Partially hydrogenated 2-amino[1,2,4]triazolo[1,5-a]pyrimidines as synthons for the preparation of polycondensed heterocycles: Reaction with chlorocarboxylic acid chlorides

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Graphical Abstract

Partially hydrogenated 2-

Leave this area blank for abstract info.

amino[1,2,4]triazolo[1,5-a]pyrimidines as

synthons for the preparation of

polycondensed heterocycles: reaction with

chlorocarboxylic acid chlorides

a*

a

Victor M. Chernyshev, Dmitry A. Pyatakov, Andrey N. Sokolov, Alexander V. Astakhov, Eugene S.

b

Gladkov, Svetlana V. Shishkina and Oleg V. Shishkin

a

South-Russia State Technical University, Prosveschenya 132, 346428 Novocherkassk, Russian Federation

State Scientific Institution ‘Institute for Single Crystals’ of National Academy of Sciences of Ukraine, Lenin

b

Ave. 60, 61001 Kharkiv, Ukraine

O

R''

Cl

N

R'

R

N

R'

R

R'

R

n

o

N

n = 2

DMF, 80-90 C

N

HN

H N

2

O

N

H

o

N

H

0-5 C

n = 1-3

O

N

H

n

Cl

R''

N

R''

Cl

N

NH

R'

R

H

R

R' H N

N

2

N

HN

N

O

HN

O

N

O

^N^H2

O

N

R

H

O

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1

Tetrahedron

journal homepage: www.elsevier.com

Partially hydrogenated 2-amino[1,2,4]triazolo[1,5-a]pyrimidines as synthons for the

preparation of polycondensed heterocycles: reaction with chlorocarboxylic acid

chlorides

a*

a

Victor M. Chernyshev, Dmitry A. Pyatakov, Andrey N. Sokolov, Alexander V. Astakhov, Eugene S.

b

bс

Gladkov, Svetlana V. Shishkina and Oleg V. Shishkin

a

South-Russia State Technical University, Prosveschenya 132, 346428 Novocherkassk, Russian Federation

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

V. N. Karazin Kharkiv National University, 4 Svobody sq., Kharkiv 61202, Ukraine

b

с

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

Partially hydrogenated 2-amino[1,2,4]triazolo[1,5-a]pyrimidines and 2-amino[1,2,4]triazolo[5,1-

b]quinazolines react with the chlorides of chloroacetic, 3-chloropropanoic and 4-chlorobutanoic

acids at 0-5 °C to give amides through acylation of the 2-amino group. Heating the

corresponding 3-chloropropanoyl derivatives at 80-90 °C in DMF leads to selective

intramolecular alkylation at N-3 to form the chlorides of partially hydrogenated

Available online

[

1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ones

and

pyrimido[2',1':3,4][1,2,4]triazolo[5,1-

b]quinazolin-12-ones. It may be more convenient to prepare such compounds through one-pot

processes. Some reactions of the synthesized chlorides of polycondensed heterocycles have been

studied. Conditions have been found to effect the selective synthesis of free bases, oxidative

aromatization or hydrolysis of the dihydropyrimidine cycle, and the selective hydrolytic

cleavage or elimination of the pyrimidone ring. Some of the resulting compounds represent new

mesoionic heterocycles.

Keywords:

Polycondensed heterocycles

[1,2,4]Triazolo[1,5-a:4,3-a']dipyrimidine

Pyrimido[2',1':3,4][1,2,4]triazolo[5,1-b]quinazoline

Tautomerism

Mesoionic compounds

2

—

——

*

Corresponding author. Tel.: +7-903-437-24-03; fax: +7-86-352-276-19; e-mail: chern13@yandex.ru.

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2

Tetrahedron

Introduction

such reactions are being investigated as promising antitumor

2a,b

agents.

In addition, partially hydrogenated triazolopyrimidines I and

In recent years, much attention has been paid to the

development of new methods for the synthesis of

1,2,4]triazolo[1,5-a]pyrimidines (I-III) with various degrees of

[

II behave as polydentate N-nucleophiles in many reactions with

electrophiles,

1

2a,3a-c,e,f

saturation of the pyrimidine ring (Scheme 1). Such interest is

reactivity that is analogous to that of C-

based on the fact that I-III are purine analogs that exhibit various

amino-1,2,4-triazoles. Compounds I and II could serve as

precursors to polycondensed heterocycles through reactions

involving the nitrogen atoms of the triazole fragment, but the

potential utility of this approach remains unexplored. We

hypothesized that partially hydrogenated [1,2,4]triazolo[1,5-

a]pyrimidines could be used as novel N,Nɑ -binucleophilic

synthons for the preparation of polycondensed heterocycles. In

short preliminary communication we disclosed the reaction of

4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidines (II) with 3-

chloropropanoic acid chloride. The obtained results demonstrate

that it is possible to form a new ring through annelation reactions

2

of the 2-NH and N-3 atom, while alternative ring systems can be

formed through ₉atoms N-3 and N-4 of the starting

triazolopyrimidine.

2

a-c

2d

2g

biological properties, including anticancer,

antidiabetic,

2

e

2f

anticonvulsant,

antihypertensive, and antiviral activity.

Moreover, the partially hydrogenated [1,2,4]triazolo[1,5-

a]pyrimidines I and II are polyfunctional compounds that can

3

,4

react with various electrophiles. This versatility allows for

design of the triazolopyrimidine scaffold and the construction of

2

,3

more

complex

heterocyclic

systems.

The

4,7-

dihydro[1,2,4]triazolo[1,5-a]pyrimidines I (R = H) have been

9

applied to the synthesis of new polycondensed heterocycles

2

a,b,4

(

Scheme 1).

Compounds of type I can be obtained readily

from the condensation of aminotriazoles IV with ɑ ,ß-unsaturated

1

,2a,b,f,g,3a,b,f,g,4e,5

1,3a,6

carbonyls

or Mannich bases.

Such compounds

can also be obtained from three-component reactions between

aminotriazoles IV, methylene-active carbonyl compounds and

Herein we report the results from detailed investigations of the

reactions of partially hydrogenated 2-amino[1,2,4]triazolo[1,5-

1

,2d,f,g,3a,4a,5d,7

aldehydes.

Compounds of type I are especially useful

because the dihydropyrimidine motif is amenable to both

2

a]pyrimidines of type I and II (R = NH ) as well as their analogs,

2

d,g,3a,b,4c,5a,b,e,6,8

aromatization by various oxidizing agents

reduction by sodium borohydride (Scheme 1).

and

g,3a-c,e,f,7a

partially hydrogenated 2-amino[1,2,4]triazolo[5,1-

2

b]quinazolines, with chlorocarboxylic acid chlorides. Finally, we

discuss the structural features and chemical properties of the

obtained polycondensed heterocycles.

Annelation of new cycles to the molecules of compounds I have

been realized by various electrophilic reactions through the

3

1

electron-rich position 6 and a substituent (R or R ) at position 5

or 6. Some of the polycondensed heterocycles obtained from

R¹

R¹Ar

R²

N

_R1

N

O

R₃

(a)

R

R³

N

O

R⁴

III

H

V

[

O]

R⁴

N

R¹

N

R³

NH(Me)₂

Cl

H

N

1

2

-

N

R

2

N N

N

_N7

R = R = H

(b)

(c)

NH

N

O

6

NH₂

R

4

N

+

3

N

IV

N

H

5

R

_R3

3

N

VII

I

VI

R²

R³

Ph

O

NaBH4

_R1 _R4

+

R¹

R²

N

O

N

or

N

Ph

N

_R5

N

H

N

R

N

R³

H

N

VIII

IX

H

II

Scheme 1. Synthesis of dihydrotriazolopyrimidines I and their use for preparation of triazolopyrimidines II, III and polycondensed heterocycles V-IX.

3

2a,b,4a

Reagents: (a) ArCHO, I - R = substituted 2-hydroxyphenyl;

(b) NaNO

2

in AcOH, then heating with polyphosphoric acid or para-nitrobenzoyl chloride in

1

3

4d

1

3

1

3

4b,c,e,f

pyridine, I – R = aryl, R = Me, aryl; (c) ɑ ,ß-unsaturated carbonyls or analogs, I – R = aryl, R = Me or R = Me, R = Ph.

Results and discussion

added as a potential catalyst to enable nucleophilic substitution.

However, the 3-chloropropanoyl derivative 3a cyclized readily

upon being heated at 80-90 °C in DMF to give the corresponding

2

.1 Reactions of 2-aminosubstituted triazolopyrimidines and

triazoloquinazolines with chlorocarboxylic acid chlorides

8-oxo-1,2,3,4,7,8,9,10-octahydro[1,2,4]triazolo[1,5-a:4,3-

a']dipyrimidin-5-ium chloride 5a (Scheme 2). We found that it is

more convenient to carry out annelation of dihydropyrimidone

moiety to 2-aminotriazolopyrimidines in a one-pot procedure,

which afforded the polycondensed compounds 5a-e in yields of

Reaction of tetrahydrotriazolopyrimidine 1a with 2-

chloroacetyl, 3-chloropropanoyl or 4-chlorobutanoyl chloride in

acetonitrile in the presence of pyridine at 0-5 °C gave amides 2,

a, and 4 (Scheme 2), respectively. Attempts to cyclize the

chloroacetyl and 4-chlorobutanoyl derivatives 2 and 4 by heating

in DMF were unsuccessful. Heating these solutions at

temperatures from 80 °C to reflux led only to recovery of the

starting materials, even when tetramethylammonium iodide was

3

50-77%. Aminoheterocycles 1a-e were first treated with 3-

chloropropanoyl chloride in DMF in the presence of equimolar

amounts of pyridine at 0-5 °C. The reaction mixtures were

subsequently heated at 80-90 °C (Scheme 2, Method B). It should

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3

be noted that the cyclizations of 3-chloropropanoyl derivatives of

type 3 are very sensitive to steric factors. For example,

compounds 3f and 3g did not undergo cyclization even after

prolonged heating in DMF; only the starting compounds were

isolated from the reaction mixtures (Scheme 2).

O

n

Ar

Method A

Cl

n = 1-3

N

Cl

N

n = 2, R' = H

H N

2

HN

N

R'

a,f,g

Ph

O

N

R'

Ph

o

O

N

H

Ph

CH CN + Py, 0-5 oC

n

DMF, 80-90 C

3

Cl

1

5a (59%)

2

,3a,f,g,4 (61-83%)

Method B

4

5

6

3

2

O

Ar

o

Cl

6

11',1

8

0 - 90 C,

5

N

4

Cl

10'

1

13a'

3'

N

Cl

N

6a

3

N

9'

8'

1

h

N₁₂_'10a'

H N

2

HN

^H^N1'

O

N

^H^N11

_N11a

N

2

R

N ₅_a_'

N

O

6a'

7'

8

^O2'

DMF + Py,

0 - 5 C,

5 min

H

o

9

10

4'

H

Cl

3'

1a-e

1

3a-e

5a-d (50-77%)

5e (59%)

a,f,g: Ar = 4-MeOC H , R = Ph (50%)

2: n = 1 1a,2,3a,4: R' = H

6

4

b: Ar = R = Ph (77%)

c: Ar = Ph, R = 4-MeC H (63%)

3a-g: n = 2

4: n = 3

3f: R' = Me

3g: R' = Bn

6

4

d: Ar = Ph, R = Me (65%)

Scheme 2. Synthesis of amides 2, 3a,f,g,4 and polycondensed compounds 5a-e.

The reactivity of 2-amino-substituted triazolopyrimidines 6a-f

and triazoloquinazolines 6g,h towards 3-chloropropanoyl

chloride in DMF is generally similar to that of the compounds 1

rings of compounds 8b-f. Another side reaction that occurs in

addition to oxidative aromatization is hydrolytic cleavage of

dihydropyrimidine fragment of compounds 8b-f during the

reaction between compounds 6b-f and 3-chloropropanoyl

chloride. Thus, by prolonging the reaction times up to 8 h, we

were able to isolate compounds 9c-f, 10 and chalcon 11c from

the reaction mixtures (Schemes 4 and 5). However, the reaction

(

0

Schemes 3-5). Intermediate acylamino compounds 7 formed at

-5 °C can be converted into the polycondensed heterocycles 8a-

h by heating at 80-90 °C. Isolating and purifying acylamino

compounds, for example 7a (Scheme 3) or 7c (Scheme 5),

showed no significant advantages over the one-pot procedure.

Compounds 8b-f, with hydrogen as the substituent at position 3,

are comparatively unstable. It is possible to obtain these

compounds with low isolated yields (10-28%), providing that the

cyclization reaction time is limited to 3-5 min (Scheme 4).

Extending the reaction times to 20 min increased the yields of

3

of compound 6b (R = CH ) with 3-chloropropanoyl chloride

under these condition gave an inseparable mixture of products in

which benzylideneacetone was detected by GC-MS analysis.

Compounds 9c, 10 and 11c were also obtained by heating pure

compounds 7c (Method A, Scheme 5) or 8c (Method B, Scheme

5) in DMF for 8 h. Compound 10 was prepared by an alternate

method in 50% yield by hydrolysis of compound 8c in an

ethanolic solution of hydrochloric acid.

1

compounds 8b-f to 40-60%. However, the H NMR spectra of

the isolated products showed that they contained 15-20% of

compounds 9b-f as byproducts. These compounds are the

products of oxidative aromatization of the dihydropyrimidine

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4

Tetrahedron

O

Ph

COOEt

Method A

Cl

N

HN

O

N

DMF,

CH CN + Py,

3

o

(60%)

H

o

80 - 90 C,

0

- 5 C,

0 min

Cl

4

h

3

7a (69%)

Ph

COOEt

Cl

N

COOEt

H N

2

N

HN

N

H

a

O

N

H

6

8a

Method B

O

Ph O

Cl

N

Cl

N

HN

H N

2

HN

O

N

o

N

H

O

DMF + Py,

H

80 - 90 C,

o

H

0

- 5 C,

Cl

4 h

6g

15 min

8g

7

a,g,h

(51-77%)

Cl

N

H N

2

HN

N

H

N

H

O

8h

6h

Scheme 3. Synthesis of compounds 7a, 8a,g,h.

Ar

Cl

o

N

9

0 C

HN

N

O

N

R

3

-5 min

H

O

Ar

8b-f (10-27%)

N

Cl

N

HN

N

H N

2

O

N R

N

R DMF + Py,

H

o

Cl

Ar

Cl

HN

O

Ar

0

- 5 C,

Cl

HN

N

NH

NH₂

15 min

7b-f

o

N

6

b-f

N

9

0 C

+

O

N R

R

8

h

9

c-f (21-32%)

10

11

b: Ar = Ph, R = Me,

c: Ar = R = Ph,

e: Ar = 4-MeOC H , R = Ph,

6 4

f: Ar = R = 4-ClC H₄

6

d: Ar = Ph, R = 4-MeC H ,

6

4

Scheme 4. One-pot synthesis of compounds 8b-f and 9c-f.

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5

Ph

N

Method A

HN

O

N

H

Ph

Cl

7c

air, DMF,

Cl

N

NH

O

o

N

o

8

0 - 90 C

N

HN

+

DMF, 90 C

HN

Ph

O

^N^H2

3

min

O

N

Ph

8

h

9

c

10

11c

Ph

Cl

Method A

N

Method A: (32%)

Method B: (35%)

(17%)

(30%)

(39%)

(43%)

HN

N

O

N

H

Ph

8c (28%)

Scheme 5. Synthesis of compounds 8c, 9c, 10 and 11c.

Because attempts to effect the thermal cyclization of the

chloroacetyl (2) and 4-chlorobutanoyl (4) derivatives failed, we

investigated the behavior of compounds 2, 3a and 4 in the

presence of sodium methoxide. It was anticipated that the highly

nucleophilic conjugated N-anions should form via deprotonation

of the amide nitrogens in basic media. We were interested to

learn whether such anions would cyclize and to determine the

direction of such cyclizations.

Treatment of compounds 2 and 3a with sodium methoxide in

DMF or DMSO resulted in the formation of inseparable complex

mixtures of products, while compound 4 gave pyrrolidone

derivative 12 under these conditions (Scheme 6). The attempts to

prepare polycondensed heterocycles from chloroacylated

compounds 2, 3a and 4 through base catalysis were thus

unsuccessful.

Ar

MeONa, DMF

N

O

N

o

N

HN

20 C

N

O

N

Ph

O

N

H

Ph

N

H

Ph

3

H

3

65%

Cl

4

Cl

1

2

Ar = 4-MeOC H₄

6

Scheme 6. Synthesis of compound 12.

enones 11c-f, which were detected in the reaction mixtures by

GC-MS. We have developed an improved, preparative synthesis

of compounds 14c-f employing iodine in ethanol to effect the

oxidative aromatization of precursors 8c-f (Scheme 8). However,

all attempts to aromatize compound 8b were unsuccessful. In

alkaline solution the compound 8b was almost completely

hydrolyzed, while treatment with iodine gave an inseparable,

complex mixture of products.

2

.2 Transformations of polycondensed compounds in basic

media

The behavior of the obtained polycondensed heterocycles in

the presence of bases was then studied.

In aqueous sodium carbonate solutions at room temperature,

cations of compounds 5a-e and 9c-f were deprotonated at the

amide nitrogen to afford mesoionic compounds 13a-e and 14c-f.

Cations of compounds 8a,g,h lost the proton from the NH group

of the dihydropyrimidine moiety to afford the free bases 15a,g,h,

correspondingly (Scheme 7). Cations of salts 8c-f in alkaline

media were not only deprotonated but also underwent oxidative

aromatization to form mesoionic compounds 14c-f in yields of

When compounds 5c, 8a, 14d and 15g were refluxed in

ethanol for prolonged periods in the presence of a large excess of

KOH, hydrolysis of the amide bond and a retro-Michael reaction

in which acrylic acid was eliminated occurred, and

aminoheterocycles 1c, 6a,g and 16 were formed (Scheme 9).

However, refluxing compounds 5c, 8a,g and 14d in aqueous

Na CO or with a small excess of KOH in ethanol within 2 h

2 3

resulted in selective hydrolysis of the lactam and afforded the

heterosubstituted propanoic acids 17-20 (Scheme 9).

