Chapter 2 A clean, benign, catalyst free and Green...

Chapter 2 Pyrano[2,3-c]pyrazoles…

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Chapter 2 A clean, benign, catalyst free and Green Chemistry approach towards the synthesis of pyrano[2,3-c]pyrazoles and their biological evaluation 2.1 Introduction Concerns about the environmental impact of the growth of human society have

nowadays become ubiquitous and sustainability has emerged as a prior issue in every

area of human activity. The chemical industry is a major player in human

development and, unsurprisingly, an increased pressure has been put on chemists to

develop sustainable processes. In this context, the concept of Green Chemistry has

been defined as the design of chemical products and processes to reduce or eliminate

the use and generation of hazardous substances and was developed in principles to

guide the chemists in their search towards greenness [1].

In particular, the use of solvents is a constant source of worry since it gives

rise to toxicity, hazard, pollution and waste treatment issues. Moreover, solvents

generally account for the major source of the wasted mass of a given process or a

synthetic pathway [2]. From a strict green chemistry point of view, the best answer to

this problem would be to run the reactions under neat conditions, i.e. without any

solvent. However, running a reaction in a solvent is often essential to facilitate mass

and heat transfer. In addition, the appropriate choice of the solvent allows the reaction

rates, the selectivities and the position of chemical equilibria to be acted upon [3].

Consequently, many efforts have been devoted to the finding of sustainable

reaction media, and notably the use of water as solvent has attracted much interest in

recent years [4-12]. Indeed, water offers many advantages because it is a cheap,

readily available, non-toxic and non-flammable solvent, thus being very attractive

from both an economical and an environmental point of view. At first sight, water

appears as a poor solvent for organic transformations due to the low solubility of

organic compounds in water and since it has long been considered as a contaminant.


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But it is now well established that the unique structure and physicochemical

properties of water lead to particular interactions like polarity, hydrogen bonding,

hydrophobic effect and trans-phase interactions that might greatly influence the

reaction course. However, running a reaction in water instead of an organic solvent

does not necessarily improve the environmental impact of the synthetic sequence

since many other parameters must be considered, such as atom efficiency, yield,

workup and purification processes, for example.

The present review has a twin objective, aiming to show, through

representative examples, not only the broad scope of reactions that can be conducted

in water, but also that the use of water can lead to additional sustainability benefits

which enhance the overall environmental impact of a given process.

2.2 Enhancement of reactivity and selectivity Improving the rate and the selectivity of a reaction affects importantly its

sustainability since it may allow shorter reaction time, lower temperature, lower

catalytic loadings, better yields and easier purification. In fact, the emergence of the

use of water as a solvent for organic reactions was probably impulsed by the work of

Breslow in the 1980s on the substantial rate enhancement of Diels–Alder reactions

conducted in water compared to in other organic solvents [13]. In these studies, he

observed that the cycloaddition of butenone and cyclopentadiene was 740 times faster

in water than in isooctane and that an increased selectivity could be obtained with

water (endo/exo = 21.4) compared to the same reaction in cyclopentadiene (endo/exo

= 3.85). It was all the more remarkable that the use of protic polar solvents like

methanol or ethanol led to similar results to those obtained with hydrocarbon solvents.

These observations were rationalized by the hydrophobic effect [14].

This property of water comes from the repulsive interactions between

hydrophobic molecules and water, which leads to the formation of hydrophobic

aggregates that allow reducing the contact surface between them. To maintain the

network of hydrogen bonds (related to its high cohesive energy density), water wraps

itself around these aggregates, thus acting as an internal pressure4 which accelerates

reactions with negative activation volume, like Diels–Alder reactions. In some cases,

the rate enhancements may also originate from interfacial interactions between the


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organic molecules (notably the transition states) and some free hydroxyl groups of

water [15].

+ N

N

CO2Me

CO2Me

RT N

N

CO2Me

CO2Me

Solvent Time to Completion

Toluene

Ethyle Acetate

Acetonitrile

Dichloromethane

Dimethyl Sulpoxide

Methanol

Neat

Perfluorohexane

D2O

Water

>120h

>120h

84h

72h

36h

18h

48h

36h

45min

10min

Figure 2.1 Time to completion for the cycloaddition of quadricyclane with azodicarboxylate

Sharpless et al. recently defines as ‘‘on water’’ conditions using water as

solvent for the reaction of water insoluble reactants [16]. In particular, his group

reported a very demonstrative example of the acceleration of the reaction rate ‘‘on

water’’ with the reaction of quadricyclane and dimethyl azodicarboxylate (Figure

2.1). The time to completion was measured in a broad variety of solvents and it

clearly appeared that not only the dipolar effect and hydrogen bonding enhance the

reaction rate (18 h in methanol compared to 36 h in DMSO, 72 h in dichloromethane

or more than 120 h in toluene), but heterogeneity also played an important role in

large rate acceleration with only a 10 min reaction time in water. In comparison, the

reaction conducted under neat conditions requires 48 h to reach completion.

Interestingly, when D2O is used as solvent, the reaction time increased to 45 min

which may be due to a reduction of the hydrophobic effects and a higher viscosity that

prevents a good mixing of the heterogeneous mixture [17].

Another impressive result on cycloaddition rate acceleration was reported by

the group of Engberts in their study of the Diels–Alder reaction of cyclopentadiene

and 3-aryl-1-(2-pyridyl)-2-propen-1-ones (Figure 2.2) [18]. They showed that the


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reaction carried out in water as solvent was 287-fold faster than the same reaction in

acetonitrile.

N

O

NO2

+25 °C

O N

NO2

Conditions krel

Acetonitrile

Water

Cu(OSO3C12H25)2

1

287

1.8.106

Figure 2.2 Influence of water and catalysis in the rate increase of a Diels-Alder reaction

In addition, they found that the reaction in water, combined with the use of

Lewis acid and micellar catalysis, was accelerated by a factor of 1 800 000 compared

to the reaction in acetonitrile.

N C i-Bu

HO

HO

O

+

Solvent, 25 °C O

OHN

i-Bu

O

Solvents Time (h)

Dichloromethane

Dimethylformamide

Methanol

Water

18

24

24

Conversion

50

15

0

3.5 100

Figure 2.3 Influence of solvent on Passerini reaction

Considering that reactions with negative activation volumes are likely to be

accelerated in water, the group of Pirrung studied the influence of solvent on

multicomponent transformations like Ugi and Passerini reactions [19, 20]. Indeed, as

Multicomponent reactions consist of the reaction of three or more starting materials to


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form a single product, they involve transition states resulting from the condensation of

several molecules and are therefore predicted to have negative activation volumes.

They initially studied the Passerini reaction of 3-methylbut-2-enoic acid, 3-

methylbutanal and 2-isocyano-2-methylpropane in several solvents (Figure 2.3).

They reported that dichloromethane allowed the formation of the product with a 50%

yield after 18 h, whereas no product was obtained in methanol and only a 15% yield

was observed in dimethylformamide. In contrast, the use of water furnished the

expected product quantitatively within 3.5 h. Moreover, the reaction could even be

sped up by conducting the reaction in water containing additives that increase the

hydrophobic effect, like lithium chloride (16-fold acceleration) or glucose (7-fold

acceleration).

Examples of the improvement of reactivity in aqueous media for reactions

involving free radicals have also begun to emerge recently since the strong oxygen–

hydrogen bonds of water make it a very suitable solvent for these reactions [21]. For

instance, Oshima and co-workers studied the metal free carbon-carbon bond

formation through the iodine transfer cyclization of a-iodoacetates (Figure 2.4) [22].

Solvent Yield (%)

Hexane

Benzene

Dichloromethane

Tetrahydrofuran

Acetonitrile

Methanol

Ethanol

Dimethyleformamide

Dimethyl Sulphoxide

Water

<1

<1

<1

<1

13

6

3

13

37

78

O

OI Et3B 10 mol%traces O2

Solvent, RT, 3h O

O

I

Figure 2.4 Effect of the solvent on the radical-mediated formation of lactones

In many organic solvents such as hexane, benzene, dichloromethane or

tetrahydrofuran, the use of triethylborane as a radical initiator at room temperature

could not afford the formation of the lactone. However, under the same conditions,


29

the product was obtained with a good 78% yield in water whereas low yields were

obtained in other polar solvents such as acetonitrile, alcohols, dimethylformamide or

dimethyl sulfoxide. Interestingly, these conditions were successfully applied to the

formation of medium and large rings (up to 18-membered ring).

In some cases, water can improve the yield not only through the acceleration

of the reaction but also because it eliminates or reduces side reactions. This concept

was pertinently applied at the industrial level by Novartis for the synthesis of 1-

substituted- 4-cyano-1,2,3-triazoles from 2-chloroacrylonitrile and organic azides

[23]. In this transformation, the 1,3-dipolar cycloaddition is followed by an

aromatization which generates hydrogen chloride as a by-product and the main

challenge is that 2-chloroacrylonitrile is known to polymerize under both acidic and

basic conditions. In organic solvents (Figure 2.5), the hydrogen chloride released

raises the acidity of the reaction mixture, thus favoring the polymerization of the

olefin and decreasing the yield of the product, and high dilution or excess of this

reagent has to be used in order to obtain good yields. In this context, the use of water

turned out to be a very convenient and sustainable alternative since it enabled the

reaction to take place in the organic phase while the generated hydrogen chloride was

solubilized in the aqueous phase allowing minimization of the polymerization of the

alkene.

Solvents Yields (%)

n-Haptane

Toluene

Dimethylformamide

Ethanol

Neat

Water

46

51

78

40

F

N3

F

Cl

CN+

Solvent

F

N NN

FCN

72

98

Figure 2.5 Beneficial use of water in the synthesis of triazole from azides and 2-chloroacrylonitrile.

80 °C, 24h

Selectivity is also a very important parameter for sustainability since a non-

selective transformation increases the environmental impact of a given organic

reaction not only through the wasted mass of the by-products but also through the

higher complexity of the purification steps.


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The nucleophilic opening of epoxides is a commonly used reaction in the

synthesis of natural products and the selectivity of this reaction represents an

important issue. The use of water as solvent in these reactions is being more andmore

described [24]. Recently, the group of Azizi reported that b-aminoalcohols could be

synthesized in high yields from the reaction of epoxides and amines in water at room

temperature (Figure 2.6) [25]. In most cases, a total regio- and stereoselectivity was

obtained. In the case of styrene oxide however, both the regioisomers were formed

but their yields and proportions were maximized in water compared to other organic

solvents.

O

R1

+ R2R3NH

Water, RT5-24h

R1

OH

NR2R3 + R1

NR2R3

OH

Yield (Selectivity)

N

OH

N

OOH

PhOHN

OH

PhN

OH

96% (100:0) 97% (100:0) 90% (100:0) 92% (76:24)

Figure: 2.6 Formation of β-aminoalcohols through the ring opening of epoxides in water

In 2005, the group of Kobayashi studied the asymmetric desymmetrization of

meso-epoxides with amines catalyzed by a chiral scandium complex [26]. They

showed that the reaction of aromatic epoxides with anilines led to a higher

enantiomeric excess in water compared to dichloromethane or THF/water mixtures

(Figure 2.6). In addition, the use of scandium tris(dodecylsulfate) instead of scandium

triflate resulted in a better yield and enantiomeric excess, and these conditions were

consequently successfully applied to a wide range of substrates, though the reaction is

limited to aromatic amines.

In the field of organocatalysis, water is also being more and more investigated

as a valuable solvent [27, 28], although its effects on the reaction mechanism are not

necessarily well understood and still under study and discussion [29, 30]. In 2010, the

group of Zhong reported a one-pot organocatalyzed synthesis of substituted

tetrahydronaphthalene isoxazolidines (Figure 2.7) [31].


31

Solvents

Dichloromethane

THF/Water (9:1)

Water

Water

Yields (%)

85

<5

15

89

ee (%)

74

71

85

91

O

Ph

Ph+ PhNH2

N N

HOOH 1.2 mol%

Water, RT

NHPh

PhPh

HO

Sc(OTf)3

Sc(III)

Sc(OTf)3

Sc(OTf)3

Sc(OSO3C12H25)3

Figure 2.7 Effect of the solvent on the scandium-catalyzed asymmetric desymmetrization of epoxides

This transformation allowed the diastereo- and enantioselective formation of

five stereogenic centers through a Michael addition/intramolecular [3+2] nitrone-

olefin cycloaddition sequence.

NO2

O

OEt

+ O

NH

OTMS

PhPh

RCO2H 20mol%

Water, RT, 5hPhNHOH 4 eq.

ON Ph

O

EtO

O2N

Solvents

Hexane

Dichloromethane

Water

Water

Yields (%)

35

71

56

67

dr

72:28

68:32

92:8

92:8

none

R

CH3

CH3

Ph

ee (%)

>99

>99

>99

>99

Figure 2.8 Role of the solvent in the one-pot formation of substituted tetrahydronaphthalene


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During their optimization of the reaction conditions, the authors investigated

several solvents and water afforded the best selectivities compared to hexane or

dichloromethane (Figure 2.8). The use of a carboxylic acid as an additive was

essential to obtain good conversions probably because it promoted both the enamine

formation and the hydrolysis of the iminium ion to complete the catalytic cycle.

2.3 Workup improvement Even though the use of water as the reaction medium in a given reaction is

advantageous because of no toxicity and is hazardless, it does not necessarily allow us

to eliminate organic solvents from the whole process. Indeed, the workup procedure,

through extractions or chromatography purifications for instance, may be responsible

for the consumption of a huge amount of solvent relative to the recovered mass of the

product.

The group of Hayashi developed an efficient organocatalyst, combining both

siloxy and tetrazole functional groups within a pyrrolidine scaffold, for the

organocatalyzed asymmetric Mannich reaction of several ketones with

dimethoxyacetaldehyde and p-anisidine (Figure 2.9) [32]. Practically, an aqueous

solution of the aldehyde was used and no additional amount of water was necessary to

obtain good yields and selectivities. This enables to charge directly the crude mixture

on a silica gel column for chromatography, thus bypassing the extraction step.

