synthesis of biologically active nitrogen...
TRANSCRIPT
Chapter IV
MgO, a Reusable Catalyst For Greener
Synthesis of Pyranopyrazole In Water.
This work is communicated to Catalysis Letters
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
116
CHAPTER 4
MgO, a Reusable Catalyst For Greener Synthesis of Pyranopyrazole In Water.
4.1 INTRODUCTION AND LITERATURE SURVEY
Functionalized chromene and benzopyrans are important class of
heterocyclic compounds due to their broad spectrum of biological activity and
imply wide range of applications in medicinal chemistry. The benzopyran
moiety is found in variety of natural products. Many of these exhibit interesting
biological properties.[1-2]
Some of the naturally occurring products possessing benzopyran nucleus
are puupehedione [1] and related marine derivatives, puupehenone [2] and 15-
oxopuupehenol [3] exhibiting wide range of biological properties including
antitumor, antiviral, antimalerial, antibiotic antituberculosis, antioxidant,
insecticidal and antifungal etc. The scarce availability of many bioactive
compounds led to develop simpler and more accessible analogues for broad
biological evaluation. A. F. Barrero et al[3] devised a method to synthesize
pupupehedione analogue.
O
OO
[1]
O
OOH
[2]
O
OHOH
O
[3]
Some marine invertebrates anti-inflammatory sesquiterpenes containing
a pyranofuranones grouped into monoalide (1)[4] and cacospongionolide B3(2).
Monoalide inhibit PLA2, it is believed that α,β-unsaturated compound generated
by opening of pyranofuranone [4, 5] moiety reacts with lysine residue of PlA2
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
117
on other hand, cocospongionolide B(2), which lacks the hemiacetal function in
the pyran ring showed potent inhibitory activity on recombinant human
synovial PLA2. Margherita and co-workers have synthesized monoalide and
cocospongionolide B3 analogues and examined their anti-inflammatory activity
of natural sources.
OOH
OOH
O
[4]
OOH
O
H
[5]
Iolanta Nawrot-Modranka et al[5] have synthesized phosphohydrazine
derivatives [6,7] designated as an antitumor agents against p388leukemia and
LI120 murine leukemia.
O
O H
NN
P
H
SOR1
OR1
[6]
O
O
O
NNCH3
HP OR1
OR1
S
[7]
R1
= -C2H5, -CH3, -C2H5 ; R2 = -CH3, -CH3, -H.
Naturally occurring compounds containing fused pyran rings exhibit
molluscicidal activity. Bergapten [8], ricchiocarpin A [9] and ricchiocrpin B
[10], pyranopyrazole [11] are well known for their molluscicidal property.
Fathy M. Abdelrazek reported few pyran derivatives which are effective
against Biomphalaria alexandrina.[6] Mohamed I. Hegab derived some fused
polycyclic heterocycles starting with 4-chloro-2,2 disubstituted chromene-3-
carboxaldehyde [12]. The synthesized heterocycles showed considerable anti-
inflammatory, analgesic, anticonvulsant and antiparkinson activity.[7] By the
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
118
use of salicyaldehyde, M. Al Neirabeyeh and his group synthesized 3,4-
dihydro-3-(di-n propylamino)-2H-1benzopyrans [13] as new derivatives of
benzopyran for dopaminergic activity.[8]
O O O
O
[8]
O
O
O
[9]
O
O
O O
[10]
O NH2
NNH
CN
O
[11]
O
Cl
R1
R2
CHO
[12]
O
N
R1
R2
R3
R4 [13]
R1 = OH, H, H, H ; R2 = H, H, H, OH ; R3 = H, H, H, OH ; R4= H, OH, OH, 4.2 METHODS OF SYNTHESIS
Several methods for benzopyran synthesis have been reported by the
scientists around the word which involves one step as well as multistep
synthesis.
