 128.6,

128.7, 128.8, 130.0, 137.0, 138.9, 139.5, 146.7, 165.0, 165.7; MS (EI,

70 eV): m/z (%)¼437 (1.0), 301 (3.5), 261 (18.8), 260 (85.5), 231

(20.3), 227 (28.2), 177 (48.7), 159 (17.5), 132 (13.7), 117 (12.6), 93

(99.9), 77 (17.2), 65 (27.8), 43 (33.7).

4.3.6. 2-(Benzylthio)-7-hydroxy-N-(2-methoxyphenyl)-7-methyl-5-

phenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-6-

carboxamide (4f). Yield 430 mg (86%) of colorless prisms, mp

177e178 ^ꢀC. [Found: C, 64.6; H, 5.4; N, 13.9. C₂₇H₂₇N₅O₃S requires C,

64.65; H, 5.43; N, 13.96%]; d_H(200 MHz, DMSO-d₆) 1.80 (3H, s, CH₃),

3.27 (1H, d, J 11.4 Hz, 6-CH), 3.75 (3H, s, CH₃O), 4.22 (H, d, J 12.0 Hz,

CH), 4.30 (H, d, J 12.0 Hz, CH), 4.89 (1H, d, J 11.4 Hz, 5-CH), 6.98 (1H,

s, 4-NH), 6.78e7.50 (14H, m, ArH), 7.81 (1H, s, OH), 9.31 (1H, s,

CONH); d_C(50 MHz, DMSO-d₆) 25.3, 35.7, 54.9, 56.8, 58.8, 82.1,

112.3, 121.0, 122.5, 125.3, 127.7, 128.7, 128.8, 129.0, 129.5, 139.0,

139.8, 150.5, 154.2, 156.9, 167.0; MS (EI, 70 eV): m/z (%)¼501 (1.0)

[M^þ], 294 (81.2), 261 (47.1), 207 (38.0), 173 (16.8), 149 (41.3), 131

(11.6), 123 (56.8), 108 (74.1), 91 (99.9), 43 (13.0).

4.3.2. 5-(4-Chlorophenyl)-2-(ethylthio)-7-hydroxy-7-methyl-N-phe-

nyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide

(4b). Yield 244 mg (55%) of colorless prisms, mp 179e180 ^ꢀC.

[Found: C, 56.8; H, 5.0; N, 15.8. C₂₁H₂₂ClN₅O₂S requires C, 56.81; H,

4.99; N, 15.77%]; d_H(200 MHz, DMSO-d₆) 1.28 (3H, t, J 7.1 Hz, CH₃),

1.76 (3H, s, CH₃), 2.98 (2H, q, J 7.1 Hz, SCH₂), 3.08 (1H, d, J 11.4 Hz, 6-

CH), 5.00 (1H, d, J 11.4 Hz, 5-CH), 6.78 (1H, s, 4-NH), 6.99e7.54 (9H,

m, ArH), 7.78 (1H, s, OH), 9.72 (1H, s, CONH); MS (EI, 70 eV): m/z

(%)¼443 (1.4) [M^þ], 267 (17.2), 266 (65.8), 265 (44.5), 235 (13.8),

234 (7.5), 233 (56.5), 177 (20.0), 173 (19.7), 167 (30.7), 166 (8.9), 165

(63.1), 139 (8.5), 138 (24.8), 137 (16.6), 77 (36.1), 43 (99.9), 42 (11.3).

4.3.7. 2-(Benzylthio)-5-(4-ethylphenyl)-7-hydroxy-N-(4-

methoxyphenyl)-7-methyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]py-

rimidine-6-carboxamide (4g). Yield 344 mg (65%) of colorless

prisms, mp 162e164 ^ꢀC. [Found: C, 65.7; H, 5.9; N, 13.2.

C₂₉H₃₁N₅O₃S requires C, 65.76; H, 5.90; N, 13.22%]; d_H(200 MHz,

DMSO-d₆) 1.13 (3H, t, J 7.1 Hz, CH₃), 1.79 (3H, s, CH₃), 2.56 (2H, q, J

7.1 Hz, CH₂), 3.25 (1H, d, J 11.4 Hz, 6-CH), 3.75 (3H, s, CH₃O), 4.23

(1H, d, J 13.4 Hz, CH), 4.29 (1H, d, J 13.4 Hz, CH), 4.85 (1H, d, J

11.4 Hz, 5-CH), 6.76e7.51 (13H, m, ArH), 6.98 (1H, s, 4-NH), 7.74 (1H,

s, OH), 9.27 (1H, s, CONH); MS (EI, 70 eV): m/z (%)¼529 (1.0) [M^þ],

323 (7.1), 322 (25.0), 289 (18.0), 207 (18.5), 159 (17.0), 123 (42.6),

108 (99.9), 91 (78.7), 65 (18.3), 43 (28.7).

4.3.3. 2-(Benzylthio)-7-hydroxy-7-methyl-5-(4-methylphenyl)-N-

phenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-6-

carboxamide (4c). Yield 267 mg (55%) of colorless prisms, mp

180e181 ^ꢀC. [Found: C, 66.8; H, 5.6; N,14.4. C₂₇H₂₇N₅O₂S requires C,

66.78; H, 5.60; N, 14.42%]; d_H(200 MHz, DMSO-d₆) 1.76 (3H, s, CH₃),

2.22 (3H, s, CH₃), 3.08 (1H, d, J 11.4 Hz, 6-CH), 4.18 (H, d, J 13.0 Hz,

CH), 4.22 (H, d, J 13.0 Hz, CH), 4.96 (1H, d, J 11.4 Hz, 5-CH), 6.71 (1H,

s, 4-NH), 6.96e7.41 (14H, m, ArH), 7.71 (1H, s, OH), 9.70 (1H, s,

CONH); d_C(50 MHz, DMSO-d₆) 21.3, 25.8, 35.7, 53.9, 58.4, 82.3,

120.7,124.4,127.7,128.7,129.0,129.2, 129.3, 129.5, 137.1,137.8,138.8,

139.0, 154.2, 156.9, 167.1; MS (EI, 70 eV): m/z (%)¼485 (1.1) [M^þ],

399 (1.9), 309 (33.3), 308 (99.9), 275 (33.6), 177 (65.1), 145 (27.7),

105 (16.3), 93 (30.0), 91 (20.7), 77 (23.7), 43 (29.5).

4.4. General procedure for the synthesis 2-alkylthio-N,7-

diaryl-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-

6-carboxamide 5aeg

A mixture of aminoazole 1a,b (1 mmol), acetoacetamide 2aec

(1 mmol), and aromatic aldehyde 3aee (1 mmol) in 0.1 mL of DMF

was heated to reﬂux for 10 min. Then after cooling acetone (10 mL)

was added and the precipitate formed was ﬁltered out to give the

solid compounds 5aeg, which were washed with acetone and air

dried.

4.3.4. 2-(Benzylthio)-5-(4-ethylphenyl)-7-hydroxy-N-(2-

methoxyphenyl)-7-methyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]

E.A. Muravyova et al. / Tetrahedron 67 (2011) 9389e9400

9395

Microwave-assisted synthesis of compounds 5aeg was carried

DMSO-d₆) 18.1, 35.8, 56.5, 61.2, 104.2,112.1,120.9,123.1,125.3, 127.6,

128.0,128.9,129.2,129.4,138.4,138.8,141.1,149.2,151.0,158.2,165.1;

MS (EI, 70 eV): m/z (%)¼483 (10.0), 392 (10.3), 361 (47.7), 360 (15.2),

334 (23.7), 241 (11.4), 149 (14.9), 123 (98.3), 122 (15.0), 91 (99.9).

out according to the earlier described procedure.^8d

4.4.1. 7-(4-Ethylphenyl)-2-(ethylthio)-5-methyl-N-phenyl-4,7-

dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide (5a). Yield

378 mg (90%) of colorless prisms, mp >300 ^ꢀC. [Found: C, 65.9; H,

6.0; N, 16.7. C₂₃H₂₅N₅OS requires C, 65.85; H, 6.01; N, 16.69%]; d_H

(200 MHz, DMSO-d₆) 1.10 (3H, t, J 7.1 Hz, CH₃), 1.22 (3H, t, J 7.5 Hz,

CH₃), 2.14 (3H, s, CH₃), 2.54 (2H, q, J 7.1 Hz, CH₂), 2.94 (2H, q, J 7.5 Hz,

SCH₂), 6.42 (1H, s, 7-CH), 6.95e7.51 (9H, m, ArH), 9.71 (1H, s,

CONH), 10.22 (1H, s, NH). d_C(50 MHz, DMSO-d₆) 15.7, 15.8, 17.9,

26.0, 28.4, 60.8, 105.0, 120.5, 124.0, 127.6, 128.5, 129.1, 136.8, 138.7,

139.7, 144.3, 149.4, 158.4, 165.5. MS (EI, 70 eV): m/z (%)¼419 (10.0)

[M^þ], 358 (15.6), 327 (46.7), 183 (10.5), 161 (21.7), 154 (12.1), 141

(32.4), 132 (18.6), 128 (25.9), 120 (36.5), 119 (35.0), 103 (21.3), 93

(99.5), 92 (99.9), 91 (70.1), 77 (63.6), 67 (37.1), 61 (35.6).