OMe

NH2

HMeO

OMe

O O

60% in water

+

NH

TBDPSO

NH

N

NN

10 mol%

0 °C, 25h

Directly chargedon silica gel

MeO

NH

MeO

OMe

O

Figure 2.9 Extraction free organocatalyzed asymmetricMannich reaction

78%syn:anti = 10:1

95% ee

Luo and co-workers reported an aqueous asymmetric Michael addition

between nitrostyrenes and cyclohexanone using a surfactant type chiral organocatalyst

(Figure 2.10) [33]. They could run the reaction at room temperature without any


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additional additive and the adducts were obtained in high yields and selectivities. In

general, no organic solvent was needed for the extraction since the isolation of the

crude product was performed by filtration or phase separation.

O

+ PhNO2

cat. 20 mol%

water, RT, 12h

O Ph

NO2

93%syn:anti = 97:3

97% ee

NH

N

NBu

C12H25

SO O

O

catalyst

Figure 2.10 Aqueous asymmetric Michael addition catalyzed by a surfactant-type organocatalyst

Ideally, however, the use of chromatography purifications should be avoided.

This requires not only a very efficient and selective reaction, but also a means to

isolate the product from by-products or catalysts. When they developed a convenient

copper(I)-catalyzed click glycosylation of alkynes to form unprotected

neoglycoconjugates at room temperature in water, Vauzeilles and co-workers

generated the active catalytic species with a mixture of copper(II) sulfate and sodium

ascorbate (Figure 2.11) [34].

HO

OHOHO OH

N3

OH2

+

CuSO4 5 mol%Sodium ascorbate 10 mol%

o-Phenelynediamine 15 mol%water, RT, <45min

OHOHO OH

N

OH2

NN

OH

98%

Activated charcoal and filtration

Figure 2.11 Practical synthesis of unprotected neoglycoconjugates by click chemistry

In order to separate the product from polar by-products (like the oxidation

product of ascorbate), they used a catalytic amount of ortho-phenylenediamine which

allowed the formation of quinoxaline derivatives from dehydroascorbate. These

compounds, as well as copper complexes, were then easily removed by adsorption on


34

activated charcoal at the end of the reaction, and a simple filtration led to the pure

product without the need for chromatography purification.

N

N

CN

CN

N OO

Ar

water, 20 °C, 24h

C6H4Cl-4COMe

water, 75 °C, 24h

N

N

N

H CN

HH

OO

CN

Ar

N

N

H CN

COMeH

CN

HC6H4Cl-4

91-96%

86%

Filtration

Filtration

Figure 2.12 ‘‘On water’’ 1,3-dipolar cycloaddition of phthalazinium-2-dicyanomethanide

Since in most cases the organic product is hardly water soluble, efficient

procedures for the organic solvent free purification of reactions conducted with water

as solvent (provided that the reaction has reached completion) are the filtration or

phase separation. In this context, the group of Butler showed that the 1,3-dipolar

cycloaddition of phthalazinium-2-dicyanomethanide with various alkenes led to

sparingly water soluble adducts which can be isolated from the reaction mixture by a

simple filtration (Figure 2.12) [35]. In the case of N-arylmaleimides, the reaction can

be conducted at room temperature since their slight solubility in water allows them to

react with the dipolar starting material whereas the use of insoluble dipolarophiles

(such as 4-chlorobenzylideneacetone) requires to run the reaction at their liquefaction

temperature.

R3 NC

R2

O

H H2NCO2H

R1

+water, 3-6h, 25 °C

filtration

32 compounds71-89%

NO

R2NH

R3

O

R1

Figure 2.13 Convenient access to a library of 32 β-lactams with water as solvent

To demonstrate the value of water as solvent for the high throughput synthesis

of molecules in a combinatorial chemistry approach, Pirrung and co-workers

performed the Ugi reaction of two isonitriles, four aldehydes and four acids to obtain


35

a library of 32 β-lactams (Figure 2.13) [19,20]. In most cases, the products were solid

and could be collected by filtration as the only purification.

+ Ph H

O NH.HClO4

OTMS

ArAr

water, RT, 8h

decantation and distillation

Ph

H

O

81% yieldendo/exo = 82:18

eeexo = 97%, eeendo, = 92%

Figure 2.14 Organic solvent free synthesis of a Diels–Alder adduct through asymmetric organocatalysis

During their development of an organocatalyzed asymmetric Diels–Alder

reaction of α,β-unsaturated aldehydes and dienes using a chiral diarylprolinol silyl

ether salt, the group of Hayashi showed that scaling up the reaction to a 20 mmol

scale can avoid the use of organic solvents (Figure 2.14) [36]. Indeed, the water phase

can be simply removed by decantation and distillation afforded the cycloadduct with

excellent yields and selectivities.

2.4 Mild reaction conditions From a Green Chemistry point of view, the development of mild reaction conditions

is a key issue, not only because it can lead to safer processes, but also because less

reactive reagents are generally more easily available, requiring less upstream

synthetic procedures.

The group of Charette described the racemic and asymmetric transition metal-

catalyzed cyclopropanation of various olefins in water [37]. However, this reaction

involved the synthesis and subsequent use of potentially explosive ethyl diazoacetate.

To address this issue, the same group described conditions allowing the in situ

synthesis of the diazo compound, starting from glycine ethyl ester hydrochloride salt

and adding sodium nitrite and sulfuric acid, which then reacted with the rhodium

catalyst and styrene to lead to the expected cyclopropane in good yields and moderate

selectivities (Figure 2.15). Moreover, this reaction was conducted successfully on a 3

g scale, enabling a cheap, secured and straightforward access to cyclopropane

moieties.


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NH3ClEtO

O

+ Ph

[Rh(C7H15CO2)2]2 0.5 mol%NaOAc 6 mol%NaNO2 1.16 eq.

H2SO4 cat. WaterRT, 14h

EtO2C

Ph

70% trans/cis = 1.5:1

Figure 2.15 Cyclopropanation of styrene in water using an in situ generated diazo compound

In the field of copper(I)-catalyzed alkyne azide 1,3-dipolar cycloaddition

(CuAAC), Perica’s and co-workers described a highly active copper complex

(prepared in four steps from readily available substrates), catalyzing azide-alkyne

couplings in water at room temperature with catalyst loading of 0.5 mol% [38]. In

addition, they were able to conduct the same reaction but starting from the brominated

starting material through the in situ formation of the azide (Figure 2.16), thus

avoiding the manipulation and storage of organic azides.

Ph

RBr

+

Cu(I) cat. 1 mol%NaN3 1.1 eq.

water, 40 °C, 8hN

N

NPh

R80-99% yield

N NN

Ph

OH

NN NPh

CuN

NN

Ph

Cl

Cu(I) cat

Figure 2.16 CuAAC reaction in water involving the in situ formation of the azide

Reduction of double bonds is a widely used methodology in synthesis either

for the introduction of chiral centers in organic molecules or for functional group

interconversion. However, this methodology often involves the use of hazardous

hydrogen gas and pressure reaction vessels and, lately, transfer hydrogenation has

emerged as a safer alternative [39]. Interestingly, the use of water as solvent in

transfer hydrogenation has recently gained interest [40]. For example, the group of

Xiao described in 2006 very mild conditions for the efficient and chemoselective

iridium-catalyzed reduction of aldehydes to alcohols in water (Figure 2.17) [41]. In


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particular, they showed that the reaction tolerated many functional groups like

halogens, olefins or nitro, and did not require an inert atmosphere with catalyst

loading as low as 0.002 mol%. A TOF of 1 32 000 h-1 was even achieved for the

reduction of benzaldehyde.

R1 O[Ir] cat 0.05-0.02 mol%

water, 80 °C, 0.5-9h R1 OH

H

OH

Br

OH

OOH

OHn-Bu

99% 98% 98% 97%

Figure 2.17 Aqueous transfer hydrogenation of aldehydes

The nucleophilic addition of acetylides to electrophiles is also a powerful

transformation, allowing us to access compounds that can be further converted into a

wide range of products.

H

PhR1 H

O +

R1

HN

R2

AgI1.5-3 mol%

water, 100 °C NR1 R2

R1

Ph47-99% yield

NHAr

R1

Ph

*

N

N

OO

N10 mol%

Cu(OTf) 10 mol%water, 22 °C, 4d

AuBr31 mol%

water, 100 °C12h

N

R1

R1 R2

Ph53-99% yield

48-86% yield78-97% ee

Figure 2.18 Synthesis of propargylamines in water by the A3 coupling

However, these reactions often require stoichiometric highly basic reagents

(and thus protecting groups) and/or anhydrous and inert conditions. Recently, milder

conditions have been reported to conduct some of these transformations, in which

water holds a particular place [42]. For instance, the group of Li showed that the


38

three-component coupling of an aldehyde, an amine and an alkyne (A3 coupling)

could be carried out in water using commercially available gold or silver catalysts

(Figure 2.18). In addition, they were able to develop an asymmetric version of this

reaction in water using a combination of copper(I) triflate and pybox as a catalytic

system which led to high yields and good enantioselectivities (Figure 2.18) [43].

ClR1

+ B(OH)2R2

PCy2

OMe

SO3Na

MeO

cat.

cat. 0.2-4 mol%Pd(OAc)2 0.1-2 mol%

K2CO3 3eq. water, 2-12h

R2R1

HO2C

HO

H2N

HO2C

NH2

93% (100 °C)99 % (RT)

H2N

87% (80 °C)

HO2C

H2N

92% (100 °C)

ON

CO2H

Figure 2.19 Aqueous Suzuki–Miyaura coupling of aryl chlorides

Organoboron reagents are particularly attractive compounds because they are

stable, easy to handle and have a low toxicity. In particular, they have been widely

used in cross-coupling reactions (Suzuki–Miyaura coupling). The use of water as the

sole solvent in this reaction is therefore an attractive challenge. In 2005, the group of

Buchwald described the synthesis of a new sulfonated ligand which was found to

form a highly active complex for the aqueous Suzuki–Miyaura coupling of aryl

chlorides with boronic acids (Figure 2.19) [44]. In many cases, the reaction could be

conducted at room temperature and low catalyst loadings could be used (0.1–0.5

mol%). Interestingly, a broad scope of aryl chlorides or boronic acids with different

functional groups reacted under these conditions without the need of any protecting

groups.

A very straightforward and atom-economical strategy for the formation of

carbon–carbon bonds is the direct coupling of two carbon–hydrogen bonds under

oxidative conditions (cross-dehydrogenative coupling) [45]. This methodology allows

the use of readily available substrates, thus by-passing the functionalization

/defunctionalization steps and shortening the synthetic paths. However, in order to

obtain a substantial gain in the environmental impact with these reactions, the choice


39

of oxidant is crucial, and in particular the use of clean and inexpensive molecular

oxygen is highly desirable.

2.5 Key findings from the literature survey Green chemistry is a multifaceted and complex challenge. Though complete

greenness may be difficult to reach, it is a goal chemists must aim at, through the

improvement of several aspects and parameters of a given reaction, from the synthesis

and availability of its reactants and reagents, to the separation and purification of the

product. In this context, the use of water as solvent features many benefits: not only

because water itself is innocuous, but also it can potentially improve reactivities and

selectivities, simplify the workup procedures, enable the recycling of the catalyst and

allow mild reaction conditions and protecting group free synthesis. In addition,

development of organic chemistry in water can lead to uncommon reactivities and

reverse selectivities compared to organic solvents, thus complementing the organic

chemists’ synthetic toolbox.

Moreover, the emergence of this field is also crucial for novel applications and

developments in biology and bioorganic chemistry, leading to rich research

opportunities. Studying chemistry in water is also an interesting way to gain insights

into the biosynthesis of natural products and then to learn how Nature does chemistry

and, ultimately, to which extent we can mimic it.

2.6 Reported synthetic strategies 2.6.1 Three-component synthesis of Dihydropyrano[2,3-c]pyrazoles

Laufer et al. [46] have synthesized 1,4-dihydropyrano[2,3-c]pyrazoles (Figure 2.20)

with various substituents at the 1-, 3-, and 4-position. Given the large number of

commercially available aldehydes and the easy access to hydrazines and β-keto esters,

this method should be applicable to synthesis of libraries with high diversity.

The corresponding β-keto esters were synthesized either according to Yuasa

and Tsuruta [47] or by deprotonation of esters and subsequent reaction with ethyl

acetate. This second procedure (deprotonation of esters), described in a patent

application for the synthesis of ethyl 3-oxo-3-(pyridin-4-yl)propanoate [48], is more

advantageous because the reaction can be performed using ethyl acetate as both the


40

solvent and reagent without further purification. The reaction was performed at room

temperature overnight, and nearly all products precipitated as discrete crystals.

R1

HN

NH2

+

R2 O

O O

EtOH, 3 h,

reflux N N

R2

O

R1+

NC CN

R3CHO

EtOH, base,16 h,

rtO

NN

R2R3

CN

NH2R1

Figure 2.20

R1= H, CH3, C6H5, 4-OCH3-C6H4, -CH2-C6H5R2= CH3, C3H7, C6H5, 4-F-C6H4, -CH2-C6H5, pyridineR3= C6H5, 4-F-C6H4, 4-OCH3-C6H4, 4-Cl-C6H4, 4-OH-C6H4, 2-Cl-5-NO2-C6H4, pyridine

2.6.2 Four-component pyrano[2,3-c]pyrazoles synthesis

Shestopalov et al. [49] demonstrated that a four-component reaction of aromatic

aldehydes, malononitrile, β-ketoesters, and hydrazine hydrate successfully yields 6-

aminopyrano[2,3-c]pyrazol-5-carbonitriles without the need of prior pyrazolin-5-ones

isolation [50]. The multicomponent synthesis of pyranopyrazoles was carried out by

simultaneously refluxing all four starting materials in ethanol for 15 min. in the

presence of Et3N (Scheme 2.20).

R1

CHO

+ CN

CNR2

OO

OEt

H2NNH2

*H2OEtOH, Et3N, reflux, 15 min.

O

HNN

R2R1

CN

NH2

Figure 2.21

They showed that aromatic aldehydes with electronwithdrawing, electron-

donating, withdrawing and donating groups, as well as napthaldehydes and hetero-

aromatic aldehydes can be successfully reacted with β-ketoesters, malonodinitrile, and

hydrazine hydrate to yield final pyrano[2,3-c]pyrazoles with high regio-selectivity.