A tandem Wolff rearrangement with t-amino effect found an an
effective route for synthesis of benzopyran nucleus.[9] The thermal
decomposition of 1-diazo-2-oxo-(2-N, N–disubstituted aminomethyl)phenyl
ethylphosphonates [14] in toluene extruded 1H-2-benzopyran in good to
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
119
moderate yield. Formation of 1H-2-benzopyran [16] expected to take place
through ketene intermediate [15] followed by a [1,5] hydrogen shift and
subsequent ring closure of the pminium (Scheme 4.1).
O
N
P
N2
OMe
RR
OOMe
wollf transpositionN
P(O)(OMe)2
OH
RRl
N
P(O)(OMe)2
O
H
RR
-
i
O
NRR
P(O)(OMe)2
R [CH2]2CH3
R C6H5
12 1
2
[1,5] Shift
12+
21
1, R
2=
R1 =2 =
[14] [15]
[16]
Scheme 4.1
The utility of tetrathiafulvene (TTF) as a catalyst was demonstrated by
Nadeem Bashir and co-workers.[10] They synthesized tetrahydropyran [17] by
conversion of amine into tetrahydropyran through diazonium salt. This
transformation believed to take place via radical mechanism. In this reaction
the tetrathiafulvene acts as a weak nucleophile (Scheme 4.2).
O
N2
.
O
S
S
S
S
BF4
O
BF4
OOH
+ . .
.+
-
+
-
[17]Scheme 4.2
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
120
Cordiachromen, chemically named 6-hydroxy-2-methyl-2-(4-methyl
pent -3-en-1-yl)-2H-chromene [18] present in the cordia alliodora exhibited
anti-inflammatory activity. Samir bouzbouz et al[11] have synthesized
cordiochromene enantioselectively from chroman in four step involving
bromination, dehydrohalogenation, nucleophilic substitution reaction with
Grignards reagent and alkaline hydrolysis in aqueous ethanol (Scheme 4.3).
TsO
O
H
OTs
TsO
O
Br
OTs
TsO
O OTs
TsO
O
e
O
OH
O
H
a b c,d
[18]a)NBS (1 equiv.), K2CO3, C6H5CO3H, CCl4, reflux; b) pyridine, reflux. d)Bu3SnH, C6H6,
reflux. c) BrCH2CH=C(CH3)2, Mg, THF, -20oC d) Li2CuCl4, -70 oC e) KOH, H2O, H2O/EtOH,
reflux.
Scheme 4.3
Wide range of organic compounds of pharmaceutical importance found
through solid phase synthesis of benzopyrane reported by K. C. Nicolaou et
al.[12] The synthetic strategy behind this methodology is use of selenium bound
2,2-dimethylbenzopyrans [19], synthesized from selenium bound with ortho–
prenulated phenols. It undergoes condensation, annulation, glycosidation, aryl
coupling reaction to offer various lead compounds [20, 21, 22] (Scheme 4.4).
Same author employed selenium based solid phase synthesis of medicinally
relevant small organic molecules[13] from selenium bound 2,2-
dimethylbenzopyrans for different derivatives of pyran (Scheme 4.5) .
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
121
O
Se
GlycosidationO
SeSugar-X
Condensation
O
SeO
R
aryl couplingO
Se
R
O
SeO
R
benzopyran Scaffold[19]
Scheme 4.4
O
Se
NCO
RO
O
SeO
NH
R
Y XO
SeOH
Y X
CHO
COOEt
O
Se
O
O
O
O
NH
R
Y XO
OH
O
O
benzopyran Scaffold
30 min, 25 C
25 C 12 h
a
a
a
[20]
[21]
[22]
Scheme 4.5
Bjorn C. G. Soderberg et al[14] have prepared isomeric mixture of 5-nitro-1-
benzopyrans (Scheme 4.6) [24, 25, 26] starting from 2-bromo-3- hydroxy-1-
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
122
nitrobenzene [23] by O-alkylation with 1-bromo-3-butene. Intramolecular Heck
reaction extrudes the mixture of isomeric 5-nitro-1-benzopyrans in 60 %, 15 %
and 3 % yield respectively. These mixture underwent N-heteroannulation
resulting in the formation of 3, 4 -fused indoles (Scheme 4.6).
