SYNTHESIS OF BIOLOGICALLY ACTIVE NITROGEN...

Chapter IV

MgO, a Reusable Catalyst For Greener

Synthesis of Pyranopyrazole In Water.

This work is communicated to Catalysis Letters

CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water

116

CHAPTER 4

MgO, a Reusable Catalyst For Greener Synthesis of Pyranopyrazole In Water.

4.1 INTRODUCTION AND LITERATURE SURVEY

Functionalized chromene and benzopyrans are important class of

heterocyclic compounds due to their broad spectrum of biological activity and

imply wide range of applications in medicinal chemistry. The benzopyran

moiety is found in variety of natural products. Many of these exhibit interesting

biological properties.[1-2]

Some of the naturally occurring products possessing benzopyran nucleus

are puupehedione [1] and related marine derivatives, puupehenone [2] and 15-

oxopuupehenol [3] exhibiting wide range of biological properties including

antitumor, antiviral, antimalerial, antibiotic antituberculosis, antioxidant,

insecticidal and antifungal etc. The scarce availability of many bioactive

compounds led to develop simpler and more accessible analogues for broad

biological evaluation. A. F. Barrero et al[3] devised a method to synthesize

pupupehedione analogue.

O

OO

[1]

O

OOH

[2]

O

OHOH

O

[3]

Some marine invertebrates anti-inflammatory sesquiterpenes containing

a pyranofuranones grouped into monoalide (1)[4] and cacospongionolide B3(2).

Monoalide inhibit PLA2, it is believed that α,β-unsaturated compound generated

by opening of pyranofuranone [4, 5] moiety reacts with lysine residue of PlA2


117

on other hand, cocospongionolide B(2), which lacks the hemiacetal function in

the pyran ring showed potent inhibitory activity on recombinant human

synovial PLA2. Margherita and co-workers have synthesized monoalide and

cocospongionolide B3 analogues and examined their anti-inflammatory activity

of natural sources.

OOH

OOH

O

[4]

OOH

O

H

[5]

Iolanta Nawrot-Modranka et al[5] have synthesized phosphohydrazine

derivatives [6,7] designated as an antitumor agents against p388leukemia and

LI120 murine leukemia.

O

O H

NN

P

H

SOR1

OR1

[6]

O

O

O

NNCH3

HP OR1

OR1

S

[7]

R1

= -C2H5, -CH3, -C2H5 ; R2 = -CH3, -CH3, -H.

Naturally occurring compounds containing fused pyran rings exhibit

molluscicidal activity. Bergapten [8], ricchiocarpin A [9] and ricchiocrpin B

[10], pyranopyrazole [11] are well known for their molluscicidal property.

Fathy M. Abdelrazek reported few pyran derivatives which are effective

against Biomphalaria alexandrina.[6] Mohamed I. Hegab derived some fused

polycyclic heterocycles starting with 4-chloro-2,2 disubstituted chromene-3-

carboxaldehyde [12]. The synthesized heterocycles showed considerable anti-

inflammatory, analgesic, anticonvulsant and antiparkinson activity.[7] By the


118

use of salicyaldehyde, M. Al Neirabeyeh and his group synthesized 3,4-

dihydro-3-(di-n propylamino)-2H-1benzopyrans [13] as new derivatives of

benzopyran for dopaminergic activity.[8]

O O O

O

[8]

O

O

O

[9]

O

O

O O

[10]

O NH2

NNH

CN

O

[11]

O

Cl

R1

R2

CHO

[12]

O

N

R1

R2

R3

R4 [13]

R1 = OH, H, H, H ; R2 = H, H, H, OH ; R3 = H, H, H, OH ; R4= H, OH, OH, 4.2 METHODS OF SYNTHESIS

Several methods for benzopyran synthesis have been reported by the

scientists around the word which involves one step as well as multistep

synthesis.