4.4.7. 2-(Benzylthio)-7-(4-ethylphenyl)-N-(4-methoxyphenyl)-5-

methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide

(5g). Yield 460 mg (90%) of colorless prisms, mp 260e262 ^ꢀC.

[Found: C, 68.1; H, 5.7; N, 13.7. C₂₉H₂₉N₅O₂S requires C, 68.08; H,

5.71; N, 13.69%]; d_H(200 MHz, DMSO-d₆) 1.12 (3H, t, J 7.3 Hz, CH₃),

2.13 (3H, s, CH₃), 2.53 (2H, q, J 7.3 Hz, CH₂), 3.67 (3H, s, CH₃O), 4.14

(1H, d, J 13.4 Hz, CH), 4.16 (1H, d, J 13.4 Hz, CH), 6.42 (1H, s, 7-CH),

6.78e7.42 (13H, m, ArH), 9.62 (1H, s, CONH), 10.22 (1H, s, NH); d_C

(50 MHz, DMSO-d₆) 15.8, 17.8, 28.4, 35.8, 56.0, 60.9, 105.1, 114.6,

122.2, 127.7, 128.4, 128.9, 129.4, 132.9, 136.3, 138.6, 138.8, 144.3,

149.5, 156.3, 158.1, 165.2; MS (EI, 70 eV): m/z (%)¼511 (4.5) [M^þ],

389 (21.5), 362 (69.1), 330 (18.9), 329 (79.9), 172 (12.7), 170 (27.4),

157 (14.2), 149 (34.9), 142 (20.9), 141 (37.4), 128 (24.9), 115 (46.3), 91

(99.9), 80 (53.1), 78 (85.0), 65 (40.2), 52 (56.8), 51 (51.9).

4.4.2. 7-(4-Chlorophenyl)-2-(ethylthio)-5-methyl-N-phenyl-4,7-

dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide (5b). Yield

341 mg (80%) of colorless prisms, mp >300 ^ꢀC. [Found: C, 59.2; H,

4.7; N, 16.4. C₂₁H₂₀ClN₅OS requires C, 59.22; H, 4.73; N, 16.44%]; d_H

(200 MHz, DMSO-d₆) 1.21 (3H, t, J 7.5 Hz, CH₃), 2.14 (3H, s, CH₃), 2.93

(2H, q, J 7.5 Hz, SCH₂), 6.45 (1H, s, 7-CH), 6.96e7.49 (9H, m, ArH), 9.73

(1H, s, CONH), 10.32 (1H, s, NH); MS (EI, 70 eV): m/z (%)¼425 (25.0)

[M^þ], 335 (22.9), 334 (12.1), 333 (51.7), 273 (16.9), 165 (21.0), 163

(11.2), 129 (18.0), 128 (62.2), 127 (98.3), 102 (11.0), 101 (14.8), 93

(38.0), 92 (22.7), 85 (34.4), 67 (99.9), 66 (44.1), 65 (57.9), 43 (13.0).

4.5. General procedure for the synthesis N,5-diaryl-7-

hydroxy-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]

pyrimidine 6aee

A mixture of aminoazole 1cee (1 mmol), acetoacetamide 2a,b,d

(1 mmol), and aromatic aldehyde 3b,deg (1 mmol) in 10 mL of eth-

anol was ultrasonicated at room temperature for 90 min in a round-

bottom ﬂask equipped with a condenser. The reaction mixture was

allowed to stand up to 12 h at room temperature and then was ﬁl-

tered out to give the solid compounds 6aee, which were washed

with ethanol and air dried. Reaction products were obtained in high

purity and did not require further puriﬁcation by recrystallization.

4.4.3. 2-(Benzylthio)-5-methyl-7-(4-methylphenyl)-N-phenyl-4,7-

dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide

(5c). Yield

397 mg (85%) of colorless prisms, mp 290e292 ^ꢀC. [Found: C, 69.4;

H, 5.4; N, 15.0. C₂₇H₂₅N₅OS requires C, 69.35; H, 5.39; N, 14.98%]; d_H

(200 MHz, DMSO-d₆) 2.13 (3H, s, CH₃), 2.23 (3H, s, CH₃), 4.12 (H, d, J

13.4 Hz, CH), 4.16 (H, d, J 13.4 Hz, CH), 6.41 (1H, s, 7-CH), 6.95e7.51

(14H, m, ArH), 9.73 (1H, s, CONH),10.24 (1H, s, NH). MS (EI, 70 eV): m/

z (%)¼467 (2.7) [M^þ], 376 (9.4), 375 (15.9), 344 (12.9), 128 (15.7), 91

(99.9), 90 (9.7).

4.5.1. 7-Hydroxy-5-(4-hydroxy-3-methoxyphenyl)-7-methyl-N⁶-

phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3,6-

dicarboxamide (6a). Yield 371 mg (85%) of colorless prisms, mp

164e165 ^ꢀC. [Found: C, 60.4; H, 5.3; N, 16.0. C₂₂H₂₃N₅O₅requires C,

60.40; H, 5.30; N, 16.01%]; d_H(200 MHz, DMSO-d₆) 1.82 (3H, s, CH₃),

3.19 (1H, d, J 11.7 Hz, 6-CH), 3.69 (3H, s, CH₃O), 4.94 (1H, d, J 11.7 Hz,

5-CH), 6.37 (1H, s, 4-NH), 6.58 (1H, s, OH), 6.68e7.39 (8H, m, ArH),

7.36 (2H, br s, CONH₂), 7.71 (1H, s, 2-CH), 8.96 (1H, s, NH), 9.74 (1H,

s, OH); d_C(50 MHz, DMSO-d₆) 26.8, 53.0, 56.6, 58.2, 82.5, 96.4, 112.7,

116.9,120.1,120.7,124.1,126.0,129.3,130.9,140.4,147.4,150.3,164.4,

166.5; MS (EI, 70 eV): m/z (%)¼437 (10.1) [M^þ], 311 (1.2), 310 (2.8),

177 (24.2), 126 (21.7), 119 (38.9), 95 (43.1), 93 (99.9), 65 (27.2).

4.4.4. 2-(Benzylthio)-7-(4-ethylphenyl)-N-(2-methoxyphenyl)-5-

methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide

(5d). Yield 435 mg (85%) of colorless prisms, mp 240e242 ^ꢀC.

[Found: C, 68.1; H, 5.7; N, 13.7. C₂₉H₂₉N₅O₂S requires C, 68.08; H,

5.71; N, 13.69%]; d_H(200 MHz, DMSO-d₆) 1.14 (3H, t, J 7.3 Hz, CH₃),

2.22 (3H, s, CH₃), 2.55 (2H, q, J 7.3 Hz, CH₂), 3.71 (3H, s, OCH₃), 4.14 (H,

d, J 13.4 Hz, CH), 4.16 (H, d, J 13.4 Hz, CH), 6.37 (1H, s, 7-CH), 6.81e7.64

(13H, m, ArH), 8.70 (1H, s, CONH), 10.29 (1H, s, NH); MS (EI, 70 eV):

m/z (%)¼511 (22.2) [M^þ], 363 (12.2), 362 (42.9), 329 (23.3), 271

(10.4),170(14.4),150(13.1),149 (99.9),120 (20.5), 91 (28.1), 51 (12.5).

4.5.2. 5-(3,4-Dimethoxyphenyl)-N⁶-(2,4-dimethylpheny)l-7-

hydroxy-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3,6-

dicarboxamide (6b). Yield 408 mg (85%) of colorless prisms, mp

195e196 ^ꢀC. [Found: C, 62.6; H, 6.1; N, 14.6. C₂₅H₂₉N₅O₅requires C,

62.62; H, 6.10; N, 14.60%]; d_H(200 MHz, DMSO-d₆) 1.78 (3H, s, CH₃),

1.89 (3H, s, CH₃), 2.18 (3H, s, CH₃), 3.25 (1H, d, J 11.5 Hz, 6-CH), 3.72

(6H, s, 2CH₃O), 4.91 (1H, d, J 11.5 Hz, 5-CH), 6.43 (1H, s, 4-NH), 6.63

(1H, s, OH), 6.80e7.08 (6H, m, ArH), 7.25 (2H, br s, CONH₂), 7.72 (1H,

s, 2-CH), 9.27 (1H, s, NH); d_C(50 MHz, DMSO-d₆) 17.8, 21.0, 25.5,

54.0, 56.6, 57.4, 82.5, 96.5, 113.2, 121.5, 125.8, 127.0, 131.4, 132.6,

133.6,135.5,138.2,147.4,149.8,150.1,166.5,167.9; MS (EI, 70 eV): m/

z (%)¼479 (8.8) [M^þ], 419 (1.0), 203 (9.5), 202 (85.7), 200 (78.9), 82

(25.2), 81 (31.0), 77 (53.6), 76 (99.3), 51 (99.9), 45 (49.0).

4.4.5. 2-(Benzylthio)-7-(4-bromophenyl)-N-(2-methoxyphenyl)-5-

methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide

(5e). Yield 478 mg (85%) of colorless prisms, mp >300 ^ꢀC. [Found:

C, 57.6; H, 4.3; N, 12.4. C₂₇H₂₄BrN₅O₂S requires C, 57.65; H, 4.30; N,

12.45%]; d_H(200 MHz, DMSO-d₆) 2.13 (3H, s, CH₃), 3.67 (3H, s,

CH₃O), 4.12 (1H, d, J 13.2 Hz, CH), 4.20 (1H, d, J 13.2 Hz, CH), 6.42

(1H, s, 7-CH), 6.79e7.54 (13H, m, ArH), 9.62 (1H, s, CONH), 10.30

(1H, s, NH); MS (EI, 70 eV): m/z (%)¼562 (10.5) [M^þ], 414 (18.2), 149

(24.3), 124 (14.8), 123 (53.8), 91 (99.9).