Br
OH
NO2
Br
KOH, NaI, DMSO
O
Br
NO2
Pb(OAc)2, Et3N
P(o-Tol)3
O O
NO2
O
NO2
+ +
[23] [24] [25] [26]
Scheme 4.6 Biomolecular cyclization reaction between salicyaldehyde with
conjugated olefins such as acrylate derivatives or α,β-unsaturated ketene
resulting to form different substituted chromene [28] is quite routine, Min Shi
[15] demonstrated reaction of salicylaldehyde with allenic ketone [27] and ester
under basic condition. A systematic study of this reaction catalyzed by various
bases including K2CO3, KOH, PPh3, DABCO and DMAP in a variety of
solvents concluded that K2CO3 system gives good yield of the product
(Scheme 4.7).
O
H
OH
R
O
R
RCBU
DMSOO
R
O
ROH
R
R H, Me, OMeCl, Br etc
R = Me, Bn
R =Me, OMe
+1
2
310mol %
1
2 3
1=
2
3
[27] 28 ][
Scheme 4.7
A series of benzo[c]chromen-6-ones [31] prepared by a Suzuki coupling
and lactonisation reported by Geradus J. Kemperman et al.[16] The starting
compounds in this reaction were 2-methoxyphenylboronic acids [29] and
methyl 2-bromobenzoate [30] derivatives. The ionic liquids [BMIm][PF6],
[Bmim][Al2Cl7] accelerates the rate of reaction (Scheme 4.8).
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
123
B(OH)2
OMe Br
COOMe
Pd(PPh3)4
aq.Na2CO3O
[BMIM][PF6]
OMe
MeO2C
KOHEtOH
reflux
OMe
HOOCreflux
SOCl2
CH2Cl2
AlCl3
O O
+
100 C
1
2. [29] [30]
[31]
Scheme 4.8
In recent years resin catalyzed reactions have gained valuable synthetic
importance. Various report on Amberlyst, dowex catalyzed reactions were
found in the literature. Enrique Alvarez-Manzaneda described an
enantiospecific route towards the cationic resin promoted Friedel–Craft
alkylation of alkoxyarenes with α,β-unsaturated ketone [32], further reaction of
ketone with 3,4-methylenedioxyphenol offers corresponding chromene [33] [17]
(Scheme 4.9).
OO
O
OH
Amberlyst A-
molecular sieves,benzene,reflux,
O
OO
+15, 4A
1 h 40 min. [33][32]
Scheme 4.9
Previous report describe two component coupling between
salicyaldehyde and allenic ketones/ester .Yong–Ling Shi et al[18] have reported
the chromene synthesis by replacing salicyaldehyde by salicyl N-tosylamines
[34], which on reaction with acetylenecarboxylate ester [35] in the presence of
DABCO as catalyst (Scheme 4.10). The resultant substituted benzopyran [36]
obtained at 80 0C temperature in dichloromethane.
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
124
OH
R
R
R
NTs
COOMeDABCO,
O
O
R
R
RNHTs
COOMe
CH2Cl2,1
2
3
+25 mol %
80 C1
2
3
[34] [35] [36]
Scheme 4.10
Phenylene linked bis-naphthopyrans were synthesized in good yields via
the one pot reaction of bis-propargyl alcohols [37] with naphthols. These
synthesized pyrans [38] exhibited temperature dependant photochromism [19]
(Scheme 4.11)
OO
PhPh
sodium acetylide,
DMSO, C2H2, OHOHPhPh
(4 equiv.)
23 C, 2-3 ho
[37]
(MeO)3CH,PPTS(CH2Cl)2,reflux,
OPh
O
Ph
OHOHPhPh
2-naohthol2.2-3 equiv.
4 equiv.
