Chapter 2 Pyrano[2,3-c]pyrazoles…
24
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.
Chapter 2 Pyrano[2,3-c]pyrazoles…
25
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
26
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
27
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
28
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,
Chapter 2 Pyrano[2,3-c]pyrazoles…
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.
Chapter 2 Pyrano[2,3-c]pyrazoles…
30
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].
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
32
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
33
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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.
Chapter 2 Pyrano[2,3-c]pyrazoles…
36
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
37
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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-
Chapter 2 Pyrano[2,3-c]pyrazoles…
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).
Chapter 2 Pyrano[2,3-c]pyrazoles…
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].
Chapter 2 Pyrano[2,3-c]pyrazoles…
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.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Yield: 78%; mp 188-190 ºC; IR (cm-1): 3473 (N-H stretching of free primary amine),
3227 (N-H stretching of pyrazole ring), 3117 (C-H stretching of aromatic ring), 2196
(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: 0.67-0.71 (t, 3H, Ha), 1.18-
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%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Yield: 81%; mp 184-186 ºC; IR (cm-1): 3487 (N-H stretching of free primary amine),
3234 (N-H stretching of pyrazole ring), 3057 (C-H stretching of aromatic ring), 2196
(C≡N stretching of the nitrile group), 1631 (C=N stretching of pyrazole ring), 1604
(N-H deformation pyrazole ring), 1182 (N-N deformation of pyrazole ring), 1049 (C-
H in plane bending of aromatic ring), 826 (C-H out of plane bending for 1,4-
disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.67-0.71 (t, 3H, Ha), 1.18-
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-
5-carbonitrile (YUG-104)
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
Yield: 72%; mp 188-190 ºC; IR (cm-1): 3475 (N-H stretching of free primary amine),
3230 (N-H stretching of pyrazole ring), 3043 (C-H stretching of aromatic ring), 2195
(C≡N stretching of the nitrile group), 1635 (C=N stretching of pyrazole ring), 1599
(N-H deformation pyrazole ring), 1186 (N-N deformation of pyrazole ring), 1053 (C-
H in plane bending of aromatic ring), 813 (C-H out of plane bending for 1,4-
Chapter 2 Pyrano[2,3-c]pyrazoles…
63
disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.67-0.71 (t, 3H, Ha), 1.19-
1.35 (m, 2H, Hb), 2.03-2.22 (m, 2H, Hc), 4.56 (s, 1H, Hd), 6.58 (s, 2H, He), 7.15-7.21
(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'
Yield: 69%; mp 180-183 ºC; IR (cm-1): 3475 (N-H stretching of free primary amine),
3240 (N-H stretching of pyrazole ring), 3022 (C-H stretching of aromatic ring), 2193
(C≡N stretching of the nitrile group), 1643 (C=N stretching of pyrazole ring), 1600
(N-H deformation pyrazole ring), 1184 (N-N deformation of pyrazole ring), 1051 (C-
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-
5-carbonitrile (YUG-106)
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%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
64
2.10.3.7 6-amino-4-(3-chlorophenyl)-1,4-dihydro-3-propylpyrano[2,3-c]pyrazole-
5-carbonitrile (YUG-107)
O
NNH
CN
NH2
H3CCl
ab
c
d
e
ff'
g h
i
Yield: 76%; mp 188-191 ºC; IR (cm-1): 3454 (N-H stretching of free primary amine),
3244 (N-H stretching of pyrazole ring), 3057 (C-H stretching of aromatic ring), 2193
(C≡N stretching of the nitrile group), 1635 (C=N stretching of pyrazole ring), 1591
(N-H deformation pyrazole ring), 1184 (N-N deformation of pyrazole ring), 1051 (C-
H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.67-0.71 (t, 3H,
Ha), 1.19-1.35 (m, 2H, Hb), 2.09-2.20 (m, 2H, Hc), 4.57 (s, 1H, Hd), 6.61 (s, 2H, He),
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-
5-carbonitrile (YUG-108)
a
bc
d
e
f f'
g
hO
NNH
CN
NH2
H3C
Br
g'
Yield: 80%; mp 218-220 ºC; IR (cm-1): 3471 (N-H stretching of free primary amine),
3223 (N-H stretching of pyrazole ring), 3039 (C-H stretching of aromatic ring), 2196
(C≡N stretching of the nitrile group), 1633 (C=N stretching of pyrazole ring), 1600
(N-H deformation pyrazole ring), 1184 (N-N deformation of pyrazole ring), 1051 (C-
H in plane bending of aromatic ring), 813 (C-H out of plane bending for 1,4-
disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.69-0.72 (t, 3H, Ha), 1.21-
1.38 (m, 2H, Hb), 2.04-2.12 (m, 2H, Hc), 4.54 (s, 1H, Hd), 6.49 (s, 2H, He), 7.08-7.12
(m, 2H, Hff’, J = 13.40 Hz), 7.41-7.44 (m, 2H, Hgg’, J = 13.12 Hz), 11.96 (s, 1H, Hh);
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Yield: 88%; mp 148-151 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%.