41

2.6.3 1,4-dihydropyrano[2,3-c]pyrazoles synthesis in aqueous media

Shi et al. [51] report one-pot synthesis of 1,4-dihydropyrano[2,3-c]pyrazole

derivatives by three-component reaction in aqueous media. When aromatic aldehydes,

malononitrile, 3-methyl-1-phenyl-2-pyrazolin-5-one, and triethylbenzylammonium

chloride (TEBA) were stirred at 90 °C for 6-10 h in water, the products were obtained

in good yields (Figure 2.22).

N N

H3C

O

Ph

O

NN

H3C R

CN

NH2Ph

CN

CN

+H2O, TEBA

90 °C

Figure 2.22

OR

The three-component reaction of aromatic aldehydes, malononitrile, and 3-

methyl-1-phenyl-2-pyrazolin-5-one to 6-amino-5-cyano-4-aryl-1,4-dihydropyrano[2,3

-c]pyrazoles has been efficiently performed in aqueous media. The easy purification

of products by simple crystallization, and the use of water as solvent combined with

the exploitation of the multicomponent strategy open to this process suggest good

prospects for its industrial applicability.

2.6.4 Base-catalyzed rout of Dihydropyrazolo[3,4-b]pyrans

2.6.4.1 By using Ammonium acetate

Li et al. [52] reported the preparation of 2H,4H-dihydropyrazolo[3,4-b]pyrans from

the reaction of 4-Arylidene-3-methyl-1-phenyl-5-pyrazolones and β-ketoester using

ammonium acetate as a catalyst (Figure 2.23).

F3C OEt

O O+

NN

OPh

R

O NN

EtO2C

R CH3

HOF3C

Ph

NH4OAc

C2H5OH, rt

R = C6H5, p-CH3C6H4, p-CH3OC6H4, p-NO2C6H4, p-BrC6H4, o-CH3C6H4, o-FC6H4, m-ClC6H4, o-OHC6H4

Figure 2.23


42

Ammonium acetate has been used widely as a base or a catalyst in Biginelli

reactions [53, 54], Hantzsch reactions [55] and other reactions [56, 57]. With this aim

in view, they applied the ammonium acetate to this reaction. Treatment of 3-methyl-1-

phenyl-4-phenylidene-5-pyrazolone with 1 equiv. of ammonium acetate followed by

β-ketoester in ethanol at room temperature for 2 h gave the corresponding 1,4,5,6-

tetrahydropyrazolo[3,4-b]pyrans.

2.6.4.2 By using TEA

Mixing equimolecular amounts of ethyl acetoacetate with hydrazine hydrate,

benzaldehyde and malononitrile has produced corresponding pyranopyrazoles (Figure

2.24). This same product could be obtained in almost the same yield by reacting 3-

amino-2-pyrazoline-5-one and arylidenemalononitriles in ethanol in the presence of

chitosan or, as originally reported, in the presence of piperidine. Despite the recently

claimed isolation of Michael adduct, this could not be repeated even when the

reaction was conducted at room temperature for a short period. Only either unchanged

starting materials or cyclic products were isolated. It is of value to report that after an

induction period the reaction is exothermic and temperature control is somewhat

difficult.

H2NNH2

+

R1 O

O O

EtOH Et3N

N NH

R1

O

OHN

N

R1CN

NH2

Figure 2.24

CN

CN

R2

O

reflux15 min

+R3

R2

CN

CN

R3R2R3

The reaction of compound 4-(p-Methylphenylaminomethylidine)-1-phenyl-

3,5-pyrazolidinedione with active nitriles and cyclic ketones, namely malononitrile,

cyanoacetamide, cyanothioacetamide, cyanoacetic hydrazide, 1-phenyl-3,5-

pyrazolidinedione, 3-methyl-1-phenyl-5-pyrazolone, cyclopentanone, cyclohexanone


43

and cycloheptanone in the presence of a catalytic amount of triethylamine gave

pyrano[2,3-c]pyrazole derivatives (Figure 2.25) [58]. The reaction pathway of such

compound was assumed to follow a preliminary formation of carbanion of the active

methylene reagent, which was added to the double bond followed by a nucleophilic

attack of the NH group at the CN, CO, and CS groups with the elimination of a water

molecule in the case of cyanoacetamide and a H2S molecule in the case of

cyanothioacetamide [59].

Here, 4-(p-Methylphenylaminomethylidine)-1-phenyl-3,5-pyrazolidinedione

was prepared from the reaction of 1-phenylpyrazolidine-3,5-dione with ethyl

orthoformate and p-toluidine in boiling dimethylformamide.

HN

NPh

O

O

NH2

CH3

HC

OEt

OEt

OEt

DMF

HN

N

O

OPh HN CH3

HN

N

O

OPh HN CH3

CN

Y

Dioxane / TEAY = CN, CONH2, CSNH2

O

HNN

Ph

O HN

CN

NH2

Ar

Figure 2.25

2.6.4.3 Synthesis of spiro-dihydropyrazolo[3,4-b]pyrans

Figure 2.26

N

O

R1

+ N

HN

O

R2

+ CH2(CN)2

O

HNN

N

R2

R1

CN

NH2

R1 = CH3, CH3CO, COOEtR2 = CH3, CH3OCH2, CH3CH2CH2


44

Evans et al. [60] describe a three-component condensation in which substituted

piperidin-4-ones have been used in place of aromatic aldehydes to synthesize a new

spiro heterocyclic system. They report that the base-catalyzed reaction of substituted

piperidin-4-ones, pyrazol-5-ones, and malononitrile proceeds in ethanol at 20 °C with

the formation of substituted 6-amino-5-cyanospiro-4-(piperidine-4’)-2H,4H-

dihydropyrazolopyrans (Figure 2.26).

Three-component condensation of 4-piperidinones, 5-pyrazolones, and

malononitrile proceeds chemically and electrochemically and is a convenient one-step

means of synthesis of substituted 6-amino-5-cyanospiro-4-(piperidine-4’)-2H,4H-

dihydropyrazolo[3,4-b]pyrans. The electrochemical reactions proceed under milder

conditions and with yields 12-15% greater than those of the reactions catalyzed by

chemical bases.

2.6.4.4 Dihydropyrazolopyrans from 1H-indole-2,3-dione

Aly H. Atta [61] reported the synthesis of a new series of compounds containing both

the two moieties is likely to result in the formation of some interesting bioactive

compounds. The one-pot reaction of 1H-indole-2,3-dione, 3-methyl-1-phenyl-2-

pyrazolin-5-one, and active methylenes, namely malononitrile, ethyl cyanoacetate,

pyrazolone, and acetyl acetone afforded the products. These products can be obtained

via reaction of 3-[3-methyl-5-oxo-1-phenyl-1,5-dihydro-pyrazol-(4Z)-ylidene]-1,3-

dihydro-indol-2-one with the corresponding active methylenes (Figure 2.27).

NH

O

O + NN

CH3

PhO

X

CN

X = CN, COOC2H5

NH

O

O

NN

CH3

PhX

H2N

Figure 2.27

2.6.4.5 Pyrazolopyrans from pyrazole-aldehydes

Thumar and Patel [62] reported a series of 4-pyrazolyl-4H-pyrazolopyran derivatives

by one-pot three-component cyclocondensation reaction of 1-phenyl-3-(het)aryl-

pyrazole-4-carbaldehyde, malononitrile and substituted pyrazolin-5-ones in the


45

presence of piperidine as catalyst. The mixture refluxing under ethanol or acetonitrile

gives pyran derivatives (Figure 2.28).

The reaction occurs via an in situ initial formation of the heterylidenenitrile,

containing the electron-poor C=C double bond, from the Knoevenagel condensation

between pyrazole-4-carbaldehyde and malononitrile by loss of water molecules.

Finally, Michael addition into the initially formed unsaturated nitrile, i.e. nucleophilic

attack of hydroxyl moiety to the cyano moiety affords cyclized pyran derivatives.

Ar

O

CH3

+

NHNH2

AcOH / EtOH

NHNCH3

Ar

DMF / POCl3

90 °C - 4 h

N N

Ar

CHO

N N

Ar

CHO

+NC

NC

EtOH

Piperidine

NHN

O

+

O

HNN

NN

Ar

CN

NH2

Figure 2.28

2.6.4.6 Pyranopyrazoles by using heteropolyacid as a catalyst

Heravi et al. [63] reported facile method for the synthesis of 1,4-dihydropyrano[2,3-c]

pyrazole derivatives via three-component one-pot condensation of 3-methyl-1-phenyl-

1H-pyrazol-5(4H)-one, aldehydes and malononitrile in the presence of a catalytic

amount of preyssler type heteropolyacid as a green and reusable catalyst in water or

ethanol under refluxing conditions (Figure 2.29).

There has been considerable interest in the use of heteropolyacids as

environmentally benign catalysts due to their unique properties such as high thermal

stability, low cost, ease of preparation and recyclability. Numerous chemical reactions

can occur in the presence of heteropolyacids [64]. Preyssler type heteropolyacid,

H14[NaP5W30O110], is remarkable owing to its exclusive physicochemical properties.

These include strong Bronsted acidity, reversible transformations, solubility in polar

and non-polar solvents, high hydrolytic and thermal stability, which are all essential in


46

catalytic processes. Preyssler polyanion, as a large anion, can provide many ‘‘sites’’

on the oval-shaped molecule that are likely to render the catalyst effective [65]. This

heteropolyanion with [66] acidic protons, is an efficient ‘‘supper acid’’ solid catalyst

which can be used both in the homogeneous and heterogeneous phases [67].

NC

NC

NN

CH3

O

+

O

NN

Ar

CN

NH2

H3C

Figure 2.29

Ph

+ ArCHOH14[NaPW12O40]

Water or EthanolRefluxing

Ph

O

NN

ArH3C

PhN

N

CH3

Ph

2.6.4.7 Synthesis of aminochromenes

A four component Knoevenagel-Michael addition-cyclization sequence has been

studied for the synthesis of dihydropyranopyrazole derivatives from hydrazine

hydrate, a malonitrile, a β-ketoester, and an aldehyde or a ketone.

H2NNH2

+

Me OEt

O O

N NH

Me

O

O

CN

NH2

Figure 2.30

CN

CN

30 °C, 5-10 min.

+

CHO

OH

R

NHN

H2O

Me OH

R

O

CN

NH

R


47

The reaction was described under catalyst- and solvent-free conditions [68]

and using piperidine in ultrapure aqueous media [69], both at room temperature. But

this methodology was intensively developed by Shestopalov and co-workers since

they used a wide range of aldehydes, ketones, and β-ketoesters to form a series of

these fused heterocyclic skeletons, even if substituted hydrazines were unreactive in

this protocol [49].

More recently, an adaptation of this four-component transformation in water

was proposed as a green combinatorial synthesis of novel aminochromene derivatives

bearing an hydroxymethyl pyrazole functional group in the four-position, instead of a

fused skeleton. In this unexpected transformation, 2-hydroxybenzaldhyde plays a

crucial role by reacting selectively with malonitrile to form the chromene intermediate

(Figure 2.30) [70].

2.6.4.8 Solvent-free multicomponent synthesis of pyranopyrazoles

The conventional synthesis of 2-amino-3-cyano-4H-pyrans use organic solvent, but

these solvents make the workup procedure complicated and lead to poor yields of

products [71]. In recent years, 2-amino-3-cyano-4H-pyrans have also been

synthesized under microwave [72], with ultrasound irradiation [73], or in aqueous

media [51, 74, 75]. Some two-component [76] and three-component [74] condensa-

tions have been introduced for the synthesis of 2-amino-3-cyano-4H-pyrans. Each of

these methods has its own merit, with at least one of the limitations of low yields,

long reaction time, effluent pollution, harsh reaction conditions, and tedious workup

procedues. All of these reasons spur us to study the possibility of synthesis of 2-

amino-3-cycano-4-aryl-7,7-dimethyl-5,6,7,8-tetrahydrobenzo[b]pyrans and 6-amino-

5-cyano-4-aryl-1,4-dihydro-pyrano[2,3-c]pyrazoles under solvent-free conditions.

NC

NC+

O

Ar

CN

NH2

Figure 2.31

+ ArCHOD,L-proline

rt

O

OR

R

O

R

R

Li et al. [77] report a highly efficient procedure for the synthesis of 2-amino-

3-cycano-4-aryl-7,7-dimethyl-5,6,7,8-tetrahydrobenzo[b]pyrans and 6-amino-5-cyano


48

-4-aryl-1,4-dihydropyrano[2,3-c]pyrazoles via a one-pot grinding method under

solvent-free conditions using an inexpensive and commercially available D,L-proline

as catalyst (Figure 2.31 & 2.32).

NC

NC

NN

CH3

O

+O

NN

Ar

CN

NH2

H3C

Figure 2.32Ph

+ ArCHOD,L-proline

rtPh

In a typical general experimental procedure, aromatic aldehydes,

malononitrile, dimedone [1,3-cyclohexanedione or 3-methyl-1-phenyl-2-pyrazolin-5-

one], and a catalytic amount of D,L-proline are added to a mortar. The mixture is

ground by mortar and pestle at room temperature for a period. The solid product is

obtained from an intermediate melt and then is laid up at room temperature for 30

min. The mixture is transferred to ice water and then is filtered off. The crude

products are purified by recrystallization by ethanol to afford the products in good

yields.

NH2H2N +

O

CN

NH2

Figure 2.33

CN

CN Mixing, rt

per-6-ABCD

OO

O

+

R

CHO

HNN

R

A simple, green and efficient protocol is developed with per-6-amino-b-

cyclodextrin (per-6-ABCD) which acts simultaneously as a supramolecular host and

as an efficient solid base catalyst for the solvent-free syntheses of various

dihydropyrano[2,3-c]pyrazole derivatives involving a four-component reaction

(Figure 2.33).

Per-6-amino-b-cyclodextrin (per-6-ABCD) is used extensively as a

supramolecular chiral host and as a base catalyst for Cu-catalyzed N-arylation [78]

and for Michael addition of nitromethane to chalcones [79]. Kanagaraj and

Pitchumani [80] have utilized per-6-ABCD as an excellent supramolecular host for


49

the synthesis of pyranopyrazole derivatives, in an efficient and ecofriendly four-

component reaction protocol under solventfree conditions at room temperature. It is

also interesting to note that the catalyst can be recovered and reused several times.