4.4.6. 2-(Benzylthio)-N-(2-methoxyphenyl)-5-methyl-7-phenyl-4,7-

dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide

(5f). Yield

4.5.3. 5-(4-Bromophenyl)-3-cyano-7-hydroxy-N-(2-methoxyphenyl)-

7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carboxamide

(6c). Yield 410 mg (85%) of colorless prisms, mp 215e216 ^ꢀC.

[Found: C, 54.8; H, 4.2; N, 14.5. C₂₂H₂₀BrN₅O₃requires C, 54.78; H,

4.18; N, 14.52%]; d_H(200 MHz, DMSO-d₆) 1.84 (3H, s, CH₃), 3.33 (1H,

d, J 11.7 Hz, 6-CH), 3.75 (3H, s, CH₃O), 4.88 (1H, d, J 11.7 Hz, 5-CH),

435 mg (90%) of colorless prisms, mp 247e248 ^ꢀC. [Found: C, 67.0; H,

5.2; N, 14.5. C₂₇H₂₅N₅O₂S requires C, 67.06; H, 5.21; N, 14.48%]; d_H

(200 MHz, DMSO-d₆) 2.23 (3H, s, CH₃), 3.71 (3H, s, CH₃O), 4.14 (1H, d,

J 13.2 Hz, CH), 4.25 (1H, d, J 13.2 Hz, CH), 6.42 (1H, s, 7-CH), 6.81e7.59

(14H, m, ArH), 8.74 (1H, s, CONH), 10.31 (1H, s, NH); d_C(50 MHz,

9396

E.A. Muravyova et al. / Tetrahedron 67 (2011) 9389e9400

6.81e7.54 (8H, m, ArH), 7.00 (1H, s, 4-NH), 7.26 (1H, s, OH), 7.67 (1H,

s, 2-CH), 8.87 (1H, s, NH); MS (EI, 70 eV): m/z (%)¼482 (10.1) [M^þ],

373 (2.8), 275 (15.6), 274 (34.9), 211 (23.5), 209 (32.4), 207 (62.3),

182 (12.1), 149 (99.9), 120 (20.7), 65 (54.0).

302 mg (65%) of colorless prisms, mp 295e296 ^ꢀC. [Found: C, 56.9;

H, 3.9; N, 15.0. C₂₂H₁₈BrN₅O₂requires C, 56.91; H, 3.91; N, 15.08%];

d_H(200 MHz, DMSO-d₆) 2.25 (3H, s, CH₃), 3.73 (3H, s, CH₃O), 6.44

(1H, s, 7-CH), 6.84e7.58 (8H, m, ArH), 7.82 (1H, s, 2-CH), 8.87 (1H, s,

NH), 10.43 (1H, s, 4-NH); d_C(50 MHz, DMSO-d₆) 17.8, 56.4, 60.6,

73.5, 104.3, 112.1, 114.8, 122.1, 123.5, 125.6, 127.8, 130.1, 132.1, 137.3,

140.6, 142.8, 151.2, 164.9. MS (EI, 70 eV): m/z (%)¼464 (9.9) [M^þ],

465 (44.0), 343 (22.1), 342 (18.0), 108 (99.9).

4.5.4. 3-Cyano-7-hydroxy-N-(2-methoxyphenyl)-7-methyl-5-

phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carboxamide

(6d). Yield 343 mg (85%) of colorless prisms, mp 200e202 ^ꢀC.

[Found: C, 65.5; H, 5.2; N, 17.3. C₂₂H₂₁N₅O₃requires C, 65.50; H,

5.25; N, 17.36%]; d_H(200 MHz, DMSO-d₆) 1.84 (3H, s, CH₃), 3.31 (1H,

d, J 11.5 Hz, 6-CH), 3.75 (3H, s, CH₃O), 4.88 (1H, d, J 11.5 Hz, 5-CH),

6.74e7.50 (9H, m, ArH), 7.00 (1H, s, 4-NH), 7.26 (1H, s, OH), 7.66 (1H,

s, 2-CH), 9.28 (1H, s, NH); d_C(50 MHz, DMSO-d₆) 27.1, 54.7, 56.6,

56.8, 71.8, 82.6, 112.6, 121.0, 125.4, 128.7, 128.9, 129.3, 130.4, 130.8,

139.6, 141.2, 149.2, 166.9; MS (EI, 70 eV): m/z (%)¼403 (10.1) [M^þ],

294 (1.4), 196 (14.7), 131 (14.1), 123 (99.9), 120 (11.0), 108 (30.3), 80

(33.6), 78 (17.8), 64 (26.5).

4.6.4. 3-Cyano-N-(2-methoxyphenyl)-5-methyl-7-phenyl-4,7-

dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

(7d). Yield

230 mg (60%) of colorless prisms, mp 243e244 ^ꢀC. [Found: C, 68.5;

H, 4.9; N, 18.2. C₂₂H₁₉N₅O₂requires C, 68.54; H, 4.96; N, 18.15%]; d_H

(200 MHz, DMSO-d₆) 2.26 (3H, s, CH₃), 3.72 (3H, s, CH₃O), 6.44 (1H,

s, 7-CH), 6.79e7.59 (9H, m, ArH), 7.80 (1H, s, 2-CH), 8.81 (1H, s, NH),

10.39 (1H, s, 4-NH); MS (EI, 70 eV): m/z (%)¼385 (7.9) [M^þ], 221

(12.4), 192 (13.7), 159 (78.5), 158 (45.3), 157 (21.7), 155 (40.8), 133

(25.1), 129 (43.1), 128 (80.6), 127 (99.9), 123 (42.8), 102 (26.0), 94

(25.6), 67 (45.7), 65 (69.5).

4.5.5. Methyl-5-(4-chlorophenyl)-7-hydroxy-6-{[(2-methoxyphenyl)

amino]carbonyl}-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimi-

dine-3-carboxylate (6e). Yield 245 mg (52%) of colorless prisms, mp

207e209 ^ꢀC. [Found: C, 58.6; H, 4.9; N, 11.9. C₂₃H₂₃ClN₄O₅requires

C, 58.66; H, 4.92; N, 11.90%]; d_H(200 MHz, DMSO-d₆) 1.82 (3H, s,

CH₃), 3.30 (1H, d, J 11.7 Hz, 6-CH), 3.73 (3H, s, CH₃O), 3.75 (3H, s,

CH₃O), 4.86 (1H, d, J 11.7 Hz, 5-CH), 6.83e7.55 (8H, m, ArH), 7.01

(1H, s, 4-NH), 7.27 (1H, s, OH), 7.67 (1H, s, 2-CH), 8.89 (1H, s, NH);

MS (EI, 70 eV): m/z (%)¼470 (1.2) [M^þ], 469 (2.4), 330 (14.5), 261

(48.5), 209 (32.5), 150 (28.9), 139 (99.9), 111 (48.9), 59 (23.6).

4.6.5. Methyl-7-(4-chlorophenyl)-6-{[(2-methoxyphenyl)amino]car-

bonyl}-5-methyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-

carboxylate (7e). Yield 230 mg (50%) of colorless prisms, mp

230e231 ^ꢀC. [Found: C, 61.0; H, 4.6; N, 12.4. C₂₃H₂₁ClN₄O₄requires

C, 61.00; H, 4.67; N, 12.37%]; d_H(200 MHz, DMSO-d₆) 2.32 (3H, s,

CH₃), 3.73 (6H, s, 2CH₃O), 6.44 (1H, s, 7-CH), 6.84e7.55 (8H, m, ArH),

7.67 (1H, s, 2-CH), 8.89 (1H, s, NH), 8.96 (1H, s, 4-NH); d_C(50 MHz,

DMSO-d₆) 18.2, 51.3, 56.6, 60.3, 95.8, 104.8, 112.4, 121.0, 121.4, 125.5,

128.0, 129.1, 129.7, 133.6, 137.4, 140.5, 140.9, 141.2, 151.2, 163.3, 165.1.

MS (EI, 70 eV): m/z (%)¼452 (21.8) [M^þ], 454 (7.7), 453 (6.5), 330

(18.5), 300 (39.9), 299 (21.1), 298 (99.9).

4.6. General procedure for the synthesis of 5-methyl-N,7-

diaryl-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

7aee

4.7. General procedure for the synthesis of 7-hydroxy-7-

methyl-N,5-diaryl-4,5,6,7-tetrahydropyrazolo[1,5-a]-

pyrimidine-6-carboxamides 8aei

A mixture of aminoazole 1cee (1 mmol), acetoacetamide 2a,b,d

(1 mmol), and aromatic aldehyde 3b,deg (1 mmol) in 0.1 mL of DMF

was heated to reﬂux for 10 min. After cooling acetone (10 mL) was

added. The precipitate formed was ﬁltered out to give the solid

dihydropyrimidines 7aee, which were washed with acetone and air

dried.