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
Yield: 77%; mp 198-200 ºC; IR (cm-1): 3485 (N-H stretching of free primary amine),
3230 (N-H stretching of pyrazole ring), 3034 (C-H stretching of aromatic ring), 2195
(C≡N stretching of the nitrile group), 1631 (C=N stretching of pyrazole ring), 1599
(N-H deformation pyrazole ring), 1184 (N-N deformation of pyrazole ring), 1051 (C-
H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.66-0.70 (t, 3H,
Ha), 1.17-1.33 (m, 2H, Hb), 2.04-2.21 (m, 2H, Hc), 4.55 (s, 1H, Hd), 6.12 (s, 2H, He),
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%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Yield: 79%; mp 208-210 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, 18.87%.
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%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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'
Yield: 86%; mp 270-273 ºC; IR (cm-1): 3473 (N-H stretching of free primary amine),
3232 (N-H stretching of pyrazole ring), 3105 (C-H stretching of aromatic ring), 2193
(C≡N stretching of the nitrile group), 1637 (C=N stretching of pyrazole ring), 1597
(N-H deformation pyrazole ring), 1184 (N-N deformation of pyrazole ring), 1053 (C-
H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.63-0.67 (t, 3H,
Ha), 1.11-1.31 (m, 2H, Hb), 2.05-2.28 (m, 2H, Hc), 5.14 (s, 1H, Hd), 6.47 (s, 2H, He),
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%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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'
Yield: 75%; mp 138-140 ºC; IR (cm-1): 3369 (N-H stretching of free primary amine),
3240 (N-H stretching of pyrazole ring), 3099 (C-H stretching of aromatic ring), 2187
(C≡N stretching of the nitrile group), 1653 (C=N stretching of pyrazole ring), 1606
(N-H deformation pyrazole ring), 1159 (N-N deformation of pyrazole ring), 1047 (C-
H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.63-0.67 (t, 3H,
Ha), 1.11-1.31 (m, 2H, Hb), 2.05-2.28 (m, 2H, Hc), 5.14 (s, 1H, Hd), 6.47 (s, 2H, He),
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%.
2.10.3.17 6-amino-4-(2-chlorophenyl)-1,4-dihydro-3-propylpyrano[2,3-c]pyrazole-
5-carbonitrile (YUG-117)
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%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Yield: 83%; mp 188-190 ºC; MS: m/z 340; Anal. Calcd. for C18H20N4O3: C, 61.05; H,
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
Yield: 77%; mp 183-185 ºC; MS: m/z 340; Anal. Calcd. for C18H20N4O3: C, 61.05; H,
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
Yield: 79%; mp 181-183 ºC; MS: m/z 370; Anal. Calcd. for C19H22N4O4: C, 61.61; H,
5.99; N, 15.13;. Found: C, 61.58; H, 5.97; N, 15.08%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Yield: 85%; mp 145-148 ºC; IR (cm-1): 3400 (N-H stretching of free primary amine),
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-
disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.93-1.00 (t, 3H, Ha), 1.23-
1.44 (m, 2H, Hb), 2.02-2.18 (m, 2H, Hc), 3.76 (s, 3H, Hd), 4.58 (s, 1H, He), 6.85-6.85
(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%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Yield: 81%; mp 150-152 ºC; 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%.
