1.1 INTRODUCTION - INFLIBNET Centreshodhganga.inflibnet.ac.in/bitstream/10603/20755/7/07... · 2020. 4. 24. · Chapter I Synthesis of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amines

Chapter I

Synthesis of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amines and pyrazolo[3,4-d] pyrimidines.

1

1.1 INTRODUCTION

Fused heterocyclic systems including a pyrimidine ring, in particular

triazolopyrimidines, can be regarded as synthetic analogues of natural compounds,

therefore, they attract interest as potential physiologically active substances. 1,2,4-

triazolo[1,5-a] pyrimidines (TPs), a subtype of purine analogs, have been widely

investigated and identified to possess multifaceted pharmacological properties,

including antihypertensive, cardiac stimulant, antimalarial, antifungal, anti-HBV,

antimicrobial and anticancer activities.1,2 In addition, triazolopyrimidines are

versatile ligands and their coordination compounds can be considered as model

systems for metal-ligand interactions observed in biological systems.3,4

The most widely known triazolopyrimidine derivative is the simple

molecule of Trapidil (1), which acts as a platelet-derived growth factor antagonist

and as a phosphodiesterase inhibitor.5

Cevipabulin (2) and its analogs, a class of triazolopyrimidine, were proved

to be potent anticancer agents with a unique mechanism of action in promoting

tubulin polymerization reported by Beyer et. al.,6

N

N

N

N

N

1

FOHN

FN

N

N

A

HN

FFF

Cl

2 The triazolopyrimidine hetero bicycle constitutes a well established

scaffold in crop protection chemistry. For instance, the herbicide family of

[1,2,4]triazolo[1,5-a]pyrimidine sulfonanilides (3) and (4) are potent inhibitors of

acetohydroxy acid synthase (AHAS).7,8

Chapter I


2

HN

S N

NN

N

F

F

O O

3

HN

S N

NNN

O OCl

O

OCl

4 Similarly, BAS6009 (5) is a new class of fungicides active against a broad

range of different plant diseases. Such compounds, which were discovered by

Shell in the early 1990s, have now been identified as promoters of tubulin

polymerization with a paclitaxel like mode of action.

F

F

N

N

N

N

N Cl

F

5 In addition, very similar molecules, such as TTI- 2378 (6), were claimed as

potent anti-cancer agents by Wyeth et. al., in the context of a program directed

toward the synthesis of analogues of this class of fungicides with improved

biological properties.

F

OHN

N

N

N

N

NH

Cl

F

F FF

6 Wenquan Yu et. al.,10 have designed and synthesized triazolo-pyrimidine

derivatives (7 -9) as novel inhibitors of Hepatitis B virus surface Antigen (HBsAg)

secretion.

Chapter I


3

R1

N

NH

N

NR2

7

R1

N

N

N

NR2

8

R1

N

NH

N

NR2

9R1 = di substituted with Cl and FR2 = mono and di substituted with Cl,F,OMe, Me

In the course of investigating pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]

pyrimidine A2A antagonists, Joel M. Harris et. al.,11 prepared series of [1,2,4]-

triazolo[4,3-c]pyrimidin-3-ones (10-13) with potent and selective (vs A1) A2A

antagonist activity.

NN

N

N O

NH2

NN

NN

ONH2

10 11

NN

NN

ONH2

HO

12

Christine M. Richardson et. al.,12 have reported triazolo[1,5-a]pyrimidines

(13-14) as novel CDK2 inhibitors with selectivity over glycogen synthase kinase-

3β (GSK-3β).

HN

SO2NH2

N

N

N

N

OX

N

NHN

N

O

NH

SO2NH2

14X =( CH2)0

13NU6102

Recently, from our lab, Shridhar et. al.,13 has reported “synthesis,

characterization, antibacterial and antifungal activity of thienopyrimidines (15)

and triazolothienopyrimidines.”

Chapter I


4

SN

N

NN

R

O

O

R = 9-xanthyl,9-floryl,2-chloro phenyl, 3-benzyl,2-naphthyl,4-methyl-thiophen-2-yl,pyren-1-yl,4-methyl-furan-2-yl.

15

There is a report on the synthesis and antimicrobial activity of some novel

thienopyrimidines (16) and triazolothienopyrimidines (17) by N. S. Shetty et. al.,14

SN

NNN

R

SN

NNN

R

OR = H,Me,Et16 17

Chloroethyl derivatives (N-substituted) and some of their metabolites show

great potential as effective chemotherapeutic alkylating agents for the

chemotherapy of several types of cancers including glioma, lymphoma,

melanoma, myeloma, and small cell lung cancers.15-18 It was discovered that

introduction of a 2-chloroethyl chain on the nitrogen atom bearing the nitroso

group of nitrosoureas and nitrosocarbamate derivatives led to much increased

anticancer activity. These chloroethyl derivatives were lipophilic enough to cross

the blood-brain barrier and therefore were useful in the treatment of brain tumors.

Most nitrosoureas contain one chloroethyl chain on the nitrosated nitrogen, which

allows them to act as DNA cross-linking agents. It was evident that the unusual

antitumor activity of certain mono functional nitrogen mustards was determined

by the chemical structure of the heterocyclic nucleus that was attached through a

side chain to the mono -2- chloro ethyl amino group.19

Fabio Carraro et. al.,20 have reported a series of pyrazolo[3,4-d]-pyrimidine

derivatives (18-19) having substituted chloroethyl side chain as potent

Chapter I


5

antiproliferative and proapoptotic agents toward, A431 and 8701-BC Cells in

culture via inhibition of c-Src Phosphorylation.20

N

N NN

CH2CHC6H5Cl

R

S

N

N NN

CH2CHC6H5Cl

R

S

18 19 Nitrogen mustard-armed combi-molecules (20-21) have been reported for

the selective targeting of epidermal growth factor receptor over expressing solid

tumors.21

N

N

HNN

NHNN

R

Cl

Cl

N

N

HNN

NHNN

Cl

Cl

O

20 21 Synthetic approaches

Triazolo [4,3-c] pyrimidines and triazolo[l,5-c]pyrimidines were generally

prepared by cyclization of appropriate pyrimidine derivatives, have been reported

in the literature. The most common procedure consisted of cyclization of 4-

hydrazinopyrimidines with various reagents such as orthoesters,22 cyanogen

chloride,23 carbon disulfide,24 isothiocyanates,25 and ethyl chloroformate.26 These

cyclizations led either to [4,3-c] isomers or directly to rearranged [1,5-c]

derivatives. A Dimroth rearrangement allowed the preparation of the

corresponding [1,5-c] derivatives.

Shridhar et. al.,27 have reported the synthesis of triazolopyrimidine by the

reaction of imidoformate intermediate with acid hydrazide.

S

N

NH2S N

N

C OH S N

N

NN

R

Triethyl orthoformate

reflux

C NHNH2R

O

AcOH, reflux2223 24

Chapter I


6

Joel et. al.,28 have reported the synthesis of [1,2,4]-triazolo[4,3-c]

pyrimidin-3-ones by using triphosgene as cyclising agent.

3

N N

NH2

ClCl

R1B(OH)2,Pd(PPh3)4

K2CO3,CH3CN60-70%

N N

NH2

ClR1

hydrazine

EtOH 96%

N N

NH2

NR1NH2

H25 26 27

N N

NH2

NR1N

H

PhH

28

phosgeneDIPEA

THF,00C30%,2 steps

N N

NH2

R1N

N

O

Ph

PhCHO,AcOH

CH2Cl2,then NaBH3(CN)

29

Utilising the applicability of imidates (30), triazolpyrimidines ring system

has been constructed. With a simple and fast synthesis of 3-amino-1,2,4-triazoles

(31), from imidates which on interamolecular cyclization gives 7-amino-1,2,4-

triazolopyrimidines (32).29

R CN CN

NHNHCH2CH2CN

MeOH

reflux,10 h

NN

N

R

NH2

CH2CH2CN

Toluene

reflux,48 hN

NN

N

R

NH2

30 31 32

Reaction of α,β-unsaturated ketones with 1H-1,2,4-triazol-3-amine in

DMFat refluxing condition gave dihydrotriazolo-pyrimidine analogues (35).30

R1

O

R2 NN

N

NH

R2

R1

NN

N

NH

R2

R1

3435

33

NaBH4,MeOH,

N

NH

N

H2N

The oxidative cyclization of a range of benzothieno[2,3-d]pyrimidine

hydrazones (36) catalysed by lithium iodide or sodium carbonate under mild

conditions afforded the 1,2,4-triazolo[4,3-c]pyrimidines (37).31

Chapter I


7

N

N

R3

NN R2H

R1 N

N

R3R1

N NR2

Lil, DMSO or DMF

1100c, 24Hrs

3637

A new synthetic strategy is described in the patent literature, where the

‘Dimroth-type rearrangement’ induced cyclization was used for the formation of

fused ring system (39).32

N N

NH

NH2

HN R

OHN

N

Dimorth-type rearrangment

N N

NH2

HNN

N

NR

38 39 In view of the pharmacological significance of triazolopyrimidines,

presence of the liphophilic 2-chloroethyl group and also in continuation of our

work on biologically active fused heterocyclic ring systems, we here in report the

synthesis of some novel pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine for the

evaluation of their pharmacological properties.

Chapter I


8

1.2 PRESENT WORK The work carried out during the present investigation deals with the

synthesis of novel nitrogen bridgehead fused tricyclic pyrazolo[4,3-

e][1,2,4]triazolo[1,5-c]pyrimidin-5-amines and bicyclic pyrazolo[3,4-d]pyrimidine

derivatives. A multi step synthetic protocol was employed to accomplish the

synthesis of title compounds starting from 5-amino-1-(2-chloroethyl)-1H-

pyrazole-4-carbonitrile precursor. The reaction sequence employed for the

synthesis of title compounds is outlined in the following schemes (1-4) and

explained briefly.

The required starting material 5-amino-1-(2-chloroethyl)-1H-pyrazole-4-

carbonitrile (I) was prepared by the reaction of 2-(ethoxymethylene)malononitrile

with 2-hydroxyethyl hydrazine followed by chlorination of hydroxyl group using

thionyl chloride in good yield (Scheme 1).

NH

NH2CN

CNEtO

HN N

H2NCN

HO

HO N N

H2NCN

Cl

iii

I

Reagents and conditions: i) Dry ethanol, reflux ii) SOCl2, 80 ˚C

Scheme 1

Two different routes A & B were designed for the synthesis of

pyrazolo[4,3-e] [1,2,4]triazolo[1,5-c]pyrimidin-5-amines. Routes A & B differ in

the formation of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine intermediate.