A mixture of aminoazole 1fei (1 mmol), acetoacetamides 2aec

(1 mmol), and aromatic aldehyde 3bef (1 mmol) in 10 mL of

ethanol was ultrasonicated at room temperature for 90 min in

a round-bottom ﬂask equipped with condenser. The reaction

mixture was allowed to stand up to 12 h at room temperature and

then was ﬁltered to give the solid compounds 8aei, which were

washed with ethanol and air dried. Reaction products were ob-

tained in high purity and did not require further puriﬁcation by

recrystallization.

4.6.1. 7-(4-Hydroxy-3-methoxyphenyl)-5-methyl-N⁶-phenyl-4,7-

dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide

(7a). Yield

230 mg (55%) of colorless prisms, mp 284e285 ^ꢀC. [Found: C, 63.0;

H, 5.0; N, 16.6. C₂₂H₂₁N₅O₄requires C, 63.00; H, 5.05; N, 16.70%]; d_H

(200 MHz, DMSO-d₆) 2.23 (3H, s, CH₃), 3.61 (3H, s, CH₃O), 6.36 (1H,

s, 7-CH), 6.51e7.54 (8H, m, ArH), 7.01 (1H, s, CONH₂), 7.52 (1H, s,

CONH₂), 7.78 (1H, s, 2-CH), 8.57 (1H, s, NH), 8.96 (1H, s, OH), 9.71

(1H, s, 4-NH); d_C(50 MHz, DMSO-d₆) 18.2, 56.7, 60.4, 98.5, 105.1,

112.8, 116.2, 120.4, 120.6, 123.9, 129.1, 133.2, 135.9, 138.9, 139.8,

141.0, 147.3, 148.1, 165.6, 165.9; MS (EI, 70 eV): m/z (%)¼419 (24.9)

[M^þ], 327 (99.9), 310 (32.9), 296 (2.5),160 (31.4), 119 (16.0), 56 (9.6).

4.7.1. 2-(4-Chlorophenyl)-7-hydroxy-N-(2-methoxyphenyl)-3,7-

dimethyl-5-(4-methylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]py-

rimidine-6-carboxamide (8a). Yield 440 mg (85%) of colorless

prisms, mp 151e152 ^ꢀC. [Found: C, 67.4; H, 5.6; N, 10.8.

C₂₉H₂₉ClN₄O₃requires C, 67.37; H, 5.65; N, 10.84%]; d_H(200 MHz,

DMSO-d₆) 1.86 (3H, s, CH₃), 1.95 (3H, s, CH₃), 2.26 (3H, s, CH₃), 3.18

(1H, d, J 11.4 Hz, 6-CH), 3.78 (3H, s, CH₃O), 4.81 (1H, d, J 11.4 Hz, 5-

CH), 6.37 (1H, s, 4-NH), 6.98 (1H, s, OH), 6.79e7.62 (12H, m, ArH),

9.41 (1H, s, NH); d_C(50 MHz, DMSO-d₆) 9.0, 21.0, 25.0, 55.0, 55.9,

58.2, 88.5, 95.3, 111.1, 117.2, 120.3, 125.1, 125.5, 127.5, 127.8, 129.1,

129.7, 132.1, 133.3, 136.1, 138.0, 141.1, 146.3, 147.9, 169.0; MS (EI,

70 eV): m/z (%)¼516 (1.1) [M^þ], 514 (2.1), 316 (2.7), 276 (15.7), 275

(83.2), 274 (99.9), 260 (13.3), 207 (45.6), 172 (10.4), 149 (23.7), 130

(17.1), 123 (41.9), 115 (13.7), 108 (75.2), 104 (12.0), 91 (10.8), 80

(23.5), 77 (15.4), 43 (18.7).

4.6.2. 7-(3,4-Dimethoxyphenyl)-N⁶-(2,4-dimethylphenyl)-5-methyl-

4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide (7b). Yield

300 mg (65%) of colorless prisms, mp 287e288 ^ꢀC. [Found: C, 65.1;

H, 5.9; N, 15.2. C₂₅H₂₇N₅O₄requires C, 65.06; H, 5.90; N, 15.17%]; d_H

(200 MHz, DMSO-d₆) 1.83 (3H, s, CH₃), 1.89 (3H, s, CH₃), 2.30 (3H, s,

CH₃), 3.65 (3H, s, CH₃O), 3.69 (3H, s, CH₃O), 6.30 (1H, s, 7-CH),

6.73e7.74 (6H, m, ArH), 7.01 (1H, s, CONH₂), 7.44 (1H, s, CONH₂),

7.76 (1H, s, 2-CH), 8.58 (1H, s, NH), 8.64 (1H, s, 4-NH); MS (EI,

70 eV): m/z (%)¼461 (1.9) [M^þ], 412 (16.7), 322 (99.9), 312 (38.6),

258 (28.9), 252 (14.5), 222 (14.4), 158 (46.6), 134 (19.0), 133 (43.3),

132 (64.3), 106 (19.4), 41 (19.6).

4.7.2. 5-(4-Bromophenyl)-2-(4-chlorophenyl)-7-hydroxy-N-(2-

methoxyphenyl)-3,7-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]py-

rimidine-6-carboxamide (8b). Yield 495 mg (85%) of colorless

prisms, mp 165e166 ^ꢀC. [Found: C, 57.8; H, 5.0; N, 9.6.

4.6.3. 7-(4-Bromophenyl)-3-cyano-N-(2-methoxyphenyl)-5-methyl-

4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

(7c). Yield

E.A. Muravyova et al. / Tetrahedron 67 (2011) 9389e9400

9397

C₂₈H₂₆BrClN₄O₃requires C, 57.80; H, 4.50; N, 9.63%]; d_H(200 MHz,

DMSO-d₆) 1.88 (3H, s, CH₃),1.96 (3H, s, CH₃), 3.22 (1H, d, J 11.7 Hz, 6-

CH), 3.77 (3H, s, CH₃O), 4.85 (1H, d, J 11.7 Hz, 5-CH), 6.53 (1H, s, 4-

NH), 7.13 (1H, s, OH), 6.82e7.67 (12H, m, ArH), 9.48 (1H, s, NH); d_C

(50 MHz, DMSO-d₆) 8.7,18.6, 52.3, 56.6, 60.3, 94.1, 101.5,112.1,121.0,

122.5, 124.7, 128.9, 129.3, 130.0, 130.8, 131.9, 132.5, 133.8, 136.3,

137.7, 138.3, 139.9, 142.1, 157.8; MS (EI, 70 eV): m/z (%)¼581 (1.1)

[M^þ], 579 (1.2), 414 (7.2), 377 (20.6), 376 (32.7), 375 (94.6), 374

(99.9), 373 (85.9), 372 (70.6), 191 (21.8), 157 (16.3), 138 (13.2), 130

(29.7), 115 (26.6), 102 (9.8).

mp 170e171 ^ꢀC. [Found: C, 66.8; H, 5.4; N, 11.1. C₂₈H₂₇ClN₄O₃re-

quires C, 66.86; H, 5.41; N, 11.14%]; d_H(200 MHz, DMSO-d₆) 1.86

(3H, s, CH₃), 2.26 (3H, s, CH₃), 3.24 (1H, d, J 11.4 Hz, 6-CH), 3.78

(3H, s, CH₃O), 4.84 (1H, d, J 11.4 Hz, 5-CH), 6.63 (1H, s, 4-NH),

6.80e7.62 (12H, m, ArH), 9.38 (1H, s, NH); d_C(50 MHz, DMSO-d₆)

21.8, 26.9, 30.6, 52.3, 56.8, 88.8, 112.4, 112.7, 121.1, 122.4, 125.2,

127.8, 129.0, 129.1, 129.3, 130.0, 130.2, 130.6, 132.7, 139.6, 141.0,

142.3, 150.5, 160.2, 165.7; MS (EI, 70 eV): m/z (%)¼502 (1.1) [M^þ],

500 (1.0), 297 (21.9), 296 (22.6), 295 (65.7), 294 (30.2), 207 (67.6),

206 (29.9), 205 (13.2), 204 (99.9), 149 (29.5), 123 (55.5), 108 (65.0),

80 (15.5).

4.7.3. 2-(4-Chlorophenyl)-7-hydroxy-N-(2-methoxyphenyl)-3,7-

dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-

carboxamide (8c). Yield 435 mg (87%) of colorless prisms, mp

133e134 ^ꢀC. [Found: C, 66.9; H, 5.4; N, 11.1. C₂₈H₂₇ClN₄O₃requires

C, 66.86; H, 5.41; N, 11.14%]; d_H(200 MHz, DMSO-d₆) 1.87 (3H, s,

CH₃), 1.96 (3H, s, CH₃), 3.21 (1H, d, J 11.2 Hz, 6-CH), 3.77 (3H, s,

CH₃O), 4.85 (1H, d, J 11.2 Hz, 5-CH), 6.50 (1H, s, 4-NH), 7.11 (s, 1H,

OH), 6.78e7.65 (m, 13H, ArH), 9.43(9.27) (1H, s, NH); d_C(50 MHz,

DMSO-d₆) 8.9, 25.4, 52.4, 55.1, 59.5, 84.9, 92.3, 111.9, 121.0, 122.1,

125.0, 128.7, 129.0, 129.1, 129.5, 130.6, 132.0, 136.9, 139.6, 140.8,

141.0,144.1,149.5,150.2,158.8,166.5,167.7; MS (EI, 70 eV): m/z (%)¼

502 (1.1) [M^þ], 500 (1.0), 362 (11.5), 337 (12.9), 336 (56.9), 335

(28.3), 334 (99.9), 297 (15.8), 296 (28.4), 295 (43.4), 294 (40.2), 207

(23.1), 123 (21.0), 108 (16.1), 80 (6.4).