A tandem Wolff rearrangement with t-amino effect found an an

effective route for synthesis of benzopyran nucleus.[9] The thermal

decomposition of 1-diazo-2-oxo-(2-N, N–disubstituted aminomethyl)phenyl

ethylphosphonates [14] in toluene extruded 1H-2-benzopyran in good to


119

moderate yield. Formation of 1H-2-benzopyran [16] expected to take place

through ketene intermediate [15] followed by a [1,5] hydrogen shift and

subsequent ring closure of the pminium (Scheme 4.1).

O

N

P

N2

OMe

RR

OOMe

wollf transpositionN

P(O)(OMe)2

OH

RRl

N

P(O)(OMe)2

O

H

RR

-

i

O

NRR

P(O)(OMe)2

R [CH2]2CH3

R C6H5

12 1

2

[1,5] Shift

12+

21

1, R

2=

R1 =2 =

[14] [15]

[16]

Scheme 4.1

The utility of tetrathiafulvene (TTF) as a catalyst was demonstrated by

Nadeem Bashir and co-workers.[10] They synthesized tetrahydropyran [17] by

conversion of amine into tetrahydropyran through diazonium salt. This

transformation believed to take place via radical mechanism. In this reaction

the tetrathiafulvene acts as a weak nucleophile (Scheme 4.2).

O

N2

.

O

S

S

S

S

BF4

O

BF4

OOH

+ . .

.+

-

+

-

[17]Scheme 4.2


120

Cordiachromen, chemically named 6-hydroxy-2-methyl-2-(4-methyl

pent -3-en-1-yl)-2H-chromene [18] present in the cordia alliodora exhibited

anti-inflammatory activity. Samir bouzbouz et al[11] have synthesized

cordiochromene enantioselectively from chroman in four step involving

bromination, dehydrohalogenation, nucleophilic substitution reaction with

Grignards reagent and alkaline hydrolysis in aqueous ethanol (Scheme 4.3).

TsO

O

H

OTs

TsO

O

Br

OTs

TsO

O OTs

TsO

O

e

O

OH

O

H

a b c,d

[18]a)NBS (1 equiv.), K2CO3, C6H5CO3H, CCl4, reflux; b) pyridine, reflux. d)Bu3SnH, C6H6,

reflux. c) BrCH2CH=C(CH3)2, Mg, THF, -20oC d) Li2CuCl4, -70 oC e) KOH, H2O, H2O/EtOH,

reflux.

Scheme 4.3

Wide range of organic compounds of pharmaceutical importance found

through solid phase synthesis of benzopyrane reported by K. C. Nicolaou et

al.[12] The synthetic strategy behind this methodology is use of selenium bound

2,2-dimethylbenzopyrans [19], synthesized from selenium bound with ortho–

prenulated phenols. It undergoes condensation, annulation, glycosidation, aryl

coupling reaction to offer various lead compounds [20, 21, 22] (Scheme 4.4).

Same author employed selenium based solid phase synthesis of medicinally

relevant small organic molecules[13] from selenium bound 2,2-

dimethylbenzopyrans for different derivatives of pyran (Scheme 4.5) .


121

O

Se

GlycosidationO

SeSugar-X

Condensation

O

SeO

R

aryl couplingO

Se

R

O

SeO

R

benzopyran Scaffold[19]

Scheme 4.4

O

Se

NCO

RO

O

SeO

NH

R

Y XO

SeOH

Y X

CHO

COOEt

O

Se

O

O

O

O

NH

R

Y XO

OH

O

O

benzopyran Scaffold

30 min, 25 C

25 C 12 h

a

a

a

[20]

[21]

[22]

Scheme 4.5

Bjorn C. G. Soderberg et al[14] have prepared isomeric mixture of 5-nitro-1-

benzopyrans (Scheme 4.6) [24, 25, 26] starting from 2-bromo-3- hydroxy-1-


122

nitrobenzene [23] by O-alkylation with 1-bromo-3-butene. Intramolecular Heck

reaction extrudes the mixture of isomeric 5-nitro-1-benzopyrans in 60 %, 15 %

and 3 % yield respectively. These mixture underwent N-heteroannulation

resulting in the formation of 3, 4 -fused indoles (Scheme 4.6).