18-30% (Scheme 8). Low yields of products 14c-f from the

oxidative aromatization of compounds 8c-f in basic media were

due to concurrent hydrolysis of the dihydropyrimidine ring of the

intermediate free bases 15c-f. This process occurred through

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6

Tetrahedron

Ar

N

Cl

HN

N

OH^-

N

O

N

R

N

Ar'

7

7-89%

O

N

O

N

H

3e

H

5

a-e,9c-f

1

3a: Ar = 4-MeOC H , R = Ph

3b: Ar = R = Ph

3c: Ar = Ph, R = 4-MeC H

14c: Ar = Ar' = Ph

4d: Ar = Ph, Ar' = 4-MeC H

6 4

14e: Ar = 4-MeOC H , Ar' = Ph

6

4

1

6

4

6 4

13d: Ar = Ph, R = Me

14f: Ar = Ar' = 4-ClC H

6

4

Ph O

N

Cl

N

OH^-

N

OEt

N

HN

O

HN

O

HN

N

O

N

O

N

H

8a,g,h

15a (79%)

15g (90%)

15h (68%)

Scheme 7. Transformations of compounds 5a-e, 8a,g,h, 9c-f in basic media at room temperature.

Ar

N

Ar

OH^-

air

N

+

HN

O

+

HN

O

N

^N^H2

O

N

Ar'

O

Ar'

Ar

Cl

15c-f

14c-f (18-30%)

11c-f

N

HN

Ar

O

N

H

c-f

Ar'

o

1

2

. I , EtOH, 78 C

2

N

. Na S O + Na CO , H O

8

2

3

2

3

2

N

O

N

Ar'

14c-f (62-76%)

Scheme 8. Synthesis of compounds 14c-f by oxidative aromatization of compounds 8c-f.

Ph

N

excess of KOH in EtOH,

refluxing for 24 h

H2N

N

H N

2

N

H

Ar

(54-74%)

1c, 6a,g

16

Ph

N

HN

N

H N

2

O

N

H

Ar

5

c,8a,g,13c,14d,

O

Na CO , H O

1

5g

2

3

2

O

17

O

18

or

eq. KOH in EtOH,

refluxing for 2 h

Ph

Ph O

COOEt

N

H N

H2N

O

2

(53-70%)

N

H

N

2

0

O

O 19

Na

1

6-18: Ar = 4-CH C H

3 6 4

Scheme 9. Transformations of polycyclic compounds in basic media with heating.

ACCEPTED MANUSCRIPT

7

2

.3 Structure determination

1

A distinctive feature of the H NMR spectra of the salts 5a-e

is the sufficient downfield displacement of the NH signal of

tetrahydropyrimidine (9.9-10.4 ppm) in relation to the acylated

The structures of the synthesized compounds were established

by elemental analysis, mass-spectrometry and NMR spectral

1

13

data, including H- C heteronuclear correlation HSQC and

HMBC spectra for the majority of compounds (see

Supplementary Materials), and X-Ray diffraction studies. pKa

measurements, alkylation experiments and quantum chemical

calculations were also performed to elucidate the tautomeric

structure of free bases 13-15.

3e,f

derivatives 2,3a,4 (~7.4 ppm) and amines 1a-e (6.4-7.0 ppm).

The minimal changes between the

1

H

NMR spectral

characteristics of the tetrahydropyrimidine ring in the polycyclic

products 5a-e, 13a-e and their precursors 3a, 1a-e suggests that

the spatial configuration of this ring has not undergone

significant changes during the annelation of pyrimidone moiety.

2

.3.1 Spectral data, pKa and alkylation

The question of the tautomeric structure of compounds 13a-e

and 15a,g,h deserves a separate discussion (see also Section 2.3.2

below). Deprotonation of cationic salts 5a-e and 8a,g,h can occur

from the NH groups of any of the pyrimidine rings to afford

tautomers A and B (Scheme 10). A priori, a third possible

participant in the prototropic equilibrium is diimino tautomer C.

However, this tautomer may be present at only very low

concentrations because computational results suggest that it

should be significantly less stable than the amino-imino form B.

These computational data are presented in Section 2.3.2, and

similar results were obtained for the analogous tautomeric forms

1

3

Unfortunately, we were unable to obtain acceptable C NMR

spectra for compounds 7c and 8b-f because they gradually

decomposed in solution while the spectra were being recorded.

Small signals corresponding to impurities, the integral intensity

of which increased over longer recording times, were also

observed in the H NMR spectra of these compounds. The

NMR spectrum of compound 17 was also not obtained due to its

1

13

C

insufficient solubility in common NMR solvents.

1

13

The H and C NMR spectra of compounds 2, 3a,f,g, 4, 7a

and 7c are analogous to the spectra of the acylated derivatives of

partially hydrogenated 2-aminosubstituted [1,2,4]triazolo[1,5-

1

2

of 3,5-diamino[1,2,4]triazole. In light of our computational

results (Section 2.3.2) and literature data on the tautomerism of

3

e,f,8a

13

a]pyrimidines, which have been described in the literature.

lactams and acylated aminoheterocycles, it can be concluded

that hydroxy form D, the fourth possible tautomer, is also likely

to be present only in minor concentrations. Therefore, in the

experimental studies of the tautomerism, the only problem to be

addressed is the identification of the two tautomeric forms, A and

B.

Cyclization of 3-chloropropanoyl derivatives results in an ~8-

0 ppm upfield shift in the signal of the triazole carbon bonded to

1

the amide group (Fig. 1). Analogous displacements were

observed upon alkylation or protonation of C-amino-1,2,4-

triazoles at the N-4 atom of the triazole ring (i.e., the atom

3

e,10,11

bonded to two carbons in the triazole ring).

It should be

noted that the signal of the triazole carbon bonded to the amide

nitrogen (C-6a in compounds similar to 5a-d, C-13a in

compounds similar to 8g) is significantly broadened. In the

spectra of some compounds, for example 8a and 13c, this signal

merges into the background due to quadrupole interactions with

the neighboring nitrogen atoms. Nevertheless, cross-peaks

between the signals from both carbons of the triazole ring and

N

HN

O

N

H

N

A

B

protons of 10-CH (4-CH in pyrimidotriazoloquinazolines) are

2 2

1 13

H

N

observed in most of the H- C HMBC spectra of the synthesized

polycondensed heterocycles (Fig. 1) that proves the direction of

the annelation of pyrimidone cycle. Moreover, well-defined

cross-peaks between the signals from the triazole carbons and

N

HO

N

O

D

C

protons of NCH

9 and 20 serve as additional unambiguous evidence for the

assigned annelation (Fig. 1).

2 2

CH CO in the HMBC spectra of compounds 10,

Scheme 10. Putative tautomeric forms of free bases 13a-e, 15a,g,h.

1

In the H NMR spectra of compounds 13a-e the signal of 1-

NH (6ɑ -NH in compound 13e) is significantly broadened and

substantially merged into the background, apparently due to rapid

exchange with solvent. Similar broadening was observed for the

Cl

O

144.1-144.5

Cl

N

n

HN

O

N

signals of the NH and NH

structurally analogous mesoionic compounds 21 and 22 (Fig.

). The predominance of the mesoionic tautomer A in solutions

of compounds 13a-e in polar solvents is supported by

comparisons of the рK values for compounds 13a, 21, and 22

groups in the spectra of the

N

2

N

H

3e 11

H

1

52.6-154.3

CH2

HMBC

2

,3a,4,7a

5a-e

а

149.9-151.2 Cl

with the рK values for compounds 23 and 24, the fixed forms of

а

1

48.4

NH2

HMBC

N

145.1 N NH

tautomer B (Fig. 2). Compounds 13a, 21 and 22 (protonation at

the nitrogen atom of the ionized amide group, Fig. 2) are 50-80

fold less basic than compounds 23 and 24 (protonation at the

imino nitrogen of the tetrahydropyrimidine ring, Fig. 2).

Moreover, the mesoionic structures of compounds of type 13

were indirectly supported by selective alkylation of compound

H2N

N

HN

N

H2C

CH₂

O

HMBC

10

O

1

3a at the amide nitrogen, which gave compound 23 in the

absence of strong bases (Scheme 11). The structure of compound

3 was confirmed by its HMBC spectrum, in which cross-peaks

between the signals of the benzylic protons (4.63-4.81 ppm) and

19,20

1

3

Figure 1. The characteristic C NMR signals (ppm) of some compounds

2

1

13

(

6

DMSO-d ) and the key correlations in the H- C HMBC spectra.

ACCEPTED MANUSCRIPT

8

Tetrahedron

carbons C-6a (143.35 ppm) and С-8 (165.73 ppm) were

observed (Scheme 11). In their crystalline states, compounds

3a-e apparently also exist in the mesoionic tautomeric form A.

This is supported by the fact that their FTIR spectra do not show

spectra of mesoionic compounds 13a-e. This signal can be

attributed to the NH proton of the amide group (tautomer B,

Scheme 10) as well as the dihydropyrimidine ring (tautomer A,

1

a

Scheme 10). However the very similar pK values (Scheme 12)

-

1

the C=O bands at 1697-1711 cm that are observed in the FTIR

spectra of salts 5a-e (the crystal structure of 5d was confirmed by

X-ray analysis, Section 2.3.3) and compound 23 (representative

of the fixed form of tautomer B). The intense bands near 1647-

of compounds 15a and 25, which is the fixed form of tautomer B,

suggests that tautomer B predominates in solution for compounds

15a,g,h. Furthermore, in contrast to the mesoionic compounds

13a-e, compounds 15a,g,h were not amenable to alkylation in

DMF in the absence of strong bases. However, in the presence of

sodium hydride, which can deprotonate nitrogen, compound 15a

was selectively alkylated at the amide nitrogen to give compound

25 (Scheme 12). The position of the benzyl group in compound

25 was unequivocally confirmed by HMBC spectrum. The close

similarity between ν (C=O) in the FTIR spectra of compounds

-

1

1667 cm in the FTIR spectra of compounds 13a-e were

attributed to complex vibrations predominantly involving the

valence stretching of C11a—N1 and the antisymmetrical

stretching of N6—C6a—N7 based on evidence from quantum

chemical calculations on model structure 13A (Section 2.3.2

below). Unfortunately, we were unable to prepare a crystal

suitable for X-ray analysis of the structure of compounds 13a-e.

However, the mesoionic nature of compound 22, a structural

analog of the mesoionic compounds 13a-e, has been confirmed

-

1

15a,g,h (1685-1706 cm ) to the corresponding signal in

-

1

compound 25 (1680-1699 cm , combined band of C=O amide

and ester) supports the hypothesis that these compounds exist as

tautomeric structure B in the crystalline state. This has also been

confirmed by X-ray analysis of compound 15a (Section 2.3.3).

1

by X-ray analysis.

Well-defined NH singlets are observed at 11.25-11.53 ppm in

1

the H NMR spectra of compounds 15a,g,h, in contrast to the

Ar

N

Ar

N

Ar

Ph

N

Ar

Ph

N

H2N

N

O

NH₂

Ph

O

Ph

O

N

H

Ph

O

N

H

Ph

22

Ph

24

pKa = 9.79±0.05

Ph

21

13a

23

pKa = 7.31±0.03

pKa = 7.90±0.02

pKa = 7.51±0.04

pKa = 9.01±0.06

Ar = 4-MeOC H

6

4

3

e

11

3e

Figure 2. The pK

a

values for compounds 13a, 23 and their analogs 21, 22, 24, determined by potentiometric titration in 80% ethanol.

HMBC

H Ph

Ar

Ph

N

Br

NH aq

N

BnBr

N

3

N

H

N

N₆_a

^O8

O

N

Ph

o

DMF, 20 C

N

H

Ph

N

Ph

O

71%

H

13a

23

Scheme 11. Synthesis of compound 23.

HMBC

Ph O

Ph

Ph O

N

O

H Ph

H

N

NaH

Na

N

OEt

N

BnCl

70%

N

OEt

HN

O

N₆_a

N

o

N

DMF, 20 C

N

O

O ₈

1

5a

25

pK = 3.97±0.06

pK = 4.03±0.02

a

Scheme 12. Synthesis of compound 25 and the pK values for compounds 15a and 25 (titration by 0.1 M HCl in 80% ethanol).

the difference between the conformer energies of tautomers 13D

and 15D may be 6.1 kcal/mol, depending on the internal rotation

around the С8—O bond (see Supplementary Material). The

2.3.2 Theoretical calculations

2

98

relative Gibbs free energies (ꢀG ), dipole moments (ꢁ) and

Boltzmann populations (x) of tautomers A-D were calculated in a

vacuum and in DMSO and aqueous solutions and are presented

in Table 1. The calculations were based on the assumption that

only most stable conformers were present in the equilibrium

mixtures. The Boltzmann populations of tautomeric forms A-D

were computed from standard Gibbs free energy functions,

through the relationship ꢀG = ɑ RTlnK, where ꢀG denotes the

difference between Gibbs free energy for a given tautomer and

that calculated for the lowest energy, and K is the equilibrium

constant for these species.

A computational study on the tautomeric structures of

compounds 13a-e and 15a,g,h was performed on model

molecules 13A-D and 15A-D, which contain only hydrogen

atoms as substituents in the partially hydrogenated pyrimidine

ring.

Optimized structures of the model molecules for the most

stable tautomers of compounds 13 and 15 are presented in Figure

3

. Each of the possible tautomers A-D (Scheme 10) has multiple

298

stable conformers, but the largest ꢀG between conformers of

each tautomer is only 0.6 kcal/mol. A notable exception is that

ACCEPTED MANUSCRIPT

9

As shown by the values of the dipole moments (Table 1), the

mesoionic tautomer A should be the most polar molecule. On the

other hand, in most cases tautomer B should be the least polar

molecule in the equilibrium mixtures. According to the

computational results determined in vacuo, and consequently in

nonpolar solvents, tautomer B should predominate for both

compounds 13 and 15. In polar media, compounds of type 13

should exist predominantly in tautomeric form A. Compounds

of type 15 should remain mostly in tautomeric form B, although

equilibrium concentrations of tautomer A increase significantly

with increasing polarity of the medium (Table 1). It should be

noted that the computational results are in good agreement with

the experimental results discussed in Section 2.3.1.

Figure 3. Optimized structures of tautomeres 13A and 15B in water.

2

98

a

Table 1. Relative Gibbs Free Energies ꢀG (kcal/mol) , dipole moments ꢁ (D) and relative populations x (%) of tautomers A-D

of model compounds 13 and 15 at 25 °C calculated by the B3LYP/6-311++G(2d,2p) method

298

Tautomer

ꢀG

ꢁ

x

Tautomer

ꢀG

ꢁ

x

Vacuum (ε = 1)

13A

13B

13C

13D

15.63

0

14.49

1.98

6.95

1.53

0.00

100.00

0.00

15A

15B

15C

15D

18.74

0

13.41

0.26

5.31

3.31

0.00

100.00

0.00

12.22

9.74

14.06

9.56

0.00

Dimethyl sulfoxide (ε = 46.7)

13A

13B

13C

13D

0

21.21

2.45

97.62

2.38

0.00

15A

1.58

0

19.99

0.31

8.34

5.21

6.46

93.54

0.00

2.20

10.21

10.82

15B

15C

15D

10.16

2.86

9.98

8.41

0.00

Water ( ε = 78.4)

13A

13B

13C

13D

0

21.37

2.45

98.21

1.79

0.00

15A

15B

15C

15D

0.74

0

20.18

0.35

8.42

5.24

22.42

77.58

0.00

2.37

10.30

10.96

10.24

2.89

9.87

8.31

0.00

a

Total Energies, Zero Point Energies, Thermal corrections to Gibbs Free Energies and Relative Energies are presented in Tables S1-S4 of the Supplementary

Material.

2

2.3.3 X-Ray diffraction study

Csp =N(2) bonds (1.313 Å) and shorter than the mean value for

2

1

4

Csp -N(3) bonds (1.349 Å). In addition, the hydrogen atom at

N4 was found from difference Fourier synthesis. Refining this

atom in an isotropic approximation revealed the pyramidal

configuration of the N4 atom (the sum of the bond angles

centered at the nitrogen atom is 355° in 5d-A and 354° in 5d-B).

Taken together, these facts allow for the assumption that the

structure of the organic cation can be described as a superposition

Crystallographic numbering systems will be used for the

subsequent discussion of the structures of 5d, 14c and 15a (Fig.

-6).

4

Compound 5d exists in the crystal phase as a cationic organic

salt with a chloride counterion (Fig. 4). The asymmetric part of

the crystal unit cell contains two organic cations (5d-A and 5d-

B), which differ in some geometric parameters, and two chloride

anions (Cl1 and Cl2). Analysis of the bond lengths in the tricyclic

fragment of 5d demonstrates that the bonds centered at atom C5

are very similar (the N3-C5 bond is 1.323(6) Å in molecules 5d-

A and 5d-B; the N4-C5 bond is 1.341(6) Å in 5d-A and 1.337(6)

Å in 5d-B; the N5-C5 bond is 1.341(6) Å in 5d-A and 1.338(6) Å

in 5d-B). These bond lengths are longer than the mean value for

of three resonance structures (i-iii) with

a predominant

contribution from structure ii (Scheme 13). The

tetrahydropyrimidine ring adopts a half-chair conformation (the

1

5

puckering parameters are: S = 0.74, Θ = 30.9°, and Ψ = 26.5°

for 5d-A and S = 0.75, Θ = 31.0°, and Ψ = 29.2° for 5d-B). The

C3 and C4 atoms deviate from the mean plane of the other atoms

in the ring by 0.33 Å and -0.36 Å, respectively, in 5d-A. The

ACCEPTED MANUSCRIPT

1

0

Tetrahedron

corresponding atoms in 5d-B deviate from the plane by -0.36 Å

and 0.35 Å, respectively. The phenyl and methyl substituents are

oriented equatorially. The C5-N3-C2-C10 torsion angle is

138.3(4)° in 5d-A and 138.6(4)° in 5d-B; the C5-N4-C4-C9

torsion angle is -166.2(4)° in 5d-A and -165.4(4)° in 5d-B. The

tetrahydropyrimidone ring adopts a twist-boat conformation; the

puckering parameters are S = 0.59, Θ = 49.9°, and Ψ = 29.2° for

5d-A and S = 0.60, Θ = 51.1°, and Ψ = 28.8° for 5d-B. The N5

and C6 atoms deviate from the mean plane of the other atoms of

the ring by 0.33 Å and 0.75 Å, respectively, in 5d-A and by -0.34

Å and -0.76 Å, respectively, in 5d-B.

N

HN

O

HN

O

N

O

H

i

ii

Scheme 13. Resonance structures of the cation of compound

d.

iii

5

Figure 5. The molecular structure of compound 14c according to X-ray

diffraction data. Thermal ellipsoids are shown at the 50 % probability level.

Figure 4. The molecular structure of compound 5d according to X-ray

diffraction data (only one of two crystallographically independent molecules

is shown). Thermal ellipsoids are shown at the 50 % probability level.