Route A: In this route (Scheme 2), pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]

pyrimidines (III) were prepared by the reaction of imidoformate II with various

substituted acid hydrazides under sealed-tube condition. Treatment of III with

hydrochloric acid at reflux temperature induced pyrimidine ring opening to furnish

the hydrolyzed intermediates, 5-amino-4-(1H-1,2,4-triazol-5-yl)pyrazoles (IV)

which were subsequently cyclised along with introduction of NH2 group at C-5

position of pyrimidine ring by the reaction with cynogen bromide to afford title

compounds V.

Chapter I


9

NN

N

Cl

O

CN + R NH

ONH2

NN

NNN

NR

Cl

N N

H2NCN

Cl

NN

HNH2NN

NR

ClN

N

NNN

NR

Cl

H2N

i

ii

iiiiv

I II

IIIIVV

V: a, R = Phenyl; b, R = 4-Cl-phenyl; c, R = 3-Cl-phenyl; d, 2-Cl-phenyl; e, 4-

NO2-phenyl; f, 3-NO2-phenyl; g, R = 2,4-dichlorophenoxy methyl; h, R = 4-OMe-

phenyl; i, R = Benzyl; j, R = 2-Me-phenyl; k, R = 4-OMe-benzyl; l, R = 4-F-

phenyl; m, R = cyclohexyl ; n, R = Benzisoxazole methyl; o, R = 4-F-benzyl; p, R

= 2-chloro-4-nitrophenyl; q, R = 4-Pyridyl; r, R = 3-Pyridyl; s, R = 2-Napthyl; t,

R1= 4-t-butyl benzyl; u, R = 2-Furyl.

Reagents and conditions: i) HC(OEt)3,toluene, reflux ii)AcOH, toluene, reflux,

sealed tube, iii) HCl, dioxane, reflux iv) CNBr, DMAP, acetonitrile, reflux.

Scheme 2

Route B: In this route (Scheme 3), we attempted to prepare intermediate

pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines (III) via amino-imine

intermediated. Imidoformate II was treated with hydrazine hydrate to afford

amino-imine intermediate which in turn on condensation with aldehydes gave

pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines (III). Further formation of title

compounds proceeds in similar fashion to route A.

Chapter I


10

NN

NN

NH

NH2

Cl

NN

NN

N

N

Cl

CHO

NN

N

Cl

O

CNN N

H2NCN

Cl

NN

HNH2NN

N

ClN

N

NN

N

N

Cl

NH2

Ri ii

iii

ivv

amino- imine intermediatedI II

IIIIVV

RR R

V: a,R = Phenyl; b, R = 4-Cl-phenyl.

Reagents and conditions: i) HC(OEt)3,toluene, reflux ii) N2H4.H2O, RT iii)

Methanol, reflux, iv) HCl, dioxane, reflux v) CNBr, DMAP, acetonitrile, reflux.

Scheme 3

Difficulty in isolation of amino-imine intermediate, incomplete conversion

to pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and poor over all yield made

us to adopt route A.

In another set of reactions, bicyclic pyrazolo[3,4-d]pyrimidine ring system

was prepared (Scheme 4). Pyrazolo[3,4-d]pyrimidin-4-ones (VI) were prepared

from I on refluxing with formic acid and acetic acid. pyrazolo[3,4-d]pyrimidin-4-

amine (VII) was prepared by treating imidoformate II with anhydrous ethanolic

ammonia and the intermediate were cyclised with sodium ethoxide in

dimethylformamide. pyrazolo[3,4-d]pyrimidin-4-amine can also be synthesized

directly from I on treatment with formamide.

Chapter I


11

N NCl

H2NCN

NN

NHN

OCl

NN

NN

ClNH2

R

NN

N

Cl

O

CNi ii

iviii

IVI II

VII

VI: a,R = H; b, R = Me.

Reagents and conditions: i) RCOOH, reflux ii) HC(OEt)3,toluene, reflux

iii) NH3, NaOEt iv) HCONH2, reflux.

Scheme 4

Note: Structures of all the newly synthesized compounds were established by

analytical and spectral data.

Chapter I


12

1.3 RESULTS AND DISCUSSION 5-amino-1-(2-chloroethyl)-1H-pyrazole-4-carbonitrile (I) served as starting

material for the synthesis of title compounds was prepared by the known literature

procedure. Formation of 5-amino-1-(2-chloroethyl)-1H-pyrazole-4-carbonitrile (I)

was characterized by the presence of band at 2220 cm-1 due to cyano group and N-

H stretching bands at 3363 and 3214 cm-1 in their IR spectrum. Further it was also

supported by the presence of D2O exchangeable broad singlet at 6.68 ppm due to -

NH2 group and singlet at 7.58 ppm for C3-H of pyrazole ring in 1H NMR

spectrum.

The formation of N1 substituted regio isomer 5-amino-1-(2-chloroethyl)-

1H-pyrazole-4-carbonitrile (I) over the formation N2 substituted regio isomer 3-

amino-1-(2-chloroethyl)-1H-pyrazole-4-carbonitrile (Ib) was confirmed by its

single crystal X-ray diffraction studies.

-EtOHOEtNH2

HN

R NH

NR

NN N N

N N

HNCN

Cl

N N

H2NCN

ClI

5-amino substituted isomer

HH

Mechanism for formation of 5-amino-1-(2-chloroethyl)-1H-pyrazole-4-

carbonitrile (I)

Imidoformate II was prepared in excellent yield by treating I with triethyl

orthoformate in refluxing toluene. Transformation of 5-amino-1-(2-chloroethyl)-

1H-pyrazole-4-carbonitrile (I) to corresponding imidoformate II was established

by the absence of N-H in IR and the presence of a triplet at 1.46 and quartet at 4.31

ppm corresponding to protons of the ethoxy group and peak around 8.29 ppm due

Chapter I


13

to -N=CH in the 1H NMR spectrum along with the other protons resonated in the

expected region.

Imidoformate II possesses two reactive sites, a cyano group and an imidic

carbon. These imidoformate known to react with compounds containing -NH2.

Imidoformate II used as precursor for construction of fused ring system by both

route A and B.

Imidoformate II was made to reacts with appropriate acid hydrazide under

toluene reflux in the presence of few drops of acetic acid to give desired fused

tricyclic triazolopyrimidines. Plausible pathway involves two successive

nucleophilic additions of -NH2 group on the imidic carbon and on the cyano

function followed by dehydrocyclisation to give triazolopyrimidines (Scheme 2).

NN

H2N N

O

OO

NN

N N

OO

H

NN

N N

OH2N

HN O

R

-EtOH

-EtOH

NN

N N

NHHN O

R

NN

N

N

N N OH

R

H

-H2O

NN

N

N

N NR

-EtOH

III

Mechanism for formation of triazolpyrimidine (III)

The structures of these compounds were ascertained by their analytical and

spectral data. The IR spectra showed the absence of nitrile band at 2220 cm-l. 1H

NMR spectra displayed a singlet in the range of 9.00 to 9.70 ppm corresponding to

C5-H of pyrimidine ring, further presence of protons in aromatic region due to R

substituent confirms the substitution at 3 position of triazole ring in III.

Chapter I


14

The title compounds pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-

amines (V) were prepared from pyrazolo[4,3-e][1,2,4]triazolo[1,5-c] pyrimidines

(III) via an interesting ring opening and recyclization process of pyrimidine ring.

Treatment of III(a-u) with hydrochloric acid at reflux temperature induced

pyrimidine ring opening to furnish the hydrolyzed intermediates, 5-amino-4-(1H-

1,2,4-triazol-5-yl)pyrazoles (IVa-u). In IR spectra of IV the νN-H is observed in the

region 3413, 3328 and 3177 cm-1, due to –NH2 and –NH functional groups

respectively. In 1H NMR, presence of two broad D2O exchangeable singlets

around 6.0 and 14.0 ppm corresponding to –NH2 and –NH respectively confirms

the formation of ring opening product IV.

NN

N

N

N NR

H+

NN

HN

N

N NR

OH

NN

HN

N

N NR

OHH

NN

HN

N

HN NR

O

NN

HN

N

HN NR

OHH+

NN

HN

N

HN NR

OH OH

NN

N

N

HN NR

O OHH

NN

N

HN NRH2N

-HCOOH

IV

H

H+

Mechanism for hydrolysis of triazolpyrimidine (III)

Chapter I


15

The use of cynogen bromide as a ring closing agent successfully afforded

cyclization with introduction of -NH2 group at C-5 position of pyrimidine ring to

give title compounds V.

NN

N

HN NR

H2N

BrN

NN

N

N NR

H2N

-HBr

N

NN

N

N

N NR

NH

NN

N

N

N NR

NH2

H

V Mechanism for ring closing (VI)

The structures of cyclized products V were ascertained by the absence of

absorption bands due to –NH group in the IR spectra and appearance of broad D2O

exchangeable singlet around 8.0 ppm assigned for –NH2 group in 1H NMR

spectra.

Reaction of imidoformate II with hydrazine hydrate (Scheme 3) afforded

the amino-imino intermediate which was characterized by the presence of IR

bands of amino and imino functions. 1H NMR spectrum shows D2O exchangeable

singlets at 4.87 and 9.15 ppm assigned to amino and imino groups respectively

and the C5-H of pyrimidine resonated at 8.34 ppm as singlet along with other

expected signals.

Pyrazolo[3,4-d]pyrimidin-4-ones (VI) were prepared from I (Scheme 4) on

refluxing with formic acid and acetic acid. The structures of VI were ascertained

by the presence of band at 1686 cm-1 in IR spectra and a D2O exchangeable broad

Chapter I


16

singlet at 12.23 ppm for -NH in the 1H NMR spectra. The reaction of formates II

with ethanolic ammonia followed by the cyclization of intermediate with sodium

ethoxide in dimethyl formamide resulted in the formation of pyrazolo[3,4-d]

pyrimidin-4-amine (VII). Formation of the product was established by the

presence of characteristic band at 3321, 3228 cm-1 due to amino group in IR

spectrum. The 1H NMR spectrum showed the presence of D2O exchangeable

broad singlet at 5.4 ppm due to -NH2 group. Alternatively pyrazolo[3,4-d]

pyrimidin-4-amine (VII) was also prepared directly from the 5-amino-1-(2-

chloroethyl)-1H-pyrazole-4-carbonitrile (I) by reacting with formamide.

These compounds were further confirmed by their 13C NMR and mass spectral

data. (See figure 1.5 to 1.12 for all spectra)

Chapter I


17

1.4 CRYSTAL STRUCTURE STUDIES Crystal and molecular structure of 5-Amino-1-(2-chloro-ethyl)-1H-pyrazole-

4-carbonitrile (I)

Crystals of the compound for the diffraction studies were grown from DMF

by slow evaporation technique. The perspective structure [Fig. 1.1(a), 1.1(b) and

1.1(c)] and crystal data of 5-Amino-1-(2-chloro-ethyl)-1H-pyrazole-4-carbonitrile

(I) are given below.