Br

OH

NO2

Br

KOH, NaI, DMSO

O

Br

NO2

Pb(OAc)2, Et3N

P(o-Tol)3

O O

NO2

O

NO2

+ +

[23] [24] [25] [26]

Scheme 4.6 Biomolecular cyclization reaction between salicyaldehyde with

conjugated olefins such as acrylate derivatives or α,β-unsaturated ketene

resulting to form different substituted chromene [28] is quite routine, Min Shi

[15] demonstrated reaction of salicylaldehyde with allenic ketone [27] and ester

under basic condition. A systematic study of this reaction catalyzed by various

bases including K2CO3, KOH, PPh3, DABCO and DMAP in a variety of

solvents concluded that K2CO3 system gives good yield of the product

(Scheme 4.7).

O

H

OH

R

O

R

RCBU

DMSOO

R

O

ROH

R

R H, Me, OMeCl, Br etc

R = Me, Bn

R =Me, OMe

+1

2

310mol %

1

2 3

1=

2

3

[27] 28 ][

Scheme 4.7

A series of benzo[c]chromen-6-ones [31] prepared by a Suzuki coupling

and lactonisation reported by Geradus J. Kemperman et al.[16] The starting

compounds in this reaction were 2-methoxyphenylboronic acids [29] and

methyl 2-bromobenzoate [30] derivatives. The ionic liquids [BMIm][PF6],

[Bmim][Al2Cl7] accelerates the rate of reaction (Scheme 4.8).


123

B(OH)2

OMe Br

COOMe

Pd(PPh3)4

aq.Na2CO3O

[BMIM][PF6]

OMe

MeO2C

KOHEtOH

reflux

OMe

HOOCreflux

SOCl2

CH2Cl2

AlCl3

O O

+

100 C

1

2. [29] [30]

[31]

Scheme 4.8

In recent years resin catalyzed reactions have gained valuable synthetic

importance. Various report on Amberlyst, dowex catalyzed reactions were

found in the literature. Enrique Alvarez-Manzaneda described an

enantiospecific route towards the cationic resin promoted Friedel–Craft

alkylation of alkoxyarenes with α,β-unsaturated ketone [32], further reaction of

ketone with 3,4-methylenedioxyphenol offers corresponding chromene [33] [17]

(Scheme 4.9).

OO

O

OH

Amberlyst A-

molecular sieves,benzene,reflux,

O

OO

+15, 4A

1 h 40 min. [33][32]

Scheme 4.9

Previous report describe two component coupling between

salicyaldehyde and allenic ketones/ester .Yong–Ling Shi et al[18] have reported

the chromene synthesis by replacing salicyaldehyde by salicyl N-tosylamines

[34], which on reaction with acetylenecarboxylate ester [35] in the presence of

DABCO as catalyst (Scheme 4.10). The resultant substituted benzopyran [36]

obtained at 80 0C temperature in dichloromethane.


124

OH

R

R

R

NTs

COOMeDABCO,

O

O

R

R

RNHTs

COOMe

CH2Cl2,1

2

3

+25 mol %

80 C1

2

3

[34] [35] [36]

Scheme 4.10

Phenylene linked bis-naphthopyrans were synthesized in good yields via

the one pot reaction of bis-propargyl alcohols [37] with naphthols. These

synthesized pyrans [38] exhibited temperature dependant photochromism [19]

(Scheme 4.11)

OO

PhPh

sodium acetylide,

DMSO, C2H2, OHOHPhPh

(4 equiv.)