Figure 6. The molecular structure of compound 15a according to X-ray

diffraction data (only one of two crystallographically independent molecules

is shown). Thermal ellipsoids are shown at the 50 % probability level.

The triazolopyrimidine fragment in mesoionic compound 14c

(

Fig. 5) is planar within 0.02 Å. The absence of hydrogen atoms

at N1 and N2 and equalization of the N1-C1 and N2-C1 bonds

1.336(2) Å and 1.334(2) Å, respectively, the mean value for the

The asymmetric part of crystal unit cell of compound 15d

contains two molecules (15a-A and 15a-B) differing by

conformation of partially saturated rings in the tricyclic fragment.

The dihydropyrimidine ring adopts an intermediate conformation

between a sofa and a twist-boat in 15a-A and exhibits a sofa

conformation in 15a-B. The puckering parameters are S = 0.31,

Θ = 51.9°, and Ψ = 25.9° in 15a-A and S = 0.36, Θ = 48.0°, and

Ψ = 6.1° in 15a-B. The C2 and C3 atoms in 15a-A deviate from

the mean plane of the remaining atoms of the ring by 0.40 Å and

(

2

14

Csp =N(2) bond is 1.313 Å ) allows to assume localization of

the negative charge within the –N1–C1–N2– fragment. The

positive charge is apparently concentrated mainly within the –

N4–C5–N5– region, based on the fact that the N4-C5 (1.308(2)

Å) and N5-C5 (1.343(2) Å) bonds are shorter than their mean

1

4

values (1.333

Å

and 1.380 Å, respectively).

The

tetrahydropyrimidone ring adopts a sofa conformation with

puckering parameters of S = 0.32, Θ = 35.2°, and Ψ = 6.6°. The

C6 atom deviates from the mean plane of the remaining atoms in

the ring by 0.27 Å. Benzene rings at the C2 and C4 atoms are

almost coplanar to the triazolopyrimidine fragment (the C3-C2-

C15-C20 and C3-C4-C9-C10 torsion angles are 15.0(3)° and

0.17 Å, and the C2 atom in 15a-B shows a deviation of 0.36 Å.

An opposite result is observed in the tetrahydropyrimidone ring,

which adopts a sofa conformation in 15a-A (the puckering

parameters are S = 0.52, Θ = 42.2°, and Ψ = 1.4° and the C7

atom deviates from the plane by 0.48 Å). In 15a-B the

tetrahydropyrimidone ring adopts an intermediate conformation

between a sofa and a twist-boat conformation. The puckering

parameters are S = 0.56, Θ = 42.1°, and Ψ = 24.5°, and the C7

and C8 atoms deviate from the plane by -0.63 Å and -0.23 Å,

1

0.5(3)°, respectively) resulting in the conjugation between their

π-systems.

ACCEPTED MANUSCRIPT

1

®

respectively. The phenyl substituent is almost orthogonal to the

dihydropyrimidine ring; the C5-N3-C2-C13 torsion angle is -

an InLab Expert Pro combined electrode. All GC-MS

measurements were carried out with an Agilent 7890A GC

system, equipped with an Agilent 5975C mass-selective detector

(electron impact, 70 eV) and a HP-5-MS column (30 m×0.25 mm

× 0.25 ꢁm film) using He as carrier gas at a flow of 1.0 mL/min.

The following temperature program was used in all GC-MS

measurements: initial temperature 65 °C, hold for 7 min, then 25

°C/min to 190 °C for 1 min, then 10 °C/min to 260 °C for 20

min, then 10 °C/min to 280 °C for 18 min. Retention times of

compounds were: 16.9 min for 11c, 18.07 min for 11d, 19.6 min

for 11e, 20.3 min for 11f.

99.5(3)° in 15a-A and 95.9(3)° in 15a-B. The carbonyl

functionality of the C3 substituent is coplanar with the endocyclic

C3-C4 double bond. The C4-C3-C10-O2 torsion angle is 1.6(5)°

in 15a-A and -8.7(5)° in 15a-B.

3. Conclusion

In summary, we have demonstrated the applicability of

partially hydrogenated 2-amino[1,2,4]triazolo[1,5-a]pyrimidines

and 2-amino[1,2,4]triazolo[5,1-b]quinazolines as novel 1,3-

N,Nʹ -binucleophilic reagents for the synthesis of polycondensed

heterocycles. This utility is exemplified by their reactions with

chlorocarboxylic acid chlorides. The ability of acylamino

derivatives formed in the first stage of the reaction to cyclize is

determined primarily by the nature of the chlorocarboxylic acid.

All attempts to cyclize chloroacetyl derivatives failed. The 4-

chlorobutanoyl derivative did not cyclize upon heating but

underwent intramolecular alkylation at the amide nitrogen to

form a pyrrolidin-2-one ring. Upon heating to 80-90 °C, only 3-

3e

3f

8c

5c

5b

5d

Starting compounds 1a-d,g, 1e, 6a, 6b, 6c-f, 6g and

were obtained by known methods. All other chemicals are

5g

6h

commercially available.

4.2. Quantum-chemical calculations

All calculations were performed with the Gaussian 03

software by using the hybrid Becke three-parameter Lee–Yang–

Parr DFT B3LYP functional and 6-311++G(2d,2p) basis set.

Solvent effects were modeled by the IEF-PCM method.

Geometry optimizations were followed by frequency

calculations in order to prove that the stationary points obtained

are true energy minima. The calculated energetic parameters and

atomic coordinates of all found conformers of tautomers 13A-D

and 15A-D are gathered in Supplementary material.

1

6

1

7

18

chloropropanoyl

polycondensed

derivatives

heterocycles,

could

yielding

be converted to

a

chlorides

of

or

[

1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ones

decahydropyrimido[2',1':3,4][1,2,4]triazolo[5,1-b]quinazolin-12-

ones. In most cases, the chlorides of polycondensed heterocycles

could be synthesized in a one-pot process starting from the

partially hydrogenated aminoheterocycles. Most of the obtained

chlorides of polycondensed heterocycles form free bases in

alkaline media at room temperature. Some of these compounds

exhibit mesoionic structures. Heating the polycondensed

compounds to reflux in aqueous sodium carbonate or in the

presence of equimolar amounts of potassium hydroxide in

ethanol results in cleavage of the dihydropyrimidone ring and

4

.3. X-Ray diffraction study

X-Ray diffraction studies were performed on an automatic

“

«

Bruker APEX II” diffractometer for compound 5d and

Xcalibur 3» diffractometer for 14c and 15a (graphite

monochromated MoK radiation, CCD-detector, ω-scanning).

The structure was solved by direct method using SHELXTL

package. The restrains for the bond lengths Csp -Csp (1.54 Å)

in the ethyl group were applied in the refinement of the structure

5a. Positions of the hydrogen atoms were located from electron

density difference maps and refined by “riding” model with Uiso

nUeq of the carrier atom (n = 1.5 for methyl groups and n = 1.2

for other hydrogen atoms). The hydrogen atoms of the NH

groups in 5d and 15a were refined in isotropic approximation.

The crystallographic data and experimental parameters are

presented in Supplementary Materials. Final atomic coordinates,

geometrical parameters and crystallographic data have been

deposited at the Cambridge Crystallographic Data Centre

α

1

9

3

formation

Triazolodipyrimidines

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

of

3-heterosubstituted

containing

propionic

the

acids.

4,7-

are

1

motif

that

unsubstituted at the position 3 of tricyclic core are unstable in

solution. Such compounds undergo oxidative aromatization and

hydrolysis of the dihydropyrimidine ring. Preparative methods

have been developed to facilitate the selective oxidative

aromatization or hydrolytic elimination of the dihypropyrimidine

fragment of these compounds.

=

4

. Experimental section

.1. General

(

CCDC), deposition numbers 811047 (compound 5d), 957615

compound 14c), and 957616 (compound 15a). These data can be

4

obtained

free

of

charge

via

The melting points were determined in open capillary tubes in

http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the

Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: (0044) 1223-336-033; or e-mail:

deposit@ccdc.cam.ac.uk).

a Thiele apparatus and are uncorrected. IR spectra were recorded

on a Varian 640-IR spectrometer using a single reflection

1

13

diamond ATR system as a sampling accessory. H and C NMR

spectra were recorded on a Bruker DRX 500 instrument at 500

MHz and 125 MHz, respectively, and a Bruker Avance 600

1

3

4.4. 7-(4-Methoxyphenyl)-4-methyl-5-phenyl-4,5,6,7-

tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-2-amine (1f)

instrument at 600 MHz (150 MHz for C) or Varian Unity 300 at

00 MHz in DMSO-d and using TMS as an internal standard for

3

6

1

3

majority of the compounds synthesized. C NMR spectra of

Sodium methoxide prepared from sodium (213 mg, 9.3 mmol)

and MeOH (1.5 mL) was added to a magnetically stirred

suspension of compound 1a (3 g, 9.3 mmol) in DMSO (30 mL)

and the resulted mixture was stirred at room temperature for 20

min, then cooled to 0-5 °C. Iodomethane (1.32 g, 9.3 mmol) was

added drop by drop to the reaction mixture, which was then

stirred for 1 h at 0-5 °C. Then further portions of sodium

methoxide [180 mg (7.8 mmol) of sodium in 1.5 mL of MeOH]

and iodomethane (1.11 g, 7.8 mmol) were added gradually to the

reaction mixture at 0-5 °C and stirring. The reaction mixture was

compounds 3f, 8g, 9e,d, 13d, 14e,f, 18 were recorded in

CF COOH (TFA) with addition of 5% DMSO-d or TFA-d due

3 6 1

to low solubility in DMSO. Mass spectra were recorded in the

form of m/z (intensity relative to base 100) on a Finnigan MAT

INCOS 50 instrument using electron impact ionization.

Elemental analyses were performed using a Perkin-Elmer 2400

Elemental Analyzer. The pK values of compounds 13a, 23, 15a

a

and 25 were determined by potentiometric titration in 80%

ethanol using a Mettler Toledo S40-KS instrument equipped with

ACCEPTED MANUSCRIPT

1

2

Tetrahedron

stirred at the same temperature for 2 h and then diluted with

water (90 mL). The precipitate formed was isolated by filtration

and recrystallized from acetonitrile to give compound 1f as

58.0 (C-7), 113.7, 126.5, 127.5, 128.3, 128.4, 131.8, 141.7

(carbons of benzene rings), 152.8 (C-2), 154.7 (C-3a), 158.7 (C-4

of 4-CH OC H ), 166.9 (CO). MS (EI, 70 eV), m/z (%): 375 (10)

3 6 4

-

1

+

colorless prisms (1.48 g, 52%), mp 207-208 °C. IR ν (cm ):

[M - HCl] , 240 (60), 233 (24), 153 (16), 134 (88), 119 (21), 115

(15), 91 (45), 77 (19), 65 (22), 55 (38), 38 (70), 36 (100). Anal.

Calcd for C H ClN O : C, 61.24; H, 5.38; N, 17.00. Found: C,

3

1

467, 3290, 3147, 3035, 3010, 2955, 2916, 2873, 2836, 2796,

620, 1580, 1544, 1512, 1478, 1455, 1407, 1365, 1346, 1325,

2

1

22

5

2

1

301, 1244, 1203, 1175, 1111, 1037. H NMR (500 MHz,

61.47; H, 5.44; N, 16.83.

DMSO-d ) δ: 2.25-2.35 (m, 2H, 6-CH ), 2.65 s (s, 3H, CH ), 3.75

6

2

3

(

s, 3H, CH

3

O), 4.39-4.43 (m, 1H, H-5), 4.95 (s, 2H, NH

2

), 5.08

4.5.3.

3-Chloro-N-(7-(4-methoxyphenyl)-4-methyl-5-phenyl-

dd, J=10.1, 4.8 Hz, 1H, H-7), 6.88 (d, J=8.4 Hz, 2H, Ar), 7.21

d, J=8.4 Hz, 2H, Ar), 7.31-7.34 (m, 1H, Ph), 7.38-7.42 (m, 4H,

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

yl)propanamide (3f)

1

3

Ph). C NMR (125 MHz, DMSO-d ) δ: 36.3, 43.2, 56.0, 58.1,

6

о

6

1

2

9

1.9, 114.4, 128.0, 128.7, 129.2, 129.6, 133.2, 141.5, 157.4,

59.5, 161.7. MS (EI, 70 eV), m/z (%): 335 (89) [M] , 223 (74),

00 (100), 178 (6), 165 (7), 145 (18), 131 (13), 115 (37), 103 (9),

1 (21), 77 (18), 65 (7), 51 (7), 42 (29). Anal. Calcd for

Yield 1.56 g (61%) of colorless needles, mp 211-212 C (from

AcOH/EtOH 1:3). IR ν (cm ): 3292, 3262, 3132, 3075, 3009,

2972, 2909, 2870, 2842, 1693, 1613, 1590, 1563, 1510, 1449,

1412, 1393, 1347, 1313, 1244, 1199, 1094, 1027. H NMR (500

+

-1

1

C

19

H

21

N

5

O: C, 68.04; H, 6.31; N, 20.88. Found: C 68.33; H 6.21;

6 2 3

MHz, DMSO-d ) δ: 2.36-2.42 (m, 2H, 6-CH ), 2.70 (s, 3Н, CH ),

N 21.07.

2.71-2.77 (br m, 2H, CH CO), 3.75 (s, 3H, CH O), 3.80 (t, J=6.3

2

3

2

Hz, 2H, CH Cl), 4.52 (dd, J=9.8, 4.2 Hz, 1H, H-5), 5.27 (dd,

4

.5. General procedure for the synthesis of compounds

J=9.7, 5.6 Hz, 1H, H-7), 6.91 (d, J=8.7 Hz, 2H, Ar), 7.23 (d,

J=8.7 Hz, 2H, Ar), 7.33-7.40 (m, 1H, Ph), 7.43-7.45 (m, 4H, Ph),

2,3a,f,g, 4, 7a,c

1

3

1

d

1

7

0.26 (br s, 1H, NH). C NMR (125 MHz, TFA + 5% DMSO-

A solution of the corresponding acid chloride (6.6 mmol) in

6

) δ: 34.6, 36.6, 38.5, 39.6, 55.2, 59.9, 62.2, 115.3, 126.6, 127.1,

28.7, 129.2, 129.5, 134.4, 143.0, 148.0, 159.3, 172.9. MS (EI,

0 eV), m/z (%): 425 (37) [M] , 389 (13), 362 (2), 335 (38), 306

acetonitrile (2 mL) was added drop by drop to a magnetically

stirred mixture of compound 1a,f,g, 6a,c (6.0 mmol), pyridine

+

(

0.574 g, 7.3 mmol) and acetonitrile (3 mL) at 0-5 °C. The

(

5), 290 (15), 256 (48), 223 (100), 200 (45), 191 (5), 165 (8), 145

23), 131 (19), 115 (41), 91 (29), 82 (18), 77 (16), 63 (20), 55

20), 42 (13), 36 (19). Anal. Calcd for C H ClN O : C, 62.04;

reaction mixture was stirred at the same temperature for 30 min

then diluted with water (5 mL). The precipitate formed was

isolated by filtration and recrystallized from appropriate solvent.

2

24

5

2

H, 5.68; N, 16.44. Found: C, 62.28; H, 5.71; N, 16.21.

4

.5.1.

2-Chloro-N-[7-(4-methoxyphenyl)-5-phenyl-4,5,6,7-

4

.5.4. N-(4-Benzyl-7-(4-methoxyphenyl)-5-phenyl-4,5,6,7-

tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]acetamide (2)

tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-3-

chloropropanamide (3g)

Yield 1.89 g (79%) of colorless needles, mp 278-279 °C (from

-1

CHCl

3

/EtOH 1:2). IR ν (cm ): 3342, 3304, 3141, 3034, 2999,

Yield 1.87 g (62%) of yellowish prisms, mp 165-167 °C (from

2

1

2

939, 2839, 1686, 1611, 1578, 1556, 1515, 1496, 1457, 1406,

-1

1

EtOH). IR ν (cm ): 3288, 3252, 3120, 3054, 3005, 2962, 2837,

6

378, 1335, 1313, 1252, 1175. H NMR (600 MHz, DMSO-d ) δ:

1692, 1613, 1561, 1497, 1452, 1429, 1367, 1336, 1316, 1298,

.07-2.13 (m, 1H, 6-CH ), 2.35-2.38 (m, 1H, 6-CH ), 3.72 (s, 3H,

1

2

1253, 1224, 1173, 1224, 1173, 1140, 1034. H NMR (600 MHz,

CH

3

O), 4.17 (br s, 2Н, СН

2

CO), 4.68-4.70 (m, 1H, H-5), 5.27-

DMSO-d ) δ: 2.34-2.37 (m, 1H, 6-CH ), 2.42-2.47 (m, 1Н, 6-

6

2

5

2

.29 (m, 1H, H-7), 6.88 (d, J=8.7 Hz, 2H, Ar), 7.18 (d, J=8.7 Hz,

CH

2

), 2.73 (br s, 2H, CH

2

CO), 3.71 (s, 3H, CH

3

O), 3.77 (t, J=6.3

), 4.51-4.54 (m,

), 5.26 (dd, J=10.2, 4.5

Hz, 1H, H-7), 6.86 (d, J=8.7 Hz, 2H, Ar), 7.06 (m, 2H, Ar), 7.19

d, J=8.7 Hz, 2H, Ar), 7.22-7.33 (m, 8H, Ar), 10.26 (br s, 1H,

H, Ar), 7.27-7.30 (m, 1H, Ph), 7.34-7.37 (m, 2H, Ph), 7.44-7.46

13

Hz, 2H, ClCH

), 3.94 (d, 1H, J=15.6 Hz, PhCH

2 2

(

5

1

3

m, 2H, Ph), 7.49 (br s, 1H, NH), 10.38 (br s, 1H, NH). C NMR

150 MHz, DMSO-d ) δ: 42.1 (C-6), 43.0 (CH CO), 53.8 (C-5),

1H, H-5), 4.86 (d, J=15.6 Hz, 1H, PhCH

2

6

2

5.1 (CH O), 58.1 (C-7), 113.7, 126.5, 127.6, 128.36, 128.39,

3

(

31.7, 141.6 (carbons of benzene rings), 152.6 (C-2), 154.7 (C-

13

NH). C NMR (150 MHz, DMSO-d ) δ: 38.4 (CH CO), 40.4

6

2

a), 158.8 (C-4 of 4-CH OC H ), 163.6 (CO). MS (EI, 70 eV),

3

6

4

+

(ClCH

2

), 41.4 (C-6), 50.0 (PhCH

2

), 55.0 (CH

3

O), 57.4 (C-7),

m/z (%): 397 (1) [M] , 321 (11), 223 (40), 186 (19), 134 (80),

19 (37), 115 (23), 91 (71), 77 (32), 65 (32), 50 (22), 43 (19), 36

100). Anal. Calcd for C20 : C, 60.38; H, 5.07; N,

7.60. Found: C, 60.52; H, 5.16; N, 17.31.

5

1

7

7.9 (C-5), 113.6, 127.1, 127.5, 127.7, 128.0, 128.2, 128.5,

28.6, 131.3, 136.9, 139.2 (carbons of benzne rings), 152.6 (C-2),

55.3 (C-3a), 158.7 (C-4 of 4-CH OC H ), 166.8 (CO). MS (EI,

1

(

1

5 2

H20ClN O

3

6

4

+

0 eV), m/z (%): 501 (1) [M] , 223 (26), 134 (20), 116 (16), 91

(

100), 65 (16), 55 (25), 36 (41). Anal. Calcd for C H ClN O :

28 28 5 2

4

.5.2.