4.7.8. 5-(4-Bromophenyl)-3-(4-chlorophenyl)-7-hydroxy-N-(2-

methoxyphenyl)-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimi-

dine-6-carboxamide (8h). Yield 425 mg (75%) of colorless prisms,

mp 167e168 ^ꢀC. [Found: C, 57.1; H, 4.2; N, 9.9. C₂₇H₂₄BrClN₄O₃

requires C, 57.11; H, 4.26; N, 9.87%]; d_H(200 MHz, DMSO-d₆) 1.87

(3H, s, CH₃), 3.25 (1H, d, J 11.7 Hz, 6-CH), 3.77 (3H, s, CH₃O), 4.87

(1H, d, J 11.7 Hz, 5-CH), 6.75 (1H, s, 4-NH), 6.82e7.63 (12H, m,

ArH), 9.43 (1H, s, NH); d_C(50 MHz, DMSO-d₆) 25.5, 54.7, 56.8, 58.9,

82.2, 101.4, 112.3, 121.0, 121.6, 122.5, 125.4, 127.4, 129.1, 129.3, 131.1,

131.4, 132.4, 133.1, 138.1, 140.5, 141.9, 150.5, 167.4; MS (EI, 70 eV):

m/z (%)¼567 (1.1) [M^þ], 400 (2.2), 362 (8.0), 361 (6.2), 360 (9.5),

359 (13.6), 207 (43.3), 206 (18.2), 204 (52.8), 193 (23.1), 149 (35.4),

123 (99.9), 122 (31.3), 102 (11.3), 92 (11.0), 89 (17.4), 80 (13.3), 43

(34.5).

4.7.4. 5-(4-Chlorophenyl)-7-hydroxy-N-(2-methoxyphenyl)-7-

methyl-3-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-

carboxamide (8d). Yield 365 mg (75%) of colorless prisms, mp

177e178 ^ꢀC. [Found: C, 66.3; H, 5.1; N, 11.4. C₂₇H₂₅ClN₄O₃requires

C, 66.32; H, 5.15; N, 11.46%]; d_H(200 MHz, DMSO-d₆) 1.88 (3H, s,

CH₃), 3.27 (1H, d, J 11.5 Hz, 6-CH), 3.77 (3H, s, CH₃O), 4.90 (1H, d, J

11.2 Hz, 5-CH), 6.69 (1H, s, 4-NH), 7.01 (1H, s, OH), 6.82e7.61 (8H, m,

ArH), 9.44 (1H, s, NH); MS (EI, 70 eV): m/z (%)¼487 (1.1) [M^þ], 485

(1.2), 329 (3.2), 281 (31.7), 280 (20.6), 207 (55.2), 159 (15.8), 149

(32.2), 123 (99.9), 92 (15.1), 89 (25.3), 63 (11.1).

4.7.9. 3-(4-Fluorophenyl)-7-hydroxy-5-(4-hydroxy-3-methoxy phe-

nyl)-N-(2-methoxyphenyl)-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-

a]pyrimidine-6-carboxamide (8i). Yield 415 mg (80%) of colorless

prisms, mp 136e137 ^ꢀC. [Found: C, 67.9; H, 5.2; N, 10.8.

C₂₈H₂₇FN₄O₃requires C, 67.86; H, 5.25; N, 10.80%]; d_H(200 MHz,

DMSO-d₆) 1.82 (3H, s, CH₃), 3.08 (1H, d, J 11.4 Hz, 6-CH), 3.68 (3H, s,

CH₃O), 3.69 (3H, s, CH₃O), 4.87 (1H, d, J 11.4 Hz, 5-CH), 6.44 (1H, s, 4-

NH), 6.48e7.46 (11H, m, ArH), 7.56 (1H, s, OH), 8.85 (1H, s, OH), 9.59

(1H, s, NH); MS (EI, 70 eV): m/z (%)¼518 (1.5) [M^þ], 519 (3.5),

517(1.6), 312 (13.3), 311 (90.3), 310 (32.4), 295 (12.7), 188 (99.9), 161

(12.6), 120 (10.3).

4.7.5. 5-(4-Bromophenyl)-7-hydroxy-N-(2-methoxyphenyl)-7-

methyl-3-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-

carboxamide (8e). Yield 425 mg (80%) of colorless prisms, mp

174e175 ^ꢀC. [Found: C, 60.8; H, 4.7; N, 10.5. C₂₇H₂₅BrN₄O₃requires

C, 60.80; H, 4.72; N, 10.50%]; d_H(200 MHz, DMSO-d₆) 1.87 (3H, s,

CH₃), 3.25 (1H, d, J 11.7 Hz, 6-CH), 3.77 (3H, s, CH₃O), 4.87 (1H, d, J

11.7 Hz, 5-CH), 6.69 (1H, s, 4-NH), 6.82e7.61 (13H, m, ArH), 9.44

(1H, s, NH); MS (EI, 70 eV): m/z (%)¼533 (1.1) [M^þ], 366 (2.6), 328

(10.0), 327 (28.5), 326 (19.8), 325 (19.4), 324 (13.0), 211 (10.8), 209

(10.0), 207 (62.0), 170 (99.9), 149 (22.2), 123 (44.6), 108 (70.2), 89

(15.7), 80 (13.6), 43 (18.8).

4.7.10. 2-(4-Chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-

7(4H)-one (11a). Yield 110 mg (40%) of colorless prisms, mp

>300 ^ꢀC. [Found: C, 61.4; H, 4.4; N, 15.4. C₁₄H₁₂ClN₃O requires C,

61.43; H, 4.42; N, 15.35%]; d_H(200 MHz, DMSO-d₆) 2.25 (3H, s, CH₃),

2.31 (3H, s, CH₃), 5.55 (1H, s, 6-CH), 7.52e7.77 (4H, m, ArH), 11.90

(1H, s, 4-NH); d_C(50 MHz, DMSO-d₆) 8.5, 20.1, 95.5, 97.0, 125.9,

126.3, 128.5, 133.0, 133.4, 147.5, 154.1, 155.0; MS (EI, 70 eV): m/z

(%)¼273 (88.8) [M^þ], 275 (29.6), 204 (99.9), 206 (33.3), 162 (22.2).

4.7.11. 2-[3-(4-Fluorophenyl)-7-(4-hydroxy-3-methoxyphenyl)-pyr-

azolo[1,5-a]pyrimidin-5-yl]-N-phenylacetamide (12a). Yield 50 mg

(11%) of yellow prisms, mp 279e280 ^ꢀC. [Found: C, 69.2; H, 4.5; N,

11.9. C₂₁H₂₁FN₄O₃requires C, 69.22; H, 4.52; N, 11.96%]; d_H

(200 MHz, DMSO-d₆) 3.93 (3H, s, CH₃O), 4.36 (2H, s, CH₂),

6.96e8.26 (12H, m, ArH), 7.79 (1H, s, 6-CH), 8.66 (1H, s, 2-CH),

9.75 (1H, s, OH), 10.55 (1H, s, NH); d_C(50 MHz, DMSO-d₆) 51.1,

56.8, 97.3, 107.1, 108.8, 112.3, 115.9, 116.3, 116.8, 120.1, 121.7, 124.1,

128.0, 128.2, 128.7, 129.3, 129.7, 139.8, 142.8, 144.5, 145.0, 148.9,

150.6, 156.0, 155.4, 166.1; MS (EI, 70 eV): m/z (%)¼468 (67.0) [M^þ],

470 (3.9), 469 (21.1), 350 (25.4), 349 (99.9), 348 (19.1), 334(20.4),

306 (12.7), 77 (19.4).

4.7.6. 7-Hydroxy-N-(4-methoxyphenyl)-7-methyl-3,5-diphenyl-

4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-6-carboxamide

(8f). Yield 317 mg (70%) of colorless prisms, mp 153e154 ^ꢀC.

[Found: C, 71.3; H, 5.8; N, 12.3. C₂₇H₂₆N₄O₃requires C, 71.35; H,

5.77; N, 12.33%]; d_H(200 MHz, DMSO-d₆) 1.84 (3H, s, CH₃), 3.12 (1H,

d, J 11.5 Hz, 6-CH), 3.66 (3H, s, CH₃O), 4.97 (1H, d, J 11.5 Hz, 5-CH),

6.49 (1H, s, 4-NH), 6.62 (1H, s, OH), 6.76e7.59 (14H, m, ArH), 9.59

(1H, s, NH); d_C(50 MHz, DMSO-d₆) 26.0, 54.7, 56.0, 58.2, 82.4, 102.3,

114.6, 122.0, 122.7, 125.0, 125.8, 128.6, 128.8, 129.2, 131.7, 134.3,

138.0, 141.4, 142.0, 156.7, 167.9; MS (EI, 70 eV): m/z (%)¼453 (1.1)

[M^þ], 294 (7.3), 207 (46.0), 171 (12.9), 170 (99.9), 149 (15.9), 143

(13.5), 142 (12.6), 170 (99.9), 149 (15.9), 143 (13.5), 108 (85.7), 80

(13.3), 77 (16.1), 51 (14.8), 43 (15.9).