2.6.4.9 Syntheses of Polyfunctionalized Phenols Linked to Heterocycles

Boghdadie et al. [81] reported that, a solution of 4-(hydroxyl-3-methoxybenzylidine)

malononitrile and 3-ethyl-1-phenyl-2-pyrazolin-5-one, in ethanol (50 ml) and two

drops of piperidine was heated under reflux for 2 hours, cooled and poured onto

water. The products were recrystallized from ethanol to give the corresponding

compound 6-amino-3-ethyl-4-(4-hydroxy-3-methoxyphenyl)-1-phenyl-4H-pyrano[3,2

-d]pyrazole-5-carbonitrile (Figure 2.34).

HO

H3CO

CH

O +CN

CN

EtOH / piperidine

reflux, 1/2 h HO

H3CO

CH

CCN

CN

HO

H3CO

CH

CCN

CNEtOH / piperidine

reflux, 1/2 h

NN

O

H3C

HO

H3CO

O

NN

NC NH2

H3C

Figure 2.34

2.6.5 Benzopyran Derivatives

2.6.5.1 4H-benzo[b]pyrans using TBAB as a catalyst

CNNC

Ar CHO

+ HN

NH

O

HN

NH

O

Ar

CN

NH2

O Ar

CN

NH2

O

O

O

O

O O

O

TBAB (10% mol)TBAB (10% mol)

H2O, refluxH2O, reflux

Figure 2.35


50

Fard et al. [82] reported a highly efficient procedure for the preparation of 4H-

benzo[b]pyrans and pyrano[2,3-d]pyrimidinones via a domino Knoevenagelcyclo-

condensation reaction using TBAB as a catalyst in water.

In a typical experimental procedure, a mixture of aromatic aldehyde,

malononitrile, dimedone or barbituric acid in water under reflux condition, was stirred

in the presence of a catalytic amount of TBAB (10 mol%) to afford the 4H-

benzo[b]pyrans and pyrano[2,3- d]pyrimidinones (Figure 2.35).

2.6.5.2 2-Imino-2H-chromene-3-carbonitrile using NaBH4 as a catalyst

Rai et al. [83] have reported a synthesis (Figure 2.36) in ethanol using triethylamine

to first get 2-Imino-2H-chromene-3-carbonitrile which they reduced using sodium

borohydride in methanol to give the essential 2-Amion-3-Cyanochromane derivative.

The reaction mixture here has been conventionally refluxed for 3 h.

CHO

OH

+

CN

CN

EtOH, Et3N

O

CN

NH

NaBH4

MethanolO

CN

NH2

Figure 2.36

2.6.5.3 2-Amino-3-cyanochromene using MgO as a catalyst

Kumar et al. [84] have reported an environmentally benign synthetic process using

Magnesium oxide as the catalyst and by process of grinding (Figure 2.37). This is the

classical reaction where in a benzaldehyde or ketone has first been reacted with a

malanonitrile which has got an active hydrogen site, yielding the benzylidene

malanonitrile which when reacted to a 1,3-Diketo compound herein a meldurms acid

afforded the 2-Amino-3-cyanochromene derivative the only difference than the

classical methodology is that the reaction has been carried at room temperature and it

is grinded which means there are absolutely no solvent which makes it a green

process and which is also faster and gives a higher yield.


51

CHO

+

CN

CN

MgO; R.T.

Grinding

CN

CN

O O

MgO, R.T. Grinding

O

O

CN

NH2Figure 2.37

2.6.5.4 Benzopyrans using chitosan as a catalyst

Similarly, Al-Matar et al. [85] have synthesized many compounds of this class using

chitosan as the catalyst (Figure 2.38).

CN

CN

Ph H3CCOOEt

O

O

CN

NH2H3C

EtOOC

O

OH

R1

R2

R3

R4R1

R2

R3

R4

O

NH2

NC

Ph

NC

NH2CN

Ph

CN

H

H

NC

NH2

Ph

CNH

Figure 2.38

2.6.5.5 Benzopyrans using piperidine as a catalyst

More so ever Al-Matar et al. [85] have also studied the formation of the exact product

i.e. 2-Amino-3-cyano-7-hydroxy-4H-chromene instead of 5-hydroxy derivative when

resorcinol is reacted with malanonitrile using piperidine and ethanol. They have come

out with this result using the Nuclear Overhauser Effect calculation from the proton

NMR spectrum (Figure 2.39).

CN

CN

Ph+

OH

OH

O NH2

CN

PhOH

O NH2

CN

Ph

HO

Figure 2.39


52

They have also prepared many such compounds using the same methodology

but different starting materials as shown in Figure 2.40.

CN

CN

Ph

NNH

O

O

NNH

H3C Ph

CN

NH2

S

HN

ONC

O

S

N

Ph

CN

NH2

NC

Ph

N

S

NH2

CN

PhPh

O

CN

O

HNN

H3C Ph

CN

NH2

Figure 2.40

Naliyapara et al. [86] have extended this work using 4-Hydroxy coumarin as a

starting product (Figure 2.41).

O O

OH

+CN

CNPh

O O

O

NH2

CN

Ph

Figure 2.41

O

OH

O

+ R

O

+ NC CN

R

CN

CN+

O

OH

O

O O

O

NH2

CN

RFigure 2.42


53

They have synthesized the spiro-compounds using the cyclic ketones to

produce the desired results but failed to obtain the chromenes when the aryl ketones

were used in the reaction. The reaction schemes followed are shown in Figure 2.42.

2.6.5.6 Benzopyrans using potassium carbonate as a catalyst

Kidwai et al. [87] has prepared the same class of the compounds using water as a

solvent and potassium carbonate as the required base catalyst (Figure 2.43).

CHO +CN

CN

+HO OH

O

CN

NH2HOFigure 2.43

Such compounds were prepared using different starting materials as diverse

kinds of aldehydes viz. Phenyl, Quinolyl, Indolyl and alkyl were reacted with

malanonitrile in presence of saturated potassium carbonate solution and then

microwave irradiation was induced upon the reaction mixture which afforded the 2-

Amino-3-cyano-4-substituted phenyl-7-hydroxy-4H-chromene dervatives.

2.6.5.7 Ionic liquids as catalyst for the synthesis of benzopyrans

Ar

O H+

CN

CN

60 °C, 30-80 min.

80 °C, 30-130 min.

O

O

OH

MeMe

O

MeMe

Ar

CN

NH2

NH2

CN

Ar

O

73-94 %

46-95 %

Figure 2.44

IL (5 mol%)IL: [PhCH2Me2N+CH2CH2NMe2]Cl-


54

The synthesis of 4H-benzo[b]pyran derivatives has also been proposed by means of a

basic ionic liquid-catalyzed three-component approach involving malononitrile,

aromatic aldehydes and dimedone. The conventional method, requiring the use of

refluxing DMF or acetic acid, lead to low yields and renders the isolation step

troublesome. Other procedures have been described but all of them suffer at least

from one limitation. Alternatively, it has been found that a small amount of N,N-

dimethylaminoethylbenzyl-dimethylammonium chloride catalyzed a rapid and high

yielding solvent-free transformation at 60 °C with a wide variation of the aldehyde

partner (Figure 2.44) [88].

While, Peng and Song conducted this MCR in a mixture of catalytically active

ionic liquid and water [89], and Lingaiah and co-workers reported the use of a

heterogeneous strong basic Mg/La mixed oxide catalyst in methanol [90]. Compared

to the utilization of more classical solvents and organic bases, these strategies

combine advantages in efficiency such as shorter reaction times and higher yields,

with ecological advantages in terms of recovery and reusability of the catalyst.

Ar H

O+ CN

CN

MeMe

OO TMAH (10 mol%)

H2O, rt O

CN

NH2

ArO

MeMe

79-92%

Figure 2.45

This approach has been extended to cyclic 1,3-dicarbonyls for the synthesis of

tetrahydrobenzopyrane derivatives, also known as tetrahydrochromenes, which have

attracted much attention due to their wide range of biological properties. Thus, a

mixture of an aromatic aldehyde, dimedone, and malonitrile in aqueous media

catalyzed either by (S)-proline [91] or tetramethylammonium hydroxide (TMAH) [92]

gave the bicyclic heterocycle in excellent yields (Figure 2.45).


55

2.7 Aim of current work Pyran and fused pyran derivatives have attached a great deal of interest due to their

association with various kinds of biological properties. They have been reported for

their antimicrobial [93-96], antiviral [97, 98], anticonvulsant [99], cytotoxic [100] and

antigenotoxic [101] activities. The incorporation of another heterocyclic moiety in

pyrans either in the form of a substituent or as a fused component changes its

properties and converts it into an altogether new and important heterocyclic

derivative.

Pyrazole have attracted particular interest over the last few decades due to use

of such ring system as the core nucleus in various drugs. They are well-known for

their activities such as antidiabitic [102], antipyretic [103], anti-inflammatory [104],

anti-hypertansive [105], antitumour [106], peptide deformylase inhibitor [107], and

antidepressant agents [108]. Considering the importance of pyran and pyrazole

derivatives, it was thought worthwile to synthesize new compounds incorporating

both these moieties.

It is pertinent to mention that a large number of pyrazole fused and pyrazole

substituted pyran derivatives are reported as biologically important compounds and

their chemistry have received considerable attention of chemists in recent days [109-

113]. Thus, pyranopyrazoles exhibit useful biological properties such as antimicrobial

[114], insecticidal [115], and anti-inflammatory [116]. Furthermore Dihydropyrano

[2,3-c]pyrazoles showed molluscicidal activity [117, 118] and was identified as a

screening hit for Chk1 kinase inhibitor [119].

Over the last years, the chemistry of dihydropyrano[2,3-c]pyrazoles has

received great interest. The first approach to synthesize these substances was

undertaken by Otto [120], in which he initiated the reaction sequence by the base-

catalyzed cyclization of 4-aryliden-5-pyrazolone. In a further report, this same group

showed that weak bases can also be used for a Michael-type cyclization [121].

Extending the work of Otto, Klokol and colleagues performed the direct conversion of

3-methyl-3-pyrazolin-5-one with malononitrile in the presence of a weak base [122].

Recent methods for the synthesis of 1,4-dihydropyrano[2,3-c]pyrazoles include

synthesis in aqueous media [51], under microwave irradiation [72], and under solvent-

free conditions [77, 123].


56

Thus, in view of the diverse therapeutic activity of pyrano[2,3-c]pyrazoles, we

report one-pot synthesis of pyrano[2,3-c]pyrazole derivatives (YUG 101-140) by

three-component reaction, a scaffold from which a diverse range of other biologically

important New Chemical Entities (NCE’s) could be generated. A series of novel 1,4-

dihydropyrano[2,3-c]pyrazole derivatives (YUG 101-140) has been synthesized by

one-pot three-component cyclocondensation reaction of aromatic aldehydes,

malononitrile and substituted pyrazolin-5-ones. The mixture was stirred in

ethanol/water (1:1, v/v) to give 1,4-dihydropyrano[2,3-c]pyrazole derivatives. The

products were characterized by FT-IR, mass, 1H NMR, 13C NMR spectroscopy and

elemental analyses. The structure of representative compound was elucidated using

single crystal X-ray diffraction method. The newly synthesized compounds were

subjected to various biological activities viz., antimicrobial, antimycobacterial, anti-

cancer and antiviral.


57

2.8 Reaction Scheme

O

NN

CN

NH2R1

R2

NN

R1

O

CN

CN

YUG 101-140

HO

R2

+a

Reagents & Conditions: (a) EtOH/Water (1:1, v/v), Stirring, 30 min.

Code R1 R2 M.F. M.W. M.P. ºC Yield %

Rf1 Rf2

YUG-101 H 4-OCH3 C17H18N4O2 310 168-171 70 0.55 0.70 YUG-102 H 4-CH3 C17H18N4O 294 188-190 78 0.51 0.65 YUG-103 H 4-F C16H15FN4O 298 184-186 81 0.61 0.78 YUG-104 H 4-Cl C16H15ClN4O 314 188-190 72 0.57 0.72 YUG-105 H 3-Pyridyl C15H15N5O 281 180-183 69 0.48 0.67 YUG-106 H 2-OH C16H16N4O2 296 180-182 86 0.60 0.74 YUG-107 H 3-Cl C16H15ClN4O 314 188-191 76 0.52 0.68 YUG-108 H 4-Br C16H15BrN4O 359 218-220 80 0.62 0.79 YUG-109 H 4-OH C16H16N4O2 296 148-151 88 0.50 0.68 YUG-110 H H C16H16N4O 280 198-200 77 0.56 0.76 YUG-111 H 3-OH C16H16N4O2 296 208-210 79 0.49 0.69 YUG-112 H 2,4-Cl C16H14Cl2N4O 348 220-223 82 0.47 0.68 YUG-113 H 3-Br C16H15BrN4O 358 194-196 72 0.52 0.73 YUG-114 H 2-Pyridyl C15H15N5O 281 230-232 81 0.50 0.70 YUG-115 H 2-Br C16H15BrN4O 358 270-273 86 0.58 0.74 YUG-116 H 2,6-Cl C16H14Cl2N4O 349 138-140 75 0.61 0.81 YUG-117 H 2-Cl C16H15ClN4O 314 185-187 79 0.56 0.67 YUG-118 H 3,4-OCH3 C18H20N4O3 340 188-190 83 0.49 0.65 YUG-119 H 2,5-OCH3 C18H20N4O3 340 183-185 77 0.53 0.72 YUG-120 H 3,4,5-OCH3 C19H22N4O4 370 181-183 79 0.59 0.78 YUG-121 Ph 4-OCH3 C23H22N4O2 386 145-148 85 0.60 0.79 YUG-122 Ph 4-CH3 C23H22N4O 370 150-152 81 0.61 0.82 YUG-123 Ph 4-F C22H19FN4O 374 151-153 77 0.51 0.69 YUG-124 Ph 4-Cl C23H22N4O 370 152-154 83 0.64 0.80 YUG-125 Ph 4-NO2 C22H19N5O3 401 181-183 69 0.52 0.66 YUG-126 Ph 3-NO2 C22H19N5O3 401 158-161 70 0.56 0.70 YUG-127 Ph 3-Cl C23H22N4O 370 167-168 80 0.50 0.68 YUG-128 Ph 4-Br C22H19BrN4O 434 140-143 75 0.55 0.71 YUG-129 Ph 4-OH C22H20N4O2 372 174-176 88 0.49 0.63 YUG-130 Ph H C22H20N4O 356 219-221 73 0.59 0.73 YUG-131 Ph 3-OH C22H20N4O2 372 214-216 82 0.60 0.79 YUG-132 Ph 2,4-Cl C22H18Cl2N4O 424 184-186 85 0.61 0.82 YUG-133 Ph 3-Br C22H19BrN4O 434 188-190 88 0.51 0.69 YUG-134 Ph 2-Pyridyl C21H19N5O 357 180-183 79 0.64 0.80 YUG-135 Ph 2-Br C22H19BrN4O 434 180-182 87 0.52 0.66 YUG-136 Ph 2,6-Cl C22H18Cl2N4O 424 188-191 80 0.56 0.70 YUG-137 Ph 2-Cl C23H22N4O 370 218-220 83 0.50 0.68 YUG-138 Ph 3,4-OCH3 C24H24N4O3 416 148-151 79 0.55 0.71


58

YUG-139 Ph 2,5-OCH3 C24H24N4O3 416 140-143 75 0.49 0.63 YUG-140 Ph 3,4,5-OCH3 C25H26N4O4 446 174-176 80 0.50 0.68

TLC Solvent system Rf1: Hexane: Ethyl acetate – 6:4; TLC Solvent system Rf2: Chloroform: Methanol - 9:1.