2.10.4.3 6-amino-4-(4-fluorophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3-
c]pyrazole-5-carbonitrile (YUG-123)
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
Yield: 77%; mp 151-153 ºC; IR (cm-1): 3454 (N-H stretching of free primary amine),
3061 (C-H stretching of aromatic ring), 2198 (C≡N stretching of the nitrile group),
1660 (C=N stretching of pyrazole ring), 1126 (N-N deformation of pyrazole ring),
1068 (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: 0.74-0.77 (t, 3H, Ha), 1.24-
1.42 (m, 2H, Hb), 2.03-2.19 (m, 2H, Hc), 4.67 (s, 1H, Hd), 7.07 (s, 2H, He), 7.09-7.11
(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%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
72
2.10.4.4 6-amino-4-(4-chlorophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3-
c]pyrazole-5-carbonitrile (YUG-124)
O
NN
CN
NH2
H3C
Cl
ab
cd
e
f g
h
i
jj'
kk'
i'
Yield: 83%; mp 152-154 ºC; IR (cm-1): 3454 (N-H stretching of free primary amine),
3061 (C-H stretching of aromatic ring), 2198 (C≡N stretching of the nitrile group),
1660 (C=N stretching of pyrazole ring), 1126 (N-N deformation of pyrazole ring),
1068 (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: 0.74-0.78 (t, 3H, Ha), 1.26-
1.44 (m, 2H, Hb), 2.02-2.19 (m, 2H, Hc), 4.66 (s, 1H, Hd), 7.10 (s, 2H, He), 7.25-7.30
(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-
c]pyrazole-5-carbonitrile (YUG-125)
O
NN
CN
NH2
H3C
NO2
Yield: 69%; mp 181-183 ºC; MS: m/z 401; Anal. Calcd. for C22H19N5O3: C, 65.83; H,
4.77; N, 17.45;. Found: C, 65.80; H, 4.73; N, 17.40%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
73
2.10.4.6 6-amino-1,4-dihydro-4-(3-nitrophenyl)-1-phenyl-3-propylpyrano[2,3-c]-
pyrazole-5-carbonitrile (YUG-126)
O
NN
CN
NH2
H3CNO2
Yield: 70%; mp 158-161 ºC; MS: m/z 401; Anal. Calcd. for C22H19N5O3: C, 65.83; H,
4.77; N, 17.45;. Found: C, 65.81; H, 4.74; N, 17.41%.
2.10.4.7 6-amino-4-(3-chlorophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3-
c]pyrazole-5-carbonitrile (YUG-127)
O
NN
CN
NH2
H3Cab
cd
ef
gh
i
j
k
k' Cll
l'
Yield: 80%; mp 167-168 ºC; IR (cm-1): 3462 (N-H stretching of free primary amine),
3070 (C-H stretching of aromatic ring), 2193 (C≡N stretching of the nitrile group),
1656 (C=N stretching of pyrazole ring), 1130 (N-N deformation of pyrazole ring),
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 =
8.36 Hz); MS: m/z 370; Anal. Calcd. for C23H22N4O: C, 74.57; H, 5.99; N, 15.12.
Found: C, 74.53; H, 5.96; N, 15.08%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
74
2.10.4.8 6-amino-4-(4-bromophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3-
c]pyrazole-5-carbonitrile (YUG-128)
O
NN
CN
NH2
H3C
Br
ab
cd
e
f f'
g
h
h' i
j
g'
i'
Yield: 75%; mp 140-143 ºC; IR (cm-1): 3448 (N-H stretching of free primary amine),
3057 (C-H stretching of aromatic ring), 2196 (C≡N stretching of the nitrile group),
1660 (C=N stretching of pyrazole ring), 1126 (N-N deformation of pyrazole ring),
1070 (C-H in plane bending of aromatic ring), 802 (C-H out of plane bending for 1,4-
disubstituted aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.74-0.78 (t, 3H, Ha), 1.23-
1.44 (m, 2H, Hb), 2.02-2.18 (m, 2H, Hc), 4.66 (s, 1H, Hd), 7.13 (s, 2H, He), 7.19-7.24
(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]
pyrazole-5-carbonitrile (YUG-129)
O
NN
CN
NH2
H3C
OH
Yield: 88%; mp 174-176 ºC; MS: m/z 372; Anal. Calcd. for C22H20N4O2: C, 70.95; H,
5.41; N, 15.04. Found: C, 70.91; H, 5.37; N, 14.99%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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'
Yield: 73%; mp 219-221 ºC; IR (cm-1): 3462 (N-H stretching of free primary amine),
3070 (C-H stretching of aromatic ring), 2193 (C≡N stretching of the nitrile group),