3-Chloro-N-[7-(4-methoxyphenyl)-5-phenyl-4,5,6,7-

C, 66.99; H, 5.62; N, 13.95. Found: C 66.90; H 5.78; N 13.71.

tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]propanamide

3a)

(

4.5.5. 4-Chloro-N-[7-(4-methoxyphenyl)-5-phenyl-4,5,6,7-

tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]butanamide (4)

Yield 1.88 g (76%) of colorless prisms, mp 238-239 °C (from

-

1

CHCl

1

3

/EtOH 1:2). IR ν (cm ): 3286, 3138, 3032, 2930, 1671,

Yield 2.12 g (83%) of colorless needles, mp 251-252 °C

-

1

615, 1578, 1562, 1516, 1496, 1457, 1420, 1401, 1313, 1299,

281, 1259, 1175. H NMR (600 MHz, DMSO-d

m, 1H, 6-CH ), 2.34-2.37 (m, 1H, 6-CH ), 2.70 (m, 2Н, СН ),

(CHCl /EtOH 1:2). IR ν (cm ): 3323, 3227, 3130, 3037, 2958,

3

1

6

) δ: 2.07-2.13

2838, 1659, 1601, 1573, 1551, 1516, 1496, 1465, 1443, 1384,

1

(

1348, 1310, 1288, 1249, 1179. H NMR (300 MHz, DMSO-d ) δ:

2

6

3

1

2

7

.72 (s, 3H, CH

3

O), 3.77 (t, J=6.3 Hz, 2H, CH

2

), 4.67-4.69 (m,

1.91-1.94 (m, 2H, CH

2

), 2.09-2.12 (m, 1H, 6-CH2), 2.34-2.41 (m,

2

H, H-5), 5.26 (dd, J=10.9, 4.6 Hz, 1H, H-7), 6.88 (d, J=8.7 Hz,

H, Ar), 7.17 (d, J = 8.7 Hz, 2H, Ar), 7.27-7.29 (m, 1H, Ph),

.34-7.37 (m, 2H, Ph), 7.43 (br s, 1H, NH), 7.44-7.46 (m, 2H,

3H, 1H of 6-CH + CH of 4-chlorobutanoyl), 3.60 (t, J=6.4 Hz,

2

2 3

2H, CH ), 3.72 (s, 3H, CH O), 4.67-4.70 (m, 1H, H-5), 5.26 (dd,

J=11.0, 4.6 Hz, 1H, H-7), 6.88 (d, 2H, J=8.3 Hz, Ar), 7.17 (d,

J=8.3 Hz, 2H, Ar), 7.24-7.48 (m, 6H, Ph+NH), 10.01 (br s, 1H,

1

3

Ph), 10.13 (br s, 1H, NH). C NMR (150 MHz, DMSO-d

6

) δ:

13

38.4 (CH ), 40.4 (CH ), 42.1 (C-6), 53.8 (C-5), 55.1 (CH O),

NH). C NMR (150 MHz, DMSO-d ) δ: 27.7 (CH ), 32.3 (CH ),

2

3

6 2 2

ACCEPTED MANUSCRIPT

1

3

4

2.1 (C-6), 44.8 (CH

2

), 53.8 (C-5), 55.1 (CH

3

O), 58.0 (C-7),

4.6.1. 4-(4-Methoxyphenyl)-8-oxo-2-phenyl-1,2,3,4,7,8,9,10-

113.7, 126.5, 127.5, 128.36, 128.39, 131.8, 141.7 (carbons of

octahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium chloride

benzene rings), 152.9 (C-2), 154.6 (C-3a), 158.8 (C-4 of 4-

(5a)

+

CH

89 (15), 254 (25), 223 (36), 134 (44), 119 (20), 117 (30), 115

26), 91 (44), 77 (31), 65 (20), 55 (20), 41 (76), 36 (100). Anal.

Calcd for C22 : C, 62.04; H, 5.68; N, 16.44. Found: C,

2.31; H, 5.77; N, 16.32.

3 6 4

OC H ), 169.5 (CO). MS (EI, 70 eV), m/z (%): 425 (3) [M] ,

3

(

Yield 0.58 g (59%, Method A), 0.61 g (50%, Method B),

colorless prisms, mp 276-278 °C (from MeOH). IR ν (cm ):

3206, 3038, 2947, 2582, 1711, 1665, 1632, 1614, 1557, 1516,

1484, 1452, 1422, 1376, 1325, 1291, 1251, 1184. H NMR (600

-

1

H24ClN

5

O

2

1

6

MHz, DMSO-d

3-CH ), 2.83-2.85 (m, 2Н, м, 9-CH

4.23 (m, 1H, 10-CH ), 4.39-4.43 (m, 1H, 10-CH

H, H-2), 5.37 (dd, J=10.6, 4.0 Hz, 1H, Н-4), 6.92 (d, J=8.5 Hz,

6

) δ: 2.27-2.33 (m, 1H, 3-CH

), 3.74 (s, 3H, MeO), 4.18-

), 4.95-4.97 (m,

2

), 2.50-2.51 (m, 1H,

4

.5.6. Ethyl 2-[(3-chloropropanoyl)amino]-5-methyl-7-phenyl-

2

4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (7a)

2

1

Yield 1.61 (69%) of colorless prisms, mp 245-246 °C (from

EtOH). IR ν (cm ): 3300, 3268, 3225, 3147, 2930, 2823, 1702,

2H, Ar), 7.33–7.42 (m, 5H, Ar), 7.53 (d, J = 7.5 Hz, 2H, Ar),

10.12 (br s, 1H, NH), 11.80 (br s, 1H, NH). C NMR (150 MHz,

-

1

13

1

650, 1597, 1552, 1512, 1412, 1332, 1309, 1270, 1231, 1187,

DMSO-d

55.2 (CH

129.1, 139.0 (carbons of benzene rings), 144.5 (C-6a), 146.5 (C-

11a), 159.5 (C-4 of 4-CH OC ), 166.6 (C-8). MS (EI, 70 eV),

m/z (%): 376 (3) [M - Cl] , 375 (8) [M - HCl] , 315 (26), 272

(18), 240 (100), 134 (90), 119 (14), 91 (7), 55 (7). Anal. Calcd

6

) δ: 28.8 (C-9), 38.1 (C-10), 39.5 (C-3), 53.9 (C-2),

1

161, 1110, 1073, 1019. H NMR (600 MHz, DMSO-d

CH O), 2.40 (s, 3H, Me), 274 (br s, 2Н,

CO), 3.77 (t, J=5.9 Hz, 2Н, ClСН CH CO), 3.90-3.99

CH ), 6.16 (s, 1H, H-7), 7.21-7.31 (m, 5H, Ph),

0.37 (br s, 1H, NH), 10.78 (s, 1H, NH). C NMR (150 MHz,

δ: 13.8 (CH CH O), 18.3 (CH ), 38.4

CO), 40.3 (ClСН CH CO), 59.2 (C-7), 59.3

O), 97.7 (C-6), 127.0, 127.8, 128.3, 142.1 (carbons of

6

) δ: 1.03

3

O), 58.7 (C-4), 113.9, 127.0, 128.2, 128.6, 128.7,

(

t, J=6.9 Hz, 3H, CH

3

2

ClСН

2

CH

2

3

6 4

H

+

(

m, 2H, OCH

2

3

13

1

DMSO-d

6

)

3

2

3

for C21

H

22ClN

5

O

2

: C, 61.24; H, 5.38; N, 17.00. Found: C, 61.51;

(

ClСН

CH CH

2

CH

2

H, 5.22; N, 16.73.

3

2

4.6.2.

8-Oxo-2,4-diphenyl-1,2,3,4,7,8,9,10-

benzene ring), 146.1 (C-3a), 146.2 (C-5), 154.3 (C-2), 165.0

octahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium chloride

hydrate (1:1:1) (5b)

(

COOEt), 166.9 (ClСН CH CO). MS (EI, 70 eV), m/z (%): 389

10) [M] , 353 (10), 326 (27), 312 (34), 276 (51), 248 (21), 222

47), 194 (47), 155 (14), 128 (34), 115 (12), 91 (15), 77 (27), 63

2 2

+

Yield 0.92 g (77%, Method B) of colorless prisms, mp 291-

46), 55 (49), 36 (100). Anal. Calcd for C18

H20ClN

5

O

3

: C, 55.46;

-1

2

92 °C (from MeOH). IR ν (cm ): 3610, 3414, 3196, 3063, 2962,

H, 5.17; N, 17.96. Found: C, 55.75; H, 5.08; N, 17.81.

2

908, 2827, 2778, 1710, 1656, 1554, 1492, 1459, 1428, 1365,

1

4.5.7. 3-Chloro-N-(5,7-diphenyl-4,7-dihydro[1,2,4]triazolo[1,5-

1322, 1283, 1262, 1223, 1215, 1102, 1023. H NMR (600 MHz,

a]pyrimidin-2-yl)propanamide (7c)

DMSO-d

CH ), 2.84 (t, J=6.7 Hz, 2Н, 9-СН

4.37-4.39 (m, 1H, 10-CH ), 4.97-4.99 (m, 1H, H-2), 5.43 (dd,

J=10.5, 4.1 Hz, 1H, H-4), 7.31-7.41 (m, 8H, Ar), 7.52-7.53 (m,

6

) δ: 2.27-2.33 (m, 1H, 3-CH

2

), 2.55-2.57 (m, 1H, 3-

2

), 4.20-4.22 (m, 1H, 10-CH

2

),

Yield 1.60 g (70%) of colorless prisms, mp °C (CHCl

3

/EtOH

2

-

1

CH

5

(

7

(

9

:3). IR ν (cm ): 3284, 3157, 3061, 3030, 2924, 2855, 1665,

1

3

604, 1587, 1561, 1449, 1406, 1340, 1318, 1295, 1221, 1069,

2H, Ar), 10.1 (br s, 1H, NH), 11.81 (br s, 1H, NH). C NMR

(150 MHz, DMSO-d ) δ: 28.8 (C-9), 38.1 (C-10), 39.5 (C-3) ,

1

029, 1001. H NMR (300 MHz, DMSO-d

6

) δ: 2.73 (br s, 2H,

), 5.20 (d, J=2.3 Hz, 1H, Н-

), 6.11 (d, J=3.7 Hz, 1H, H-7), 7.27-7.41 (m, 8Н, Ar), 7.58-7.61

m, 2H, Ar), 10.04 (br s, 1Н, NH), 10.36 (br s, 1Н, NH). MS (EI,

6

2

), 3.78 (t, J=6.3 Hz, 2H, ClCH

2

53.8 (C-2), 59.1 (C-4), 127.0, 127.7, 128.3, 128.4, 128.5, 128.6,

137.0, 138.9 (carbons of benzene rings), 144.5 (C-6a), 146.6 (C-

11a), 166.5 (C-8). MS (EI, 70 eV), m/z (%): 346 (5) [M - Cl -

+

0 eV), m/z (%): 379 (8) [M] , 343 (17), 302 (29), 289 (15), 266

69), 219 (15), 212 (100), 191 (36), 129 (13), 115 (23), 104 (30),

1 (16), 77 (45), 63 (38), 55 (41), 36 (89). Anal. Calcd for

O: C, 63.24; H, 4.78; N, 18.44. Found: C, 63.48; H,

H

2

O] , 345 (22) [M - HCl - H

77 (52), 55 (100), 36 (92). Anal. Calcd for C20

60.07; H, 5.55; N, 17.51. Found: C, 60.31; H, 5.31; N, 17.78.

2

O] , 240 (99), 115 (27), 104 (63),

5 2

H22ClN O

: C,

20 5

C H18ClN

4.88; N, 18.12.

4.6.3.

2-(4-Methylphenyl)-8-oxo-4-phenyl-1,2,3,4,7,8,9,10-

octahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium chloride

4

8

.6. General procedure for the synthesis of compounds 5a-e,

a,g,h

(5c)

Yield 0.75 g (63%, Method B) of colorless prisms, mp 282-

84 °C (from EtOH). IR ν (cm ): 3057, 3001, 2935, 2887, 2818,

766, 1703, 1684, 1651, 1558, 1496, 1450, 1375, 1340, 1292,

Method A. A solution of 3-chloropropanamide 3a,7a (2.4

mmol) in DMF (2 mL) was heated at 80-90 °C and stirring for

-1

2

1

2

3

1

h (4 h in case of compound 7a), then cooled to 20 °C. The

1

258, 1220, 1185, 1096, 1025. H NMR (600 MHz, DMSO-d

6

) δ:

), 2.51-2.53 (m, 1H,

), 4.16-4.19 (m, 1H, 10-

), 4.90-4.92 (m, 1H, H-2), 5.40

dd, J=10.7, 4.2 Hz, 1H, H-4), 7.22 (d, J=7.9 Hz, 2H, Ar), 7.32-

precipitate formed was isolated by filtration, washed with

acetone and recrystallized.

.25-2.27 (m, 1H, 3-CH

-CH ), 2.84 (t, J=6.9 Hz, 2Н, 9-CH

), 4.31-4.33 (m, 1H, 10-CH

2 3

), 2.30 (s, 3H, CH

2

CH

2

Method B. A solution of 3-chloropropanoyl chloride (0.41 g,

(

7

3

.3 mmol) in acetonitrile (1 mL) was added drop by drop to a

13

.41 (m, 7H, Ar), 10.93 (br s, 1H, NH). C NMR (150 MHz,

) δ: 20.7 (CH ), 28.8 (C-9), 37.9 (C-10), 39.6 (C-3),

3.6 (C-2), 59.2 (C-4), 126.9, 127.7, 128.41, 128.45, 129.1,

magnetically stirred mixture of amine 1a-e, 6a,g,h (3.0

DMSO-d

6

3

mmol), pyridine (0.26 g, 3.3 mmol) and dry DMF (3 mL) at

5

1

-

C

5

20 °C. The resulted mixture was stirred at the same

35.9, 137.0, 137.7 (carbons of benzene rings), 144.5 (C-6a),

temperature for 15 min, then heated at 80-90 °C and stirring

for 1 h (4 h at the synthesis of compounds 8a,8g,h) and

cooled to 20 °C. The precipitate formed was isolated by

filtration, washed with acetone and recrystallized.

46.6 (C-11a), 166.5 (C-8). MS (EI, 70 eV), m/z (%): 360 (4) [M

+

HCl] , 254 (100), 104 (13), 55 (16), 36 (19). Anal. Calcd for

21

H

22ClN

5

O: C, 63.71; H, 5.60; N, 17.69. Found: C, 64.01; H,

.48; N, 17.47.

ACCEPTED MANUSCRIPT

1

4

Tetrahedron

4

.6.4.

octahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium chloride

5d)

2-Methyl-8-oxo-4-phenyl-1,2,3,4,7,8,9,10-

Yield 0.92 g (77%, Method B) of cream-colored prisms, mp 266-

-1

267 °C (from AcOH/EtOH 1:4). IR ν (cm ): 3075, 3016, 2965,

(

2881, 2820, 2774, 2647, 1733, 1717, 1668, 1656, 1588, 1492,

1

462, 1439, 1367, 1335, 1281, 1249, 1222, 1139. H NMR (500

Yield 0.62 g (65%, Method B) of colorless needles, mp 289-

90 °C (from MeOH). IR ν (cm ): 3125, 3030, 2964, 2933, 2870,

6 3 3

MHz, DMSO-d ) δ: 1.03 (s, 3H, CH ), 1.09 (s, 3H, CH ), 2.18-

-

1

2

1

2.28 (m, 2H, CH ), 2.67-2.80 (m, 2H, CH ), 2.88 (t, J=6.9 Hz,

2

754, 1697, 1672, 1639, 1560, 1494, 1458, 1439, 1400, 1380,

333, 1321, 1262, 1223, 1207, 1158. H NMR (600 MHz,

2Н, 3-CH

2

), 4.42-4.44 (m, 2Н, 4-СН

2

), 6.18 (s, 1H, CH), 7.32-

1

13

7.39 (m, 5H, Ph), 11.99 (br s, 1Н, NH). C NMR (125 MHz,

DMSO-d

6

) δ: 1.33 (d, J=6.3 Hz, 3H, CH

3

), 1.87-1.92 (m, 1H, 3-

6

TFA + 5% DMSO-d ), δ: 25.4, 26.7, 27.9, 32.5, 39.3, 39.4, 48.7,

CH ), 2.42-2.45 (m, 1H, 3-CH ), 2.83 (t, J=6.9 Hz, 2Н, 9-CH ),

60.1, 109.9, 127.2, 128.9, 129.8, 135.9, 140.0, 145.5, 150.2,

169.3, 200.0. MS (EI, 70 eV), m/z (%): 363 (30) [M - HCl] , 286

2

+

3

.83-3.88 (m, 1H, H-2), 4.23- 4.27 (m, 1H, 10-CH

2

), 4.41-4.44

(

m, 1H, 10-CH ), 5.25 (dd, J=11.0, 4.8 Hz, 1H, Н-4), 7.33–7.40

(99), 232 (9), 115 (7), 77 (13), 55 (64), 36 (100). Anal. Calcd for

C H22ClN O : C 60.07; H 5.55; N, 17.51. Found: C, 60.29; H,

20 5 2

2

1

3

m, 5H, Ph), 10.40 (br s, 1H, NH), 11.71 (br s, 1H, NH).

C

NMR (150 MHz, DMSO-d ) δ: 19.4 (CH ), 28.8 (C-9), 38.1 (C-

5.63; N, 17.30.