59

2.9 Plausible Reaction Mechanism

CHO

R2

O

CN

NH2

R2

NN O

NN

R1

R1

CN

CN

CH

R2

NC CN

NN O

R1

CN

CN

NN O

R1

CN

CNN

NOH

R1

CN

CN

O

CN

NH

R2

NN

R1

O

CN

NH

R2

NN

R1

-H2O

R2

R2

R2

The mechanism reaction occurs via an in situ initial formation of the arylidene of

malononitrile, containing the electron-poor C=C double bond, from the Knoevenagel

condensation between aromatic aldehydes and malononitrile by loss of water

molecules. Finally, Michael addition of pyrazolone to the initially formed unsaturated

nitrile, i.e. nucleophilic attack of hydroxyl moiety to the cyano moiety affords

cyclized pyran derivatives.


60

2.10 Experimental 2.10.1 Materials and Methods

Melting points were determined in open capillary tubes and are uncorrected.

Formation of the compounds was routinely checked by TLC on silica gel-G plates of

0.5 mm thickness and spots were located by iodine. IR spectra were recorded

Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were

recorded on Shimadzu GC-MS-QP-2010 model using Direct Injection Probe

technique. 1H NMR and 13C NMR was determined in DMSO-d6 solution on a Bruker

Ac 400 MHz spectrometer. Elemental analysis of the all the synthesized compounds

was carried out on Elemental Vario EL III Carlo Erba 1108 model and the results are

in agreements with the structures assigned.

2.10.2 Synthesis of 3-isopropyl-1H-pyrazol-5(4H)-one/3-isopropyl-1-phenyl-1H-

pyrazol-5(4H)-one

Synthesis of 3-propyl-1H-pyrazol-5(4H)-one/3-propyl-1-phenyl-1H-pyrazol-5 (4H)-

one was prepared by known literature method [122].

2.10.3 General procedure for the synthesis of 6-amino-4-(aryl)-1,4-dihydro-3-

propylpyrano[2,3-c]pyrazole-5-carbonitrile (YUG -101 to 120)

A mixture of the malononitrile (0.01 mol), 3-propyl-1H-pyrazol-5(4H)-one (0.01 mol)

and an appropriate aromatic aldehyde (0.01 mol) in 8-10 mL of EtOH/H2O (1:1) was

stirred for 30 min. After completion of the reaction, the reaction mixture was filtered

to give the solid products YUG-101 to 120, which were recrystallized from ethanol.

2.10.3.1 6-amino-1,4-dihydro-4-(4-methoxyphenyl)-3-propylpyrano[2,3-c]pyrazole

-5-carbonitrile (YUG-101)

O

NNH

CN

NH2

H3C

OCH3

1

2

34

5

6

7

8

91011

12

13

14

15

8

10

O

NNH

CN

NH2

H3C

OCH3

a

bc

d

ef

g g'

h h'

i


61

Yield: 70%; mp 168-171 ºC; IR (cm-1): 3514 (N-H stretching of free primary amine),

3254 (N-H stretching of pyrazole ring), 3093 (C-H stretching of aromatic ring), 2183

(C≡N stretching of the nitrile group), 1635 (C=N stretching of pyrazole ring), 1600

(N-H deformation pyrazole ring), 1188 (N-N deformation of pyrazole ring), 1053 (C-

H in plane bending of aromatic ring), 806 (C-H out of plane bending for 1,4-

disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.68-0.72 (t, 3H, Ha), 1.21-

1.35 (m, 2H, Hb), 2.04-2.22 (m, 2H, Hcc), 3.76 (s, 1H, Hd), 4.50 (s, 3H, He), 6.22 (s,

2H, Hf), 6.79-6.82 (m, 2H, Hgg’, J = 11.56 Hz), 7.06-7.10 (m, 2H, Hhh’, J = 14.2 Hz),

11.84 (s, 1H, Hi); 13C NMR (DMSO-d6) δ ppm: 13.15, 20.87, 26.32, 35.85, 54.73,

58.77, 97.10, 113.34, 120.62, 128.27, 136.19, 139.86, 154.68, 157.96, 160.31; MS:

m/z 310; Anal. Calcd. for C17H18N4O2: C, 65.79; H, 5.85; N, 18.05. Found: C, 65.75;

H, 5.81; N, 18.01%.

2.10.3.2 6-amino-1,4-dihydro-3-propyl-4-p-tolylpyrano[2,3-c]pyrazole-5-carbo-

nitrile (YUG-102)

1

2

3

4

5

6

7 8

9

10

11

12

13

14

15

10

O

NNH

CN

NH2

H3C

CH3

9a

bc

d

e

f

g h

O

NNH

CN

NH2

H3C

CH3

i j

k







1.36 (m, 2H, Hb), 2.02-2.24 (m, 2H, Hc), 2.30 (s, 1H, Hd), 4.50 (s, 3H, He), 6.40 (s, 2H,

Hf), 7.01-709 (m, 2H, Hg-j, J = 16.92 Hz), 11.88 (s, 1H, Hk); 13C NMR (DMSO-d6) δ

ppm: 13.16, 20.60, 26.30, 30.46, 36.27, 58.27, 97.05, 120.64, 127.19, 128.65, 135.65,

139.75, 141.26, 154.68, 160.47; MS: m/z 294; Anal. Calcd. for C17H18N4O: C, 69.37;

H, 6.16; N, 19.03. Found: C, 69.33; H, 6.12; N, 18.99%.


62

2.10.3.3 6-amino-4-(4-fluorophenyl)-1,4-dihydro-3-propylpyrano[2,3-c]pyrazole-

5-carbonitrile (YUG-103)

1

2

3

4

5

6

7

9

10

11

12

13

14

98

O

NNH

CN

NH2

H3C

F

a

bc

de

f f'g g'

hO

NNH

CN

NH2

H3C

F

7







1.36 (m, 2H, Hb), 2.03-2.22 (m, 2H, Hc), 4.56 (s, 1H, Hd), 6.40 (s, 3H, He), 6.98-7.03

(t, 2H, Hff’, J = 17.02 Hz), 7.16-7.19 (m, 2H, Hgg’, J = 13.84 Hz), 11.92 (s, 1H, Hk); 13C NMR (DMSO-d6) δ ppm: 13.13, 20.86, 26.30, 35.96, 58.05, 96.73, 114.63, 120.47,

128.93, 140.22, 154.63, 159.82, 160.48, 162.24; MS: m/z 298; Anal. Calcd. for

C16H15FN4O: C, 64.42; H, 5.07; N, 18.78. Found: C, 64.38; H, 5.03; N, 18.75%.

2.10.3.4 6-amino-4-(4-chlorophenyl)-1,4-dihydro-3-propylpyrano[2,3-c]pyrazole-


1

2

34

5

6 7

8

9

11

12

13

14

10

9

O

NNH

CN

NH2

H3C

Cl

a

bc

de

f f'g g'

hO

NNH

CN

NH2

H3C

Cl

8







63



(m, 2H, Hff’, J = 14.40 Hz), 7.27-7.30 (m, 2H, Hgg’, J = 10.76 Hz), 11.92 (s, 1H, Hh); 13C NMR (DMSO-d6) δ ppm: 13.17, 20.88, 26.28, 36.08, 57.46, 96.49, 120.44, 128.10,

128.98, 131.57, 139.76, 143.21, 154.63, 160.62; MS: m/z 314; Anal. Calcd. for

C16H15ClN4O: C, 61.05; H, 4.80; N, 17.80. Found: C, 61.01; H, 4.70; N, 17.70%.

2.10.3.5 6-amino-1,4-dihydro-3-propyl-4-(pyridin-3-yl)pyrano[2,3-c]pyrazole-5-

carbonitrile (YUG-105)

O

NNH

CN

NH2

H3C Na

b

c

d

e

f

g

h

i

h'





H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.68-0.72 (t, 3H,

Ha), 1.24-1.37 (m, 2H, Hb), 2.06-2.22 (m, 2H, Hc), 4.63 (s, 1H, Hd), 6.20 (s, 2H, He),

7.30-7.32 (d, 1H, Hf, J = 4.88 Hz), 7.54-7.56 (d, 1H, Hg, J = 7.6 Hz), 8.47 (s, 2H, Hh)

11.93 (s, 1H, Hi); MS: m/z 281; Anal. Calcd. for C15H15N5O: C, 64.04; H, 5.37; N,

24.90. Found: C, 64.01; H, 5.33; N, 24.87%.

2.10.3.6 6-amino-1,4-dihydro-4-(2-hydroxyphenyl)-3-propylpyrano[2,3-c]pyrazole-


O

NNH

CN

NH2

OH

Yield: 86%; mp 180-182 ºC; MS: m/z 296; Anal. Calcd. for C16H16N4O2: C, 64.85; H,

5.44; N, 18.91. Found: C, 64.81; H, 5.41; N, 18.89%.


64



O

NNH

CN

NH2

H3CCl

ab

c

d

e

ff'

g h

i







7.12-7.14 (t, 2H, Hff’, J = 8.16 Hz), 7.20-7.23 (m, 1H, Hg), 7.27-7.31 (t, 1H, Hh),

12.02 (s, 1H, Hi); MS: m/z 314; Anal. Calcd. for C16H15ClN4O: C, 61.05; H, 4.80; N,

17.80. Found: C, 61.03; H, 4.76; N, 17.76%.

2.10.3.8 6-amino-4-(4-bromophenyl)-1,4-dihydro-3-propylpyrano[2,3-c]pyrazole-


a

bc

d

e

f f'

g

hO

NNH

CN

NH2

H3C

Br

g'








(m, 2H, Hff’, J = 13.40 Hz), 7.41-7.44 (m, 2H, Hgg’, J = 13.12 Hz), 11.96 (s, 1H, Hh);


65

MS: m/z 359; Anal. Calcd. for C16H15BrN4O: C, 53.50; H, 4.21; N, 15.60. Found: C,

53.47; H, 4.19; N, 15.56%.

2.10.3.9 6-amino-1,4-dihydro-4-(4-hydroxyphenyl)-3-propylpyrano[2,3-c]pyra-

zole-5-carbonitrile (YUG-109)

O

NNH

CN

NH2

OH


5.44; N, 18.91. Found: C, 64.81; H, 5.41; N, 18.89%.

2.10.3.10 6-amino-1,4-dihydro-4-phenyl-3-propylpyrano[2,3-c]pyrazole-5-carbo-

nitrile (YUG-110)

1

2

3

4

5

6 7

9

10

11

12

13

14

10

9

8

O

NNH

CN

NH2

H3C

O

NNH

CN

NH2

H3Ca

b

c

d

e

f g

hi i'

j







7.16-7.22 (m, 3H, Hf-h), 7.26-7.30 (m, 2H, Hii’), 11.88 (s, 1H, Hj); 13C NMR (DMSO-

d6) δ ppm: 13.07, 20.81, 26.31, 36.65, 58.67, 96.87, 120.52, 126.48, 127.28, 127.98,

139.96, 143.95, 154.69, 160.42; MS: m/z 280; Anal. Calcd. for C16H16N4O: C, 68.55;

H, 5.75; N, 19.99. Found: C, 68.51; H, 5.72; N, 19.95%.


66

2.10.3.11 6-amino-1,4-dihydro-4-(3-hydroxyphenyl)-3-propylpyrano[2,3-c]pyraz-

ole-5-carbonitrile (YUG-111)

O

NNH

CN

NH2

OH


5.44; N, 18.91. Found: C, 64.81; H, 5.41; N, 18.87%.

2.10.3.12 6-amino-4-(2,4-dichlorophenyl)-1,4-dihydro-3-propylpyrano[2,3-c]-

pyrazole-5-carbonitrile (YUG-112)

O

NNH

CN

NH2

Cl

Cl

Yield: 82%; mp 220-223 ºC; MS: m/z 348; Anal. Calcd. for C16H14Cl2N4O: C, 55.03;

H, 4.04; N, 16.04. Found: C, 55.00; H, 4.01; N, 16.00%.

2.10.3.13 6-amino-4-(3-bromophenyl)-1,4-dihydro-3-propylpyrano[2,3-c]pyrazole-5-ca-

rbonitrile (YUG-113)

O

NNH

CN

NH2

Br

Yield: 72%; mp 194-196 ºC; MS: m/z 358; Anal. Calcd. for C16H15BrN4O: C, 53.50;

H, 4.21; N, 15.60. Found: C, 53.46; H, 4.18; N, 15.56%.