Crystal data and structure refinement

Crystal data

Empirical formula C6H7ClN4 Formula weight 170.61 Temperature 296 K Crystal system, space group Monoclinic, P21/c Unit cell dimensions

a , b & c (Å) 4.8215 (2) 11.2648 (6) & 14.5553 (7)

α, β & γ 90°, 95.275 (2)°, 90° Volume 787.20 (7) Å3 Z, 4 Calculated density (Mg/m3) 1.576 Absorption coefficient (mm-1) 0.42 Index range h h = −6→5 k k = −14→14 l l = −16→18 Reflections collected/unique 9050/1712 [R(int) = 0.024] Completeness to theta 27.0° Refinement Refinement method Full-matrix least-squares F2 R[F2 > 2σ(F2)], wR(F2), S 0.053, 0.142, 1.20 No. of reflections 1712 No. of parameters 106 H-atom treatment H atom parameters are constrained Δρmax, Δρmin (e Å−3) 0.42, −0.55

Chapter I


Fig. 1.1(a): ORTEP diagram of (I) with the atom numbering scheme.

Displacement ellipsoids are drawn at the 50% probability level. H

atoms are presented as small spheres of arbitrary radius

Intermolecular Features

In the title compound, the pyrazole ring is substituted with amino,

carbonitrile and the 2-chloro-ethyl groups. The N(1)-N(2) and C(5)-N(1) bond

lengths in the pyrazole ring are shorter{1.375(2)Å and 1.349(1)Å} than the

distance characteristics of a single N-N bond (1.45 Å) and C-N(1.45 Å). The cis

orientation of 2-chloro-ethyl group with respect to the C5-N1 bond is described by

the torsion angle C(5)-N(1)-C(2)-C(1) [-107.795(4)°]. The N(1) atom of the

pyrazole ring is in the planar trigonal configuration. The molecular structure of the

title compound is stabilized by intermolecular N-H…N and C-H…Cl interactions.

There are two types of N-H…N intermolecular interactions (Table 1.1); N4-

H4B…N3 hydrogen bond forms centrosymmetric head-to-head dimers about

inversion centres corresponding to graph set R22(12) motif23. While the N4-

H4A…N2 hydrogen bonds generate chains of molecules in a zigzag pattern along

the crystallographic ‘a’ axis.

Chapter I


Fig. 1.1(b): Packing of the molecules in crystal of the title compound. Dotted lines

indicate, N-H….N intermolecular interaction; the hydrogen’s are

omitted for clarity. The C-H…Cl intermolecular interaction forms two

dimensional molecular chains along the crystallographic ‘b’ axis.

Fig. 1.1(c): Packing of the molecules in crystal of the title compound. Dotted lines

indicate, C-H….Cl intermolecular interaction.

Chapter I


20

Table 1.1: Non-bonded interactions and possible hydrogen bonds (Å) for the title

Compound

(D-donor; A-acceptor; H-hydrogen) D—H· · ·A D—H H· · ·A D· · ·A D—H· · ·A

N4-H4A ...N2i 0.879 2.233 3.083(3) 162

N4-H4A ...N2i 0.789 2.254 3.775(2) 171

C3-H3...Cl1ii 0.930 2.888 3.775(2) 161 Symmetry code: (i) -x+1,+y+1/2,-z+1/2 (ii) -x,-y+1,-z+1 (iii) -x,+y-1/2,z+1/2

Table 1.2: Bond lengths [Å] for non H-atoms of with ends in parenthesis

Bonds Length (Ao) Bonds Length (Ao) C(1)-C(2) 1.506(2) C(5)-N(1) 1.3489(19 C(1)-Cl(1) 1.7787(16) C(6)-N(3) 1.137(2) C(2)-N(1) 1.4467(18 N(1)-N(2) 1.375(2) C(3)-N(2) 1.310(2) C(2)-C(1)-Cl(1) 111.81(11) C(3)-C(4) 1.393(2) N(1)-C(2)-C(1) 112.66(13) C(4)-C(5) 1.397(2) N(2)-C(3)-C(4) 112.57(15) C(4)-C(6) 1.408(2) C(3)-C(4)-C(5) 104.98(13) C(5)-N(4) 1.333(2) C(3)-C(4)-C(6) 127.99(14)

Table 1.3: Bond angles [°] for non H-atoms of with ends in parenthesis

Bonds angles [°] Bonds angles [°] C(5)-C(4)-C(6) 127.03(14) C(5)-N(1)-N(2) 112.25(12) N(4)-C(5)-N(1) 124.61(14) C(5)-N(1)-N(2) 112.25(12) N(4)-C(5)-C(4) 129.67(14) C(5)-N(1)-C(2) 129.26(13) N(1)-C(5)-C(4) 105.73(13) N(2)-N(1)-C(2) 118.47(13) N(3)-C(6)-C(4) 178.68(19) C(3)-N(2)-N(1) 104.47(13)

Chapter I


21

Crystal and molecular structure 7-(2-chloroethyl)-2-(pyridin-3-yl)-7H-

pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (IIIr)


by slow evaporation technique.The perspective structure [Fig. 1.2(a) and 1.2(b)]

and Crystal and molecular structure 7-(2-chloroethyl)-2-(pyridin-3-yl)-7H-

pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (IIIr) are given below.


Crystal data

Empirical formula C13H10ClN7 Formula weight 299.73 Temperature 100 Crystal system, space group Triclinic, Pī

Unit cell dimensions a , b & c (Å)

5.5082 (2), 10.0431 (4) & 12.5745 (5)

α, β & γ 77.699 (2), 89.151 (3) & 75.195 (2)

Volume 656.50 (4) Å3 Z, 2 Radiation type Mo Kα Crystal size (mm) 0.18 × 0.16 × 0.16 Data collection

Diffractometer Bruker Smart APEX CCD detector

Absorption correction Multi-scan No. of measured, independent and observed [I > 2σ(I)] reflections

8907, 2452, 1923

Rint 0.027 (sin θ/λ)max (Å−1) 0.606 Refinement R[F2 > 2σ(F2)], wR(F2), S 0.057, 0.161, 0.99 No. of reflections 2452 No. of parameters 190 H-atom treatment H atom parameters are constrained Δρmax, Δρmin (e Å−3) 0.39, −0.57

Chapter I


Fig. 1.2(a): ORTEP diagram of IIIr

Fig. 1.2(b): Packing diagram of IIIr, molecules in compound in --- showing

C-H…O dimers

Chapter I


23


Bonds Length (Ao) Bonds Length (Ao) Cl(1)-C(11) 1.776(4) N(6)-N(7) 1.368(3) N(1)-C(2) 1.325(3) N(6)-C(13) 1.441(4) N(1)-N(2) 1.365(3) N(7)-C(6) 1.312(4) N(2)-C(8) 1.375(4) C(1)-C(5) 1.383(4) N(2)-C(7) 1.382(3) C(2)-C(3) 1.471(4) N(3)-C(4) 1.322(4) C(3)-C(4) 1.326(4) N(3)-C(9) 1.405(5) C(3)-C(10) 1.386(4) N(4)-C(7) 1.312(4) C(5)-C(6) 1.407(4) N(4)-C(2) 1.372(3) C(5)-C(7) 1.413(4) N(5)-C(8) 1.295(4) C(9)-C(12) 1.368(5) N(5)-C(1) 1.375(3) C(10)-C(12) 1.375(4) N(6)-C(1) 1.353(3) C(11)-C(13) 1.496(5)


Bonds angles [°] Bonds angles [°] C(2)-N(1)-N(2) 101.9(2) C(4)-C(3)-C(10) 123.0(3) N(1)-N(2)-C(8) 125.4(2) C(4)-C(3)-C(2) 116.4(3) N(1)-N(2)-C(7) 109.4(2) C(10)-C(3)-C(2) 120.6(3) C(8)-N(2)-C(7) 125.1(2) N(3)-C(4)-C(3) 118.3(3) C(4)-N(3)-C(9) 122.6(3) C(1)-C(5)-C(6) 104.6(3) C(7)-N(4)-C(2) 102.9(2) C(1)-C(5)-C(7) 116.1(2) C(8)-N(5)-C(1) 114.0(2) C(6)-C(5)-C(7) 139.3(3) C(1)-N(6)-N(7) 110.4(2) N(7)-C(6)-C(5) 111.2(3) C(1)-N(6)-C(13) 129.2(2) N(4)-C(7)-N(2) 110.0(2) N(7)-N(6)-C(13) 120.4(2) N(4)-C(7)-C(5) 135.8(2) C(6)-N(7)-N(6) 106.3(2) N(2)-C(7)-C(5) 114.3(2) N(6)-C(1)-N(5) 124.4(3) N(5)-C(8)-N(2) 122.3(2) N(6)-C(1)-C(5) 107.4(2) C(12)-C(9)-N(3) 118.1(3) N(5)-C(1)-C(5) 128.2(3) C(12)-C(10)-C(3) 118.3(3) N(1)-C(2)-N(4) 115.8(3) C(13)-C(11)-Cl(1) 112.5(2) N(4)-C(2)-C(3) 122.3(2) N(6)-C(13)-C(11) 113.3(3)

Chapter I


24

Crystal and molecular structure of 7-(2-chloroethyl)-2-(furan-2-yl)-7H-

pyrazolo [4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Vu)


by slow evaporation technique. The perspective structure [Fig. 1.2(a) and 1.2(b)]

and crystal data of 7-(2-chloroethyl)-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]

triazolo[1,5-c]pyrimidine (Vu) are given below.


Crystal data

Empirical formula C12H10Cl N7O Formula weight 303.72 Temperature 296(2) K Wavelength 0.71073 A Crystal system, space group Monoclinic, C 2/c Unit cell dimensions

a , b & c (Å) 24.3943(5), 7.41950(10) & 14.3306(3) β (°) 99.19(10) Volume 2560.45(8)Å3 Z, 8 Calculated density (Mg/m3) 1.576 Absorption coefficient (mm-1) 0.310 F(000) 1248 Index range h -30

Chapter I


Fig.1.3(a). ORTEP diagram of Vu with the atom numbering scheme.

Displacement ellipsoids are drawn at the 50% probability level. H

atoms are presented as small spheres of arbitrary radius.

Fig. 1.3(b). Packing of the Vu, molecule in crystal of the title compound. Dotted

lines indicate, C-H….Cl intermolecular interaction.