23 C, 2-3 ho

[37]

(MeO)3CH,PPTS(CH2Cl)2,reflux,

OPh

O

Ph

OHOHPhPh

2-naohthol2.2-3 equiv.

4 equiv.

5-8 h

[38] Scheme 4.11

Annamaria Deagostiono et al[20] synthesized benzopyrans starting from

dienylboronates and 2-iodophenol in the presence of a Pd catalyst. The reaction

marches through the cross coupling intermediates which cyclizes to the

chromene derivatives, which on hydrolysis offers 2, 2-dimethylchromen-4-one

[39], which is known to be an important building block for the synthesis of

many important pharmaceuticals. (Scheme 4.12)


125

B

R

ROO

OEt

INHPG

PdCl2(PPh3)2, THF

K2CO3,R

OH

OEt

HOH

R

i

-HO

OEt

H O

H

OR

O

R = H, MeR =H, H, Me

1

2

+

50 Co

+

+1

+2

+1

1

2

[39]

Scheme 4.12

An enantioselective Oxa-Michael–Henry reaction of substituted

salicyldehyde with nitro olefins [40] that proceeds through an aromatic

iminium activation (AIA) has been developed using a chiral secondary amine

organocatalyst and salicylic acid as a co-catalyst. The corresponding 3-nitro-

2H-chromene [41] were obtained in moderate to good yields under mild

conditions, reported by Dan-Quin xu et al.[21] Different amine were screened

for their catalytic activity. Amongst them pyrrolidine thioimidazole is the most

effective catalyst in terms of stereo control (Scheme 4.13).

O

H

OHO

NO2

O

NO2

OSalicylic acidDMSO,r.t.

+

20 mol % pyrrolidine thioimidazole

[40] [41]

Scheme 4.13

An effective enantioselective access to benzopyran [44] was given by

Magnus Pueping[22] et al by reaction between cyclic 1,3-diketone [42] and α,β -


126

unsaturated aldehyde [43] in the presence of organocatalyst, diarylprolinol silyl

ether. The reaction offered good enantioselectivity in dichloromethane at 10 oC

(Scheme 4.14).

O

O

O

H

Ph

NH

ArAr

OTMS

Dichloromethane O

O Pr

OHAr =PhAr = -(CF3)-Ph

+

3,5 [42] [43] [44]

Scheme 4.14

Liang-Yeh chen et al[23] have introduced a novel carbanian-olefin

intramolecular cyclization where 2-aroyl-3, 4–dihydro-2H-benzopyrans [45]

obtained from salicyaldehyde. It is based on strategy that salicyaldehyde

underwent Wittig reaction with methyltriphenylphosphonium bromide

(MTPPB) and potassium tertbutoxide as base and subsequent reaction with 2-

bromoacetophenone without isolation, afforded condensation product which

again on heating with tert-butoxide yielded benzopyran (Scheme 4.15).

OH

CHO

CH3 P(Ph)3

tert BuOk

THF, rt,OH

OBr

reflux

OO

tert-BuOK

OO

++

1 h+

[45]

Scheme 4.15


127

Mechanism

OO

tert-BuOK

OO

H

OBu tert tert BuOH

OO

-

OO

- K

OO

tert BuOH

+

tert-BuOH

+

Solvent free and catalyst free organic synthesis is most demanded

synthetic approach. One pot synthesis of 3, 3`-(benzylene)-bis (4-hydroxy-2H-

chromene-2-one) [46] derivatives have been synthesized by Shaterian Hamid

Reza et al[24] through the coupling of aldehydes and 2 mol. equivalent of 4-

hydroxycoumarine. The reaction proceeds at 130 oC without use of any

externally added catalyst. The product obtained in an excellent yields (Scheme

4. 16).