6

3

10), 38.7 (C-3), 46.1 (C-2), 58.8 (C-4), 127.3, 128.3, 128.5, 137.6

(

8

carbons of benzene ring), 144.3 (C-6a), 146.1 (C-11a), 166.5 (C-

4.6.8.

2'-Oxo-1',3',4',6',7',8',9',10'-octahydro-2'H-

+

). MS (EI, 70 eV), m/z (%): 284 (7) [M - Cl] , 283 (58) [M -

spiro[cyclohexane-1,11'-pyrimido[2',1':3,4][1,2,4]triazolo[5,1-

b]quinazolin[12]ium] chloride (8h)

+

HCl] , 269 (13), 268 (100), 179 (23), 138 (19), 115 (10). Anal.

Calcd for C15 O: C, 56.34; H, 5.67; N, 21.90. Found: C,

6.48; H, 5.78; N, 21.62.

H18ClN

5

Yield 0.66 g (63%, Method B) of colorless prisms, mp 277-

-

1

2

1

78 °C (from EtOH). IR ν (cm ): 3123, 2981, 2939, 2868, 2760,

703, 1679, 1628, 1559, 1496, 1448, 1386, 1368, 1336, 1313,

292, 1262, 1223, 1158, 1046, 1011. H NMR (300 MHz,

4

.6.5. 2'-Oxo-1',3',4',6',6a',7',8',9',10',10a'-decahydro-2'H-

spiro[cyclohexane-1,11'-pyrimido[2',1':3,4][1,2,4]triazolo[5,1-

b]quinazolin[12]ium] chloride (5e)

1

DMSO-d ) δ: 1.10-2.28 (m, 18H), 2.84 (t, J=6.7 Hz, 2Н, 3-СН ),

6

2

4

.21 (t, J=6.7 Hz, 2Н, 4-СН

2

), 11.30 (br s, 1Н, NH), 11.96 (br s,

Yield 0.60 g (59%, Method B) of colorless prisms, mp 302-

04 °C (from EtOH). IR ν (cm ): 3132, 3053, 2940, 2890, 2769,

13

-

1

1Н, NH). C NMR (150 MHz, DMSO-d

6

) δ: 21.2, 21.6, 22.4,

3

1

2

4

23.5, 23.8, 25.6, 28.6 (C-3ɑ ), 33.6, 38.1 (C-4ɑ ), 62.7 (C-11ɑ ),

705, 1676, 1638, 1551, 1494, 1442, 1386, 1364, 1331, 1292,

1

111.4 (C-10aɑ ), 126.2 (C-6aɑ ), 141.1, 144.5 (carbons of triazole

ring), 166.6 (C-2ɑ ). MS (EI, 70 eV), m/z (%): 313 (67) [M -

HCl] , 270 (100), 257 (34), 242 (8), 202 (6), 55 (9). Anal. Calcd

for C17H24ClN O: C, 58.36; H, 6.91; N, 20.02. Found: C, 58.56;

5

H, 7.05; N, 20.21.

263. H NMR (600 MHz, DMSO-d ) δ: 0.96-1.03 (m 1H, CH),

6

.24-1.77 (m, 14H, CH), 1.88-2.00 (m, 2H, CH), 2.18-2.26 (m,

+

ɑ

H, CH), 2.81-2.84 (m, 2H, 3-C H ), 3.94 (m, 1H, H-6aɑ ), 4.21-

2

ɑ

.30 (m, 2H, 4-C H

2

), 9.85 (br s, 1H, NH), 11.71 (br s, 1H, NH).

1

3

C NMR (150 MHz, DMSO-d ) δ: 18.8, 19.8, 20.9, 21.1, 24.3,

6

2

6

4.3, 28.1, 28.6 (C-3ɑ ), 30.3, 34.5, 36.0, 37.8 (C-4ɑ ), 45.9 (C-

aɑ ), 61.5, 144.1 (C-13aɑ ), 144.2 (C-5aɑ ), 166.4 (C-2ɑ ). MS

4.7. General procedure for the synthesis of compounds 8b-f

+

(

2

(

EI, 70 eV), m/z (%): 316 (15) [M - Cl] , 315 (100) [M - HCl] ,

86 (11), 272 (75), 260 (15), 244 (22), 233 (34), 217 (17), 192

38), 153 (39), 138 (13), 83 (21), 67 (15), 55 (39). Anal. Calcd

for C H ClN O: C, 58.03; H, 7.45; N, 19.90. Found: C, 58.34;

Method A. A solution of 3-chloropropanoyl chloride (0.41 g, 3.3

mmol) in acetonitrile (1 mL) was added drop by drop to a

magnetically stirred mixture of amine 6b-f (3.0 mmol), pyridine

(0.26 g, 3.3 mmol) and dry DMF (2 mL) at 0-5 °C. The resulted

mixture was stirred at the same temperature for 15 min, then

heated rapidly up to 88-90 °C and stirred at the same temperature

for 3-5 min, then cooled to 0-5 °C and diluted with cold acetone

1

7

26

5

H, 7.53; N, 19.68.

4.6.6. 3-(Ethoxycarbonyl)-2-methyl-8-oxo-4-phenyl-1,4,7,8,9,10-

hexahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium

chloride (8a)

(

5 mL). The precipitate formed was isolated by filtration, washed

with acetone and dried at room temperature. All attempts of

crystallization of the substances 8b-f from various solvents led to

their partial destruction and contamination by compounds 9.

Yield 0.56 g (60%, Method A), 0.60 g (51%, Method B),

-

1

colorless prisms, mp 301-302 °C (from EtOH). IR ν (cm ): 3066,

3

1

028, 2958, 2908, 2769, 2717, 1716, 1663, 1580, 1496, 1475,

Method B. A solution of 3-chloropropanamide 7c (3.0 mmol) in

DMF (3 mL) was heated rapidly up to 88-90 °C and stirred at the

same temperature for 3 min, then cooled to 0-5 °C and diluted

with cold acetone (5 mL). The precipitate of compound 8c was

isolated by filtration, washed with acetone and dried at room

temperature.

454, 1373, 1322, 1275, 1258, 1232, 1186, 1149, 1103, 1076,

1

021. H NMR (600 MHz, DMSO-d ) δ: 0.99 (t, J=7.1 Hz, 3H,

6

CH

3 2 3 2

CH O), 2.50 (s, 3H, CH ), 2.83-2.86 (m, 2Н, 9-СН ), 3.91-

4.00 (m, 2H, CH CH O), 4.34-4.37 (m, 2Н, 10-СН ), 6.20 (s, 1H,

3

2

1

3

H-4), 7.32-7.38 (m, 5H, Ph), 11.97 (br s, 1H, NH). C NMR

(

150 MHz, DMSO-d ) δ: 13.6 (CH CH O), 18.2 (CH ), 28.5 (C-

6

3

2

3

9

1

), 38.8 (C-10), 60.0 (2C, CH

27.9, 128.5, 128.7, 139.6 (carbons of benzene ring), 146.2 (C-

3

2

CH O and C-4), 101.1 (C-3),

4

.7.1.

2-Methyl-8-oxo-4-phenyl-1,4,7,8,9,10-

hexahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium

chloride (8b)

1a), 164.1 (C-2), 166.5 (2C, C-8 and COOEt). MS (EI, 70 eV),

+

m/z (%): 353 (16) [M - HCl] , 324 (46), 277 (15), 276 (100), 248

(

50), 55 (16). Anal. Calcd for C18

5 3

H20ClN O : C, 55.46; H, 5.17;

Yield 0.18 g (19%, Method A) of colorless prisms, mp 278-

N, 17.96. Found: C, 55.57; H, 5.11; N, 17.76.

-1

2

80 °C. IR ν (cm ): 3085, 3023, 2893, 2732, 1700, 1661, 1634,

1

4

.6.7. 8,8-Dimethyl-2,10-dioxo-11-phenyl-1,2,3,4,6,7,8,9,10,11-

decahydropyrimido[2',1':3,4][1,2,4]triazolo[5,1-b]quinazolin-

2-ium chloride (8g)

1573, 1497, 1458, 1373, 1319, 1285, 1257, 1226, 1133, 1029. H

NMR (300 MHz, DMSO-d ) δ: 2.00 (s, 3Н, CH ), 2.84 (t, J=6.7

Hz, 2Н, 9-СН ,), 4.28-4.33 (m, 2Н, 10-СН ), 4.95 (d, J=1.3 Hz,

Н, H-3), 6.00 (d, J=1.3 Hz, 1Н, H-4), 7.25-7.40 (m, 5Н, Ph),

1.94 (br s, 2Н, 2NH). MS (EI, 70 eV), m/z (%): 281 (9) [M -

6

3

1

2

1

ACCEPTED MANUSCRIPT

1

5

+

HCl] , 204 (100), 150 (21), 128 (6), 77 (9), 55 (21), 36 (16).

Anal. Calcd for C15 O: C, 56.69; H, 5.08; N, 22.04.

Found: C, 57.11; H, 4.95; N, 22.40.

4.8. General procedure for the synthesis of compounds 9c-

f

H16ClN

5

A solution of 3-chloropropanoyl chloride (0.41 g, 3.3 mmol) in

acetonitrile (1 mL) was added drop by drop to a magnetically

stirred mixture of amine 6c-f (3.0 mmol), pyridine (0.26 g, 3.3

mmol) and dry DMF (3 mL) at 0-5 °C. The resulted mixture was

stirred at the same temperature for 15 min, then heated at 80-90

°C and stirring for 8 h, cooled to 0-5 °C and diluted with cold

acetone (5 mL). The precipitate formed was isolated by filtration,

washed successively with acetone, water, again acetone then

recrystallized from DMF/EtOH 1:4.

4

.7.2. 8-Oxo-2,4-diphenyl-1,4,7,8,9,10-

hexahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium

chloride (8c)

Yield 0.26 g (23%, Method A), 0.32 g (28%, Method B),

-

1

colorless needles, mp 283-285 °C. IR ν (cm ): 3178, 3048, 2994,

2906, 2865, 2711, 1712, 1656, 1622, 1487, 1457, 1374, 1325,

1

1285, 1254, 1223, 1157, 1108, 1074, 1028. H NMR (300 MHz,

DMSO-d

6

) δ: 2.88 (t, J=7.3 Hz, 2Н, 9-СН

), 5.58 (d, J=3.5 Hz, 1Н, H-3), 6.21 (d, J=3.5 Hz, 1Н, Н-

), 7.25-7.60 (m, 10H, Ar), 11.81 (br s, 1H, NH), 12.04 (br s, 1H,

2

), 4.38-4.42 (m, 2Н,

1

4

0-СН

2

4.8.1.

8-Oxo-2,4-diphenyl-7,8,9,10-

+

tetrahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium

chloride (9c)

NH). MS (EI, 70 eV), m/z (%): 343 (8) [M - HCl] , 266 (72), 212

(

11), 207 (27), 131 (13), 105 (13), 103 (19), 77 (68), 73 (25), 55

34), 51 (34), 44 (49), 42 (28), 36 (100). Anal. Calcd for

Yield 0.24 g (21%) of cream-colored prisms, mp 275-276 °C.

C

20

H

18ClN

5

O: C, 63.24; H, 4.78; N, 18.44. Found: C, 62.87; H,

-1

IR ν (cm ): 3126, 3047, 3024, 2948, 2890, 2832, 2770, 2527,

5.09; N, 18.83.

1709, 1633, 1607, 1596, 1555, 1520, 1497, 1413, 1378, 1372,

4

.7.3.

2-(4-Methylphenyl)-8-oxo-4-phenyl-1,4,7,8,9,10-

1354, 1331, 1288, 1274, 1258, 1249, 1225, 1196, 1183, 1162,

1

hexahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium

chloride (8d). Yield 0.27 г (23%, Method A) of colorless prisms,

mp 233-235 °C. IR ν (cm ): 3143, 3061, 2986, 2942, 2906, 2874,

746, 1720, 1651, 1614, 1572, 1489, 1458, 1376, 1354, 1322,

1103, 1075, 1043, 1020, 1000. H NMR (600 MHz, DMSO-d

3.09 (t, J=7.1 Hz, 2Н, 9-СН ), 4.65 (t, J=7.1 Hz, 2Н, 10-СН

7.67-7.79 (m, 6Н, Ar), 8.23-8.24 (m, 2H, Ar), 8.55-8.56 (m, 2H,

6

) δ:

2

),

-

1

13

2

1

d

Ar), 8.67 (s, 1H, H-3), 12.88 (br s, 1Н, NH). C NMR (150

MHz, DMSO-d ) δ: 28.6 (C-9), 37.8 (C-10), 110.9 (C-3), 127.6,

1

282, 1255, 1200, 1086, 1024, 999. H NMR (300 MHz, DMSO-

6

128.6, 128.9, 129.4, 130.2, 133.0, 133.3, 133.8 (carbons of

benzene rings), 146.1 (C-6a), 149.7 (C-4), 151.9 (C-11a), 163.6

(C-2), 166.9 (C-8). MS (EI, 70 eV), m/z (%): 341 (51) [M -

6

) δ: 2.34 (s, 3H, CH

3

), 2.88 (t, J=6.9 Hz, 2H, 9-СН

), 5.50 (d, J=3.7 Hz, 1H, H-3), 6.21 (d,

J=3.7 Hz, 1H, H-4), 7.28 (d, J=8.2 Hz, 2H, Ar), 7.37-7.48 (m,

H, Ph), 7.55 (d, J=8.2 Hz, 2H, Ar), 11.75 (br s, 1H, NH), 12.00

2

), 4.19 (t,

J=6.9 Hz, 2H, 10-СН

2

+

5

(

HCl] , 313 (98), 285 (84), 272 (41), 232 (40), 218 (11), 204 (19),

+

s, 1H, NH). MS (EI, 70 eV), m/z (%): 357 (7) [M - HCl] , 280

64), 226 (15), 91 (7), 77 (12), 55 (25), 36 (100). Anal. Calcd for

C H20ClN O: C, 64.04; H, 5.12; N, 17.78. Found: C, 64.31; H,

21 5

189 (59), 165 (14), 129 (35), 115 (15), 102 (28), 77 (77), 55

(100), 44 (21), 36 (55). Anal. Calcd for C20

5

H16ClN O: C, 63.58;

H, 4.27; N, 18.54. Found: C, 63.77; H, 4.34; N, 18.28.

4.97; N, 17.49.

4.8.2. 2-(4-Methylphenyl)-8-oxo-4-phenyl-7,8,9,10-

4

.7.4.

4-(4-Methoxyphenyl)-8-oxo-2-phenyl-1,4,7,8,9,10-

tetrahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium

chloride (9d)

hexahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium

chloride (8e)

Yield 0.29 g (25%) of colorless prisms, mp 261-263 °C. IR ν

(cm ): 3055, 2887, 2781, 2725, 2695, 1723, 1636, 1604, 1560,

-

1

Yield 0.12 г (10%, Method A) of colorless needles, mp 255-

-

1

2

1

9

57 °C. IR ν (cm ): 3181, 3006, 2865, 1713, 1651, 1617, 1659,

1524, 1449, 1404, 1379, 1354, 1287, 1253, 1227, 1195, 1159,

1

514, 1487, 1445, 1377, 1320, 1284, 1246, 1182, 1113, 1068,

1129, 1085, 1039, 1013. H NMR (500 MHz, DMSO-d

(s, 3H, CH

6

) δ: 2.47

), 4.66 (t, J = 6.5 Hz,

), 7.51-7.52 (m, 2H, Ar), 7.76-7.80 (m, 3H, Ar), 8.23-

8.25 (m, 2H, Ar), 8.48-8.50 (m, 2H, Ar), 8.65 s (1H, H-3), 12.89

1

025. H NMR (300 MHz, DMSO-d

6

) δ: 2.87 (t, J=6.9 Hz, 2Н,

), 5.51

3 2

), 3.10 (t, J = 6.5 Hz, 2H, 9-CH

-СН

2

), 3.75 (s, 3Н, ОMe), 4.39 (t, J=6.9 Hz, 2Н, 10-СН

2

2H, 10-CH

2

(

d, J=3.6 Hz, 1Н, Н-3), 6.17 (d, J=3.6 Hz, 1Н, Н-4), 6.98 (d,

13

J=8.7 Hz, 2Н, Ar), 7.40 (d, J=8.7 Hz, 2Н, Ar), 7.48-7.50 (m, 3H,

Ar), 7.64-7.67 (m, 2H, Ar), 11.76 (br s, 1H, NH), 12.01 (br s, 1H,

NH). MS (EI, 70 eV), m/z (%): 373 (5) [M - HCl] , 266 (38), 240

6

(br s, 1H, NH). C NMR (125 MHz, DMSO-d ), δ: 21.6, 29.1,

38.2, 111.0, 128.1, 129.0, 129.3, 130.5, 130.6, 131.5, 133.3,

+

144.5, 146.5, 149.9, 152.2, 163.9, 167.3. MS (EI, 70 eV), m/z

+

(

14), 134 (20), 77 (34), 55 (37), 44 (20), 38 (34), 36 (100). Anal.

Calcd for C21 : C, 61.54; H, 4.92; N, 17.09. Found: C,

1.07; H, 5.18; N, 16.72.

(%): 355 (55) [M - HCl] , 327 (34), 301 (14), 286 (11), 246 (6),

H

20ClN

5

O

2

55 (11), 36 (100). Anal. Calcd for C21

5

H18ClN O: C, 64.37; H,

6

4.63; N, 17.87. Found: C, 64.29; H, 4.78; N, 17.69.

4

.7.5. 2,4-Bis(4-chlorophenyl)-8-oxo-1,4,7,8,9,10-

4.8.3.