Chapter I


26


Bonds Length (Ao) Bonds Length (Ao) Cl(1)-C(12) 1.776(4) N(5)-N(6) 1.364(4) N(1)-C(3) 1.375(4) N(5)-C(10) 1.448(5) N(1)-N(2) 1.375(4) N(7)-C(6) 1.320(4) N(1)-C(6) 1.394(4) N(7)-H(7A) 0.8600 N(3)-C(3) 1.333(4) N(7)-H(7B) 0.8600 N(3)-C(5) 1.364(4) N(6)-C(9) 1.309(5) N(4)-C(6) 1.311(4) C(7)-O(1) 1.346(5) N(4)-C(4) 1.361(4) C(8)-C(11) 1.316(5) C(1)-C(4) 1.400(5) C(8)-O(1) 1.433(5) C(1)-C(3) 1.404(5) C(8)-H(8) 0.9300 C(1)-C(9) 1.413(5) C(9)-H(9) 0.9300

C(2)-C(11) 1.364(4) C(10)-C(12) 1.497(5) C(2)-C(7) 1.370(4) C(10)-H(10A) 0.9700 C(2)-H(2) 0.9300 C(10)-H(10B) 0.9700 N(2)-C(5) 1.328(4) C(11)-H(11) 0.9300 C(4)-N(5) 1.347(4) C(12)-H(12A) 0.9700 C(5)-C(7) 1.448(4) C(12)-H(12B) 0.9700


Bonds Length (Ao) Bonds Length (Ao) C(3)-N(1)-N(2) 110.3(3) O(1)-C(7)-C(2) 110.2(3) C(3)-N(1)-C(6) 124.9(3) O(1)-C(7)-C(5) 134.7(3) N(2)-N(1)-C(6) 124.7(3) C(2)-C(7)-C(5) 115.2(3) C(3)-N(3)-C(5) 102.7(3 C(11)-C(8)-O(1) 107.0(3) (3)-C(3)-N(1) 109.3(3) C(11)-C(8)-H(8) 126.5

N(3)-C(3)-C(1) 135.0(3) C(10)-C(12)-Cl(1) 109.6(3) N(1)-C(3)-C(1) 115.7(3) C(10)-C(12)-H(12A) 109.7

C(6)-N(7)-H(7A) 120.0 Cl(1)-C(12)-H(12A) 109.7 C(6)-N(7)-H(7B) 120.0 C(1)-C(9)-H(9) 124.2

H(7A)-N(7)-H(7B) 120.0 C(7)-O(1)-C(8) 105.8(3) N(4)-C(6)-N(7) 122.8(3) N(5)-C(10)-C(12) 111.2(3) N(4)-C(6)-N(1) 120.7(3) N(5)-C(10)-H(10A) 109.4

Chapter I


27

Crystal and molecular structure of 1-(2-Chloroethyl)-1H-pyrazolo[3,4-d]

pyrimidin-4(5H)-one (VIa)

Crystals of the compound for the diffraction studies were grown from

ethanol by slow evaporation technique. The perspective structure [Fig. 1.4(a) and

1.4(b)] and crystal data of 5-(2-Chloroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-

one (VIa) are given below.


Crystal data

Empirical formula C7H9ClN4O Formula weight 200.63 Temperature 296K Crystal system, space group Monoclinic P21/n Unit cell dimensions a , b & c (Å)

4.6448 (1), 8.0792 (1) & 22.7335 (4)

α, β & γ 90°, 93.554 (1)° ,90°

Volume 851.46 (3) Å3 Z, 4 Radiation type Mo Kα radiation Wave length 0.71073 Å Crystal size (mm) 0.18×0.16 ×0.16 mm Data collection Diffractometer Bruker Smart APEX CCD detector

No. of measured, independent and observed [I > 2σ(I)] reflections

7660, 1548 ,1353

Rint 0.023 (sin θ/λ)max (Å−1) θmax = 25.2°, θmin = 1.8° Refinement R[F2 > 2σ(F2)], wR(F2), S 0.035, 0.100, 0.87 No. of reflections 1548 No. of parameters 118 H-atom treatment H atom parameters are constrained Δρmax, Δρmin (e Å−3) 0.19, −0.37

Chapter I


Fig. 1.4(a): ORTEP diagram of (VI) of the title compound with the atom

numbering scheme. Displacement ellipsoids are drawn at the 50%

probability level. H atoms are presented as small spheres of arbitrary

radius.

Intermolecular Features

In the title compound (Fig. 1.4(a)), the fused pyrazolopyrimidine ring is

substituted with 2-chloro-ethyl group on one side and the oxo group on the other

side. The pyrazolopyrimidine ring is planar with the maximum deviation from the

mean statistical plane being 0.0115 (14) Å for C3. The cis orientation of 2-chloro-

ethyl group with respect to the C2-N2 bond is described by the torsion angle N2-

C2-N3-C3, -2.204 (4)°.

The crystal structure is stabilized by some interesting features that

comprise of intermolecular N-H···O, C-H···O, C-H···N and C-H···Cl interactions

(Fig. 1.4(b) and Table 1.8). The C-H···O and the N-H···O interactions result in

centrosymmetric head-to-head dimers corresponding to the graph set R22(10) and

R22(8) motif. There are two types of C-H···N interactions, one of which forms a

helix, the other forms sheets along the crystallographic b-axis. The C-H···Cl

intermolecular interaction result in one dimensional molecular chain along b-axis.

The bond lengths and bond angles in the title molecule agree very well with the

corresponding bond distances and bond angles reported in a closely related

compound.

Chapter I


Fig. 1.4(b): Packing of the molecules in crystal of the title compound. Dotted lines

indicate intermolecular hydrogen bonds.

Table 1.8: Hydrogen-bond geometry (Å) for the title Compound

(D-donor; A-acceptor; H-hydrogen) D—H· · ·A D—H H· · ·A D· · ·A D—H· · ·A

N1—H1---O1i 0.86 1.96 2.810(2) 170

C5—H5A---N4ii 0.93 2.79 3.676 (2) 160

C2—H2A---Cl1iii 0.97 164 2.84 3.779 (2) 164

C2—H2B---N2iv 0.97 2.59 3.463 (2) 150

C3—H3---O1v 0.93 2.35 3.254 (2) 163 Symmetry code (i) -x + 1;-y + 2;-z + 2; (ii) x; y + 1; z; (iii) -x + 3/2; y - 12;-z + 3/2;(iv) -x +52; y -1/2;-z + 32; (v) -x +1;-y + 1;-z + 2.


Bonds Length (Ao) Bonds Length (Ao) C(1)-N(2) 1.299(2) C(4)-Cl(1) 1.788(2) C(1)-N(1) 1.357(2) C(5)-O(1) 1.231(2) C(2)-N(3) 1.344(2) C(5)-N(1) 1.389(2) C(2)-N(2) 1.362(2) C(5)-C(6) 1.424(2) C(2)-C(6) 1.388(2) C(6)-C(7) 1.403(3) C(3)-N(3) 1.451(2) C(7)-N(4) 1.320(2) C(3)-C(4) 1.501(3) N(3)-N(4) 1.371(2)

Chapter I


30


Bonds angles [°] Bonds angles [°]

N(2)-C(1)-N(1) 125.45(17) C(2)-C(6)-C(5) 118.38(16)

N(3)-C(2)-N(2) 125.45(15) C(7)-C(6)-C(5) 136.61(17)

N(3)-C(2)-C(6) 106.86(15) N(4)-C(7)-C(6) 111.23(16)

N(2)-C(2)-C(6) 127.68(16) C(1)-N(1)-C(5) 124.71(15)

N(3)-C(3)-C(4) 113.08(15) C(1)-N(2)-C(2) 111.97(15)

C(3)-C(4)-Cl(1) 112.00(14) C(2)-N(3)-N(4) 111.42(13)

O(1)-C(5)-N(1) 120.63(16) C(2)-N(3)-C(3) 128.26(15)

O(1)-C(5)-C(6) 127.58(17) N(4)-N(3)-C(3) 120.30(15)

N(1)-C(5)-C(6) 111.79(14) C(7)-N(4)-N(3) 105.48(15)

C(2)-C(6)-C(7) 105.00(16)

Chapter I


31

1.5 EXPERIMENTAL Synthesis of 5-Amino-4-cyano-1-(β-hydroxyethyl)pyrazole

Equimolar quantities of 2-Hydroxyethylhydrazine and

(ethoxymethylene) malononitrile were dissolved in EtOH

and stirred for 30 minutes, later the mixture was heated at 70

˚C for 15 h. After completion of the reaction, solvent was

evaporated. The solid was washed with ether and recrystallized from ethanol to

afford crystalline solid in good yield.1,2

Synthesis of 5-amino-1-(2-chloroethyl)-1H-pyrazole-4-carbonitrile (I)

5-Amino-4-cyano-1-(β-hydroxyethyl)pyrazole was refluxed in excess of

thionyl chloriode (5 volumes) under stirring for 15 h. After completion of reaction

excess of thionyl chloride was distilled off, cooled to 0 ˚C and diluted with water.

Slowly basified with sat. NaHCO3, solid separated out was filtered, washed with

excess of water and dried.33,34

Yield 78%; white solid; m.p. 176-178 ˚C; IR (KBr) νcm-1:

3363, 3214, 2934, 2850, 2220, 1664, 1577, 1541; 1H NMR

(300 MHz, DMSO-d6) ppm: 3.88 (t, J = 6.0 Hz, 2H), 4.24 (t,

J = 6.0 Hz, 2H), 6.68 (s, 2H, NH2, D2O exchangeable), 7.59 (s, 1H); MS m/z: 170

(M+), 172(M+2); Anal. calcd. for C6H7ClN4 (%): C, 42.24; H, 4.14; Cl, 20.78; N,

32.84; Found: C, 42.22; H, 4.15; N, 32.83. [Fig. 1.5(a-c)]

Synthesis of Ethyl N-1-(2-chloroethyl)-4-cyano-1H-pyrazol-5-ylformimidate

(II)

A mixture of I (5.8 mmol) and triethyl orthoformate (17.4mmol) was heated to

reflux in toluene 10 mL for 20h. Excess of toluene was removed under vacuum.

The residue was treated with petroleum ether. Solid that separated was

recrystallized with ethanol to afford white crystals.

Yield 80%; white solid; m.p. 150-152 ˚C; IR (KBr) νcm-1:

2977, 2935, 2882, 2224, 1663, 1616, 1541; 1H NMR (400

MHz, DMSO-d6) ppm: 1.46 (t, J = 6.0 Hz, 3H ), 3.81 (t, J =

6.00 Hz, 3H), 3.90 (t, J = 6.0 Hz, 2H),), 4.31 (q, J = 5.20

N NCl

CNH2N

NN

N

Cl

O

CN

N NHO

CNH2N

Chapter I


32

Hz, 2H), 8.02 (s, 1H), 8.29 (s, 1H); MS m/z: 226(M+), 228(M+2); Anal. calcd. for

C9H11ClN4O (%): C, 47.69; H, 4.89; N, 24.72; Found: C, 47.70; H, 4.86; N, 24.74.