CHOX

O O

OH

Solvent free

O O

OH

O

OH

+ 2catalyst free

[46]

Scheme 4.16

Electrochemically induced multi-component condensation[25] of

resorcinol, malononitrile and various aldehydes in propanol in an undivided

cell in the presence of NaBr as an electrolyte results in the formation of 2-

amino-4H-chromenes reported by S. Makarem et al.[26]


128

All methods discussed above has its own merit but overled by long

reaction time, use of costly reagent and lack of reusability of the catalyst. As

far as greener methodology is concern, the solvent is at centre point. Therefore

use of nontoxic, nonflammable, non-volatile solvent has prime importance.In

recent years ionic liquids, supercritical fluids are some alternatives but water is

the best among them because it is cheap, easily available, non-toxic, non-

flammable and non-volatile.

4.2 PRESENT WORK

Pyranopyrazole is one of the important pyran derivatives. Which exhibit

molluscicidal activity. Very few methods have been reported in the literature

for its synthesis. Routine method describe its synthesis involving reaction

between pyrazole derivative and cyanoolefins formed by Knoevenagel

condensation between aldehydes and malononitrile under basic condition. The

limitation of this method is that both reactant coupled in this reaction requires

more time for condensation. However, this problem could be solved by one

step multicomponent synthesis to some extent. Gnanasambandam Vasuki et al

have demonstrated four component one step synthesis of pyranopyrazole by

condensation of ethylacetoacetate, hydrazine hydrate, arylaldehyde and

malononitrile in water at room temperature, using piperdine as base. Reaction

took place at room temperature. In recent years, MgO successfully catalyzed

organic reactions altering the use of organic bases like piperidine, morpholine,

trimethylamine etc. MgO is non toxic inorganic base required in catalytic

amount and can be reused. Taking into account the merits of MgO, we decided

to explore catalytic efficiency of MgO for synthesis of pyranopyrazole [51] by

condensing hydrazine hydrate [47], ethylacetoacetate [48], arylaldehyde [49]

and malononitrile [50] (Scheme 4. 17).


129

NH2

NH2O O

OAr

O

H

CN

CN

MgO

Water

ONH

N NH2

CN+ +

20 mol %

50 Co

[47] [48]

[49]

[ 50 ] [51]

Scheme 4.17

4.4 RESULT AND DISCUSSION

In initial attempts, ethylacetoacetate, hydrazine hydrate was stirred for 5

min. then aldehyde, malononitrile and catalytic amount of MgO were added in

water and the reaction mixture stirred at room temperature. It was found that

reaction between ethylacetoacetate and hydrazine hydrate occurred under

catalyst free condition, forming water soluble pyrazolone. After stirring for one

hr. the progress of reaction was examined by running TLC of reaction mixture,

which indicated the formation of pyranopyrazole along with unreacted

cynoolefine. After continuous stirring for few hours, desired condensation

product, pyranopyrazole wasn’t obtained considerably. Moreover, increased

catalytic quantity of MgO over 20 mol % and continous stirring the reaction

mixture was failed to emit a satisfactory yield. Therefore, attempts were made

to modify the thermal conditions of reaction which might be a hurdle for

progress of reaction towards formation pyranopyrazole. In next experimental

trial a mixture of ethylacetoacetate, hydrazine hydrate, benzaldehyde and

malononitrile in equivalent amount was stirred in preheated oil bath at 80 oC.

We noticed that cyanoolefin and pyrazolone get consumed but some side

reaction product was observed along with pyranopyrazole on TLC. In

optimization of thermal condition, we tried the reaction at 50 oC with stirring

and the progress of the reaction was examined by TLC. After 1 hr it was

observed that reaction went on completion without formation of any side

reaction. Finally reaction mass was filtered at the pump. The separated catalyst


130

was recycled three time without loosing its catalytic activity. The purified

sample matched with the physical constant reported in literature. The IR

spectrum exhibited bands at 3540 cm-1 for N-H stretching, 3370, 3210 cm-1

asymmetric and symmetric stretching frequency for primary amino group,

medium intensity band at 2199 cm-1 for -CN group. The 1H NMR showed

expected signal at δ 5.5 for methine proton and protons of primary amino group

as broad singlet at δ 4.2. The remaining protons of the structure appeared in the

aromatic region in the form of multiplet. This result encouraged us to extend

this protocol for variety of aldehydes bearing an electron donating and

withdrawing groups in them. (Table 4.1).