4.8. General procedure for the synthesis of compounds

13aee, 14aee, and 15ael

4.7.7. 3-(4-Chlorophenyl)-7-hydroxy-N-(2-methoxyphenyl)-7-

methyl-5-(4-methylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimi-

dine-6-carboxamide (8g). Yield 380 mg (75%) of colorless prisms,

A mixture of aminoazole 1jem (1 mmol), acetoacetamide

2a,b,d,e (1 mmol), and aromatic aldehyde 3b,d,f,g,heo (1 mmol) in

9398

E.A. Muravyova et al. / Tetrahedron 67 (2011) 9389e9400

0.1 mL of DMF was heated to reﬂux for 10 min. After cooling ace-

tone (10 mL) was added and the precipitate formed was ﬁltered out

to give the solid compounds 13aee, 14aee or 15ael, which were

washed with acetone and air dried.

140.6, 145.9, 146.9, 148.2, 168.8; MS (EI, 70 eV): m/z (%)¼404 (8.5)

[M^þ], 390 (9.1), 389 (31.3), 312 (35.2), 285 (40.2), 284 (99.9), 267

(26.7), 255 (45.7), 174 (31.3), 148 (18.1), 77 (47.9).

4.8.7. 4-(3,4-Dihydroxyphenyl)-3,6-dimethyl-N-phenyl-4,7-dihydro-

1H-pyrazolo[3,4-b]pyridine-5-carboxamide (14b). Yield 132 mg

(35%) of colorless prisms, mp 178e180 ^ꢀC. [Found: C, 67.0; H, 5.4; N,

14.9. C₂₁H₂₀N₄O₃requires C, 67.01; H, 5.36; N, 14.88%]; d_H

(200 MHz, DMSO-d₆) 1.81 (3H, s, CH₃), 2.07 (3H, s, CH₃), 5.09 (1H, s,

4-CH), 6.46e7.48 (8H, m, ArH), 8.49 (1H, s, NH), 8.52 (1H, s, OH),

8.63 (1H, s, OH), 9.03 (1H, s, 7-NH), 11.47 (1H, s, 1-NH); MS (EI,

70 eV): m/z (%)¼374 (10.5) [M^þ], 282 (43.5), 119 (35.5), 93 (99.9), 92

(61.1), 91 (40.3), 65 (33.9), 41 (17.6).

4.8.1. 7-(4-Cyanophenyl)-2,5-dimethyl-N-phenyl-4,7-dihydropyra-

zolo[1,5-a]pyrimidine-6-carboxamide (13a). Yield 204 mg (55%) of

colorless prisms, mp 163e164 ^ꢀC. [Found: C, 71.5; H, 5.1; N, 18.9.

C₂₂H₁₉N₅O requires C, 71.53; H, 5.18; N, 18.96%]; d_H(200 MHz,

DMSO-d₆) 2.01 (3H, s, CH₃), 2.16 (3H, s, CH₃), 5.42 (1H, s, 7-CH), 6.45

(1H, s, 3-CH), 6.97e7.74 (9H, m, ArH), 9.53 (1H, s, NH), 9.58 (1H, s, 4-

NH); MS (EI, 70 eV): m/z (%)¼370 (9.5) [M^þ], 369 (21.7), 278 (20.2),

277 (60.6), 250 (4.6), 249 (99.9), 127 (13.0), 93 (44.6).

4.8.2. 7-(4-Bromophenyl)-2,5-dimethyl-N-phenyl-4,7-dihydropyra-

zolo[1,5-a]pyrimidine-6-carboxamide (13b). Yield 212 mg (50%) of

colorless prisms, mp 153e154 ^ꢀC. [Found: C, 59.6; H, 4.5; N, 13.2.

C₂₁H₁₉BrN₄O requires C, 59.59; H, 4.52; N, 13.24%]; d_H(200 MHz,

DMSO-d₆) 2.00 (3H, s, CH₃), 2.15 (3H, s, CH₃), 5.37 (1H, s, 7-CH),

6.37 (1H, s, 3-CH), 6.97e7.48 (9H, m, ArH), 9.43 (1H, s, NH), 9.55

(1H, s, 4-NH); d_C(50 MHz, DMSO-d₆) 14.4, 18.3, 59.8, 87.0, 102.3,

120.5, 121.2, 123.7, 129.1, 129.6, 131.8, 137.8, 139.6, 140.0, 142.8,

148.5, 166.2; MS (EI, 70 eV): m/z (%)¼423 (14.2) [M^þ], 424 (15.6),

422 (18.7), 332 (99.9), 331 (99.1), 330 (98.7), 302 (43.6), 122 (43.0),

93 (72.9).

4.8.8. 4-(3,4-Dimethoxyphenyl)-3,6-dimethyl-N-phenyl-4,7-

dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

(14c). Yield

182 mg (45%) of colorless prisms, mp 240e242 ^ꢀC. [Found: C, 68.3;

H, 5.9; N, 13.8. C₂₃H₂₄N₄O₃requires C, 68.30; H, 5.98; N, 13.85%]; d_H

(200 MHz, DMSO-d₆) 1.82 (3H, s, CH₃), 2.07 (3H, s, CH₃), 3.57 (3H, s,

CH₃O), 3.63 (3H, s, CH₃O), 5.17 (1H, s, 4-CH), 6.63e7.51 (8H, m, ArH),

8.55 (1H, s, NH), 9.17 (1H, s, 7-NH), 11.50 (1H, s, 1-NH); d_C(50 MHz,

DMSO-d₆)

d 10.4, 19.3, 39.5, 56.4, 102.5, 104.5, 113.0, 120.1, 120.5,

123.1, 128.9, 129.2, 135.3, 140.0, 140.5, 140.6, 148.0, 148.3, 149.2,

168.8; MS (EI, 70 eV): m/z (%)¼404 (16.2) [M^þ], 312 (99.9), 146

(21.7), 93 (40.6), 77 (43.7).

4.8.3. 2,5-Dimethyl-7-(4-nitrophenyl)-N-phenyl-4,7-dihydropyrazolo

[1,5-a]pyrimidine-6-carboxamide (13c). Yield 254 mg (65%) of col-

orless prisms, mp 169e170 ^ꢀC. [Found: C, 64.8; H, 4.9; N, 17.9.

C₂₁H₁₉N₅O₃requires C, 64.77; H, 4.92; N, 17.98%]; d_H(200 MHz,

DMSO-d₆) 2.00 (3H, s, CH₃), 2.17 (3H, s, CH₃), 5.43 (1H, s, 7-CH), 6.51

(1H, s, 3-CH), 6.97e8.11 (9H, m, ArH), 9.58 (1H, s, NH), 9.60 (1H, s, 4-

NH); d_C(50 MHz, DMSO-d₆) 14.4, 18.4, 59.8, 87.3, 101.7, 120.5, 123.8,

124.2, 128.6, 129.1, 138.3, 139.9, 147.6, 148.8, 150.5, 166.0; MS (EI,

70 eV): m/z (%)¼389 (11.8) [M^þ], 297 (32.6), 223 (35.4), 148 (99.9),

122 (33.5), 93 (42.0), 77 (36.9).

4.8.9. 4-(4-Hydrophenyl)-3,6-dimethyl-N-phenyl-4,7-dihydro-1H-

pyrazolo[3,4-b]pyridine-5-carboxamide (14d). Yield 151 mg (42%) of

colorless prisms, mp 264e266 ^ꢀC. [Found: C, 69.9; H, 5.6; N, 15.5.

C₂₁H₂₀N₄O₂requires C, 69.98; H, 5.59; N, 15.54%]; d_H(200 MHz,

DMSO-d₆) 1.79 (3H, s, CH₃), 2.06 (3H, s, CH₃), 5.09 (1H, s, 4-CH),

6.53e7.44 (9H, m, ArH), 8.49 (1H, s, NH), 9.05 (1H, s, OH), 9.09 (1H,

s, 7-NH), 11.46 (1H, s, 1-NH); d_C(50 MHz, DMSO-d₆) 15.0, 23.4, 39.6,

115.3, 120.1, 120.5, 123.0, 124.3, 126.4, 128.9, 129.1, 129.2, 130.8,

139.5, 158.1, 167.3, 168.8; MS (EI, 70 eV): m/z (%)¼360 (8.0) [M^þ],

359 (11.3), 267 (99.9), 263 (28.5), 210 (25.3),170 (32.5), 94 (43.6), 77

(28.1), 66 (78.3).