[Fig. 1.6(a-b)]

Synthesis of 7-(2-chloroethyl)-2-(aryl/heteroaryl)-7H-pyrazolo[4,3-e][1,2,4]

triazolo[1,5-c]pyrimidines (IIIa-u)

A mixture of imidoformate (II) (4.4 mmol) and

various substituted acid hydrazide was stirred at

room temperature in toluene (20 mL), catalytic

amount of AcOH was then added and the reaction mixture was further refluxed in

sealed tube condition till the completion of reaction. Reaction mixture was washed

with water, dried over sodium sulphate and toluene was striped off to obtain solid.

The solid was washed with cold ethanol to get analytically pure product.

7-(2-chloroethyl)-2-phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine

(IIIa)

Yield 80%; white solid; m.p. 210-214 ˚C; IR

(KBr) νcm-1: 3112, 3061, 2925, 1651; 1H NMR

(400 MHz, DMSO-d6) ppm: 4.24 (t, J = 5.6 Hz,

2H). 4.43 (t, J = 5.6 Hz, 2H), 7.636-7.654 (m, 3H), 8.31-8.33 (m, 2H), 8.70 (s,

1H), 9.76 (s, 1H); MS m/z: 298(M+), 300(M+2); Anal. calcd. for C14H11ClN6 (%):

C, 56.29; H, 3.71; N, 28.13 Found: C, 56.27; H, 3.70; N, 28.15.

7-(2-chloroethyl)-2-(4-chlorophenyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]

pyrimidine (IIIb)


(KBr) νcm-1: 3120, 3055, 2930, 1648; 1H

NMR (500 MHz, CDCl3) ppm: 4.19 (t, J = 5.6

Hz, 2H), 4.87 (t, J = 5.7 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 8.27 (d, J = 8.6 Hz,

2H), 8.65 (s, 1H), 9.71 (s, 1H); MS m/z: 332(M+), 336(M+4); Anal. calcd. for

C14H10Cl2N6 (%): C, 50.47; H, 3.03; N, 25.22 Found: C, 50.49; H, 3.01; N, 25.24.

NN

NN

N

NR

Cl

NN

NN

N

N

Cl

NN

NN

N

N

Cl

Cl

Chapter I


33


pyrimidine (IIIc)


(KBr) νcm-1: 3122, 3050, 2928, 1646; 1H NMR

(500 MHz, CDCl3) ppm: 4.07 (t, J = 6.2 Hz,

2H), 4.90 (t, J = 6.2 Hz, 2H), 7.48 (dd, J = 7.5, 4.6 Hz, 2H), 8.20-8.22 (m, 1H),

8.33 (d, J = 1.8 Hz, 1H), 8.46 (s, 1H), 9.16 (s, 1H); MS m/z: 332(M+), 336(M+4);

Anal. calcd. for C14H10Cl2N6 (%): C, 50.47; H, 3.03; N, 25.22 Found: C, 50.50; H,

3.01; N, 25.19.


pyrimidine (IIId)


(KBr) νcm-1: 3126, 3048, 2935, 1652; 1H NMR

(500 MHz, CDCl3) ppm: 4.08 (t, J = 6.2 Hz, 2H),

4.91 (t, J = 6.2 Hz, 2H), 7.34–7.50 (m, 2H), 7.49–7.66 (m, 1H), 8.01–8.16 (m,

1H), 8.47 (s, 1H), 9.23 (s, 1H); MS m/z: 332(M+), 336(M+4); Anal. calcd. for

C14H10Cl2N6 (%):C, 50.47; H, 3.03; N, 25.22 Found: C, 50.52; H, 3.04; N, 25.21.

7-(2-chloroethyl)-2-(4-nitrophenyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]

pyrimidine (IIIe)

Yield 78%; yellow solid; m.p. 202-204 ˚C;

IR (KBr) νcm-1: 3135, 3045, 2895, 1662; 1H

NMR (500 MHz, CDCl3) ppm: 4.09 (t, J =

6.1 Hz, 2H), 4.91 (t, J = 6.1 Hz, 2H), 8.39 (d, J = 8.9 Hz, 2H), 8.48 (s, 1H), 8.52

(d, J = 8.9 Hz, 2H), 9.19 (s, 1H); Anal. calcd. for C14H10ClN7O2 (%): C, 48.92; H,

2.93; N, 28.52; Found: C, 48.95; H, 2.94; N, 28.51.


pyrimidine (IIIf)

Yield 68%; yellow solid; m.p. 191-193 ˚C; IR

(KBr) νcm-1: 3133, 3042, 3112, 1658; 1H

NMR (500 MHz, CDCl3) ppm: 4.19 (t, J = 5.6

Hz, 2H), 4.89 (t, J = 5.6 Hz, 2H), 7.89-7.92 (m, 1H), 8.43 (ddd, J = 8.2, 2.4, 1.0

NN

NN

N

N

Cl Cl

NN

NN

N

N

Cl Cl

NN

NN

N

N

Cl

NO2

NN

NN

N

N

Cl NO2

Chapter I


34

Hz, 1H), 8.6–8.62 (m, 1H), 8.70 (s, 1H), 8.96-9.0 (m, 1H), 9.77 (s, 1H); MS m/z:

343(M+), 345(M+2); Anal. calcd. for C14H10ClN7O2 (%): C,48.92; H, 2.93; N,

28.52; Found: C, 48.93; H, 2.90; N, 28.52.

7-(2-chloroethyl)-2-((2,4-dichlorophenoxy)methyl)-7H-pyrazolo[4,3-e][1,2,4]

triazolo[1,5-c]pyrimidine (IIIg)

Yield 89%; white solid; m.p. 187-189 ˚C;

IR (KBr) νcm-1: 3139, 3054, 2998, 1684; 1H NMR (500 MHz, CDCl3) ppm: 4.06 (t,

J = 6.1 Hz, 2H), 4.89 (t, J = 6.1 Hz, 2H),

5.44 (s, 2H), 7.08 (d, J = 8.8 Hz, 1H), 7.18 (dd, J = 8.8, 2.5 Hz, 1H), 7.40 (d, J =

2.5 Hz, 1H), 8.41 (s, 1H), 9.13 (s, 1H); Anal. calcd. for C15H11Cl3N6O (%): C,

45.31; H, 2.79; N, 21.13; Found: C, 45.30; H, 2.81; N, 21.15.

7-(2-chloroethyl)-2-(4-methoxyphenyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo-

[1,5-c] pyrimidine (IIIh)


(KBr) νcm-1: 3140, 3054, 2968, 1667; 1H

NMR (500 MHz, DMSO-d6) ppm: 3.86 (s,

3H), 4.18 (t, J = 5.7 Hz, 2H), 4.86 (t, J = 5.7 Hz, 2H), 7.14 (d, J = 8.9 Hz, 2H),

8.20 (d, J = 8.9 Hz, 2H), 8.62 (s, 1H), 9.66 (s, 1H); MS m/z: 328(M+), 330(M+2);

Anal. calcd. for C15H13ClN6O (%):C, 54.80; H, 3.99; N, 25.56; Found: C, 54.83;

H, 3.97; N, 25.54.

2-benzyl-7-(2-chloroethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine

(IIIi)


(KBr) νcm-1: 3139, 3050, 2971, 1659; 1H NMR


4.30 (s, 2H), 4.85 (t, J = 6.2 Hz, 2H), 7.21-7.29 (m, 1H), 7.34 (dd, J = 10.3, 4.8

Hz, 2H), 7.41 (d, J = 7.3 Hz, 2H), 8.36 (s, 1H), 9.07 (s, 1H); 13C NMR (125 MHz,

CDCl3) ppm: 35.3, 41.9, 49.2, 102.4, 126.9, 128.7, 129.0, 132.5, 136.8, 138.5,

147.0, 148.5, 167.8; MS m/z: 312(M+), 314(M+2); Anal. calcd. for C15H13ClN6

(%): C, 57. 57; H, 4.19; N, 26.87 Found: C, 57. 60; H, 4.17; N, 26.90.

NN

NN

N

N

Cl

O

Cl

Cl

NN

NN

N

N

Cl

O

NN

NN

N

N

Cl

Chapter I


35

7-(2-chloroethyl)-2-(o-tolyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]

pyrimidine (IIIj)


(KBr) νcm-1: 3128, 3046, 2958, 1648; 1H NMR

(500 MHz, CDCl3) ppm: 2.23(s, 3H,), 4.01 (t, J =

6.2 Hz, 2H), 4.82 (t, J = 6.2 Hz, 2H), 7.32–7.48 (m, 2H), 7.51–7.64 (m, 1H), 8.01–

8.16 (m, 1H), 8.45 (s, 1H), 9.15 (s, 1H); MS m/z: 312(M+), 314(M+2); Anal. calcd.

for C15H13ClN6 (%):C, 57.60; H, 4.19; N, 26.87 Found: C, 57.61; H, 4.20; N,

26.85.

7-(2-chloroethyl)-2-(4-methoxybenzyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo-

[1,5-c ]pyrimidine (IIIk)


(KBr) νcm-1: 3112, 3061, 2972, 1651; 1H NMR

(400 MHz, DMSO-d6) ppm: 3.78 (s, 3H), 4.03

(t, J = 6.40 Hz, 2H), 4.24 (s, 2H), 4.85 (t, J =

6.40 Hz, 2H), 6.88 (d, J = 8.40 Hz, 2H), 7.33 (d, J = 8.40 Hz, 2H), 8.35 (s, 1H),

9.06 (s, 1H); 13C NMR (125 MHz, CDCl3) ppm: 34.0, 43.4, 49.2, 55.4, 101.9,

114.2, 129.6, 130.4, 132.4, 140.4, 147.2, 148.2, 158.4, 167.5; MS m/z: 342(M+),

344(M+2); Anal. calcd. for C16H15ClN6O (%): C, 56.06; H, 4.41; N, 24.52; Found:

C, 56.08; H, 4.43; N, 24.50. [Fig. 1.7(a-d)]

7-(2-chloroethyl)-2-(4-fluorophenyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]

pyrimidine (IIIl)


(KBr) νcm-1: 3124, 3041, 2945, 1631; 1H


6.2 Hz, 2H), 4.91 (t, J = 6.2 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 8.34 (dd, J = 8.4,

5.6 Hz, 2H), 8.47 (s, 1H), 9.16 (s, 1H); MS m/z: 316(M+), 318(M+2); Anal. calcd.

for C14H10ClFN6 (%): C, 53.09; H, 3.18; N, 26.53 Found: C, 53.11; H, 3.15; N,

26.50.