1656 (C=N stretching of pyrazole ring), 1130 (N-N deformation of pyrazole ring),
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 =
7.84 Hz); MS: m/z 356; Anal. Calcd. for C22H20N4O: C, 74.14; H, 5.66; N, 15.72.
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-
c]pyrazole-5-carbonitrile (YUG-131)
O
NN
CN
NH2
H3COH
Yield: 82%; mp 214-216 ºC; MS: m/z 372; Anal. Calcd. for C22H20N4O2: C, 70.95; H,
5.41; N, 15.04. Found: C, 70.91; H, 5.37; N, 15.01%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
76
2.10.4.12 6-amino-4-(2,4-dichlorophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3
-c]pyrazole-5-carbonitrile (YUG-132)
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
Yield: 85%; mp 184-186 ºC; IR (cm-1): 3462 (N-H stretching of free primary amine),
2989 (C-H stretching of aromatic ring), 2196 (C≡N stretching of the nitrile group),
1660 (C=N stretching of pyrazole ring), 1128 (N-N deformation of pyrazole ring),
1068 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.73-0.77
(t, 3H, Ha), 1.21-1.42 (m, 2H, Hb), 2.03-2.19 (m, 2H, Hc), 5.17 (s, 1H, Hd), 7.23 (s,
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-
c]pyrazole-5-carbonitrile (YUG-133)
O
NN
CN
NH2
H3CBr
Yield: 88%; mp 188-190 ºC; 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%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
77
2.10.4.14 6-amino-1,4-dihydro-1-phenyl-3-propyl-4-(pyridin-2-yl)pyrano[2,3-c]
pyrazole-5-carbonitrile (YUG-134)
O
NN
CN
NH2
H3CN
Yield: 79%; mp 180-183 ºC; MS: m/z 357; Anal. Calcd. for C21H19N5O: C, 70.57; H,
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]-
pyrazole-5-carbonitrile (YUG-135)
O
NN
CN
NH2
H3C
Br
Yield: 87%; mp 180-182 ºC; MS: m/z 435; Anal. Calcd. for C22H19BrN4O: C, 60.70;
H, 4.40; N, 12.87. Found: C, 60.76; H, 4.36; N, 12.83%.
2.10.4.16 6-amino-4-(2,6-dichlorophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3
-c]pyrazole-5-carbonitrile (YUG-136)
O
NN
CN
NH2
H3Ca
bc
d
e
fg
h
i
jk
ll'
ClCl
Chapter 2 Pyrano[2,3-c]pyrazoles…
78
Yield: 80%; mp 188-191 ºC; IR (cm-1): 3450 (N-H stretching of free primary amine),
3088 (C-H stretching of aromatic ring), 2198 (C≡N stretching of the nitrile group),
1662 (C=N stretching of pyrazole ring), 1134 (N-N deformation of pyrazole ring),
1068 (C-H in plane bending of aromatic ring); 1H NMR (DMSO-d6) δ ppm: 0.69-0.73
(t, 3H, Ha), 1.11-1.41 (m, 2H, Hb), 2.07-2.19 (m, 2H, Hc), 5.71 (s, 1H, Hd), 7.10 (s,
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%.
2.10.4.17 6-amino-4-(3-chlorophenyl)-1,4-dihydro-1-phenyl-3-propylpyrano[2,3-
c]pyrazole-5-carbonitrile (YUG-137)
O
NN
CN
NH2
H3C
Cl
Yield: 83%; mp 218-220 ºC; 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%.