The aryl aldehyde with an electron donating group took longer reaction

time as compared to electron withdrawing groups on arylaldehydes. In an

efforts to minimize the amount of MgO, 20 mol % of MgO was sufficient for

completion of reaction. Increasing the amount of MgO over 20 % does not

affect on yield and time of the reaction considerably (Table 4.2).

One important aspect of this methodology is the survival of the

functional groups like –OH, -CH3, -NO2 present on arylaldehyde. All the

compounds were obtained in an excellent yields. The recrystalization of the

product in ethyl alcohol gives analytically pure pyranopyrazoles. Other basic

catalysts like K2CO3, DABCO showed less catalytic activity giving lower yield

under identical conditions for this reaction.

The plausible mechanism involving the formation of pyrazolone [52]

and cynoolefin [53] through the reaction between hydrazine hydrate and

ethylacetoacetate and aldehyde and malononitrile. The Michael addition of

active methylene group of pyrazolone to an electron deficient carbon of

cyanoolefin gives an intermediate [54] which rearranges to give targeted

pyranpyrazole (Scheme 4.18).


131

NH2

NH2

O O

O

Ar

O

HCN

CN

NH

NO

Ar

N

CN

NH

N

Ar

O

CN

N

HHNNH

O NH2

CNAr ON

NNH

CNHH

-

+

+

[52]

Pyranopyrazole

[53]

[54]

Scheme 1.18


132

Table 4.1 Reaction time and yield of Pyranopyrazoles.

Entry Compound Time (min) Yielda

%

1.

ONH

N NH2

CN

55

88

2.

ONH

N NH2

CN

OH

110

85

3.

ONH

N NH2

CN

NO2

50

90

4.

ONH

N NH2

CN

Cl

30

95


133

Entry Compound Time (min) Yield (a)

(%)

5.

OH

ONH

N NH2

CN

85

88

6.

ONH

N NH2

CN

No2

40

92

7.

ONH

N NH2

CN

Cl

85

88

8.

ONH

N NH2

CNCl

40

90

9.

ONH

N NH2

CN

NO2

45

87

10

Me

ONH

N NH2

CN

150

79


134

11.

O

NHN NH2

CN

OMe

145

75

a -refers to pure isolated compounds.

Table 4.2 Effect of catalyst amount of on MgO the yield of

pyranpyrazole.

4.5 SPECTRAL ANALYSIS

The structures of synthesized compounds (Table 4.1, Entry 1-5) were

confirmed on the basis of IR, 1H and 13C NMR and mass spectroscopic data.

The spectroscopic data were in full agreement with the literature values.

In 6-amino-3-methyl-4-phenyl-2,4dihydropyrano[2,3-c]pyrazole-5-

carbonitrile, (Table -4.1, entry 1) the IR spectrum shows band at 3373, 3310

cm-1 are due to asymmetric and asymmetric stretching of free primary amino

group and a band at 2192 cm-1 for cyano stretching frequency (Spectrum 4.1). 1H NMR spectrum of same compound exhibits a singlet resonate at δ 1.763 for

methyl protons linked to pyrazole ring and a sharp singlet for one methine

proton appeared at δ 4.575 and a broad singlet for amino protons resonate at δ

6.868 While aromatic protons gave downfield shift in form of multiplet

between δ 7.3-7.1. The NH proton of pyrazole ring is strongly deshielded

observed at δ 12 .096 (Spectrum 4.2). In 13C NMR (Spectrum 4.3) following

peaks were observed at δ 10.17, 36.67, 57.64, 98.09, 121.24, 127.19, 127.91,

Amount of MgO

(mol %)

5 10 15 20

Yield in (%)

55

67

80

91


135

128.89, 136.03, 144.89, 155.21, 161.31. The mass spectrum exhibited spectral

lines at (m/z) 253 (M+), 226, 187, 170, 146, 142, 129, 115 (Spectrum 4.4).