67

2.10.3.14 6-amino-4-(2-bromophenyl)-1,4-dihydro-3-propylpyrano[2,3-c]pyrazole-5-ca-

rbonitrile (YUG-114)

O

NNH

CN

NH2

N

Yield: 81%; mp 230-232 ºC; MS: m/z 281; Anal. Calcd. for C15H15N5O: C, 64.04; H,

5.37; N, 24.90. Found: C, 64.01; H, 5.33; N, 24.87%.

2.10.3.15 6-amino-4-(2-bromophenyl)-1,4-dihydro-3-propylpyrano[2,3-c]pyraz-

ole-5-carbonitrile (YUG-115)

a

b

c

d

e

f

g h

O

NNH

CN

NH2

H3C

i

Br

f'







7.03-7.13 (m, 2H, Hff’), 7.22-7.33 (m, 1H, Hg), 7.45-7.56 (m, 1H, Hh) 11.92 (s, 1H,

Hj); MS: m/z 358; Anal. Calcd. for C16H15BrN4O: C, 53.50; H, 4.21; N, 15.60. Found:

C, 53.46; H, 4.18; N, 15.56%.


68

2.10.3.16 6-amino-4-(2,6-dichlorophenyl)-1,4-dihydro-3-propylpyrano[2,3-c]pyr-

azole-5-carbonitrile (YUG-116)

ab c

d

e

f

g

hO

NNH

CN

NH2

H3CCl Cl

f'







7.03-7.13 (m, 2H, Hff’), 7.22-7.33 (m, 1H, Hg), 7.45-7.56 (m, 1H, Hh) 11.92 (s, 1H,

Hj); MS: m/z 349; Anal. Calcd. for C16H14Cl2N4O: C, 55.03; H, 4.04; N, 16.04. Found:

C, 55.00; H, 4.00; N, 16.00%.



O

NNH

CN

NH2

Cl

Yield: 79%; mp 185-187 ºC; MS: m/z 314; Anal. Calcd. for C16H15ClN4O: C, 61.05;

H, 4.80; N, 17.80. Found: C, 61.01; H, 4.76; N, 17.76%.


69

2.10.3.18 6-amino-1,4-dihydro-4-(3,4-dimethoxyphenyl)-3-propylpyrano[2,3-c]p-

yrazole-5-carbonitrile (YUG-118)

O

NNH

CN

NH2

O

O


4.80; N, 17.80. Found: C, 61.01; H, 4.76; N, 17.77%.

2.10.3.19 6-amino-1,4-dihydro-4-(2,5-dimethoxyphenyl)-3-propylpyrano[2,3-c]-

pyrazole-5-carbonitrile(YUG-119)

O

NNH

CN

NH2

O

O


4.80; N, 17.80. Found: C, 61.01; H, 4.76; N, 17.77%.

2.10.3.20 6-amino-1,4-dihydro-4-(3,4,5-trimethoxyphenyl)-3-propylpyrano[2,3-

c]pyrazole-5-carbonitrile (YUG-120)

O

NNH

CN

NH2

O

O

O


5.99; N, 15.13;. Found: C, 61.58; H, 5.97; N, 15.08%.


70

2.10.4 General procedure for the synthesis of 6-amino-1,4-dihydro-3-isopropyl-4-

(aryl)-1-phenylpyrano[2,3-c]pyrazole-5-carbonitrile (YUG -121 to 140)

A mixture of the malononitrile (0.01 mol), 3-propyl-1-phenyl-1H-pyrazol-5(4H)-one

(0.01 mol) and an appropriate aromatic aldehyde (0.01 mol) in 8-10 mL of EtOH/H2O

(1:1) was stirred for 30 min. After completion of the reaction, the reaction mixture

was filtered to give the solid products YUG-121 to 140, which were recrystallized

from ethanol.

2.10.4.1 6-amino-1,4-dihydro-4-(4-methoxyphenyl)-1-phenyl-3-propylpyrano[2,3

-c]pyrazole-5-carbonitrile (YUG-121)

O

NN

CN

NH2

H3C

OCH3

ab

c

d

e

f f'

g

h h'

i

jj'

kk'

O

NN

CN

NH2

H3C

OCH3

1

2

34

5

617

10

1112

13

14

98 7

10

11

19

13

15

16

18

14


3026 (C-H stretching of aromatic ring), 2193 (C≡N stretching of the nitrile group),

1629 (C=N stretching of pyrazole ring), 1176 (N-N deformation of pyrazole ring),

1070 (C-H in plane bending of aromatic ring), 812 (C-H out of plane bending for 1,4-



(d, 2H, Hff’, J = 8.56 Hz), 6.99 (s, 2H, Hg), 7.14-7.16 (d, 2H, Hhh’, J = 8.56 Hz), 7.26-

7.35 (m, 1H, Hi), 7.43-7.48 (m, 2H, Hjj’), 7.79-7.87 (dd, 2H, Hkk’, J = 7.84 Hz) 11.92

(s, 1H, Hj); 13C NMR (DMSO-d6) δ ppm: 13.57, 20.72, 28.93, 30.52, 36.36, 54.87,

54.87, 58.95, 98.16, 113.62, 119.88, 125.76, 128.62, 128.99, 135.67, 137.66, 143.72,

149.06, 158.20, 159.04; MS: m/z 386; Anal. Calcd. for C23H22N4O2: C, 71.48; H, 5.74;

N, 14.50. Found: C, 71.44; H, 5.70; N, 14.46%.


71

2.10.4.2 6-amino-1,4-dihydro-1-phenyl-3-propyl-4-p-tolylpyrano[2,3-c]pyrazole

-5-carbonitrile (YUG-122)

O

NN

CN

NH2

H3C

CH3


5.99; N, 15.12. Found: C, 74.53; H, 5.95; N, 15.08%.

2.10.4.3 6-amino-4-(4-fluorophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3-


1

2

3

4

5

6

1811

9

8

710

11

12

13

16

178

14O

NN

CN

NH2

H3C

F

ab

cd

ej'

i'

h i

j

f f'

g g'

O

NN

CN

NH2

H3C

F

10

13

15







(t, 2H, Hff’), 7.26-7.30 (m, 3H, Hgg’h), 7.44-7.48 (t, 2H, Hii’), 7.81-7.83 (t, 2H, Hjj’); 13C NMR (DMSO-d6) δ ppm: 13.52, 20.71, 28.93, 36.42, 58.51, 97.78, 115.12, 119.94,

125.81, 129.40, 137.63,139.79, 143.79, 148.96, 159.18, 160.00, 162.43, 169.99; MS:

m/z 374; Anal. Calcd. for C22H19FN4O: C, 70.57; H, 5.11; N, 14.96. Found: C, 70.54;

H, 5.08; N, 14.92%.


72

2.10.4.4 6-amino-4-(4-chlorophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3-


O

NN

CN

NH2

H3C

Cl

ab

cd

e

f g

h

i

jj'

kk'

i'







(t, 3H, Hf-h), 7.32-7.36 (t, 2H, Hii’), 7.40-7.48 (m, 2H, Hjj’), 7.80-7.82 (d, 2H, Hkk’, J =

8.00 Hz); MS: m/z 370; Anal. Calcd. for C23H22N4O: C, 74.57; H, 5.99; N, 15.12.

Found: C, 74.53; H, 5.95; N, 15.08%.

2.10.4.5 6-amino-1,4-dihydro-4-(4-nitrophenyl)-1-phenyl-3-propylpyrano[2,3-


O

NN

CN

NH2

H3C

NO2


4.77; N, 17.45;. Found: C, 65.80; H, 4.73; N, 17.40%.


73

2.10.4.6 6-amino-1,4-dihydro-4-(3-nitrophenyl)-1-phenyl-3-propylpyrano[2,3-c]-


O

NN

CN

NH2

H3CNO2


4.77; N, 17.45;. Found: C, 65.81; H, 4.74; N, 17.41%.



O

NN

CN

NH2

H3Cab

cd

ef

gh

i

j

k

k' Cll

l'




1072 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.76-

0.80 (t, 3H, Ha), 1.24-1.46 (m, 2H, Hb), 2.05-2.22 (m, 2H, Hc), 4.65 (s, 1H, Hd), 6.94

(s, 2H, He), 7.19-7.34 (m, 5H, Hf-j), 7.44-7.47 (t, 2H, Hkk’), 7.79-7.80 (d, 2H, Hll’, J =


Found: C, 74.53; H, 5.96; N, 15.08%.


74

2.10.4.8 6-amino-4-(4-bromophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3-


O

NN

CN

NH2

H3C

Br

ab

cd

e

f f'

g

h

h' i

j

g'

i'







(dd, 2H, Hff’), 7.27-7.34 (m, 2H, Hgg’), 7.40-7.51 (m, 2H, Hhh’), 7.88-7.90 (d, 1H, Hj);

MS: m/z 434; Anal. Calcd. for C22H19BrN4O: C, 60.70; H, 4.40; N, 12.87. Found: C,

60.76; H, 4.36; N, 12.83%.

2.10.4.9 6-amino-1,4-dihydro-4-(4-hydroxyphenyl)-1-phenyl-3-propylpyrano[2,3-c]


O

NN

CN

NH2

H3C

OH


5.41; N, 15.04. Found: C, 70.91; H, 5.37; N, 14.99%.


75

2.10.4.10 6-amino-1,4-dihydro-1,4-diphenyl-3-propylpyrano[2,3-c]pyrazole-5-

carbonitrile (YUG-130)

O

NN

CN

NH2

H3Cab

cd

e

f g

hi

j

k l

l' mm'




1072 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.73-0.77

(t, 3H, Ha), 1.23-1.43 (m, 2H, Hb), 2.02-2.19 (m, 2H, Hc), 4.62 (s, 1H, Hd), 6.88 (s,

2H, He), 7.23-7.34 (m, 6H, Hf-k), 7.40-7.47 (m, 2H, Hll’), 7.79-7.81 (d, 2H, Hmm’, J =


Found: C, 74.10; H, 5.62; N, 15.68%.

2.10.4.11 6-amino-1,4-dihydro-4-(3-hydroxyphenyl)-1-phenyl-3-propylpyrano[2,3-


O

NN

CN

NH2

H3COH


5.41; N, 15.04. Found: C, 70.91; H, 5.37; N, 15.01%.


76

2.10.4.12 6-amino-4-(2,4-dichlorophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3


O

NN

CN

NH2

H3C

Cl

Cl

O

NN

CN

NH2

H3Cab

cd

e

fg

h

i

j k

ll'

Cl

Cl

1

2

3

4

5

67

8

9

10 11

12

13

14

15

16

1718

19

20

9

13






2H, He), 7.28-7.38 (m, 3H, Hf-h), 7.45-7.52 (m, 3H, Hi-k), 7.79-7.81 (d, 2H, Hll’, J =

7.76 Hz); 13C NMR (DMSO-d6) δ ppm: 13.51, 20.91, 28.88, 30.55, 56.53, 96.81,

99.49, 119.35, 120.00, 125.99, 127.86, 128.70, 129.07, 132.26, 132.50, 133.00,

137.53, 144.18, 148.62, 159.76; MS: m/z 424; Anal. Calcd. for C22H18Cl2N4O: C,

62.13; H, 4.27; N, 13.17. Found: C, 62.09; H, 4.23; N, 13.13%.

2.10.4.13 6-amino-4-(3-bromophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3-


O

NN

CN

NH2

H3CBr


H, 4.40; N, 12.87. Found: C, 60.76; H, 4.36; N, 12.83%.


77

2.10.4.14 6-amino-1,4-dihydro-1-phenyl-3-propyl-4-(pyridin-2-yl)pyrano[2,3-c]


O

NN

CN

NH2

H3CN


5.36; N, 19.59. Found: C, 70.53; H, 5.32; N, 19.55%.

2.10.4.15 6-amino-4-(2-bromophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3-c]-


O

NN

CN

NH2

H3C

Br


H, 4.40; N, 12.87. Found: C, 60.76; H, 4.36; N, 12.83%.

2.10.4.16 6-amino-4-(2,6-dichlorophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3


O

NN

CN

NH2

H3Ca

bc

d

e

fg

h

i

jk

ll'

ClCl


78






2H, He), 7.25-7.32 (m, 3H, Hf-h), 7.43-7.47 (m, 3H, Hi-k), 7.78-7.80 (d, 2H, Hll’, J =

8.00 Hz); MS: m/z 424; Anal. Calcd. for C22H18Cl2N4O: C, 62.13; H, 4.27; N, 13.17.

Found: C, 62.09; H, 4.23; N, 13.13%.



O

NN

CN

NH2

H3C

Cl


5.99; N, 15.12. Found: C, 74.53; H, 5.95; N, 15.08%.

2.10.4.18 6-amino-1,4-dihydro-4-(3,4-dimethoxyphenyl)-1-phenyl-3-propylpyrano[2,3-c]


O

NN

CN

NH2

H3CO

O


5.81; N, 13.45. Found: C, 69.18; H, 5.77; N, 13.41%.


79

2.10.4.19 6-amino-1,4-dihydro-4-(2,5-dimethoxyphenyl)-1-phenyl-3-propylpyrano[2,3-c]


O

NN

CN

NH2

H3C

O

O


5.81; N, 13.45. Found: C, 69.18; H, 5.78; N, 13.41%.

2.10.4.20 6-amino-1,4-dihydro-4-(3,4,5-trimethoxyphenyl)-1-phenyl-3-propylpyr-

ano[2,3-c]pyrazole-5-carbonitrile (YUG-140)

O

NN

CN

NH2

H3CO

O

O


5.87; N, 12.55. Found: C, 67.21; H, 5.83; N, 12.51%.


80

2.11 Spectral discussion 2.11.1 Mass spectral study

Mass spectra were recorded on Shimadzu GC-MS-QP-2010 model using Direct

Injection Probe technique. Systematic fragmentation pattern was observed in mass

spectral analysis. Molecular ion peak was observed in agreement with molecular

weight of respective compound. Mass fragmentation pattern for a representative

compound of each series is depicted below.

2.11.2 IR spectral study

IR spectra were recorded on Shimadzu FT-IR-8400 model using KBr pellet method.

Various functional groups present in molecule were identified by characteristic

frequency obtained for them. For pyrano[2,3-c]pyrazoles (YUG-101 to 140),

confirmatory bands for primary amine (-NH2) and nitrile (C≡N) stretching band was

observed at 3473-3500 cm-1. Another characteristic band for N-H deformation was

observed at 1597-1610 cm-1, which suggested the formation of pyranopyrazoles ring

system.