4.8.4. 7-(4-Carboxyphenyl)-2,5-dimethyl-N-phenyl-4,7-

dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

(13d). Yield

4.8.10. 4-[4-(Dimethylamino)phenyl]-3,6-dimethyl-N-phenyl-4,7-

195 mg (50%) of colorless prisms, mp 183e184 ^ꢀC. [Found: C, 68.0; H,

5.2; N, 14.4. C₂₂H₂₀N₄O₃requires C, 68.03; H, 5.19; N, 14.42%]; d_H

(200 MHz, DMSO-d₆) 2.00 (3H, s, CH₃), 2.17 (3H, s, CH₃), 5.40 (1H, s,

7-CH), 6.48 (1H, s, 3-CH), 6.97e7.48 (9H, m, ArH), 9.54 (1H, s, NH),

9.58 (1H, s, 4-NH); MS (EI, 70 eV): m/z (%)¼386 (5.6) [M^þ], 295 (15.1),

294 (99.9), 250 (20.2), 154 (14.6), 97 (14.7), 92 (11.6), 65 (12.6).

dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

(14e). Yield

195 mg (50%) of colorless prisms, mp 247e248 ^ꢀC. [Found: C, 71.3;

H, 6.5; N, 18.1. C₂₃H₂₅N₅O requires C, 71.29; H, 6.50; N, 18.07%]; d_H

(200 MHz, DMSO-d₆) 1.79 (3H, s, CH₃), 2.06 (3H, s, CH₃), 2.76 (6H, s,

2CH₃), 5.10 (1H, s, 4-CH), 6.70e7.49 (9H, m, ArH), 8.51 (1H, s, NH),

9.09 (1H, s, 7-NH), 11.50 (1H, s, 1-NH); MS (EI, 70 eV): m/z (%)¼386

(8.9) [M^þ], 343 (25.8), 267 (99.9), 147 (27.5), 132 (16.6), 120 (48.8),

119 (18.7), 95 (14.1), 77 (12.1).

4.8.5. N-(4-Chlorophenyl)-2,5-dimethyl-7-(4-nitrophenyl)-4,7-

dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

(13e). Yield

212 mg (50%) of colorless prisms, mp 158e160 ^ꢀC. [Found: C, 59.5;

H, 4.3; N, 16.5. C₂₁H₁₈ClN₅O₃requires C, 59.51; H, 4.28; N, 16.52%];

d_H(200 MHz, DMSO-d₆) 2.00 (3H, s, CH₃), 2.17 (3H, s, CH₃), 5.44 (1H,

s, 7-CH), 6.51 (1H, s, 3-CH), 7.29e8.12 (8H, m, ArH), 9.63 (1H, s, NH),

9.72 (1H, s, 4-NH); d_C(50 MHz, DMSO-d₆) 14.4, 18.4, 59.8, 87.4,

101.5, 122.1, 124.1, 127.6, 128.5, 129.0, 138.8, 139.6, 147.7,148.9, 150.4,

166.1; MS (EI, 70 eV): m/z (%)¼423 (9.4) [M^þ], 425 (3.6), 424 (3.0),

297 (99.9), 296 (31.2), 269 (32.6), 148 (39.2).

4.8.11. 7-(4-Hydroxy-3-methoxyphenyl)-5-methyl-N,2-diphenyl-4,7-

dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

(15a). Yield

250 mg (55%) of colorless prisms, mp 235e237 ^ꢀC. [Found: C,

71.7; H, 5.3; N, 12.4. C₂₇H₂₄N₄O₃requires C, 71.67; H, 5.35; N,

12.38%]; d_H(200 MHz, DMSO-d₆) 2.20 (3H, s, CH₃), 3.60 (3H, s,

CH₃O), 5.99 (1H, s, 7-CH), 6.49 (1H, s, 3-CH), 6.55e7.69 (13H, m,

ArH), 8.89 (1H, s, OH), 9.50 (1H, s, NH), 9.57 (1H, s, 4-NH); MS (EI,

70 eV): m/z (%)¼453 (20.9) [M^þ], 360 (16.3), 333 (64.0), 332

(99.9), 210 (23.8), 184 (22.2), 119 (46.7), 93 (27.0), 92 (22.9), 91

(29.8), 77 (22.9).

4.8.6. 4-(3-Ethoxy-4-hydroxyphenyl)-3,6-dimethyl-N-phenyl-4,7-

dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

(14a). Yield

225 mg (50%) of colorless prisms, mp 238e240 ^ꢀC. [Found: C, 68.3;

H, 6.0; N, 13.8. C₂₃H₂₄N₄O₃requires C, 68.30; H, 5.98; N, 13.85%]; d_H

(200 MHz, DMSO-d₆) 1.19 (3H, t, J 7.1 Hz, CH₃), 1.81 (3H, s, CH₃), 2.06

(3H, s, CH₃), 3.80 (2H, q, J 7.1 Hz, CH₂O), 5.09 (1H, s, 4-CH), 6.50e7.47

(8H, m, ArH), 8.50 (1H, s, NH), 8.53 (1H, s, OH), 9.10 (1H, s, 7-NH),

11.48 (1H, s, 1-NH); d_C(50 MHz, DMSO-d₆) 10.3,15.4,19.3, 40.0, 65.1,

102.8, 104.7, 115.1, 116.2, 120.1, 121.0, 123.1, 128.9, 135.4, 139.0, 139.9,

4.8.12. 7-(4-Carboxyphenyl)-2-(4-chlorophenyl)-5-methyl-N-phe-

nyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

(15b). Yield 252 mg (52%) of colorless prisms, mp 238e240 ^ꢀC.

[Found: C, 66.9; H, 4.5; N, 11.6. C₂₇H₂₁ClN₄O₃requires C, 66.87; H,

4.36; N, 11.55%]; d_H(200 MHz, DMSO-d₆) 2.30 (3H, s, CH₃), 5.72 (1H,

s, 7-CH), 6.99 (1H, s, 3-CH), 7.40e8.05 (13H, m, ArH), 8.98 (1H, s,

NH), 9.89 (1H, s, 4-NH), 12.36 (1H, s, COOH); MS (EI, 70 eV): m/z

E.A. Muravyova et al. / Tetrahedron 67 (2011) 9389e9400

9399

(%)¼484 (26.0) [M^þ], 327 (29.6), 325 (99.9), 324 (37.8), 138 (35.8),

(13H, m, ArH), 9.62 (1H, s, NH), 9.64 (1H, s, 4-NH); d_C(50 MHz,

DMSO-d₆) 18.3, 55.9, 60.0, 84.0, 102.5, 114.7, 120.6, 123.8, 127.0,

127.1, 128.9, 129.1, 129.2, 132.9, 138.0, 140.0, 140.4, 142.1, 151.0,

159.8, 166.1; MS (EI, 70 eV): m/z (%)¼470 (28.4) [M^þ], 472 (11.0),

93 (99.9), 378 (80.2), 377 (40.3), 379 (31.6), 380 (26.1), 350 (66.6),

92 (49.5).

136 (27.6), 101 (19.2), 77 (27.3), 76 (36.3), 51 (22.9).

4.8.13. 2-(4-Chlorophenyl)-7-(4-cyanophenyl)-5-methyl-N-phenyl-

4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

(15c). Yield

260 mg (55%) of colorless prisms, mp 290e292 ^ꢀC. [Found: C, 69.6;

H, 4.3; N,15.0. C₂₇H₂₀ClN₅O requires C, 69.60; H, 4.33; N,15.03%]; d_H

(200 MHz, DMSO-d₆) 2.20 (3H, s, CH₃), 6.10 (1H, s, 7-CH), 6.63 (1H,

s, 3-CH), 7.03e7.78 (13H, m, ArH), 9.68 (1H, s, NH), 9.78 (1H, s, 4-

NH); d_C(50 MHz, DMSO-d₆) 18.3, 60.4, 84.9, 111.2, 119.2, 120.5,

123.9, 127.5, 128.2, 129.2, 132.9, 133.1, 138.2, 139.8, 140.6, 148.1,

150.2, 168.9; MS (EI, 70 eV): m/z (%)¼466 (5.0) [M^þ], 371 (26.4), 345

(26.7), 111 (37.0), 93 (99.9), 77 (46.3), 64 (45.3).

4.8.19. 7-(4-Hydroxy-3-methoxyphenyl)-2-(4-methoxyphenyl)-5-

methyl-N-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-

carboxamide (15i). Yield 250 mg (52%) of colorless prisms, mp

240e241 ^ꢀC. [Found: C, 69.7; H, 5.4; N, 11.6. C₂₈H₂₆N₄O₄requires C,

69.70; H, 5.43; N, 11.61%]; d_H(200 MHz, DMSO-d₆) 2.19 (3H, s,

CH₃), 3.60 (3H, s, CH₃O), 3.73 (3H, s, CH₃O), 5.90 (1H, s, 7-CH), 6.46

(1H, s, 3-CH), 6.53e7.65 (12H, m, ArH), 8.88 (1H, s, OH), 9.46 (1H, s,

NH), 9.55 (1H, s, 4-NH); d_C(50 MHz, DMSO-d₆) 18.2, 55.9, 56.5,

60.2, 83.8, 103.1, 112.5, 114.7, 116.1, 120.0, 120.4, 123.6, 127.0, 129.1,

134.3, 137.6, 140.1, 146.9, 148.0, 150.5, 159.6, 166.4; MS (EI, 70 eV):

m/z (%)¼482 (46.6) [M^þ], 483 (12.0), 390 (99.9), 389 (55.4), 361

(18.2).

4.8.14. 2-(4-Chlorophenyl)-5-methyl-7-(4-nitrophenyl)-N-phenyl-

4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (15d). Yield

320 mg (55%) of colorless prisms, mp 278e280 ^ꢀC. [Found: C, 64.3;

H, 4.1; N, 14.4. C₂₆H₂₀ClN₅O₃requires C, 64.27; H, 4.15; N, 14.41%];

d_H(200 MHz, DMSO-d₆) 2.21 (3H, s, CH₃), 6.11 (1H, s, 7-CH), 6.68

(1H, s, 3-CH), 6.98e8.12 (13H, m, ArH), 9.69 (1H, s, NH), 9.82 (1H, s,

4-NH); d_C(50 MHz, DMSO-d₆) 18.4, 60.3, 85.0, 102.0, 120.6, 123.9,

124.3, 127.5, 128.6, 129.1, 132.9, 138.3, 138.4, 139.8, 139.9, 140.7,

147.8, 150.0, 150.3, 165.9; MS (EI, 70 eV): m/z (%)¼486 (4.4) [M^þ],

487 (5.2), 485 (13.3), 365 (99.9), 366 (42.4), 367 (31.5), 393 (61.6),

394 (22.9), 93 (65.4), 92 (27.0), 119 (46.7), 120 (24.5), 218 (45.1), 244

(55.1), 243 (11.5), 319 (37.8), 318 (23.2).