4-(4-Methoxyphenyl)-8-oxo-2-phenyl-7,8,9,10-

hexahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium

tetrahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium

chloride (8f)

chloride (9e)

Yield 0.36 г (27%, Method A) of yellowish prisms, mp 279-

Yield 0.39 g (32%) of colorless prisms, mp 268-269 °C. IR ν

(cm ): 3118, 3054, 3005, 2941, 2882, 2846, 2608, 1717, 1638,

-

1

-1

2

1

82 °C. IR ν (cm ): 3054, 2874, 2757, 1708, 1676, 1658, 1621,

1

570, 1490, 1402, 1378, 1288, 1260, 1025, 1091, 1063, 1012. H

1613, 1599, 1556, 1512, 1412, 1382, 1355, 1307, 1275, 1250,

1

NMR (300 MHz, DMSO-d

.35-4.41 (m, 2H, 10-CH ), 5.57 (d, J=3.3 Hz, 1H, H-3), 6.26 (d,

J=3.3 Hz, 1H, H-4), 7.51-7.70 (m, 8H, Ar), 11.87 (br s, 1H, NH),

2.03 (br s, 1Н, NH). MS (EI, 70 eV), m/z (%): 413 (4) [M -

6

) δ: 2.87 (t, J=6.7 Hz, 2H, 9-СН

2

),

1183, 1025. H NMR (600 MHz, DMSO-d

6

) δ: 3.08 (t, J=6.9 Hz,

4

2

2Н, 9-СН

2

), 3.96 (s, 3H, OCH

3

), 4.64 (t, J=6.9 Hz, 2Н, 10-СН ),

2

7.32 (d, J=8.7 Hz, 2Н, Ar), 7.71-7.75 (m, 3H, Ar), 8.37 (d, J=8.7

1

Hz, 2Н, Ar), 8.55-8.57 (m, 2H, Ar), 8.63 (s, 1H, H-3), 12.87 (br

+

13

HCl] , 409 (20), 382 (15), 380 (15), 357 (37), 355 (64), 340 (17),

02 (16), 55 (78), 44 (48), 36 (100). Anal. Calcd for

O: C, 53.70; H, 3.63; N, 15.28. Found: C, 53.53; H,

.59; N, 15.61.

s, 1Н, NH). C NMR (125 MHz, TFA-d

1

) δ: 18.8, 28.2, 45.4,

3

C

3

100.6, 105.5, 109.9, 118.7, 119.9, 122.5, 123.7, 124.7, 136.8,

H16Cl

3

N

5

140.6, 141.9, 154.4, 157.7, 160.6. MS (EI, 70 eV), m/z (%): 371

20

+

(32) [M - HCl] , 343 (63), 317 (30), 302 (30), 287 (12), 262 (18),

ACCEPTED MANUSCRIPT

1

6

Tetrahedron

2

32 (11), 129 (10), 77 (26), 55 (71), 36 (100). Anal. Calcd for

Method B. A magnetically stirred solution of compound 8c

(1.14 g, 3.0 mmol) in DMF (3 mL) was heated at 80-90 °C for 8

h then treated by analogy with method A to give 0.39 g (yield

C H ClN O : C, 61.84; H, 4.45; N, 17.17. Found: C, 61.98; H,

2

1

18

5

2

4.56; N, 17.06.

3

0

5%) of compound 9c, 0.17 g (yield 30%) of compound 10 and

.269 g (43%) of compound 11.

4

.8.4.

2,4-Bis(4-chlorophenyl)-8-oxo-7,8,9,10-

tetrahydro[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium

chloride (9f)

4.11. 1-[7-(4-Methoxyphenyl)-5-phenyl-4,5,6,7-

tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]pyrrolidin-

2-one (12)

Yield 0.36 g (27%) of colorless prisms, mp 281-282 °C. IR ν

-1

(

cm ): 3095, 3058, 3022, 2963, 2864, 2565, 1714, 1637, 1611,

1

591, 1561, 1523, 1492, 1401, 1369, 1281, 1253, 1228, 1193,

A sodium methoxide prepared by dissolution of sodium (56 mg,

2.4 mmol) in MeOH (0.8 mL) was added to a magnetically

stirred solution of compound 4 (1 g, 2.3 mmol) in DMF (4 mL).

The resulted mixture was stirred at room temperature for 12 h,

then neutralized by addition of a few drops of acetic acid and

diluted with water (8 mL). The precipitate formed was isolated

by filtration and recrystallized from DMF-ethanol mixture (1:3)

to give compound 12 (0.58 g, yield 65%) as colorless prisms, mp

1

6

1093, 1009. H NMR (500 MHz, DMSO-d ) δ: 3.05 (t, J = 7.0

Hz, 2H, 9-CH ), 4.68 (t, J=7.0 Hz, 2Н, 10-СН ,), 7.76 (d, J=7.1

Hz, 2H, Ar), 7.82 (d, J=7.1 Hz, 2H, Ar), 8.29 (d, J=7.1 Hz, 2H,

Ar), 8.60 (d, J=7.1 Hz, 2H, Ar), 8.78 (s, 1H, H-3), 13.1 (br s, 1Н,

2

1

3

NH). C NMR (125 MHz, TFA + 5% DMSO-d

6

) δ: 28.1, 37.6,

10.5, 124.5, 129.3, 129.4, 129.6, 130.6, 131.3, 141.0, 141.4,

46.0, 150.2, 150.7, 166.1, 169.7. MS (EI, 70 eV), m/z (%): 410

0.4) [M - HCl] , 381 (4), 355 (4), 286 (7), 79 (100), 52 (78), 36

27). Anal. Calcd for C20 O: C, 53.77; H, 3.16; N, 15.68.

1

(

+

-1

242-244 °C. IR ν (cm ): 3290, 3061, 3035, 2992, 2960, 2911,

H14Cl

3

N

5

2889, 2836, 1713, 1609, 1584, 1538, 1514, 1483, 1453,1426,

1

Found: C, 53.98; H, 3.25; N, 15.32.

1375, 1350, 1317, 1296, 1254, 1174, 1107, 1053, 1037. H NMR

(

6 2

600 MHz, DMSO-d ) δ: 1.96-1.99 (m, 2H, CH ), 2.03-2.09 (m,

4.9. Hydrochloride of 3-amino-5,6-dihydro[1,2,4]triazolo[4,3-

1Н, 6ɑ -CH ), 2.34-2.39 (m, 3H, 1H of 6ɑ -CH₂+ CH₂of

2

a]pyrimidin-7(8H)-one (10)

pyrrolidin-2-one), 3.60-3.70 (m, 2H, CH

.68-4.69 (m, 1Н, H-5ɑ ), 5.29 (dd, J=10.6, 4.5 Hz, 1Н, H-7ɑ ),

6.88 (d, J=8.5 Hz, 2H, Ar), 7.15 (d, J=8.5 Hz, 2H, Ar), 7.27-7.44

(m, 5H, Ph), 7.52 (s, 1H, NH). C NMR (150 MHz, DMSO-d₆)

δ: 17.8 (C-4), 31.7 (C-3), 42.4 (C-6ɑ ), 47.6 (C-5), 53.7 (C-5ɑ ),

2 3

), 3.72 (s, 3H, CH O),

4

A mixture of compound 8c (0.5 g, 1.3 mmol), ethanol (5 mL)

and concentrated hydrochloric acid (1 mL) was refluxed for 1 h,

then evaporated in vacuo. The resulted residue was treated with

hot acetonitrile (3 mL). After cooling to 20 °C the precipitate

formed was filtered off and recrystallized from water-acetonitrile

mixture (1:4) to give compound 10 as colorless prisms. Yield 123

1

3

55.1 (CH O), 58.1 (C-7ɑ ), 113.7, 126.5, 127.6, 128.3, 128.4,

3

131.8, 141.5 (carbons of benzene rings), 153.6 (C-2ɑ ), 154.9 (C-

3aɑ ), 158.7 (C-4 of 4-CH OC H ), 172.4 (C-2). MS (EI, 70 eV),

3

6

4

-1

+

mg (50%), mp 295-296 °C. IR ν (cm ): 3467, 3307, 3089, 2918,

m/z (%): 389 (11) [M] , 254 (41), 223 (60), 200 (15), 145 (29),

1

2

789, 1727, 1705, 1676, 1609, 1553, 1469, 1385, 1305, 1077. H

NMR (600 MHz, DMSO-d ) δ: 2.79 (t, J=6.9 Hz, 2Н, 6-СН ),

.13 (t, J=6.9 Hz, 2Н, 5-СН ), 8.62 (s, 2H, NH ), 11.71 (br s, 1Н,

134 (35), 131 (26), 117 (100), 104 (25), 91 (45), 77 (37), 69 (31),

6

2

55 (26), 41 (75). Anal. Calcd for C22

23 5 2

H N O : C, 67.85; H, 5.95;

4

N, 17.98. Found: C, 68.02; H, 6.11; N, 17.63.

2

1

3

NH), 13.40 (br s, 1Н, NH). C NMR (150 MHz, DMSO-d

6

) δ:

4.12. General procedure for the synthesis of compounds

28.7 (C-6), 37.4 (C-5), 145.1 (C-8a), 148.4 (C-3), 166.8 (C-7).

+

13a-e, 15a,g,h

MS (EI, 70 eV), m/z (%): 153 (71) [M - HCl] , 99 (55), 69 (23),

5 (100), 43 (85), 36 (82). Anal. Calcd for C H ClN O: C, 31.67;

5

8

5

A suspension of finely ground compound 5a-e, 8a,g,h (1

mmol) in 10% water solution of Na CO (3 mL) was stirred at

H, 4.25; N, 36.94. Found: C, 31.89; H, 4.33; N, 36.61.

2

3

4.10. Synthesis of compounds 9c, 10 and 11

room temperature for 1 h. The precipitate formed was isolated by

filtration, washed with water and recrystallized from ethanol.

Method A. A magnetically stirred solution of compound 7c

1.14 g, 3.0 mmol) in DMF (3 mL) was heated at 80-90 °C for 8

4

.12.1.

4-(4-Methoxyphenyl)-8-oxo-2-phenyl-1,2,3,4,9,10-

(

hexahydro-8H-[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium-7-

ide (13a)

h. A precipitate of compound 10, formed in hot solution, was

isolated by filtration and dissolved in hot water (~ 8 mL).

Resulted water solution of compound 10 was treated with

charcoal (0.2 g), filtered, evaporated to a small volume (~ 0.5

mL), then diluted with acetonitrile (2 mL) and cooled to 0-5 °C.

The formed precipitate was isolated by filtration and dried at

Yield 0.33 g (86%) of colorless prisms, mp 211-212 °C. IR ν

-1

(

cm ): 3057, 3030, 2977, 2950, 2903, 2833, 1667, 1611, 1525,

1514, 1487, 1450, 1423, 1374, 1324, 1263, 1237, 1173, 1096,

1

6

1026. H NMR (600 MHz, DMSO-d ) δ: 1.83-1.89 (m, 1H, 3-

1

20 °C to give 0.097 g (yield 17%) of compound 10. The

CH ), 2.34-2.38 (m, 1H, 3-CH ), 2.55-2.65 (m, 2Н, 9-СН ), 3.72

2

reaction mixture after isolation of compound 10 was diluted with

water (5 mL). The formed oily precipitate was isolated by

filtration and crystallized from DMF-ethanol mixture (1:3) to

give compound 9c (0.36 g, yield 32%). A mother solution after

crystallization of 9c was evaporated to dryness at reduced

pressure and the oily residue was diluted in chloroform (8 mL).

The resulted solution was washed by water, then dried under

sodium sulphate and subjected to a column chromatography

(

s, 3H, CH

3

O), 3.75-3.81 (m, 2H, 10-CH

2

), 4.68 (dd, J=11.0, 2.4

Hz, 1H, H-2), 5.05 (dd, J = 10.7, 4.2 Hz, 1H, H-4), 6.87 (d, J=8.6

Hz, 2H, Ar), 7.19-7.23 (m, 3H, Ar), 7.30-7.32 (m, 2H, Ar), 7.44

13

(

d, J=7.5 Hz, 2H, Ar). C NMR (150 MHz, DMSO-d ) δ: 29.2

C-9), 35.6 (C-10), 41.9 (C-3), 55.1 (CH

6

3

O), 55.7 (C-2), 58.1 (C-

4), 113.6, 126.6 (2C), 128.0, 128.6, 131.7, 144.3 (carbons of

benzene rings), 145.6 (C-6a), 147.7 (C-11a), 158.8 (C-4 of 4-

CH OC H ), 168.4 (C-8). MS (EI, 70 eV), m/z (%): 375 (11)

3

6

4

(

Al

2

O

3

, CHCl

3

) to give 0.243 g (yield 39%) of (2E)-1,3-

+

2

0

[M] , 241 (18), 134 (100), 119 (12), 91 (14). Anal. Calcd for

: C, 67.18; H, 5.64; N, 18.65. Found: C, 67.36; H,

.57; N, 18.41.

^dⁱ^p^h^eⁿ^y^l^p^r^o^p^-²^-^eⁿ^-¹^-^oⁿ^e⁽¹¹⁾^,^m^p⁵⁴^-⁵⁶^°^C^,^lⁱ^t^.+ mp 55-57 °C.

GC-MS (EI, 70 eV), m/z (%): 207 (100) [M] , 179 (22), 165

C H N O

21 21 5 2

5

(

100), 131 (34), 103 (31), 89 (7), 77 (60), 51 (17).

ACCEPTED MANUSCRIPT

1

7

+

4

.12.2.

8-Oxo-2,4-diphenyl-1,2,3,4,9,10-hexahydro-8H-

70 eV), m/z (%): 315 (62) [M] , 272 (29), 233 (13), 192 (14),

81 (19), 79 (17), 67 (28), 55 (100), 43 (21), 41 (82). Anal. Calcd

O: C, 64.73; H, 7.99; N, 22.20. Found: C, 64.95; H,

8.15; N, 19.91.

[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium-7-ide (13b)

25 5

for C17H N

Yield 0.31 g (89%) of colorless needles, mp 219-220 °C. IR ν

-1

(

cm ): 3065, 2980, 2940, 2853, 1647, 1591, 1579, 1520, 1497,

4

.12.6. Ethyl 2-methyl-8-oxo-4-phenyl-7,8,9,10-tetrahydro-4H-

1466, 1441, 1428, 1365, 1333, 1316, 1306, 1256, 1197, 1147,

1

[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidine-3-carboxylate (15a)

1

CH

020. H NMR (600 MHz, DMSO-d

), 2.38-2.42 (m, 1H, 3-CH ), 2.51-2.61 (m, 2Н, 9-СН

.80 (m, 2H, 10-CH ), 4.68-4.69 (m, 1H, H-2), 5.08 (dd, J=10.6,

.5 Hz, 1H, H-4), 7.19-7.32 (m, 8H, Ar), 7.42-7.44 (m, 2H, Ar).

6

) δ: 1.80-1.86 (m, 1H, 3-

2

), 3.72-

Yield 0.279 g (79%) of colorless needles, mp 276-277 °C. IR

ν (cm ): 3158, 3074, 2985, 2933, 2900, 2764, 1713, 1686, 1641,

1603, 1531, 1504, 1457, 1372, 1335, 1272, 1222, 1191, 1149,

3

4

2

-1

13

C NMR (150 MHz, DMSO-d

6

) δ: 29.2 (C-9), 35.6 (C-10), 42.1

1

3

107, 1076. H NMR (300 MHz, DMSO-d

6

) δ: 0.98 (t, J=7.0 Hz,

), 2.74 (t, J=7.0 Hz, 2Н, СН ), 3.84-

), 6.04 (s, 1H, H-4), 7.22-7.29 (m, 5H, Ph),

(

C-3), 55.7 (C-2), 58.5 (C-4), 126.58, 126.62, 127.3, 127.5,

H, CH

3

), 2.33 (s, 3H, CH

.94 (m, 4H, 2CH

3

2

128.0, 128.2, 140.1, 144.4 (carbons of benzene rings), 146.5 (C-

2

6a), 148.0 (C-11a), 169.1 (C-8). MS (EI, 70 eV), m/z (%): 345

13

+

11.50 (br s, 1H, NH). C NMR (125 MHz, DMSO-d

6

) δ: 14.1

), 58.5 (CH CH O),

0.1 (С-4), 96.9 (С-3), 127.2, 127.8, 128.2, 143.2 (carbons of

benzene ring), 144.8 and 146.7 (C-6a and C-11a), 159.4 (С-2),

165.9 (CO), 167.0 (CO). MS (EI, 70 eV), m/z (%): 353 (16) [M] ,

(

22) [M] , 240 (99), 115 (27), 104 (63), 77 (52), 55 (10), 51 (32),

(

CH

3

), 24.4 (CH

3

), 29.0 (CH

2

), 35.9 (CH

2

3

2

42 (18). Anal. Calcd for C20

19 5

H N O: C, 69.55; H, 5.54; N, 20.28.

6

Found: C, 69.63; H, 5.65; N, 20.03.

+

4.12.3. 2-(4-Methylphenyl)-8-oxo-4-phenyl-1,2,3,4,9,10-

hexahydro-8H-[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium-7-

324 (46), 276 (100), 248 (50), 194 (6), 128 (4), 55 (16). Anal.

ide (13c)

Calcd for C18

H

19

N

5

O

3

: C, 61.18; H, 5.42; N, 19.82. Found: C,

61.39; H, 5.51; N, 19.61.

Yield 0.32 g (88%) of colorless needles, mp 245-247 °C. IR ν

cm ): 3058, 3028, 2976, 2953, 2908, 2577, 1663, 1601, 1519,

-1

4.12.7.

8,8-Dimethyl-11-phenyl-3,4,7,11-tetrahydro-8H-

(

1

(

2

(

pyrimido[2',1':3,4][1,2,4]triazolo[5,1-b]quinazoline-

2,10(1H,9H)-dione (15g)

483, 1457, 1410, 1370, 1333, 1309, 1295, 1257, 1197, 1175,

1

153, 1095, 1021. H NMR (600 MHz, DMSO-d

), 2.26 (s, 3H, CH ), 2.37-2.39 (m, 1H, 3-CH

.59-2.61 (m, 2Н, 9-СН ), 3.74-3.81 (m, 2H, 10-CH ), 4.63-4.65

6

) δ: 1.82-1.84

m, 1H, 3-CH

2

3

2

),

Yield 0.327 g (90%) of yellowish needles, mp 288-289 °C. IR

2

-1

ν (cm ): 3097, 3062, 2961, 2947, 2905, 2871, 2781, 1706, 1632,

m, 1H, H-2), 5.08-5.09 (m, 1H, H-4), 7.11 (d, J=7.5 Hz, 2H,

13

1619, 1595, 1538, 1515, 1453, 1424, 1382, 1363, 1322, 1282,

Ar), 7.26–7.32 (m, 7H, Ar). C NMR (150 MHz, DMSO-d

6

) δ:

1

1231, 1170, 1132, 1059, 1005. H NMR (600 MHz, DMSO-d

6

) δ:

2

(

7

1

0.6 (CH ), 29.2 (C-9), 35.6 (C-10), 42.0 (C-3), 55.4 (C-2), 58.6

3

0

.95 (s, 3H, CH

), 2.12 (d, J=16.1 Hz, 1H, 9-CH

2.77 (t, J=7.0 Hz, 2H, 3-CH ), 3.94-4.03 (m, 2H, 4-CH

H, H-11), 7.19-7.28 (m, 5H, Ph), 11.53 (br s, 1H, NH).