2.11.3 1H NMR spectral study 1H NMR spectra were recorded in DMSO-d6 solution on a Bruker Ac 400 MHz

spectrometer using TMS as an internal standard. Number of protons and their

chemical shifts were found to support the structure of the synthesized compounds. 1H

NMR spectra confirmed the structures of pyrano[2,3-c]pyrazoles (YUG-101 to 140)

on the basis of following signals: singlet for primary amino group proton was

observed at 6.12-7.23 δ ppm and a singlet for the methine proton of pyran ring at

4.58-5.71 δ ppm. The aromatic ring protons and J value were found to be in

accordance with substitution pattern on phenyl ring.

2.11.4 13C NMR spectral study 13C NMR spectra were recorded in DMSO-d6 solution on a Bruker Ac 400 MHz

spectrometer. Number of carbons and their chemical shifts were found to support the

structure of the synthesized compounds. 13C NMR spectra confirmed the structures of

pyrano[2,3-c]pyrazoles (YUG-101 to 140) on the basis of sfollowing signals: signal

for chiral carbon of pyran ring was observed at 20-22 δ ppm. Signal for carbon of


81

cyano group was observed at 110-120 δ ppm, indicates the involvement of

malanonitrile in cyclization process.


82

Mass Spectrum of YUG-101

IR Spectrum of YUG-101

400600800100012001400160018002000240028003200360040001/cm

45

52.5

60

67.5

75

82.5

90

97.5

%T

3607

.01

3514

.42

3381

.33

3254

.02

3093

.92

2960

.83

2870

.17 28

37.3

8

2183

.49

1649

.19 16

35.6

93

1510

.31

1489

.10

1406

.15

1300

.07

1257

.63

1238

.34

1168

.90

1103

.32

1068

.60

1026

.16

868.

0080

8.20 75

2.26

734.

9068

6.68

443.

64

YUG-101


83

1H NMR Spectrum of YUG-101

Expanded 1H NMR Spectrum of YUG-101


84




85

13C NMR Spectrum of YUG-101



86


400600800100012001400160018002000240028003200360040001/cm

45

52.5

60

67.5

75

82.5

90

97.5

105

112.5

120%T

3473

.91

3227

.02

3117

.07

3039

.91

2964

.69

2870

.17

2196

.99

1635

.69

1600

.97

1516

.10

1487

.17

1396

.51

1220

.98

1188

.19

1053

.17

939.

3686

9.92

806.

2774

2.62

650.

03

YUG-102



87




88




89


400600800100012001400160018002000240028003200360040001/cm

-0

10

20

30

40

50

60

70

80

90

100%T

3487

.42

3234

.73

3223

.16

3182

.65

3163

.36

3091

.99

3057

.27

3045

.70 29

76.2

629

62.7

628

77.8

9

2196

.99

1631

.83 16

04.8

315

93.2

515

27.6

715

04.5

314

92.9

514

54.3

814

33.1

613

96.5

112

92.3

512

30.6

312

15.1

911

82.4

011

55.4

010

91.7

510

49.3

1

862.

21 823.

63 781.

2075

0.33 73

4.90

445.

5741

4.71

YUG-103 1H NMR Spectrum of YUG-103


90




91




92


40060080010001200140016001800200024002800320036001/cm

30

40

50

60

70

80

90

100

110

120

130%T

3475

.84

3230

.87

3113

.21

3043

.77

2966

.62

2872

.10

2359

.02

2195

.07

1635

.69

1599

.04

1523

.82

1489

.10

1396

.51

1286

.56

1219

.05

1186

.26

1089

.82

1053

.17

1022

.31

866.

0781

3.99

750.

33

671.

25

YUG-104



93




94




95


400600800100012001400160018002000240028003200360040001/cm

20

30

40

50

60

70

80

90

100

110

120

130%T

3321

.53

3294

.53 32

65.5

932

40.5

231

11.2

830

99.7

130

84.2

830

22.5

530

10.9

829

56.9

7 2895

.25

2193

.14

1643

.41

1612

.54

1600

.97

1492

.95

1427

.37

1406

.15

1350

.22 12

86.5

612

17.1

211

78.5

5

1049

.31

873.

78

736.

83

628.

8160

1.81

412

78



96




97



400600800100012001400160018002000240028003200360040001/cm

30

40

50

60

70

80

90

100

110

120

130%T

3454

.62

3244

.38

3113

.21

3057

.27

2962

.76 28

72.1

0

2193

.14

1635

.69

1591

.33

1527

.67

1491

.02

1433

.16

1402

.30

1301

.99

1284

.63

1184

.33

1076

.32

1051

.24

997.

2397

0.23

889.

21

785.

0574

4.55

711.

7668

2.82

YUG-107


98




99




100


400600800100012001400160018002000240028003200360040001/cm

30

40

50

60

70

80

90

100

110

120

130%T

3471

.98

3223

.16 31

15.1

430

39.9

129

64.6

928

70.1

7

2196

.99

1633

.76

1600

.97

1525

.74

1487

.17

1394

.58

1219

.05

1184

.33

1070

.53

1051

.24

1012

.66

858.

3581

3.99

746.

48

617.

24

488.

01

406

99



101




102



400600800100012001400160018002000240028003200360040001/cm

40

50

60

70

80

90

100

110

120

130%T

3485

.49

3230

.87

3111

.28

3034

.13

2968

.55

2874

.03

2818

.09

2195

.07

1631

.83

1599

.04

1529

.60

1489

.10

1452

.45

1398

.44

1294

.28 12

53.7

712

19.0

511

84.3

3

1051

.24

910.

4386

0.28

812.

06

734.

9070

0.18

408

92

YUG-110


103




104




105



400600800100012001400160018002000240028003200360040001/cm

37.5

45

52.5

60

67.5

75

82.5

90

97.5

105%T

3473

.91

3232

.80 31

05.5

029

64.6

928

72.1

0 2818

.09

2193

.14

1637

.62

1597

.11

1525

.74

1489

.10

1438

.94

1398

.44

1327

.07

1265

.35

1215

.19

1163

.11

1053

.17

862.

2181

2.06

740.

69

655.

8261

5.31

422.

4240

892

YUG-115


106




107




108


400600800100012001400160018002000240028003200360040001/cm

30

40

50

60

70

80

90

100

110

120%T

3639

.80

3541

.42

3369

.75

3304

.17

3240

.52

3109

.35

3099

.71

2829

.67

2187

.35 16

53.0

516

06.7

6

1529

.60

1494

.88

1431

.23

1406

.15

1292

.35

1222

.91

1159

.26

1070

.53

1047

.38

873.

7882

5.56

779.

2774

6.48

441.

7164



109




110



400600800100012001400160018002000240028003200360040001/cm

10

20

30

40

50

60

70

80

90

100

%T

3400

.62 33

23.4

632

65.5

932

05.8

030

26.4

129

58.9

0 2933

.83 28

39.3

1

2193

.14

1660

.77

1629

.90

1599

.04

1516

.10

1491

.02

1456

.30

1398

.44

1255

.70

1176

.62

1128

.39

1107

.18

1070

.53

1028

.09

910.

4384

6.78

812.

0675

4.19 68

8.61

669.

32

515.

0146

6.79

414

71

YUG-121


111




112




113



400600800100012001400160018002000240028003200360040001/cm

52.5

60

67.5

75

82.5

90

97.5

105

%T

3458

.48 33

23.4

632

59.8

132

13.5

130

66.9

229

60.8

328

74.0

3

2198

.92

1664

.62

1595

.18

1516

.10

1456

.30

1392

.65

1332

.86

1265

.35

1224

.84 11

28.3

910

70.5

310

22.3

1

817.

8575

4.19

682.

82

515.

01

YUG-123


114




115




116


400600800100012001400160018002000240028003200360040001/cm

37.5

45

52.5

60

67.5

75

82.5

90

97.5

105%T

3454

.62 33

23.4

631

98.0

830

61.1

329

55.0

4 2870

.17

2198

.92

1660

.77

1595

.18

1518

.03

1489

.10

1454

.38

1394

.58

1263

.42 11

78.5

511

26.4

7 1087

.89

1068

.60

1018

.45

908.

50

806.

2775

2.26 68

8.61

516.

94

412

78



117




118



400600800100012001400160018002000240028003200360040001/cm

45

52.5

60

67.5

75

82.5

90

97.5

105%T

3462

.34

3335

.03

3070

.78

2960

.83

2874

.03

2193

.14

1656

.91

1591

.33

1518

.03

1485

.24

1454

.38

1392

.65

1325

.14

1259

.56

1184

.33

1130

.32

1072

.46

1030

.02 89

8.86

786.

9875

2.26

688.

61

YUG-127


119




120




121


400600800100012001400160018002000240028003200360040001/cm

15

30

45

60

75

90

105

120

%T

3448

.84 33

21.5

332

54.0

232

13.5

132

00.0

130

57.2

729

51.1

929

28.0

428

68.2

4

2196

.99

1660

.77

1624

.12

1589

.40

1516

.10

1489

.10

1454

.38

1398

.44

1329

.00

1282

.71

1261

.49 11

76.6

211

26.4

710

99.4

610

70.5

310

16.5

2

908.

5082

9.42

802.

4175

0.33 68

0.89

650.

0357

8.66

516.

94 503.

4447

6.43



122




123



400600800100012001400160018002000240028003200360040001/cm

45

52.5

60

67.5

75

82.5

90

97.5

105%T

3462

.34

3335

.03

3070

.78

2960

.83

2874

.03

2193

.14

1656

.91

1591

.33

1518

.03

1485

.24

1454

.38

1392

.65

1325

.14

1259

.56

1184

.33

1130

.32

1072

.46

1030

.02 89

8.86

786.

9875

2.26

688.

61

YUG-127


124




125




126


400600800100012001400160018002000240028003200360040001/cm

-10

0

10

20

30

40

50

60

70

80

90

100%T

3462

.34

3323

.46

3230

.87

3209

.66

2989

.76

2960

.83

2870

.17

2196

.99

1660

.77

1589

.40 15

81.6

815

18.0

314

69.8

114

54.3

813

96.5

113

83.0

1

1265

.35

1128

.39

1101

.39

1068

.60

840.

9981

3.99

750.

3368

6.68

426.

2841

471



127




128




129


400600800100012001400160018002000240028003200360040001/cm

-0

10

20

30

40

50

60

70

80

90

100%T

3454

.62

3338

.89

2995

.55

2958

.90

2852

.81

2193

.14

1654

.98

1591

.33

1581

.68

1518

.03

1454

.38

1388

.79

1261

.49

1186

.26

1128

.39

1070

.53

1028

.09

786.

9875

0.33

684.

75

455.

2242

6.28



130




131



400600800100012001400160018002000240028003200360040001/cm

-0

10

20

30

40

50

60

70

80

90

100%T

3450

.77

3163

.36

3088

.14

2955

.04

2868

.24

2195

.07

1658

.84

1624

.12

1599

.04

1518

.03

1496

.81

1452

.45

1433

.16

1400

.37

1381

.08

1330

.93

1265

.35 11

88.1

911

32.2

5 1070

.53

1030

.02

898.

8683

3.28

783.

1375

0.33 68

4.75

640.

39

422.

42

YUG-136


132




133



134

2.12 X-Ray Diffraction Study of pyrano[2,3-c]pyrazole 2.12.1 Single Crystal X-Ray Diffraction Analysis of 6-amino-1,4-dihydro-4-phenyl-

3-propylpyrano[2,3-c]pyrazole-5-carbonitrile (YUG-110)

Single crystal X-ray diffraction is the most common experimental method for

obtaining a detailed picture of a small molecule that allows resolution of individual

atoms. It is performed by analyzing the diffraction of x-rays from an ordered array of

many identical molecules. Many molecular substances, including proteins, polymers

and other solidify in to crystals under the proper conditions. When solidifying in to

the crystalline state, these individual molecules typically adapted as one of only a few

possible orientations. A crystal is a three dimensional array of those molecules that

are held together by Van der Waals and noncovalent bonding. The smallest

representative unit of this crystal is referred to as the unit cell. Understanding the unit

cell of these arrays simplifies the understanding of a crystal as a whole.

2.12.2 Procedure for the development of single crystal

In the present study, the pure, single spot (on TLC) compound was taken in ethanol

and heated with stirring till it dissolved. A small quantity of charcoal was added for

decolorizing. The solution was then heated to boiling and immediately filtered while

hot in corkable 50 ml conical flask using Whatmann filter paper. The flask was

corked and kept for several days. The crystals thus grown by thin film evaporation

technique were isolated and washed with chilled methanol. The functional groups and

proton and carbon framework of 6-amino-1,4-dihydro-4-phenyl-3-propylpyrano[2,3-

c]pyrazole-5-carbonitrile was supported by IR, 1H NMR, 13C NMR and Mass Spectral

studies.

2.12.3 Single Crystal X-ray Diffraction and Structure Determination

X-ray single-crystal data was collected using Mo Kα radiation (λ=0.71073 Å)

radiation on a SMART APEX diffractometer equipped with CCD area detector. Data

collection, data reduction and structure solution/refinement were carried out using the

software package of SMART APEX. Table 1 shows the unit cell parameters and other

crystallographic details. All the structures were solved by direct method and refined

in a routine manner. In most of the cases, nonhydrogen atoms were treated


135

anisotropically. Whenever possible, the hydrogen atoms were located on a difference

Fourier map and refined. In other cases, the hydrogen atoms were geometrically

fixed. CCDC no. 893155 contains the supplementary crystallographic data for this

article. These data can be obtained from www.ccdc.cam.ac.uk/conts/retrieving.html

free of charge (or from the Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB21EZ, UK; fax: (+44) 1223-336-033; or [email protected]).