NN

NN

N

N

Cl

NN

NN

N

N

Cl

F

NN

NN

N

N

Cl

O

Chapter I


36

7-(2-chloroethyl)-2-cyclohexyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]

pyrimidine (IIIm)

Yield 85%; white solid; m.p. 201-203˚C; IR

(KBr) νcm-1: 3148, 3025, 2914, 1615; 1H NMR

(500 MHz, CDCl3) ppm: 1.36-1.93 (m, 8H), 2.15-

2.19 (m, 2H), 2.97-3.03(m, 1H), 4.06 (t, J = 6.2 Hz, 2H), 4.88 (t, J = 6.2 Hz, 2H),

8.41 (s, 1H), 9.08 (s, 1H); Anal. calcd. for C14H17ClN6 (%): C, 55.17; H, 5.62; N,

27.57 Found: C, 55.15; H, 5.61; N, 27.58

3-((7-(2-chloroethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-2-yl)

methyl) benzo[d]isoxazole (IIIn)


(KBr) νcm-1: 3159, 3023, 2918, 1624; 1H


6.2 Hz, 2H), 4.73 (s, 2H), 4.88 (t, J = 6.2 Hz, 2H), 7.26-7.34 (m, 1H), 7.53-7.58

(m, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 8.39 (s, 1H), 9.09 (s,

1H); MS m/z: 353(M+), 355(M+2); Anal. calcd. for C16H12ClN7O (%): C, 54.32; H,

3.42; N, 27.72 Found: C, 54.30; H, 3.41; N, 27.71.

7-(2-chloroethyl)-2-(4-fluorobenzyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]

pyrimidine (IIIo)


(KBr) νcm-1: 3152, 3011, 2938, 1644; 1H NMR


4.29 (s, 2H), 4.88 (t, J = 6.2 Hz, 2H), 7.05 (d, J =

8.7 Hz, 2H), 7.39 (dd, J = 8.5, 5.4 Hz, 2H), 8.39 (s, 1H), 9.09 (s, 1H); MS m/z:

330(M+), 332(M+2); Anal. calcd. for C15H12ClFN6 (%): C, 54.47; H, 3.66; N, 25.41

Found: C, 54.48; H, 3.65; N, 25.40.

NN

NN

N

N

Cl

NN

NN

N

N

Cl NO

NN

NN

N

N

Cl

F

Chapter I


37

2-(2-chloro-4-nitrophenyl)-7-(2-chloroethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo

[1,5-c] pyrimidine (IIIp)


(KBr) νcm-1: 3167, 3029, 2954, 1618; 1H NMR

(500 MHz, CDCl3) ppm: 4.11 (t, J = 6.1 Hz,

3H), 4.94 (t, J = 6.1 Hz, 3H), 8.30 (dd, J = 8.6, 2.2 Hz, 1H), ), 8.40 (d, J = 8.6 Hz,

1H), 8.49 (d, J = 2.2 Hz, 1H), 8.50 (s, 1H), 9.27 (s, 1H); MS m/z: 377(M+),

379(M+2); Anal. calcd. for C14H9Cl2N7O2 (%): C, 44.46; H, 2.40; N, 25.93; Found:

C, 44.45; H, 2.41; N, 25.90.

7-(2-chloroethyl)-2-(pyridin-4-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]

pyrimidine (IIIq)

Yield 85%; off white solid; m.p. 174-176 ˚C; IR

(KBr) νcm-1: 3158, 3018, 2942, 1612; 1H NMR


4.92 (t, J = 6.2 Hz, 2H), 7.50 (dd, J = 7.9, 4.8 Hz, 1H), 8.49 (s, 1H), 8.60- 8.62 (m,

1H), 8.78 (dd, J = 4.8, 1.6 Hz, 1H), 9.20 (s, 1H), 9.57 (d, J = 1.6 Hz, 1H); MS m/z:

299(M+), 301(M+2); Anal. calcd. for C13H10ClN7 (%): C, 52.10; H, 3.36; N, 32.71

Found: C, 52.12; H, 3.36; N, 32.73.

7-(2-chloroethyl)-2-(pyridin-3-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]

pyrimidine (IIIr)


(KBr) νcm-1: 3155, 3022, 2940, 1614; 1H NMR (500

MHz, CDCl3) ppm: 4.10 (t, J = 6.2 Hz, 2H), 4.92 (t,

J = 6.2 Hz, 2H), 7.39 - 7.51 (m, 1H), 7.90-7.93 (m, 1H), 8.40 (s, 1H), 8.49 (s, 1H),

8.87 (d, J = 4.7 Hz, 1H), 9.25 (s, 1H); Anal. calcd. for C13H10ClN7 (%): C, 52.10;

H, 3.36; N, 32.71 Found: C, 52.55; H, 3.34; N, 32.69.

7-(2-chloroethyl)-2-(naphthalen-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]

pyrimidine (IIIs)

Yield 72%; white solid; m.p. 201-202 ˚C; IR (KBr)

νcm-1 : 3146, 3031, 2946, 1618; 1H NMR (500 MHz,

NN

NN

N

N

Cl Cl

NO2

NN

NN

N

N

Cl

N

NN

NN

N

N

ClN

NN

NN

N

N

Cl

Chapter I


38

CDCl3) ppm: 4.11 (t, J = 6.2 Hz, 2H). 4.94 (t, J = 6.2 Hz, 2H), 7.72 – 7.57 (m,

3H), 7.98 (d, J = 8.1 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.45 (d, J = 7.2 Hz, 1H),

8.52 (s, 1H), 9.22 (d, J = 8.6 Hz, 1H), 9.29 (s, 1H); MS m/z: 348(M+), 350(M+2);

Anal. calcd. for C18H13ClN6 (%): C, 61.98; H, 3.76; N, 24.09 Found: C, 61.98; H,

3.76; N, 24.12.

2-(4-(tert-butyl)benzyl)-7-(2-chloroethyl)-7H-pyrazolo[4,3-][1,2,4]triazolo-

[1,5-c]pyrimidine (IIIt)


(KBr) νcm-1: 3152, 3011, 2950, 1621; 1H

NMR (500 MHz, CDCl3) ppm: 1.33 (s, 9H),

4.06 (t, J = 6.2 Hz, 2H), 4.29 (s, 2H),4.87 (t, J

= 6.2 Hz, 2H), 7.33-7.42 (m, 4H), 8.38 (s, 1H),

9.09 (s, 1H); 13C NMR (125 MHz, CDCl3) ppm: 31.5, 34.4, 34.5, 43.4, 49.3,

102.0, 125.6, 129.1, 132.5, 134.7, 140.4, 147.2, 148.2, 149.3, 167.4 MS m/z:

359(M+), 361(M+2); Anal. calcd. for C19H21ClN6 (%):C, 61.87; H, 5.74; N, 22.78

Found: C, 61.88; H, 5.70; N, 22.74.

7-(2-chloroethyl)-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]

pyrimidine(IIIu)


νcm-1: 3098, 2958, 2852, 1656; 1H NMR (400

MHz, DMSO-d6) ppm: 4.18 (t, J = 5.9 Hz, 2H).

4.89 (t, J = 5.9 Hz, 2H), 6.74 (dd, J = 3.2, 1.7 Hz, 1H), 7.25 (d, J = 3.3 Hz, 1H),

7.96 (d, J = 3.3 Hz, 1H), 8.60 (s, 1H), 9.7 (s, 1H); 13C NMR (125 MHz, CDCl3)

ppm: 43.2, 48.4, 99.3, 12.6, 115.3, 132.5, 146.6, 147.3, 156.1, 160.5, 158.4; MS

m/z: 289(M+1); Anal. calcd. for C12H9ClN6O (%): C, 49.92; H, 3.14; N, 29.11;

Found: C, 49.95; H, 3.12; N, 29.13.[ Fig. 1.8(a-d)]

Synthesis of 1-(2-chloroethyl)-4-(3aryl/heteroaryl)-1H-1,2,4-triazol-5-yl)-1H-

pyrazol-5-amine IV(a-u)

The triazolopyrimidine III (10 mmol) were dissolved

in 20 mL of 1,4-dioxane, followed by addition of 5 mL

NN

NN

N

N

Cl

NN

NN

N

N

ClO

NN

HN

N

NR

Cl

H2N

Chapter I


39

of concentrated hydrochloric acid, 37% w/w into the solution. The mixture was

refluxed for 2h at 120 ˚C. Then the solution was cooled and basified with 10%

NaOH. The compounds were extracted with EtOAc, the organic layers were dried

over Na2SO4 and evaporated under vacuum to obtain the desired product.

1-(2-chloroethyl)-4-(3-phenyl-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-amine (IVa)


(KBr) νcm-1: 3328, 3187, 3110, 2931, 2847, 1619,

1599, 1567; 1H NMR (500 MHz, DMSO-d6) ppm:

3.81 (t, J = 6.2 Hz, 2H). 4.33 (t, J = 6.2 Hz, 2H), 6.31 (s, 2H, NH2, D2O

exchangeable), 7.32-7.34 (m, 3H), 7.98 (s, 1H), 8.17-8.20 (m, 2H), 13.45 (s, 1H,

NH, D2O exchangeable); MS m/z: 288(M+), 300(M+2); Anal. calcd. for C13H13ClN6 (%): C, 54.08; H, 4.54; N, 29.11; Found: C, 54.09; H, 4.52; N, 29.13.

1-(2-chloroethyl)-4-(3-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-

amine (IVb)


(KBr) νcm-1: 3339, 3177, 3120, 2939, 2850,

1617, 1600, 1560; 1H NMR (500 MHz,

DMSO-d6) ppm: 3.93 (t, J = 5.6 Hz, 2H), 4.31 (t, J = 5.7 Hz, 2H), 6.24 (s, 2H,

NH2, D2O exchangeable), 7.39 (d, J = 8.6 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H), 8.07

(s, 1H), 13.63 (s, 1H, NH, D2O exchangeable); Anal. calcd. for C13H12Cl2N6 (%):

C, 48.31; H, 3.74; N, 26.00; Found: C, 48.31; H, 3.71; N, 26.03.


amine (IVc)


(KBr) νcm-1: 3347, 3182, 3131, 2937, 2849,

1611,1599, 1561; 1H NMR (500 MHz, DMSO-d6)

ppm: 3.81 (t, J = 6.2 Hz, 2H), 4.34 (t, J = 6.2 Hz, 2H), 6.34 (s, 2H, NH2, D2O

exchangeable), 7.30 (dd, J = 7.5, 4.6 Hz, 2H), 7.86 (s, 1H), 7.87 -7.89 (m, 1H),

7.95 (d, J = 1.8 Hz, 1H), 13.53 (s, 1H, NH, D2O exchangeable); MS m/z: 332(M+),

NN

HNH2NN

N

ClCl

NN

HN

N

N

Cl

H2N

NN

HN

N

N

Cl

H2N Cl

Chapter I


40

336(M+4); Anal. calcd. for C13H12Cl2N6 (%): C, 48.31; H, 3.74; N, 26.00; Found:

C, 48.32; H, 3.71; N, 26.01.


amine (IVd)


(KBr) νcm-1: 3338, 3179, 3125, 2941, 2851,

1613,1598, 1563; 1H NMR (500 MHz, DMSO-d6)


exchangeable), 7.18–7.37 (m, 2H), 7.30-7.52 (m, 1H), 7.83-7.85 (m, 1H),7.98 (s,

1H), 13.56 (s, 1H, NH, D2O exchangeable); MS m/z: 332(M+), 336(M+4); Anal.

calcd. for C13H12Cl2N6 (%): C, 48.31; H, 3.74; N, 26.00; Found: C, 48.31; H, 3.72;

N, 26.03.