3

), 1.01 (s, 3H, CH

3

), 2.00 (d, J=16.1 Hz, 1H, 9-

C-4), 126.5, 127.3, 127.5, 128.2, 128.6, 135.6, 140.0, 141.3

CH

2

), 2.38-2.45 (m, 2H, 7-CH

2

),

carbons of benzene rings), 147.7 (C-11a), 168.4 (C-8). MS (EI,

+

2

), 6.04 (s,

0 eV), m/z (%): 359 (29) [M] , 254 (100), 240 (15), 200 (20),

13

1

C

30 (10), 117 (10), 115 (16), 104 (34), 91 (21), 77 (22), 55 (48).

6 3 3

NMR (150 MHz, DMSO-d ) δ: 27.2 (CH ), 28.9 (CH ), 28.9 (C-

Anal. Calcd for C21

21 5

H N O: C, 70.17; H, 5.89; N, 19.48. Found:

3

1

), 32.0 (C-8), 36.0 (C-4), 45.5 (C-7), 50.2 (C-8), 58.6 (C-11),

06.3 (C-10a), 127.2, 127.5, 128.0, 142.4 (carbons of benzene

C, 70.05; H, 5.95; N, 19.67.

4

.12.4. 2-Methyl-8-oxo-4-phenyl-1,2,3,4,9,10-hexahydro-8H-

ring), 144.8 (C-13a), 147.3 (C-5a), 162.8 (C-6a), 166.9 (C-2),

192.2 (C-10). MS (EI, 70 eV), m/z (%): 363 (28) [M] , 286 (100),

+

[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium-7-ide (13d)

2

32 (13), 202 (9), 115 (9), 77 (18), 55 (69). Anal. Calcd for

: C, 66.10; H, 5.82; N, 19.27. Found: C, 65.90; H,

5.65; N, 19.08.

Yield 0.24 g (83%) of colorless needles, mp 223-224 °C. IR ν

cm ): 3075, 3036, 2970, 2922, 2795, 2731, 1649, 1612, 1567,

20 21 5 2

C H N O

-1

(

1

3

2

5

500, 1459, 1420, 1384, 1335, 1294, 1260, 1263, 1211, 1196,

1

4.12.8.

3',4',7',8',9',10'-Hexahydrospiro[cyclohexane-1,11'-

149, 1060. H NMR (500 MHz, DMSO-d

H, CH ), 1.74 (m, 1H, 3-CH ), 2.27 (m, 1H, 3-CH

Н, 9-СН ), 3.68 (m, 1H, H-2), 3.80 (t, J=7.0 Hz, 2H, 10-CH

.00 (dd, J=11.0, 4.8 Hz, 1H, H-4), 7.24–7.37 (m, 5H, Ph).

) δ: 18.1, 27.8, 37.4, 38.1,

7.8, 61.3, 126.8, 129.1, 129.9, 133.4, 143.7, 145.9, 169.5. MS

6

) δ: 1.18 (d, J=6.3 Hz,

), 2.42 (m,

),

pyrimido[2',1':3,4][1,2,4]triazolo[5,1-b]quinazolin]-2'(1'H)-one

3

2

(15h)

2

1

3

C

Yield 0.213 g (68%) of colorless needles, mp 236-238 °C. IR ν

NMR (125 MHz, TFA + 5% DMSO-d

4

6

-1

(

cm ): 2975, 2928, 2858, 2839, 1685, 1605, 1534, 1483, 1449,

+

1363, 1337, 1316, 1279, 1255, 1232, 1216, 1202, 1186, 1168,

(

EI, 70 eV), m/z (%): 283 (50) [M] , 268 (100), 179 (53), 151

18), 138 (51), 115 (24), 104 (33), 91 (23), 77 (27), 55 (99), 42

25). Anal. Calcd for C15H N O: C, 63.59; H, 6.05; N, 24.72.

17 5

1

143, 1120, 1109, 1067, 1007. H NMR (600 MHz, DMSO-d

δ: 1.20-1.26 (m, 1H, CH), 1.47-1.59 (m, 7H), 1.73-1.79 (m, 4H),

.94-2.06 (m, 6H), 2.69 (t, J=7.0 Hz, 2H, CH CO), 3.72 (t, J=7.0

), 11.25 (br s, 1H, NH). C NMR (150 MHz,

) δ: 22.4, 22.7, 23.5, 24.4, 24.7, 29.3 (C-3ɑ ), 30.8,

6

),

1

2

Found: C, 63.76; H, 6.13; N, 24.44.

13

Hz, 2Н, NСН

DMSO-d

2

4.12.5. 2'-Oxo-3',4',6a',7',8',9',10',10a'-octahydro-2'H,6'H-

6

spiro[cyclohexane-1,11'-pyrimido[2',1':3,4][1,2,4]triazolo[5,1-

b]quinazolin[12]ium[1]ide] (13e)

34.2, 35.0 (C-4ɑ ), 60.3 (C-1,11ɑ ), 108.0 (C-10aɑ ), 137.3 (C-

6aɑ ), 142.4 (C-13aɑ ), 146.3 (C-5aɑ ), 167.1 (CO). MS (EI, 70

eV), m/z (%): 313 (96) [M] , 284 (25), 270 (100), 257 (69), 202

+

Yield 0.25 g (80%) of colorless prisms, mp 202-204 °C. IR ν

(9), 55 (7). Anal. Calcd for C17

22.35. Found: C, 64.87; H, 7.57; N, 22.07.

23 5

H N O: C, 65.15; H, 7.40; N,

-1

(

cm ): 3219, 2932, 2859, 1658, 1583, 1519, 1513, 1445, 1365,

1

0

2

3

2

4

328, 1256, 1198, 1104, 1060. H NMR (300 MHz, DMSO-d

.85-0.98 (m, 1Н, CH), 1.22-2.17 (m, 16Н), 2.26-2.35 (m, 2Н),

.41-2.48 (m, 2Н, 3ɑ -СН ), 3.77 (t, J=7.2 Hz, 2H, 4ɑ -CH ),

.82 (br s, 1Н, H-6aɑ ). C NMR (150 MHz, DMSO-d ) δ: 20.0,

6

) δ:

4.13. General procedure for the synthesis of compounds 14c-f

2

13

Method A. A suspension of finely ground compound 9c-f (1

mmol) in 10% water solution of Na

room temperature for 1 h. The precipitate formed was isolated by

6

2 3

CO (3 mL) was stirred at

1.1, 22.1, 22.3, 25.6, 25.7, 29.5, 30.1, 31.4, 35.8, 37.0, 38.2,

6.6, 60.8, 144.3 (C-5aɑ ), 153.5 (C-13aɑ ), 173.0 (C-2). MS (EI,

ACCEPTED MANUSCRIPT

1

8

Tetrahedron

1

filtration, washed with water and recrystallized from DMF-EtOH

mixture (1:3).

1184, 1162, 1148, 1124, 1093, 1023. H NMR (500 MHz,

DMSO-d ) δ: 2.52 (t, J=7.0 Hz, 2Н, 9-СН ), 3.91 (s, 3H, CH O),

6

2

3

4

.36 (t, J=7.0 Hz, 2Н, 10-СН ), 7.22 (d, J=8.2 Hz, 2H, Ar), 7.61-

2

Method B. A solution of KOH (0.073 g, 1.3 mmol) in water (1

mL) was added to a magnetically stirred suspension of finely

ground compound 8c-f (1 mmol) in ethanol (3 mL). The resulted

mixture was stirred at room temperature for 1 h then diluted with

water (5 mL). The precipitate formed was isolated by filtration,

washed with water and twice recrystallized from DMF-EtOH

mixture (1:3).

13

7.70 (m, 3H, Ar), 8.27 (s, 1Н, Н-3), 8.37-8.46 (m, 4H, Ar).

C

NMR (125 MHz, TFA + 5% DMSO-d

6

) δ: 28.1, 37.4, 54.8,

109.8, 114.7, 119.0, 128.0, 129.2, 131.7, 133.0, 133.9, 146.0,

149.9, 151.1, 163.7, 166.9, 169.9. MS (EI, 70 eV), m/z (%): 371

+

(

47) [M] , 343 (54), 317 (35), 302 (30), 262 (19), 247 (5), 221

6), 178 (11), 151 (6), 129 (9), 115 (5), 104 (7), 91 (14), 78 (42),

63 (61), 55 (100), 51 (11), 44 (55). Anal. Calcd for C H N O :

21 17 5 2

Method C. A magnetically stirred mixture of finely ground

C, 67.91; H, 4.61; N, 18.86. Found: C, 68.13; H, 4.70; N, 18.63.

2

compound 8c-f (1 mmol), I (0.76 g, 3.0 mmol) and ethanol (4

4

.13.4. 2,4-Bis(4-chlorophenyl)-8-oxo-9,10-dihydro-8H-

mL) was refluxed for 20 min then cooled to room temperature.

The precipitate formed was isolated by filtration and suspended

in solution of Na S O ×5H O (1.73 g, 5 mmol) and Na CO (0.74

[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium-7-ide (14f)

2

3

2

3

Yield 0.324 g (79%, Method А), 0.082 g (20%, Method B),

g, 7 mmol) in water (10 mL). The resulted mixture was

magnetically stirred within 30 min and then was filtered out to

give the solid compound 14c-f, which was then washed with

water and recrystallized from DMF-EtOH mixture (1:3).

0.261 g (64%, Method C), yellow prisms, mp 244-245 °C. IR ν

-1

(

cm ): 3062, 2972, 2927, 1645, 1623, 1590, 1569, 1522, 1493,

1464, 1441, 1409, 1371, 1337, 1259, 1224, 1178, 1167, 1146,

1

092, 1048, 1007. H NMR (500 MHz, DMSO-d

), 4.38 (t, J=6.9 Hz, 2Н, 10-СН

J=8.2 Hz, 2H, Ar), 7.80 (d, J=8.2 Hz, 2H, Ar), 8.38-8.41 (m, 3H,

6

) δ: 2.56 (t,

4.13.1. 8-Oxo-2,4-diphenyl-9,10-dihydro-8H-[1,2,4]triazolo[1,5-

J=6.9 Hz, 2Н, 9-СН

2

), 7.65 (d,

a:4,3-a']dipyrimidin-5-ium-7-ide (14c)

1

3

Ar), 8.45 (d, J=8.2 Hz, 2H, Ar). C NMR (125 MHz, TFA + 5%

DMSO-d ) δ: 28.0, 37.6, 110.5, 124.5, 129.3, 129.4, 129.6,

130.6, 131.3, 141.1, 141.5, 146.0, 150.3, 150.8, 166.1, 169.7. MS

Yield 0.277 g (81%, Method А), 0.103 g (30%, Method B),

6

0

.245 g (72%, Method C), light-yellow prisms, mp 232-233 °C.

-1

+

IR ν (cm ): 3066, 2986, 2931, 1623, 1600, 1579, 1553, 1523,

(EI, 70 eV), m/z (%): 409 (1) [M] , 381 (6), 355 (14), 189 (10),

1

491, 1451, 1424, 1375, 1322, 1292, 1253, 1224, 1193, 1159,

163 (12), 138 (10), 111 (17), 75 (24), 55 (100), 44 (22). Anal.

Calcd for C20H13Cl N O: C, 58.55; H, 3.19; N, 17.07. Found: C,

2 5

58.78; H, 3.26; N, 17.11.

1

1143, 1104, 1015. H NMR (600 MHz, DMSO-d ) δ: 2.58 (t,

6

J=7.4 Hz, 2Н, 9-СН

2

), 4.35 (t, J=7.4 Hz, 2Н, 10-СН

2

), 7.59-7.72

(

m, 6H, Ar), 8.25 (s, 1H, H-3), 8.29-8.30 (m, 2H, Ar), 8.39-8.41

13

4.14. General procedure for the synthesis of compounds 1c,

m, 2H, Ar). C NMR (150 MHz, DMSO-d

C-10), 108.4 (C-3), 127.5, 128.3, 128.6, 128.9, 129.7, 131.7,

31.9, 134.6 (carbons of benzene rings), 146.1 (C-6a), 146.7 (C-2

or C-4), 159.1 (C-2 or C-4), 160.1 (C-11a), 174.0 (C-8). MS (EI,

6

) δ: 28.1 (C-9), 37.6

6a, 6g and 16

1

A finely powdered compound 5c, 8a, 14d or 15g (0.5 mmol) was

added to a magnetically stirred solution of KOH (0.28 g, 5 mmol)

in ethanol (4 mL). The resulted mixture was refluxed for 24 h,

then neutralized by addition of acetic acid to pH 8-9 and

evaporated to dryness in vacuo. The residue was treated with

water (6 mL) giving a precipitate, which was filtered off, washed

with water and recrystallized from DMF-ethanol mixture (1:3).

+

7

(

0 eV), m/z (%): 341 (38) [M] , 313 (42), 287 (47), 272 (32), 232

40), 189 (49), 165 (13), 129 (32), 102 (23), 77 (63), 55 (100), 51

33), 44 (21). Anal. Calcd for C20 O: C, 70.37; H, 4.43; N,

0.52. Found: C, 70.56; H, 4.51; N, 20.37.

15 5

H N

2

4

.13.2. 2-(4-Methylphenyl)-8-oxo-4-phenyl-1,2,3,4,9,10-

hexahydro-8H-[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-

ium-7-ide (14d)

4.14.1. 5-(4-Methylphenyl)-7-phenyl-4,5,6,7-

tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-2-amine (1c). Yield

0.119 g (78%) of colorless plates, mp 223-224 °C, lit. mp 223-

224 °С. The product obtained was identical in both its physical

and spectral characteristics with an authentic sample of

compound 1c.

3

e

Yield 0.274 g (77%, Method А), 0.064 g (18%, Method B),

0

.270 g (76%, Method C), yellow prisms, mp 240-242 °C. IR ν

-1

(

cm ): 3063, 2917, 2858, 1645, 1624, 1568, 1520, 1496, 1467,

1

375, 1336, 1262, 1185, 1168, 1090, 1014. H NMR (300 MHz,

DMSO-d ) δ: 2.40 (s, 3H, CH ), 2.53 (t, J=7.4 Hz, 2Н, 9-СН ),

.32 (t, J=7.4 Hz, 2Н, 10-СН ), 7.41 (d, J=7.1 Hz, 2Н, Ar), 7.64-

6

3

2

4

7

4.14.2. Ethyl

2-amino-5-methyl-7-phenyl-4,7-

(6a).

2

1

3

.70 (m, 3H, Ar), 8.25 (s, 1H, H-3), 8.27-8.34 (m, 4H, Ar).

C

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

8

c

NMR (150 MHz, DMSO-d ) δ: 20.5 (CH ), 27.9 (C-9), 37.4 (C-

Yield 0.081 g (54%) of colorless plates, mp 228-230 °C, lit. mp

228-230 °С. The product obtained was identical in both its

physical and spectral characteristics with an authentic sample of

compound 6a.

6

3

1

4

0), 108.0 (C-3), 127.4, 128.1, 128.4, 129.3, 129.5, 131.6, 131.8,

42.0 (carbons of benzene rings), 145.9 (C-6a), 146.7 (C-2 or C-

), 159.3 (C-2 or C-4), 159.8 (C-11a), 173.3 (C-8). MS (EI, 70

+

eV), m/z (%): 355 (54) [M] , 327 (45), 301 (35), 286 (26), 246

(

22), 202 (10), 77 (14), 55 (100), 44 (25). Anal. Calcd for

4.14.3. 2-Amino-6,6-dimethyl-9-phenyl-5,6,7,9-

tetrahydro[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one (6g). Yield

C H N O: C, 70.97; H, 4.82; N, 19.71. Found: C, 70.65; H,

2

1

17

5

d

4.99; N, 19.51.

0.080 g (50%) of colorless plates, mp 253-255 °C, lit. mp 254-

56 °С. The product obtained was identical in both its physical

2

4.13.3. 4-(4-Methoxyphenyl)-8-oxo-2-phenyl-9,10-dihydro-8H-

and spectral characteristics with an authentic sample of

compound 6g.

[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-5-ium-7-ide (14e)

Yield 0.29 g (77%, Method А), 0.086 г (23%, Method B),

4

.14.4. 5-(4-Methylphenyl)-7-phenyl[1,2,4]triazolo[1,5-

0

(

1

.230 g (62%, Method C), orange prisms, mp 241-242 °C. IR ν

a]pyrimidin-2-amine (16). Yield 0.111 g (74%) of yellowish

plates, mp 219-220 °C, lit. mp 217-219 °С. The product

-1

cm ): 3116, 3077, 3062, 3008, 2969, 2933, 2837, 1640, 1619,

600, 1546, 1510, 1493, 1472, 1446, 1381, 1331, 1299, 1247,

8a

ACCEPTED MANUSCRIPT

1

9

obtained was identical in both its physical and spectral

characteristics with an authentic sample of compound 16.

Yield 0.260 g (70%, Method А) of colorless prisms, mp 200-

-1

202 °C (from AcOH/EtOH 1:5). IR ν (cm ): 3323, 3177, 3037,

991, 2907, 1705, 1662, 1631, 1547, 1456, 1422, 1382, 1240,

2

1

4

2

.15. General procedure for the synthesis of compounds 17-

0

1192, 1154, 1082, 1047. H NMR (600 MHz, DMSO-d

(t, J=7.1 Hz, 3Н, CH CH O), 2.32 (s, 3H, CH ), 2.67 (t, J=7.4

COO ), 3.83-3.92 (m, 4H, 2CH ), 5.92 (s, 1H,

6

) δ: 1.00

3

2

3

-

Hz, 2Н, CH

H-7), 6.30 (s, 2H, NH

MHz, DMSO-d δ: 14.1 (CH

3 2

COO ), 36.6 (CH CH COO ), 58.2 (CH CH

2

CH

2

1

3

Method A. A magnetically stirred mixture of finely powdered

compound 5c, 8a or 8g (1 mmol), water (6 mL) and Na CO (2 g,

8.9 mmol) was refluxed for 2 h. In case of the synthesis of

2

), 7.18-7.27 (m, 5H, Ph). C NMR (150

CH O), 24.4 (CH ), 32.1

O), 59.7

2

3

6

)

3

2

3

-

1

(CH

2

CH

2

compound 20 the reaction mixture was then cooled to room

temperature and the precipitate formed was isolated by filtration,

washed with cold water and recrystallized from ethanol. For the

preparation of compound 17-19 the reaction mixture was diluted

with hot water (6 mL), treated with charcoal (50 mg) and filtered.