136

2.12.3.1 ORTEP diagram of the organic compound with atom numbering scheme

(40% probability factor for the thermal ellipsoids)


137

2.12.3.2 Crystal data and structure refinement

Table 1

Empirical formula C16H16N4 O

Formula weight 280.33

Temperature 110(2) K

Wavelength 0.71073 Å

Crystal system Monoclinic

Spacegroup C2/c

Cell dimensions a = 18.891(3) Å b = 5.8705(10) Å c = 25.570(4) Å β = 90.544(3)º

Volume 2835.6(8) Å3

Z 8

Density(calculated) 1.313 Mg/m 3

Absorption coefficient 0.086 mm -1

F000 1184

Crystal size 0.30 x 0.24 x 0.04 mm

Theta range for data collection 1.59º-25.00º

Index ranges -22 ≤ h ≤ 10 -6 ≤ k ≤ 6 -30 ≤ l ≤ 30

Reflections collected 5480

Independent reflections 2478 [R(int) = 0.0333]

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 2478/0/197

Goodness-of-fit on F2 1.297

Final R indices [I>2�(I)] R1 = 0.0996, wR2 = 0.1825

R indices (all data) R1 = 0.1092, wR2 = 0.1867

Largest diff. peak and hole 0.541 and -0.462 e.Å-3


138

2.12.3.3 Bond length (Å)

Table 2

No. Atom1 Atom2 Length No. Atom1 Atom2 Length 1 O1 C1 1.372(4) 21 C8 C13 1.404(6) 2 O1 C5 1.383(5) 22 C9 H9 0.930(4) 3 N1 C1 1.351(5) 23 C9 C10 1.397(6) 4 N1 H2C 0.77(6) 24 C10 H10 0.929(4) 5 N1 H1C 0.82(6) 25 C10 C11 1.384(6) 6 N2 C7 1.148(5) 26 C11 H11 0.930(4) 7 N3 H3C 0.860(3) 27 C11 C12 1.384(6) 8 N3 N4 1.370(5) 28 C12 H12 0.930(4) 9 N3 C5 1.308(5) 29 C12 C13 1.385(6) 10 N4 C6 1.356(5) 30 C13 H13 0.930(4) 11 C1 C2 1.373(6) 31 C14 H14A 0.971(4) 12 C2 C3 1.537(5) 32 C14 H14B 0.969(4) 13 C2 C7 1.428(5) 33 C14 C15 1.528(5) 14 C3 H3 0.980(4) 34 C15 H15A 0.970(5) 15 C3 C4 1.514(5) 35 C15 H15B 0.969(4) 16 C3 C8 1.535(5) 36 C15 C16 1.527(6) 17 C4 C5 1.382(6) 37 C16 H16A 0.961(5) 18 C4 C6 1.395(5) 38 C16 H16B 0.960(4) 19 C6 C14 1.501(6) 39 C16 H16C 0.961(4) 20 C8 C9 1.392(6)


139

2.12.3.4 Bond angles (º)

Table 3

No. Atom1 Atom2 Atom3 Angle No. Atom1 Atom2 Atom3 Angle 1 C1 O1 C5 115.2(3) 34 C8 C9 H9 119.6(4)2 C1 N1 H2C 120(4) 35 C8 C9 C10 120.8(4)3 C1 N1 H1C 115(4) 36 H9 C9 C10 119.6(4)4 H2C N1 H1C 125(6) 37 C9 C10 H10 119.9(4)5 H3C N3 N4 128.4(3) 38 C9 C10 C11 120.1(4)6 H3C N3 C5 128.5(4) 39 H10 C10 C11 120.0(4)7 N4 N3 C5 103.2(3) 40 C10 C11 H11 120.2(4)8 N3 N4 C6 112.4(3) 41 C10 C11 C12 119.6(4)9 O1 C1 N1 109.8(3) 42 H11 C11 C12 120.1(4)10 O1 C1 C2 123.4(3) 43 C11 C12 H12 119.7(4)11 N1 C1 C2 126.8(4) 44 C11 C12 C13 120.7(4)12 C1 C2 C3 126.0(3) 45 H12 C12 C13 119.7(4)13 C1 C2 C7 116.2(3) 46 C8 C13 C12 120.4(4)14 C3 C2 C7 117.7(3) 47 C8 C13 H13 119.8(4)15 C2 C3 H3 108.6(3) 48 C12 C13 H13 119.8(4)16 C2 C3 C4 105.8(3) 49 C6 C14 H14A 108.5(3)17 C2 C3 C8 110.0(3) 50 C6 C14 H14B 108.5(3)18 H3 C3 C4 108.7(3) 51 C6 C14 C15 115.2(3)19 H3 C3 C8 108.7(3) 52 H14A C14 H14B 107.5(4)20 C4 C3 C8 114.9(3) 53 H14A C14 C15 108.5(3)21 C3 C4 C5 123.7(3) 54 H14B C14 C15 108.5(3)22 C3 C4 C6 132.5(3) 55 C14 C15 H15A 109.3(4)23 C5 C4 C6 103.8(3) 56 C14 C15 H15B 109.3(4)24 O1 C5 N3 119.6(3) 57 C14 C15 C16 111.6(3)25 O1 C5 C4 125.8(3) 58 H15A C15 H15B 108.0(4)26 N3 C5 C4 114.6(3) 59 H15A C15 C16 109.3(4)27 N4 C6 C4 106.0(3) 60 H15B C15 C16 109.3(4)28 N4 C6 C14 122.8(3) 61 C15 C16 H16A 109.4(4)29 C4 C6 C14 131.1(3) 62 C15 C16 H16B 109.5(4)30 N2 C7 C2 179.1(4) 63 C15 C16 H16C 109.5(4)31 C3 C8 C9 120.2(3) 64 H16A C16 H16B 109.5(4)32 C3 C8 C13 121.3(3) 65 H16A C16 H16C 109.4(4)33 C9 C8 C13 118.4(3) 66 H16B C16 H16C 109.5(4)


140

2.12.3.5 Atomic coordinates and equivalent thermal parameters of the non-

hydrogen atoms

Table 4

No. Label Xfrac + ESD Yfrac + ESD Zfrac + ESD Uequiv 1 O1 0.27988(13) 0.5584(5) 0.03168(10) 0.0202 2 N1 0.39494(19) 0.5637(7) 0.01349(15) 0.0255 3 N2 0.47364(17) 0.0578(7) 0.06343(13) 0.0255 4 N3 0.15972(16) 0.5469(6) 0.05046(12) 0.0206 5 H3C 0.1478 0.6694 0.0342 0.0250 6 N4 0.11752(16) 0.4012(6) 0.07812(12) 0.0179 7 C1 0.34311(18) 0.4460(7) 0.03756(14) 0.0166 8 C2 0.35023(19) 0.2441(7) 0.06416(14) 0.0178 9 C3 0.29078(19) 0.1148(7) 0.09211(14) 0.0163 10 H3 0.2845 -0.0336 0.0751 0.0200 11 C4 0.22434(19) 0.2547(7) 0.08346(14) 0.0169 12 C5 0.22247(19) 0.4543(7) 0.05483(14) 0.0160 13 C6 0.15430(19) 0.2237(7) 0.09867(14) 0.0147 14 C7 0.4188(2) 0.1420(7) 0.06351(15) 0.0188 15 C8 0.31109(18) 0.0756(7) 0.14967(14) 0.0163 16 C9 0.3476(2) -0.1204(7) 0.16450(16) 0.0223 17 H9 0.3576 -0.2310 0.1396 0.0260 18 C10 0.3694(2) -0.1527(8) 0.21631(17) 0.0280 19 H10 0.3943 -0.2833 0.2256 0.0340 20 C11 0.3539(2) 0.0094(8) 0.25377(16) 0.0257 21 H11 0.3684 -0.0117 0.2883 0.0310 22 C12 0.3166(2) 0.2031(8) 0.23962(16) 0.0250 23 H12 0.3056 0.3111 0.2649 0.0300 24 C13 0.29543(19) 0.2377(7) 0.18823(15) 0.0196 25 H13 0.2707 0.3691 0.1792 0.0230 26 C14 0.1206(2) 0.0432(7) 0.13175(15) 0.0207 27 H14A 0.1417 0.0493 0.1665 0.0250 28 H14B 0.1317 -0.1045 0.1170 0.0250 29 C15 0.0403(2) 0.0619(8) 0.13696(17) 0.0260 30 H15A 0.0284 0.2109 0.1507 0.0320 31 H15B 0.0184 0.0473 0.1027 0.0320 32 C16 0.0110(2) -0.1218(8) 0.17310(16) 0.0287 33 H16A 0.0227 -0.2695 0.1595 0.0430 34 H16B -0.0395 -0.1068 0.1751 0.0430 35 H16C 0.0315 -0.1047 0.2074 0.0430 36 H2C 0.386(3) 0.675(10) -0.001(2) 0.0500 37 H1C 0.435(3) 0.513(10) 0.018(2) 0.0500


141

2.12.3.6 Hydrogen-bonding geometry (Å)

Table 5

D-H...A D-H H-A D-A D-H...A Symmetry codes

N1-H1C ...O1 0.856 1.996 2.849 174.19 1/2+x,1/2-y,1/2+z

Note: D-H and H-A distances are essentially standard values and are not derived from

the experiment.


142

2.13 Biological evaluation 2.13.1 Antimicrobial evaluation

All the synthesized compounds (YUG-101 to YUG-140) were tested for their

antibacterial and antifungal activity (MIC) in vitro by broth dilution method [124, 125]

with two Gram-positive bacteria Staphylococcus aureus MTCC-96, Streptococcus

pyogenes MTCC 443, two Gram-negative bacteria Escherichia coli MTCC 442,

Pseudomonas aeruginosa MTCC 441 and three fungal strains Candida albicans

MTCC 227, Aspergillus Niger MTCC 282, Aspergillus clavatus MTCC 1323 taking

ampicillin, chloramphenicol, ciprofloxacin, norfloxacin, nystatin, and greseofulvin as

standard drugs. The standard strains were procured from the Microbial Type Culture

Collection (MTCC) and Gene Bank, Institute of Microbial Technology, Chandigarh,

India.

The minimal inhibitory concentration (MIC) values for all the newly

synthesized compounds, defined as the lowest concentration of the compound

preventing the visible growth, were determined by using microdilution broth method

according to NCCLS standards [124]. Serial dilutions of the test compounds and

reference drugs were prepared in Muellere-Hinton agar. Drugs (10 mg) were

dissolved in dimethylsulfoxide (DMSO, 1 mL). Further progressive dilutions with

melted Muellere-Hinton agar were performed to obtain the required concentrations. In

primary screening 1000 μg mL-1, 500 μg mL-1 and 250 μg mL-1 concentrations of the

synthesized drugs were taken. The active synthesized drugs found in this primary

screening were further tested in a second set of dilution at 200 μg mL-1, 100 μg mL-1,

50 μg mL-1, 25 μg mL-1, 12.5 μg mL-1, and 6.25 μg mL-1 concentration against all

microorganisms. The tubes were inoculated with 108 cfu mL-1 (colony forming

unit/mL) and incubated at 37 ºC for 24 h. The MIC was the lowest concentration of

the tested compound that yields no visible growth (turbidity) on the plate. To ensure

that the solvent had no effect on the bacterial growth, a control was performed with

the test medium supplemented with DMSO at the same dilutions as used in the

experiments and it was observed that DMSO had no effect on the microorganisms in

the concentrations studied.

The results obtained from antimicrobial susceptibility testing are depicted in

Table 1.


143

Table 1. Antibacterial and antifungal activity of synthesized compounds YUG-

101 to 140

Code Minimal inhibition concentration (µg mL-1 ) Gram-positive Gram-negative Fungal species S.a. S. p. E.c. P.a. C. a. A. n. A.c.

YUG-101 200 100 100 100 250 1000 250 YUG-102 500 500 250 250 250 200 200 YUG-103 500 500 100 250 500 500 >1000 YUG-104 500 500 250 500 500 >1000 1000 YUG-105 250 62.5 250 500 >1000 >1000 >1000 YUG-106 100 200 62.5 125 500 >1000 >1000 YUG-107 250 250 250 500 1000 500 >1000 YUG-108 200 500 62.5 500 1000 500 500 YUG-109 100 200 500 500 250 >1000 >1000 YUG-110 500 500 100 250 250 1000 250 YUG-111 500 62.5 250 250 250 200 200 YUG-112 100 250 100 250 500 500 >1000 YUG-113 500 250 250 500 500 >1000 1000 YUG-114 500 500 250 500 >1000 >1000 >1000 YUG-115 500 100 100 125 500 >1000 1000 YUG-116 200 500 250 500 1000 500 >1000 YUG-117 250 500 62.5 500 1000 500 500 YUG-118 250 500 500 500 250 >1000 >1000 YUG-119 500 500 1000 1000 500 1000 1000 YUG-120 200 100 100 500 500 1000 200 YUG-121 250 250 250 250 500 500 1000 YUG-122 100 500 500 1000 250 500 500 YUG-123 500 100 62.5 100 500 500 >1000 YUG-124 250 500 500 500 200 500 200 YUG-125 500 250 500 500 1000 1000 1000 YUG-126 500 100 500 250 1000 >1000 1000 YUG-127 250 62.5 100 125 250 1000 500 YUG-128 500 250 200 500 500 1000 >1000 YUG-129 100 250 500 1000 1000 >1000 >1000 YUG-130 500 62.5 62.5 100 250 1000 1000 YUG-131 500 500 100 250 500 500 >1000 YUG-132 500 500 250 500 500 >1000 1000 YUG-133 250 62.5 250 500 >1000 >1000 >1000 YUG-134 100 200 62.5 125 500 >1000 >1000 YUG-135 250 250 250 500 1000 500 >1000 YUG-136 200 500 62.5 500 1000 500 500 YUG-137 100 200 500 500 250 >1000 >1000 YUG-138 500 500 100 250 250 1000 250 YUG-139 500 62.5 250 250 250 200 200 YUG-140 100 250 100 250 500 500 >1000 Ampicillin 250 100 100 100 - - - Chloramphenicol 50 50 50 50 - - - Ciprofloxacin 50 50 25 25 - - - Norfloxacin 10 10 10 10 - - - Nystatin - - - - 100 100 100 Greseofulvin - - - - 500 100 100


144

2.13.2 Antimycobacterial, anticancer and antiviral evaluation

Antimycobacterial, anticancer and antiviral screening of all the newly synthesized

compounds YUG-101 to YUG-140 is currently under investigation and results are

awaited.


145

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