1-(2-chloroethyl)-4-(3-(4-nitrophenyl)-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-

amine (IVe)

Yield 68%; yellow solid; m.p. 188-189 ˚C;

IR (KBr) νcm-1: 3330, 3175, 3135, 2929,

2847, 1610,1599, 1560; 1H NMR (500 MHz,


NH2, D2O exchangeable), 7.83 (s, 1H), 8.02 (d, J = 8.9 Hz, 2H), 8.34 (d, J = 8.9

Hz, 2H), 13.83 (s, 1H, NH, D2O exchangeable); Anal. calcd. for C13H12ClN7O2

(%): C, 46.79; H, 3.62; N, 29.38; Found: C, 46.81; H, 3.63; N, 29.37.

1-(2-chloroethyl)-4-(3-(3-nitrophenyl)-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-

amine (IVf)


(KBr) νcm-1: 3328, 3179, 3128, 2943, 2851,

1609,1600, 1557; 1H NMR (500 MHz, DMSO-

d6) ppm: 3.93 (t, J = 5.6 Hz, 2H), 4.33 (t, J = 5.6 Hz, 2H), 6.42 (s, 2H, NH2, D2O

exchangeable), 7.53 -7.56 (m, 1), 8.10 (s, 1H), 8.14 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H),

8.28–8.40 (m, 1H), 8.73-8.79 (m, 1H), 13.72 (s, 1H, NH, D2O exchangeable); MS

m/z: 333(M+), 335(M+2); Anal. calcd. for C13H12ClN7O2 (%):C, 46.79; H, 3.62; N,

29.38; Found: C, 46.80; H, 3.60; N, 29.37.

NN

HNH2NN

N

ClCl

NN

HNH2NN

N

Cl

NO2

NN

HNH2NN

N

ClNO2

Chapter I


41

1-(2-chloroethyl)-4-(3-((2,4-dichlorophenoxy)methyl)-1H-1,2,4-triazol-5-yl)-

1H-pyrazol-5-amine (IVg)

Yield76%; white solid; m.p. 214-216 ˚C;

IR (KBr) νcm-1: 3321, 3167, 3131, 2939,

2845, 1611,1587, 1556; 1H NMR (500

MHz, DMSO-d6) ppm: 3.80 (t, J = 6.1 Hz,

2H), 4.33 (t, J = 6.1 Hz, 2H), 5.29 (s, 2H), 6.29 (s, 2H, NH2, D2O exchangeable),

6.88(d, J = 8.8 Hz, 1H), 7.09 (dd, J = 8.8, 2.5 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H),

7.82(s, 1H), 13.83 (s, 1H, NH, D2O exchangeable); Anal. calcd. for C14H13Cl3N6O

(%): C, 43.38; H, 3.38; N, 21.68; Found: C, 43.40; H, 3.39; N, 21.66.

1-(2-chloroethyl)-4-(3-(4-methoxyphenyl)-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-

amine (IVh)


(KBr) νcm-1: 3325, 3180, 3131, 2941, 2854,

1619,1601, 1557; 1H NMR (500 MHz,

DMSO-d6) ppm: 3.73 (s, 3H), 3.92 (t, J = 5.7 Hz, 2H), 4.30 (t, J = 5.7 Hz, 2H),

6.27 (s, 2H, NH2, D2O exchangeable), 6.88 (d, J = 8.9 Hz, 2H), 7.94 (d, J = 8.9

Hz, 2H), 8.02 (s, 1H), 13.68 (s, 1H, NH, D2O exchangeable); MS m/z: 328(M+),

330(M+2); Anal. calcd. for C14H15ClN6O (%): C, 52.75; H, 4.74; N, 26.36; Found:

C, 52.76; H, 4.73; N, 26.35.

4-(3-benzyl-1H-1,2,4-triazol-5-yl)-1-(2-chloroethyl)-1H-pyrazol-5-amine (IVi)


νcm-1: 3328, 3177, 3125, 2941, 2854, 1610,1599,

1560; 1H NMR (500 MHz, DMSO-d6) ppm: 3.77 (t,

J = 6.2 Hz, 2H), 4.19 (s, 2H), 4.29 (t, J = 6.2 Hz, 2H), 6.42 (s, 2H, NH2, D2O

exchangeable), 7.07-7.15 (m, 2H), 7.19 (dd, J = 10.2, 4.8 Hz, 2H), 7.29 (d, J = 7.3

Hz, 1H), 7.78 (s, 1H); 13.86 (s, 1H, NH, D2O exchangeable); MS m/z: 302(M+),

304(M+2); Anal. calcd. for C14H15ClN6 (%):C, 55.54; H, 4.99; N, 27.76; Found: C,

55.55; H, 4.97; N, 27.78.

NN

HNH2NN

N

Cl

O

Cl

Cl

NN

HNH2NN

N

Cl

O

NN

HNH2NN

N

Cl

Chapter I


42

1-(2-chloroethyl)-4-(3-(o-tolyl)-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-amine

(IVj)


(KBr) νcm-1: 3321, 3181, 3118, 2924, 2849,

1617,1599, 1560; 1H NMR (500 MHz, DMSO-d6)

ppm: 2.13(s, 3H), 3.75 (t, J = 6.2 Hz, 2H), 4.26 (t, J = 6.2 Hz, 2H), 6.64 (s, 2H,

NH2, D2O exchangeable), 7.15–7.29 (m, 2H), 7.36–7.49 (m, 1H), 7.82–7.97 (m,

1H), 8.04(s, 1H), 13.57 (s, 1H, NH, D2O exchangeable); MS m/z: 312(M+),

314(M+2); Anal. calcd. for C14H15ClN6 (%): C, 55.54; H, 4.99; N, 27.76; Found: C,

55.53; H, 4.98; N, 27.79.

1-(2-chloroethyl)-4-(3-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-

amine (IVk)


(KBr) νcm-1: 3338, 3181, 3131, 2947, 2861,

1621,1599, 1556; 1H NMR (400 MHz, DMSO-

d6) ppm: 3.61 (s, 3H), 3.77 (t, J = 6.40 Hz, 2H),

4.13 (s, 2H), 4.29 (t, J = 6.40 Hz, 2H), 6.41 (s, 2H, NH2, D2O exchangeable), 6.59

(d, J = 8.40 Hz, 2H), 7.09 (d, J = 8.40 Hz, 2H), 7.89 (s, 1H), 13.89 (s, 1H, NH,

D2O exchangeable); MS m/z: 332(M+), 334(M+2); Anal. calcd. for C15H17ClN6O

(%): C, 54.14; H, 5.15; N, 25.25; Found: C, 54.16; H, 5.15; N, 25.25.

1-(2-chloroethyl)-4-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-

amine (IVl)

Yield72%; white solid; m.p. 223-225 ˚C; IR

(KBr) νcm-1: 3331, 3187, 3124, 2941, 2845,

1610, 1597, 1556; 1H NMR (500 MHz, DMSO-

d6) ppm: 3.83 (t, J = 6.2 Hz, 2H), 4.35 (t, J = 6.2 Hz, 2H), 6.38 (s, 2H, NH2, D2O

exchangeable), 7.04 (d, J = 8.6 Hz, 2H), 7.87 (s, 1H), 8.18 (dd, J = 8.4, 5.6 Hz,

2H), 13.68 (s, 1H, NH, D2O exchangeable); Anal. calcd. for C13H12ClFN6 (%): C,

50.91; H, 3.94; N, 27.40; Found: C, 50.95; H, 3.90; N, 27.42.

NN

HNH2NN

N

Cl

NN

HNH2NN

N

Cl

F

NN

HNH2NN

N

ClO

Chapter I


43

1-(2-chloroethyl)-4-(3-cyclohexyl-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-amine

(IVm)

Yield 65%; white solid; m.p. 210-211˚C; IR

(KBr) νcm-1 : 3308, 3171, 3125, 2934, 2824,

1617,1599, 1557; 1H NMR (500 MHz, DMSO-d6)

ppm: 1.29-1.88 (m, 8H), 2.03-2.07 (m, 2H), 2.86-2.89(m, 1H), 3.80 (t, J = 6.2 Hz,

2H), 4.32 (t, J = 6.2 Hz, 2H), 6.29 (s, 2H, NH2, D2O exchangeable), 7.83 (s, 1H),

13.64 (s, 1H, NH, D2O exchangeable); MS m/z: 294 (M+), 296(M+2); Anal. calcd.

for C13H19ClN6 (%): C, 52.97; H, 6.50; N, 28.51; Found: C, 52.99; H, 6.52; N,

28.54.

4-(3-(benzo[d]isoxazol-3-ylmethyl)-1H-1,2,4-triazol-5-yl)-1-(2-chloroethyl)-

1H-pyrazol-5-amine (IIIn)


(KBr) νcm-1 : 3327, 3173, 3131, 2943, 2849,

1609, 1587, 1552; 1H NMR (500 MHz,

DMSO-d6) ppm: 3.81 (t, J = 6.2 Hz, 2H), 4.61 (s, 2H), 4.32 (t, J = 6.2 Hz, 2H),

6.32 (s, 2H, NH2, D2O exchangeable), 7.19- 7.25 (m, 1H), 7.41-7.46 (m, 1H), 7.49

(d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H) , 13.79 (s, 1H, NH, D2O

exchangeable); MS m/z: 343(M+), 345(M+2); Anal. calcd. for C15H14ClN7O(%): C,

52.41; H, 4.10; N, 28.52; Found: C, 52.43; H, 4.13; N, 28.50.