The filtrate was evaporated to a volume of ~5 mL, cooled to

room temperature and acidified by formic acid to pH 4-5. The

precipitate formed was isolated by filtration, washed with cold

water and recrystallized.

(C-7), 96.1 (C-6), 127.0, 127.4, 128.0, 143.7 (carbons of benzene

ring), 147.4 (C-3a), 150.0 (C-2), 159.4 (C-5), 165.9 (COOEt),

172.1 (CH CH COO ). MS (EI, 70 eV), m/z (%): 371 (0.1) [M] ,

2 2

299 (35), 270 (35), 254 (19), 226 (42), 222 (98), 194 (99), 176

(16), 155 (14), 148 (16), 140 (10), 128 (50), 115 (17), 105 (21),

102 (18), 89 (12), 77 (76), 72 (99), 67 (28), 63 (11), 55 (99), 45

-

+

(100). Anal. Calcd for C18

21 5 4

H N O : C, 58.21; H, 5.70; N, 18.86.

Found: C, 57.89; H, 5.86; N, 18.51.

4

.15.4. Sodium 3-(2-amino-6,6-dimethyl-8-oxo-9-phenyl-5,7,8,9-

tetrahydro[1,2,4]triazolo[5,1-b]quinazolin-3(6H)-yl)propanoate

20)

Method B. A 0.5 M solution of KOH (2.3 mL, 1.15 mmol) in

ethanol was added to a magnetically stirred suspension of

compound 13c or 14d (1 mmol) in ethanol (2 mL). The resulted

solution was refluxed for 2 h, then evaporated to a volume of ~

(

Yield 0.226 g (56%, Method А) of colorless needles, mp 213-215

1.5 mL, acidified with formic acid to pH 4-5 and diluted with

-1

°C (from EtOH). IR ν (cm ): 3350, 3266, 3164, 2965, 2818,

water (4 mL). After cooling the precipitate formed was isolated

by filtration, washed with cold water and recrystallized.

1674, 1582, 1527, 1487, 1390, 1238, 1190, 1131, 1071, 1029,

1

1002. H NMR (600 MHz, DMSO-d

6

3

) δ: 0.92 (s, 3H, CH ), 0.99

(

1

3

s, 3H, CH

3

), 1.93 (d, J=16.0 Hz, 1H, 7-CH

2

), 2.09 (d, J=16.0 Hz,

4

.15.1.

3-[2-Amino-5-(4-methylphenyl)-7-phenyl-4,5,6,7-

-

H, 7-CH

2

2 2

), 2.28-2.31 (m, 2H, CH COO ), 2.38 (s, 2H, 5-CH ),

tetrahydro-3H-[1,2,4]triazolo[1,5-a]pyrimidin-8-ium-3-

yl]propanoate (17)

.83 (t, J=5.5 Hz, 2H, NCH

2

), 5.90 (s, 1H, H-9), 6.88 (s, 2H,

13

NH

7.1 (CH

NCH ), 45.7 (C-5), 50.3 (C-7), 58.2 (C-9), 105.9 (C-8a), 127.0,

127.2, 127.9, 143.1 (carbons of benzene ring), 148.0 (C-3a),

2

), 7.15-7.25 (m, 5H, Ph). C NMR (150 MHz, DMSO-d

6

) δ:

-

2

(

3

), 29.1 (CH ), 31.9 (C-6), 36.9 (CH COO ), 39.3

3

2

Yield 0.245 g (65%, Method А), 0.226 g (60%, Method B),

colorless needles, mp 193-195 °C (from EtOH/CH

2

3

CN 1:5). IR ν

-1

(

cm ): 3349, 3156, 3007, 2863, 2775, 2644, 1690, 1658, 1611,

-

1

51.2 (C-2), 163.3 (C-4a), 174.4 (COO ), 191.7 (C-8). Anal.

1

579, 1514, 1483, 1429, 1387, 1360, 1265, 1251, 1201, 1124,

1

Calcd for C20 Na: C, 59.55; H, 5.50; N, 17.36. Found: C,

59.37; H, 5.69; N, 17.56.

22 5 3

H N O

1059, 1030, 1008. H NMR (300 MHz, DMSO-d ) δ: 2.12-2.22

6

-

(

m, 1H, 6-CH2), 2.24-2.28 (m, 2H, CH

CH ), 2.43-2.46 (m, 1H, 6-CH2), 3.83-3.99 (m, 2H,

CH

.89 (s, 2H, NH

Ph), 7.38 (d, J=8.1 Hz, 2H, Ar). MS (EI, 70 eV), m/z (%): 305

100), 186 (27), 207 (5), 200 (6), 131 (5), 115 (6), 104 (6), 72 (7),

5 (5). Anal. Calcd for C21 : C, 66.83; H, 6.14; N, 18.55.

Found: C, 66.47; H, 6.34; N, 18.17.

2 2

CH COO ), 2.30 (s, 3H,

3

-

4.16. 7-Benzyl-4-(4-methoxyphenyl)-2-phenyl-3,4,9,10-

tetrahydro-2H-[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidin-8(7H)-

one (23)

2

CH

2

COO ), 4.77-4.82 (m, 1H, H-5), 5.22-5.28 (m, 1H, H-7),

), 7.20 (d, J=8.1 Hz, 2H, Ar), 7.29-7.34 (m, 5H,

6

2

(

5

Benzylbromide (0.24 g, 1.4 mmol) was added to a solution of

compound 13a (0.5 g, 1.3 mmol) in dry DMF (4 mL) and the

resulted mixture was magnetically stirred at room temperature for

23 5 2

H N O

4

3

h then diluted with 5% water solution of NH (15 mL). The

4

.15.2.

3-[2-Amino-5-(4-methylphenyl)-7-phenyl-3H-

precipitate formed was isolated by filtration, washed with water

and crystallized from ethanol to give 0.43 g (yield 71%) of

compound 23 as colorless prisms, mp 234-235 °C. IR ν (cm ):

[

1,2,4]triazolo[1,5-a]pyrimidin-8-ium-3-yl]propanoate (18)

-1

Yield 0.198 g (53%, Method B) of yellowish prisms, mp 180-182

-1

3062, 3029, 2970, 2931, 2869, 2841, 1699, 1661, 1608, 1584,

°C (from EtOH/CH

3

CN 1:5). IR ν (cm ): 3338, 3054, 2957,

1516, 1497, 1450, 1419, 1395, 1374, 1338, 1293, 1251, 1225,

2

1

781, 2700, 1668, 1634, 1608, 1561, 1500, 1470, 1379, 1344,

1

1208, 1175, 1112, 1057, 1021. H NMR (300 MHz, DMSO-d

6

) δ:

), 2.91 (t, J =

O), 3.82 (t, J=6.2 Hz, 2H,

,), 4.63-4.81 (m, 3H, H-2+ PhCH ), 5.06 (dd, J=10.0, 4.2

322, 1264, 1225, 1192, 1126, 1017. H NMR (500 MHz,

) δ: 2.45 (s, 3H, CH ), 2.53-2.55 (m, 2H, CH ), 4.38-

.40 (m, 2H, CH ), 7.46-7.47 (m, 2H, Ar), 7.67-7.73 (m, 3H, Ar),

.21-8.22 (m, 2H, Ar), 8.37-8.38 (m, 3H, Ar), 9.29 (br s, 2H,

1.55-1.66 (m, 1H, 3-CH

6.2 Hz, 2Н, 9-СН ), 3.72 (s, 3H, CH

10-CH

2 2

), 2.36-2.39 (m, 1H, 3-CH

DMSO-d

4

8

6

3

2

3

2

1

3

Hz, 1H, H-4), 6.83 (d, J=8.5 Hz, 2H, Ar), 7.10–7.42 (m, 12H,

NH

2

). C NMR (125 MHz, TFA-d

1

) δ: 21.9 (2C), 29.4, 101.4,

13

Ar). C NMR (125 MHz, DMSO-d

6

) δ: 29.9, 34.6, 42.9, 44.0,

5.1, 56.4, 58.2, 113.6, 126.2, 126.6, 127.3, 127.8, 127.9, 128.3,

32.4, 136.4, 143.4 (C-6a), 145.9, 149.0 (C-11a), 158.6 (C-4 of

-CH OC ), 165.7 (CO). MS (EI, 70 eV), m/z (%): 465 (16)

117.7, 118.6, 119.4, 120.0, 120.8, 121.1, 124.0, 137.0, 137.4,

141.3, 146.5, 156.5, 167.9. MS (EI, 70 eV), m/z (%): 301 (95),

115 (7), 89 (7), 77 (13), 72 (55), 68 (11), 55 (50), 51 (10), 44

5

1

4

3

6 4

H

(

100). Anal. Calcd for C21

H

19

N

5

O

2

: C, 67.55; H, 5.13; N, 18.76.

+

[

M] , 330 (100), 268 (7), 240 (7), 134 (14), 91 (42), 55 (6). Anal.

Calcd for C28 : C, 72.24; H, 5.85; N, 15.04. Found: C,

2.45; H, 5.92; N, 15.13.

Found: C, 67.69; H, 4.95; N, 18.71.

27 5 2

H N O

7

4.15.3. 3-[2-Amino-6-(ethoxycarbonyl)-5-methyl-7-phenyl-4,7-

dihydro-3H-[1,2,4]triazolo[1,5-a]pyrimidin-8-ium-3-

yl]propanoate (19)

ACCEPTED MANUSCRIPT

2

0

Tetrahedron

4

.17. Ethyl 7-benzyl-2-methyl-8-oxo-4-phenyl-7,8,9,10-

Appl. 2012/0004203 A1, 2012; (g) Yu, W.; Goddard, C.;

Clearfield, E.; Mills, C.; Xiao, T.; Guo, H.; Morrey, J. D.; Motter,

N. E.; Zhao, K.; Block, T. M.; Cuconati, A.; Xu, X. J. Med. Chem.

tetrahydro-4H-[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidine-3-

carboxylate (25)

2

011, 54, 5660-5670.

3

.

(a) Desenko, S. M. Chem. Heterocycl. Compd. 1995, 31, 125-136;

(b) Desenko, S. M.; Orlov, V. D.; Lipson, V. V. Chem.

Heterocycl. Compd. 1990, 26, 1362-1366; (c) Desenko, S. M.;

Shishkin, O. V.; Orlov, V. D.; Lipson, V. V.; Lindeman, S. V.;

Struchkov, Yu. T. Chem. Heterocycl. Compd. 1994, 30, 851-855;

Sodium hydride (60% dispersion in mineral oil, 0.05 g, 1.1

mmol) was added to a suspension of compound 15a (0.5 g, 1.1

mmol) in dry DMF (3 mL) and the resulted mixture was stirred at

room temperature for 10 min. Benzylchloride (0.16 g, 1.4 mmol)

was added and the reaction mixture was stirred for a period of 24

h at room temperature, then diluted with water (10 mL). The

precipitate formed was isolated by filtration, washed with water,

crystallized from 2-popanol to give 0.32 g (yield 70%) of

(d) Lipson, V. V.; Svetlichnaya, N. V.; Borodina, V. V.;

Shirobokova, M. G.; Desenko, S. M.; Musatov, V. I.; Shishkina,

S. V.; Shishkin, O. V.; Zubatyuk, R. I. J. Heterocycl. Chem. 2012,

49, 1019-1025; (e) Chernyshev, V. M.; Sokolov, A. N.;

Khoroshkin, D. A.; Taranushich, V. A. Russ. J. Org. Chem. 2008,

44, 715-722; (f) Chernyshev, V. M.; Khoroshkin, D. A.; Sokolov,

A. N.; Taranushich, V. A.; Gladkov, E. S.; Shishkina, S. V.;

Shishkin, O. V.; Desenko, S. M. J. Heterocycl. Chem. 2008, 45,

1419-1427.

-1

compound 25 as colorless prisms, mp 276-277 °С. IR ν (cm ):

3

068, 3031, 2978, 2900, 1699, 1621, 1599, 1537, 1511, 1456,

1

1427, 1376, 1344, 1284, 1263, 1212, 1160, 1090, 1061. H NMR

(

2

300 MHz, DMSO-d ) δ: 1.00 (t, J=7.0 Hz, 3Н, CH CH O), 2.35

4. (a) Orlov, V. D.; Getmanskii, N. V.; Paponov, B. P.; Komykhov,

S. A. Chem. Heterocycl. Compd. 1993, 29, 1234-1235; (b) Lipson,

V. V.; Ignatenko, I. V.; Desenko, S. M.; Shishkina, S. V.;

6

3

2

s, 3H, CH

3

2

), 2.94 (t, J=6.9 Hz, 2Н, 9-СН ), 3.88 (q, J=7.0 Hz,

Н, CH CH O), 3.98 (t, J=6.9 Hz, 2Н, 10-СН ), 4.78 (s, 2H,

3 2 2

13

Shishkin, O. V.; Komykhov, S. A.; Logvinenko, N. V.; Orlov, V.

D.; Meier, H. J. Heterocycl. Chem. 2003, 40, 1081-1086; (c)

Lipson, V. V.; Desenko, S. M.; Ignatenko, I. V.; Shishkin, O. V.;

Shishkina S. V. Russ. Chem. Bull. 2006, 55, 345-350; (d) Lipson,

V. V.; Desenko, S. M.; Shishkin, O. V. Mendeleev Commun.

PhCH

(

9

(

4

(

2

), 6.11 (s, 1H, Н-4), 7.22-7.29 (m, 10Н, 2Ph). C NMR

150 MHz, DMSO-d ) δ: 14.0 (CH CH O), 24.2 (CH ), 29.2 (C-

6

3

2

3

2 3 2

), 35.6 (C-10), 44.5 (PhCH ), 58.5 (CH CH O), 59.7 (C-4), 97.0

C-3), 127.0, 127.3, 127.7, 127.8, 128.1, 128.2, 135.8, 142.5

carbons of benzene rings), 145.6 (C-6a), 147.4 (C-11a), 159.3

2

006, 16, 280-282; (e) Sidorenko, D. Yu.; Orlov, V. D. Mendeleev

Commun., 2010, 20, 170-171; (f) Sidorenko, D. Yu.; Orlov, V. D.

Ultrasonics Sonochem., 2011, 18, 300-302.

C-2), 165.3 (C-8), 165.8 (COOEt). MS (EI, 70 eV), m/z (%):

+

43 (9) [M] , 414 (11), 366 (44), 338 (7), 250 (2), 202 (1), 155

5. (a) Orlov, V. D.; Desenko, S. M.; Potekhin, K. A.; Struchkov, Yu.

T. Chem. Heterocycl. Compd. 1988, 24, 192-196; (b) Desenko, S.

M.; Kolos, N. N.; Tuéni, M.; Orlov V. D. Chem. Heterocycl.

Compd. 1990, 26, 782-784; (c) Lipson, V. V.; Desenko, S. M.;

Orlov, V. D.; Shishkin, O. V.; Shirobokova, M. G.; Chernenko, V.

N.; Zinov'eva, L. I. Chem. Heterocycl. Compd. 2000, 36, 1329-

2), 128 (7), 115 (3), 104 (3), 91 (100), 77 (10), 65 (13), 55 (12).

Anal. Calcd for C25 : C, 67.70; H, 5.68; N, 15.79. Found:

C, 68.09; H, 5.79; N, 16.14.

25 5 3

H N O

1

335; (d) Lipson, V. V.; Desenko, S. M.; Borodina, V. V.;

Shirobokova, M. G.; Musatov V. I. Russ. J. Org. Chem. 2005, 41,

14-119; (e) Ma, Zh.; Yan, G.; Zhu, Sh.; Yang, G.; Luo D. Chin.

1

Acknowledgments

J. Chem., 2009, 27, 987-992; (f) Kolos, N. N.; Kovalenko, L. U.;

Borovskoy, V. A. Chem. Heterocycl. Compd. 2011, 47, 983-988;

This work was financially supported by the Ministry of

Education and Science of Russia trough the Federal Target

Program “Research and Educational Personnel of Innovative

Russia at 2009-2013 Years” (grant no. 14.B37.21.0827) and, in

part, by Russian Foundation for Basic Research (grant no. 13-03-

(g) Desenko, S. M.; Orlov, V. D.; Éstrada Kh. Chem. Heterocycl.

Compd. 1990, 26, 839-840.

6. Desenko, S. M.; Orlov, V. D.; Lipson, V. V.; Shishkin, O. V.;

Lindeman, S. V.; Struchkov, Yu. T. Chem. Heterocycl. Compd.

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991, 27, 1242-1246.

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(a) Chebanov, V. A.; Muravyova, E. A.; Desenko, S. M.;

00253). The authors also thank Dr. Zoya A. Starikova (A. N.

Musatov, V. I.; Knyazeva, I. V.; Shishkina, S. V.; Shishkin, O. V.;

Kappe C. O. J. Comb. Chem. 2006, 8, 427-434; (b) Gladkov, E.

S.; Chebanov, V. A.; Desenko, S. M.; Shishkin, O. V.; Shishkina,

S. V.; Dallinger, D.; Kappe, C. O. Heterocycles 2007, 73, 469-

Nesmeyanov Institute of Organoelement Compounds of Russian

Academy of Sciences, Moscow) for performing X-ray analysis of

compound 5d.

4

80; (c) Chen, Q.; Jiang, L.-L.; Chen, C.-N.; Yang, G.-F. J.

Heterocycl. Chem. 2009, 46, 139–148; (d) Ryabukhin, S. V.;

Plaskon, A. S.; Boron, S. Yu.; Volochnyuk, D. M.; Tolmachev, A.

A. Mol. Diversity 2011, 15, 189-195; (e) Muravyova, E. A.;

Desenko, S. M.; Rudenko, R. V.; Shishkina, S. V.; Shishkin, O.

V.; Sen’ko, Y. V.; Vashchenko, E. V.; Chebanov, V. A.

Tetrahedron 2011, 67, 9389-9400; (f) Světlík, J.; Kettmann, V.

Tetrahedron Lett. 2011, 52, 1062-1066; (g) Li, T.; Yao, C.; Lei,

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Supplementary Material

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13

Copies of IR, H and C NMR, HSQC and HMBC spectra of

synthesized compounds, MOL files, crystallographic data and X-

ray experimental parameters for compounds 5d, 14c, 15a, and

detailed results of quantum chemical calculations are available.

Supplementary data associated with this article can be found in

online version.

Article Doi

Partially hydrogenated 2-amino[1,2,4]triazolo[1,5-a]pyrimidines as synthons for the preparation of polycondensed heterocycles: Reaction with chlorocarboxylic acid chlorides

DOI: 10.1016/j.tet.2013.11.090

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