The IR spectrum of 6-amino-3-methyl-4-[4-hydroxyphenyl]-2,4-

dihydropyrano[2,3-c]pyrazole-5-carbonitrile (Table 4.1, entry 2) exhibit sharp

peak at 3500 cm-1 due to for N-H broad stretching band at 3465 cm-1 for -O-H.

A sharp doublet encountered at 3390, 3300 cm-1 due to asymmetric and

symmetric stretching of primary amino group. Intense peak at 2176 cm-1 is for -

CN group (Spectrum 4.5). The 1H spectrum of the same compound showed

singlet at δ 1.766 for methyl protons attached to pyrazole ring whereas the

methine protons appeared as singlet at δ 4.454. The four aromatic protons of

phenyl ring gave a two sets of doublets encoutetred at δ 6.684 (J =8.4 Hz) and

δ 6.949 (J =8.4 Hz). A broad singlet at δ 6.785 is due to two protons of amino

group. The two singlet appeared at δ 9.297 and 12.049 for -OH and NH proton

(Spectrum 4.6). The 13C NMR of same compound exhibited peaks at δ 10.19,

35.91, 58.22, 98.50, 115.55, 121.35, 128.88, 135.20, 135.97, 155.19, 156.45,

161.07 (Spectrum 4.7). The mass spectrum exhibited lines at (m/z) 268 (M+),

242, 202, 186, 175, 160.(Spectrum 4.8).

IR spectrum 6-amino-3-methyl-4-[3-nitrophenyl]-2,4dihydropyrano[2,3-

c]pyrazole-5-carbonitrile (Table 4.1, entry 3) showed a band at 3474 cm-1 for

N-H stretching whereas asymmetric and symmetric band for amino group

attached to the ring were observed at 3223, 3118 cm-1. A intense peak at 2195

cm-1 is due to the presence of –CN. The band for –NO2 stretching observed at

1492 cm-1(Spectrum 4.9). The 1H NMR of same compound showed a single at

δ 1.788 for three protons of methyl group attached to pyrazole ring. Singlet at δ

4.862 is due to methine proton, whereas a triplet and multiplet at δ 7.653 and

8.131 for two protons each. A broad singlet observed at δ 7.045 for amino

group protons and a sharp singlet at δ 12.209 for N-H proton of pyrazole ring

(Spectrum 4.10). 13C NMR spectrum showed the signal peaks at δ 10.19,

36.08, 56.59, 97.11, 122.28, 122.44, 130.71, 134.84, 136.37, 147.26, 148.34,


136

161.59 (Spectrum 4.11). The mass spectrum showed spectral lines at (m/z)

298, 232, 216, 186 (Spectrum 4.12).

IR Spectrum of 6-amino-3-methyl-4-[4-chlorophenyl]-2,4-dihydro-

pyrano[2,3-c]pyrazole-5-carbonitrile (Table 4.1, entry 4) showed a band at

3373, 3311 cm-1 for -NH2 The sharp peak observed at 2193 cm-1 for –CN

group (Spectrum 4.13). In PMR spectrum, methyl protons attached to pyrazole

ring resonated at δ 1.776 whereas a singlet encountered at δ 4.619 for methine

proton. Two doublets observed at δ 7.194 (J =8.4 Hz) and 7.377 (J=8.4 Hz) for

aromatic protons. Amino protons observed as broad singlet at δ 6.923 as broad

singlet. NH proton of pyrazole ring appeared at δ 12.185 (Spectrum 4.14). 13C

NMR spectrum for the said compound showed the signal at δ 10.18, 36.00,

57.21, 97.61, 121.10, 128.90, 129.81, 131.67, 136.15, 143.93, 155.12, 161.35

in good agreement with the literature data(Spectrum 4.15). In mass spectum of

the compound, spectral lines observed at (m/z) 286 (M+), 260, 221,204, 185,

178, 129 (Spectrum 4.16).