1-(2-chloroethyl)-4-(3-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-

amine (IVo)


(KBr) νcm-1: 3331, 3165, 3129, 2932, 2817, 1611,

1581, 1563; 1H NMR (500 MHz, DMSO-d6) ppm:

3.81 (t, J = 6.2 Hz, 2H), 4.18 (s, 2H), 4.32 (t, J =

6.2 Hz, 2H), 6.28 (s, 2H, NH2, D2O exchangeable), 6.83 (d, J = 8.7 Hz, 2H), 7.09

(dd, J = 8.5, 5.4 Hz, 2H), 7.81 (s, 1H), 13.84 (s, 1H, NH, D2O exchangeable); MS

m/z: 320(M+), 322(M+2); Anal. calcd. for C14H14ClFN6 (%): C, 52.42; H, 4.40; N,

26.20; Found: C, 52.43; H, 4.41; N, 26.24.

NN

HNH2NN

N

Cl

NN

HNH2NN

N

ClN

O

NN

HNH2NN

N

ClF

Chapter I


44

4-(3-(2-chloro-4-nitrophenyl)-1H-1,2,4-triazol-5-yl)-1-(2-chloroethyl)-1H-

pyrazol-5-amine (IVp)


(KBr) νcm-1: 3325, 3167, 3129, 2937, 2844,

1612, 1589, 1567; 1H NMR (500 MHz,


NH2, D2O exchangeable), 7.91 (s, 1H), 8.13 (dd, J = 8.6, 2.2 Hz, 1H), 8.23 (d, J =

8.6 Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H) , 13.86 (s, 1H, NH, D2O exchangeable); MS

m/z: 367(M+), 369(M+2); Anal. calcd. for C13H11Cl2N7O2 (%): C, 42.41; H, 3.01;

N, 26.63; Found: C, 42.40; H, 3.01; N, 26.63.

1-(2-chloroethyl)-4-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-

amine (IVq)


(KBr) νcm-1: 3339, 3169, 3131, 2938, 2828,

1612,1587, 1551; 1H NMR (500 MHz, DMSO-

d6) ppm : 3.85 (t, J = 6.2 Hz, 2H), 4.36 (t, J = 6.2 Hz, 2H) , 6.39 (s, 2H, NH2, D2O

exchangeable), 7.33 (dd, J = 7.9, 4.8 Hz, 1H), 7.89 (s, 1H), 8.41-8.43 (m, 1H),

8.59 (dd, J = 4.8, 1.6 Hz, 1H) 9.41 (d, J = 1.6 Hz, 1H) , 13.82 (s, 1H, NH, D2O

exchangeable); MS m/z: 289(M+), 291(M+2); Anal. calcd. for 12H12ClN7 (%): C,

49.75; H, 4.17; N, 33.84; Found: C, 49.77; H, 4.17; N, 33.82.

1-(2-chloroethyl)-4-(3-(pyridin-3-yl)-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-

amine (IVr)


(KBr) νcm-1 : 3332, 3171, 3122, 2947, 2859,

1616,1600, 1564; 1H NMR (500 MHz, DMSO-d6)


exchangeable), 7.31 – 7.42 (m, 1H), 7.60-7.62 (m, 1H), 7.88 (s, 1H), 8.28 (s, 1H),

8.59 (d, J = 4.7 Hz, 1H), 13.83 (s, 1H, NH, D2O exchangeable); Anal. calcd. for

C12H12ClN7 (%): C, 49.75; H, 4.17; N, 33.84; Found: C, 49.73; H, 4.19; N, 33.83.

NN

HNH2NN

N

ClCl

NO2

NN

HNH2NN

N

Cl

N

NN

HNH2NN

N

Cl

N

Chapter I


45

1-(2-chloroethyl)-4-(3-(naphthalen-2-yl)-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-

amine (IVs)


νcm-1: 3098, 2958, 2852, 1656, 1621; 1H NMR

(500 MHz, DMSO-d6) ppm: 3.86 (t, J = 6.2 Hz,

2H), 4.38 (t, J = 6.2 Hz, 2H) , 6.23 (s, 2H, NH2,

D2O exchangeable), 7.43-7.60 (m, 3H), 7.79 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.2

Hz, 1H) 7.94 (s, 1H), 8.31 (d, J = 7.2 Hz, 1H), 9.13 (d, J = 8.6 Hz, 1H) , 13.78 (s,

1H, NH, D2O exchangeable); MS m/z: 338(M+), 340(M+2) Anal. calcd. for

C17H15ClN6 (%): C, 60.27; H, 4.46; Cl, 10.46; N, 24.81; Found C, 60.25; H, 4.45;

N, 24.79.

4-(3-(4-(tert-butyl)benzyl)-1H-1,2,4-triazol-5-yl)-1-(2-chloroethyl)-1H-pyrazol

-5-amine (IVt)


(KBr) νcm-1: 3334, 3181, 3129, 2941, 2857,

1611, 1592, 1547; 1H NMR (500 MHz, DMSO-

d6) ppm: 1.24 (s, 9H), 3.81 (t, J = 6.2 Hz, 2H),

4.18 (s, 2H), 4.31 (t, J = 6.2 Hz, 2H), 6.39 (s,

2H, NH2, D2O exchangeable), 7.28 – 7.37 (m, 4H), 7.79(s, 1H) , 13.91 (s, 1H, NH,

D2O exchangeable); MS m/z: 358(M+), 360(M+2); Anal. calcd. for C18H23ClN6C (%): C, 60.24; H, 6.46; N, 23.42 Found: C, 60.23; H, 6.48; N, 23.43

1-(2-chloroethyl)-4-(3-(furan-2-yl)-1H-1,2,4-triazol-5-yl)-1H-pyrazol-5-amine

(IVu)


νcm-1: 3328, 3177, 3125, 2947, 2856, 1610, 1599,

1560; 1H NMR (400 MHz, DMSO-d6) ppm: 3.94 (t,

J = 5.9 Hz, 2H), 4.30 (t, J = 5.9 Hz, 2H), 6.31 (s, 2H, NH2, D2O exchangeable),

6.67 (dd, J = 3.2, 1.7 Hz, 1H), 7.03 (d, J = 3.3 Hz, 1H), 7.72 (d, J = 3.3 Hz, 1H ),

7.91 (s, 1H), 13.86 (s, 1H, NH, D2O exchangeable); MS m/z: 278(M+), 280(M+2);

Anal. calcd. for C11H11ClN6O (%): C, 47.41; H, 3.98; N, 30.15; Found: C, 47.43;

H, 3.98; N, 30.13. [Fig. 1.9(a-d)]

NN

HNH2NN

N

Cl

NN

HNH2N

N

N

Cl

NN

HNH2NN

N

Cl

O

Chapter I


46

Synthesis of 7-(2-chloroethyl)-2-aryl/heteroaryl-7H-pyrazolo[4,3-e][1,2,4]

triazolo [1,5-c]pyrimidin-5-amine V(a-u)

To a solution of hydrolyzed pyrazole derivatives IVa-t (9.5 mmol) and

DMAP (10.5 mmol) in acetonitrile (25 mL) was slowly added cynogen bromide

(9.5 mmol, 5M solution in acetonitrile) and then

reaction mixture was refluxed for 4 h (TLC

monitored). The reaction mixture was diluted with

water; solid was filtered, washed with water, cold

ethanol and dried.

7-(2-chloroethyl)-2-phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-

5-amine (Va)


(KBr) νcm-1: 3437, 3318, 2987, 2852, 1667, 1631,

1610; 1H NMR (500 MHz, DMSO-d6) ppm: 3.99

(t, J = 6.2 Hz, 2H). 4.61 (t, J = 6.2 Hz, 2H), 7.48-

7.49 (m, 3H), 8.05 (s, 2H, NH2, D2O exchangeable), 8.12 (s, 1H), 8.21-8.23 (m,

2H); MS m/z: 288(M+), 300(M+2); Anal. calcd. for C14H12ClN7 (%): C, 53.59; H,

3.86; N, 31.25; Found: C, 53.56; H, 3.84; N, 31.22


pyrimidin-5-amine (Vb)


(KBr) νcm-1: 3429, 3308, 2989, 2851, 1665,

1629, 1610; 1H NMR (500 MHz, DMSO-d6)

ppm: 4.11(t, J = 5.6 Hz, 2H), 4.59 (t, J = 5.7

Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 8.12 (s, 2H, NH2, D2O exchangeable), 8.18 (d, J

= 8.6 Hz, 2H), 8.21 (s, 1H); Anal. calcd. for C14H11Cl2N7 (%): C, 48.29; H, 3.18;

N, 28.16 Found C, 48.25; H, 3.15; N, 28.18.

NN

NN

N

NR

Cl

NH2

NN

NN

N

N

Cl

NH2

NN

NN

N

N

Cl

NH2

Cl

Chapter I


47


pyrimidin-5-amine (Vc)


(KBr) νcm-1: 3431, 3313, 2989, 2841, 1676,

1634, 1613; 1H NMR (500 MHz, DMSO-d6)

ppm: 3.99 (t, J = 6.2 Hz, 2H), 4.62 (t, J = 6.2 Hz,

2H), 7.41(dd, J = 7.5, 4.6 Hz, 2H), 8.02 (s, 2H, NH2, D2O exchangeable), 8.18 (s,

1H), 8.09-8.11 (m, 1H), 8.21 (d, J = 1.8 Hz, 1H); MS m/z: 332(M+), 336(M+4);

Anal. calcd. for C14H11Cl2N7 (%): C, 48.29; H, 3.18; N, 28.16; Found: C, 48.29;

H, 3.18; N, 28.16.


pyrimidin-5-amine (Vd)


(KBr) νcm-1: 3439, 3317, 2967, 2843, 1665, 1621,

1612; 1H NMR (500 MHz, DMSO-d6) ppm: 4.00

(t, J = 6.2 Hz, 2H), 4.63 (t, J = 6.2 Hz, 2H), 7.22–

7.41 (m, 2H), 7.38-7.59 (m, 1H), 7.89-8.01 (m, 1H), 8.08 (s, 2H, NH2, D2O

exchangeable), 8.16 (s, 1H); MS m/z: 332(M+), 336(M+4); Anal. calcd. for

C14H11Cl2N7 (%): C, 48.29; H, 3.18; N, 28.16; Found: C, 48.30; H, 3.16; N, 28.15.


pyrimidin-5-amine (Ve)


(KBr) νcm-1: 3421, 3312, 2967, 2849, 1667,

1637, 1609; 1H NMR (500 MHz, DMSO-d6)

p

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1.1 INTRODUCTION - INFLIBNET Centreshodhganga.inflibnet.ac.in/bitstream/10603/20755/7/07... · 2020. 4. 24. · Chapter I Synthesis of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amines