4.8.20. 7-(4-Bromoxyphenyl)-2-(4-methoxyphenyl)-5-methyl-N-

phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

(15j). Yield 335 mg (65%) of colorless prisms, mp 243e245 ^ꢀC.

[Found: C, 62.9; H, 4.5; N, 10.9. C₂₇H₂₃BrN₄O₂requires C, 62.92; H,

4.50; N, 10.87%]; d_H(200 MHz, DMSO-d₆) 2.20 (3H, s, CH₃), 3.73

(3H, s, CH₃O), 5.95 (1H, s, 7-CH), 6.54 (1H, s, 3-CH), 6.86e7.60

(13H, m, ArH), 9.62 (1H, s, NH), 9.62 (1H, s, 4-NH); d_C(50 MHz,

DMSO-d₆) 18.3, 55.9, 60.1, 84.1, 102.5, 114.7, 120.6, 121.3, 123.8,

127.0, 127.1, 129.1, 129.5, 131.9, 138.0, 140.0, 140.4, 142.6, 151.0,

159.8, 166.1; MS (EI, 70 eV): m/z (%)¼515 (7.5) [M^þ], 516 (20.3),

514 (26.2), 422 (99.9), 423 (60.2), 424 (68.4), 421 (46.8), 394

(59.2), 240 (52.1).

4.8.15. 2-(4-Chlorophenyl)-5-methyl-N-phenyl-7-pyridin-3-yl-4,7-

dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

(15e). Yield

175 mg (40%) of colorless prisms, mp 240e241 ^ꢀC. [Found: C, 67.9;

H, 4.5; N, 15.8. C₂₅H₂₀ClN₅O requires C, 67.95; H, 4.56; N, 15.85%]; d_H

(200 MHz, DMSO-d₆) 2.22 (3H, s, CH₃), 6.07 (1H, s, 7-CH), 6.58 (1H,

s, 3-CH), 6.98e8.44 (13H, m, ArH), 9.67 (1H, s, NH), 9.74 (1H, s, 4-

NH); MS (EI, 70 eV): m/z (%)¼441 (24.0) [M^þ], 324 (22.7), 323

(40.1), 322 (63.6), 321 (78.7), 244 (31.1), 136 (13.9), 119 (99.9), 93

(20.4), 91 (48.3), 64 (17.9).

4.8.21. 7-(4-Bromoxyphenyl)-N-(2-methoxyphenyl)-2-(4-

methoxyphenyl)-5-methyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-

carboxamide (15k). Yield 355 mg (65%) of colorless prisms, mp

163e165 ^ꢀC. [Found: C, 61.6; H, 4.6; N, 10.3. C₂₈H₂₅BrN₄O₃requires

C, 61.66; H, 4.62; N,10.27%]; d_H(200 MHz, DMSO-d₆) 2.29 (3H, CH₃),

3.74 (6H, s, 2CH₃O), 5.93 (1H, s, 7-CH), 6.43 (1H, s, 3-CH), 6.83e7.72

(12H, m, ArH), 8.54 (1H, s, NH), 9.71 (1H, s, 4-NH); MS (EI, 70 eV): m/

z (%)¼546 (14.0) [M^þ], 544 (1.9), 396 (43.8), 150 (15.5), 149 (42.8),

128 (23.6), 123 (99.9), 120 (33.2), 94 (28.6), 92 (22.7), 78 (22.5), 77

(25.1), 65 (17.9).

4. 8.16. 7-(4-Bromophenyl)-2-(4-chlorophenyl)-N-(2-

methoxyphenyl)-5-methyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-

carboxamide (15f). Yield 360 mg (65%) of colorless prisms, mp

158e160 ^ꢀC. [Found: C, 59.0; H, 4.0; N,10.2. C₂₇H₂₂BrClN₄O₂requires

C, 58.98; H, 4.03; N,10.19%]; d_H(200 MHz, DMSO-d₆) 2.30 (3H, s, CH₃),

3.74 (3H, s, CH₃O), 6.05 (1H, s, 7-CH), 6.46 (1H, s, 3-CH), 6.84e7.73

(12H, m, ArH), 8.57 (1H, s, NH), 9.76 (1H, s, 4-NH); MS (EI, 70 eV): m/z

(%)¼550 (11.0) [M^þ], 426 (10.8), 244 (10.0),150 (14.3),149 (29.4),136

(21.8), 135 (22.6), 128 (18.8), 123 (99.9), 80 (19.6), 77 (14.6).

4.8.22. 7-(4-Bromoxyphenyl)-N-(2,4-dimethylphenyl)-2-(4-

methoxyphenyl)-5-methyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-

carboxamide (15l). Yield 300 mg (55%) of colorless prisms, mp

259e261 ^ꢀC. [Found: C, 64.1; H, 5.0; N, 10.3. C₂₉H₂₇BrN₄O₂requires

C, 64.09; H, 5.01; N, 10.31%]; d_H(200 MHz, DMSO-d₆) 1.84 (3H, s,

CH₃), 2.20 (3H, s, CH₃), 2.24 (3H, s, CH₃), 3.73 (3H, s, CH₃O), 5.91

(1H, s, 7-CH), 6.48 (1H, s, 3-CH), 6.87e7.63 (11H, m, ArH), 9.03 (1H,

s, NH), 9.53 (1H, s, 4-NH); d_C(50 MHz, DMSO-d₆) 18.4, 21.1, 22.0,

55.9, 60.2, 83.9, 102.1, 114.7, 121.4, 123.0, 126.4, 126.9, 127.1, 129.9,

130.0, 131.4, 131.8, 132.5, 133.5, 134.7, 135.1, 135.7, 137.4, 140.3,

142.4, 150.9, 159.7, 166.2; MS (EI, 70 eV): m/z (%)¼544 (7.8) [M^þ],

543 (6.2), 545 (2.5), 396 (57.7), 395 (36.8), 394 (34.1), 121 (99.9),

120 (42.5).

4.8.17. 2-(4-Chlorophenyl)-N-(2,4-dimethylphenyl)-7-(4-hydroxy-3-

methoxyphenyl)-5-methyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-

carboxamide (15g). Yield 260 mg (50%) of colorless prisms, mp

250e252 ^ꢀC. [Found: C, 67.6; H, 5.3; N, 10.9. C₂₉H₂₇ClN₄O₃requires

C, 67.63; H, 5.28; N, 10.88%]; d_H(200 MHz, DMSO-d₆) 1.85 (3H, s,

CH₃), 2.20 (3H, s, CH₃), 2.24 (3H, s, CH₃), 3.67 (3H, s, CH₃O), 5.98 (1H,

s, 7-CH), 6.39 (1H, s, 3-CH), 6.67e7.73 (10H, m, ArH), 8.91 (1H, s,

NH), 9.45 (1H, s, 4-NH); d_C(50 MHz, DMSO-d₆) 18.3, 18.4, 21.1, 56.7,

60.6, 84.3, 102.7, 113.2, 116.1, 120.7, 126.3, 126.9, 127.4, 129.1, 131.3,

132.6, 133.2, 133.3, 133.9, 134.8, 134.9, 137.3, 140.4, 147.2, 148.1,

149.4, 166.3; MS (EI, 70 eV): m/z (%)¼514 (4.9) [M^þ], 515 (1.9), 516

(1.7), 36.6 (99.9), 368 (50.8), 367 (22.9), 369 (10.1), 394 (19.8).

4.9. General procedure of transformation of compounds

4.8.18. 7-(4-Chlorophenyl)-2-(4-methoxyphenyl)-5-methyl-N-phe-

nyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide

(15h). Yield 310 mg (65%) of colorless prisms, mp 143e145 ^ꢀC.

[Found: C, 68.8; H, 4.9; N, 11.9. C₂₇H₂₃ClN₄O₂requires C, 68.86; H,

4.92; N, 11.90%]; d_H(200 MHz, DMSO-d₆) 2.20 (3H, s, CH₃), 3.73

(3H, s, CH₃O), 5.94 (1H, s, 7-CH), 6.55 (1H, s, 3-CH), 6.87e7.64

4aeg, 6aee into 5aeg, 7aee

Compound 4aeg or 6aee (1 mmol) was reﬂuxed in 0.1 mL of

DMF for 180 min. After cooling acetone (10 mL) was added and the

precipitate formed was ﬁltered out to give the solid compounds

5aeg or 6aee, which were washed with acetone and air dried.

9400

E.A. Muravyova et al. / Tetrahedron 67 (2011) 9389e9400

8, 427; (e) Chernyshev, V. M.; Sokolov, A. N.; Taranushich, V. A. Russ. J. Appl. Chem.

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Shujiang, T. J. Heterocycl. Chem. 2008, 45,1609; (h) Chen, Q.; Jiang, L.-L.; Chen, C.-N.;

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