2.10.4.18 6-amino-1,4-dihydro-4-(3,4-dimethoxyphenyl)-1-phenyl-3-propylpyrano[2,3-c]
pyrazole-5-carbonitrile (YUG-138)
O
NN
CN
NH2
H3CO
O
Yield: 79%; mp 148-151 ºC; MS: m/z 416; Anal. Calcd. for C24H24N4O3: C, 69.21; H,
5.81; N, 13.45. Found: C, 69.18; H, 5.77; N, 13.41%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
79
2.10.4.19 6-amino-1,4-dihydro-4-(2,5-dimethoxyphenyl)-1-phenyl-3-propylpyrano[2,3-c]
pyrazole-5-carbonitrile (YUG-139)
O
NN
CN
NH2
H3C
O
O
Yield: 75%; mp 140-143 ºC; MS: m/z 416; Anal. Calcd. for C24H24N4O3: C, 69.21; H,
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
Yield: 80%; mp 174-176 ºC; MS: m/z 446; Anal. Calcd. for C25H26N4O4: C, 67.25; H,
5.87; N, 12.55. Found: C, 67.21; H, 5.83; N, 12.51%.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
81
cyano group was observed at 110-120 δ ppm, indicates the involvement of
malanonitrile in cyclization process.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
83
1H NMR Spectrum of YUG-101
Expanded 1H NMR Spectrum of YUG-101
Chapter 2 Pyrano[2,3-c]pyrazoles…
84
Expanded 1H NMR Spectrum of YUG-101
Expanded 1H NMR Spectrum of YUG-101
Chapter 2 Pyrano[2,3-c]pyrazoles…
85
13C NMR Spectrum of YUG-101
Mass Spectrum of YUG-102
Chapter 2 Pyrano[2,3-c]pyrazoles…
86
IR Spectrum of YUG-102
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
1H NMR Spectrum of YUG-102
Chapter 2 Pyrano[2,3-c]pyrazoles…
87
Expanded 1H NMR Spectrum of YUG-102
Expanded 1H NMR Spectrum of YUG-102
Chapter 2 Pyrano[2,3-c]pyrazoles…
88
13C NMR Spectrum of YUG-102
Mass Spectrum of YUG-103
Chapter 2 Pyrano[2,3-c]pyrazoles…
89
IR Spectrum of YUG-103
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
90
Expanded 1H NMR Spectrum of YUG-103
Expanded 1H NMR Spectrum of YUG-103
Chapter 2 Pyrano[2,3-c]pyrazoles…
91
13C NMR Spectrum of YUG-103
Mass Spectrum of YUG-104
Chapter 2 Pyrano[2,3-c]pyrazoles…
92
IR Spectrum of YUG-104
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
1H NMR Spectrum of YUG-104
Chapter 2 Pyrano[2,3-c]pyrazoles…
93
Expanded 1H NMR Spectrum of YUG-104
Expanded 1H NMR Spectrum of YUG-104
Chapter 2 Pyrano[2,3-c]pyrazoles…
94
13C NMR Spectrum of YUG-104
Mass Spectrum of YUG-105
Chapter 2 Pyrano[2,3-c]pyrazoles…
95
IR Spectrum of YUG-105
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
YUG-105 1H NMR Spectrum of YUG-105
Chapter 2 Pyrano[2,3-c]pyrazoles…
96
Expanded 1H NMR Spectrum of YUG-105
Expanded 1H NMR Spectrum of YUG-105
Chapter 2 Pyrano[2,3-c]pyrazoles…
97
Mass Spectrum of YUG-107
IR Spectrum of YUG-107
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
98
1H NMR Spectrum of YUG-107
Expanded 1H NMR Spectrum of YUG-107
Chapter 2 Pyrano[2,3-c]pyrazoles…
99
Expanded 1H NMR Spectrum of YUG-107
Mass Spectrum of YUG-108
Chapter 2 Pyrano[2,3-c]pyrazoles…
100
IR Spectrum of YUG-108
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
YUG-108 1H NMR Spectrum of YUG-108
Chapter 2 Pyrano[2,3-c]pyrazoles…
101
Expanded 1H NMR Spectrum of YUG-108
Expanded 1H NMR Spectrum of YUG-108
Chapter 2 Pyrano[2,3-c]pyrazoles…
102
Mass Spectrum of YUG-110
IR Spectrum of YUG-110
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
103
1H NMR Spectrum of YUG-110
Expanded 1H NMR Spectrum of YUG-110
Chapter 2 Pyrano[2,3-c]pyrazoles…
104
Expanded 1H NMR Spectrum of YUG-110
13C NMR Spectrum of YUG-110
Chapter 2 Pyrano[2,3-c]pyrazoles…
105
Mass Spectrum of YUG-115
IR Spectrum of YUG-115
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
106
1H NMR Spectrum of YUG-115
Expanded 1H NMR Spectrum of YUG-115
Chapter 2 Pyrano[2,3-c]pyrazoles…
107
Expanded 1H NMR Spectrum of YUG-115
Mass Spectrum of YUG-116
Chapter 2 Pyrano[2,3-c]pyrazoles…
108
IR Spectrum of YUG-116
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
YUG-116 1H NMR Spectrum of YUG-116
Chapter 2 Pyrano[2,3-c]pyrazoles…
109
Expanded 1H NMR Spectrum of YUG-116