The IR spectrum of 6-amino-3-methyl-4-[3-hydroxyphenyl]-2,4-dihydro-

pyrano[2,3-c]pyrazole-5-carbonitrile (Table 4.1, entry 5) showed a peak at

3407 cm -1 for the -O-H stretching. Two sharp peaks at 3362-3332 cm-1 for

amino group and cyano group appeared at 2177 cm-1(Spectrum 4.17). 1H

NMR spectrum of same compound (Spectrum 4.18) has a sharp singlet at δ

1.805 indicating the presence of methyl group attached on aromatic ring of

pyrazole, singlet at δ 4.472 is due to methine proton. The aromatic protons

appeared at δ 6.523-6.617 and 7.057-7.109. The amino protons appeared as

broad singlet at δ 6.8. The phenolic O-H proton appeared at δ 9.318. while N-H

proton at δ 12.087. The 13C NMR of same compound exhibited peak at δ 10.22,

36.61, 57.72, 98.14, 114.29, 114.58, 118.64, 121.28, 129.73, 136.05,146.42,

155.19, 157.87, 161.29 which confirm the structure of desired compound

(Spectrum 4.19).The mass spectrum showed spectral lines observed at (m/z)

268 (M+), 252, 242, 203, 187, 175 (Spectrum 4.20).


137

4.6 EXPERIMENTAL

Materials and Methods.

All aryl aldehydes, ethylacetoacetate, hydrazine hydrate and

malononitrile were purchased from S. D. fine and spectrochem Co. and were

used without further purification.

Instrumental details and their operational conditions

NMR analysis.

NMR analysis was performed on Brucker–Avance 300 MHz, NMR

spectrophotometer. For 1H NMR analysis, DMSO was used as solvent and

tetramethylsilane as an internal standard, the chemical shifts are reported in

ppm. Multiplicities are indicated by ‘s’ (singlet), ‘d’ (doublet), ‘t’ (triplet), ‘q’

(quartet), ‘m’ (multiplet) and ‘bs’ (broad singlet). The coupling constant (J) are

reported in Hz.

IR Analysis

Infrared spectra were recorded on Perkin Elmer 1310 FT-IR spectrometer with

KBr pellets.

LCMS Analysis

LCMS analysis was performed on Mass pectromete –API 5500Qtrap (Applied

biosystems, Canada). The column used for analysis were, Atalantis dC18

(100mmx2mmx5um) Waters India Pvt Ltd, Bangalore. The mobile phase used

for sample is: 5mM ammonium formate in methanol 5mM ammonium formate

in water and flow rate was 0.4mL /min.

General Experimental procedure A mixture of ethyacetoacetate (1mmol) and hydrazine hydrate (1mmol)

were stirred in 10mL of water for 10 min. then arylaldehyde (1mmol),

malononitrile (1mmol) and 20 mol % MgO were added and the reaction was

mixture stirred at 50 oC for appropriate time on an oil bath. The product formed

was isolated by simple filtration and further purified by recrystalization to

separate desired pyrano[2,3-C]pyrazole in high yield.


138

4.7 CONCLUSION

We have reported a simple, ecofriendly and elegant protocol for the

synthesis of pyrano[2, 3-c]pyrazole through one step four component coupling

using magnesium oxide as a solid reusable and basic catalyst. The reaction

proceeds efficiently in water without any use of flammable, volatile organic

solvent. As reaction occurs in the water it excludes the cumbersome separation

methods and hence it avoids use of the harmful solvents. Therefore the use of

MgO as a catalyst renders this method environmentally benign.


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