Expanded 1H NMR Spectrum of YUG-116
Chapter 2 Pyrano[2,3-c]pyrazoles…
110
Mass Spectrum of YUG-121
IR Spectrum of YUG-121
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
111
1H NMR Spectrum of YUG-121
Expanded 1H NMR Spectrum of YUG-121
Chapter 2 Pyrano[2,3-c]pyrazoles…
112
Expanded 1H NMR Spectrum of YUG-121
13C NMR Spectrum of YUG-121
Chapter 2 Pyrano[2,3-c]pyrazoles…
113
Mass Spectrum of YUG-123
IR Spectrum of YUG-123
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
114
1H NMR Spectrum of YUG-123
Expanded 1H NMR Spectrum of YUG-123
Chapter 2 Pyrano[2,3-c]pyrazoles…
115
Expanded 1H NMR Spectrum of YUG-123
Mass Spectrum of YUG-124
Chapter 2 Pyrano[2,3-c]pyrazoles…
116
IR Spectrum of YUG-124
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
YUG-124 1H NMR Spectrum of YUG-124
Chapter 2 Pyrano[2,3-c]pyrazoles…
117
Expanded 1H NMR Spectrum of YUG-124
Expanded 1H NMR Spectrum of YUG-124
Chapter 2 Pyrano[2,3-c]pyrazoles…
118
Mass Spectrum of YUG-127
IR Spectrum of YUG-127
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
119
1H NMR Spectrum of YUG-127
Expanded 1H NMR Spectrum of YUG-127
Chapter 2 Pyrano[2,3-c]pyrazoles…
120
Expanded 1H NMR Spectrum of YUG-127
Mass Spectrum of YUG-128
Chapter 2 Pyrano[2,3-c]pyrazoles…
121
IR Spectrum of YUG-128
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
YUG-128 1H NMR Spectrum of YUG-128
Chapter 2 Pyrano[2,3-c]pyrazoles…
122
Expanded 1H NMR Spectrum of YUG-128
Expanded 1H NMR Spectrum of YUG-128
Chapter 2 Pyrano[2,3-c]pyrazoles…
123
Mass Spectrum of YUG-130
IR Spectrum of YUG-130
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
124
1H NMR Spectrum of YUG-130
Expanded 1H NMR Spectrum of YUG-130
Chapter 2 Pyrano[2,3-c]pyrazoles…
125
Expanded 1H NMR Spectrum of YUG-130
Mass Spectrum of YUG-132
Chapter 2 Pyrano[2,3-c]pyrazoles…
126
IR Spectrum of YUG-132
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
YUG-132 1H NMR Spectrum of YUG-132
Chapter 2 Pyrano[2,3-c]pyrazoles…
127
Expanded 1H NMR Spectrum of YUG-132
Expanded 1H NMR Spectrum of YUG-132
Chapter 2 Pyrano[2,3-c]pyrazoles…
128
13C NMR Spectrum of YUG-132
Mass Spectrum of YUG-133
Chapter 2 Pyrano[2,3-c]pyrazoles…
129
IR Spectrum of YUG-133
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
YUG-133 1H NMR Spectrum of YUG-133
Chapter 2 Pyrano[2,3-c]pyrazoles…
130
Expanded 1H NMR Spectrum of YUG-133
Expanded 1H NMR Spectrum of YUG-133
Chapter 2 Pyrano[2,3-c]pyrazoles…
131
Mass Spectrum of YUG-136
IR Spectrum of YUG-136
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
132
1H NMR Spectrum of YUG-136
Expanded 1H NMR Spectrum of YUG-136
Chapter 2 Pyrano[2,3-c]pyrazoles…
133
Expanded 1H NMR Spectrum of YUG-136
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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]).
Chapter 2 Pyrano[2,3-c]pyrazoles…
136
2.12.3.1 ORTEP diagram of the organic compound with atom numbering scheme
(40% probability factor for the thermal ellipsoids)
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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)
Chapter 2 Pyrano[2,3-c]pyrazoles…
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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)
Chapter 2 Pyrano[2,3-c]pyrazoles…
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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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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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.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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.
Chapter 2 Pyrano[2,3-c]pyrazoles…
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
Chapter 2 Pyrano[2,3-c]pyrazoles…
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.
Chapter 2 Pyrano[2,3-c]pyrazoles…
145
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