5-8 h
[38] Scheme 4.11
Annamaria Deagostiono et al[20] synthesized benzopyrans starting from
dienylboronates and 2-iodophenol in the presence of a Pd catalyst. The reaction
marches through the cross coupling intermediates which cyclizes to the
chromene derivatives, which on hydrolysis offers 2, 2-dimethylchromen-4-one
[39], which is known to be an important building block for the synthesis of
many important pharmaceuticals. (Scheme 4.12)
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
125
B
R
ROO
OEt
INHPG
PdCl2(PPh3)2, THF
K2CO3,R
OH
OEt
HOH
R
i
-HO
OEt
H O
H
OR
O
R = H, MeR =H, H, Me
1
2
+
50 Co
+
+1
+2
+1
1
2
[39]
Scheme 4.12
An enantioselective Oxa-Michael–Henry reaction of substituted
salicyldehyde with nitro olefins [40] that proceeds through an aromatic
iminium activation (AIA) has been developed using a chiral secondary amine
organocatalyst and salicylic acid as a co-catalyst. The corresponding 3-nitro-
2H-chromene [41] were obtained in moderate to good yields under mild
conditions, reported by Dan-Quin xu et al.[21] Different amine were screened
for their catalytic activity. Amongst them pyrrolidine thioimidazole is the most
effective catalyst in terms of stereo control (Scheme 4.13).
O
H
OHO
NO2
O
NO2
OSalicylic acidDMSO,r.t.
+
20 mol % pyrrolidine thioimidazole
[40] [41]
Scheme 4.13
An effective enantioselective access to benzopyran [44] was given by
Magnus Pueping[22] et al by reaction between cyclic 1,3-diketone [42] and α,β -
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
126
unsaturated aldehyde [43] in the presence of organocatalyst, diarylprolinol silyl
ether. The reaction offered good enantioselectivity in dichloromethane at 10 oC
(Scheme 4.14).
O
O
O
H
Ph
NH
ArAr
OTMS
Dichloromethane O
O Pr
OHAr =PhAr = -(CF3)-Ph
+
3,5 [42] [43] [44]
Scheme 4.14
Liang-Yeh chen et al[23] have introduced a novel carbanian-olefin
intramolecular cyclization where 2-aroyl-3, 4–dihydro-2H-benzopyrans [45]
obtained from salicyaldehyde. It is based on strategy that salicyaldehyde
underwent Wittig reaction with methyltriphenylphosphonium bromide
(MTPPB) and potassium tertbutoxide as base and subsequent reaction with 2-
bromoacetophenone without isolation, afforded condensation product which
again on heating with tert-butoxide yielded benzopyran (Scheme 4.15).
OH
CHO
CH3 P(Ph)3
tert BuOk
THF, rt,OH
OBr
reflux
OO
tert-BuOK
OO
++
1 h+
[45]
Scheme 4.15
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
127
Mechanism
OO
tert-BuOK
OO
H
OBu tert tert BuOH
OO
-
OO
- K
OO
tert BuOH
+
tert-BuOH
+
Solvent free and catalyst free organic synthesis is most demanded
synthetic approach. One pot synthesis of 3, 3`-(benzylene)-bis (4-hydroxy-2H-
chromene-2-one) [46] derivatives have been synthesized by Shaterian Hamid
Reza et al[24] through the coupling of aldehydes and 2 mol. equivalent of 4-
hydroxycoumarine. The reaction proceeds at 130 oC without use of any
externally added catalyst. The product obtained in an excellent yields (Scheme
4. 16).
CHOX
O O
OH
Solvent free
O O
OH
O
OH
+ 2catalyst free
[46]
Scheme 4.16
Electrochemically induced multi-component condensation[25] of
resorcinol, malononitrile and various aldehydes in propanol in an undivided
cell in the presence of NaBr as an electrolyte results in the formation of 2-
amino-4H-chromenes reported by S. Makarem et al.[26]
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
128
All methods discussed above has its own merit but overled by long
reaction time, use of costly reagent and lack of reusability of the catalyst. As
far as greener methodology is concern, the solvent is at centre point. Therefore
use of nontoxic, nonflammable, non-volatile solvent has prime importance.In
recent years ionic liquids, supercritical fluids are some alternatives but water is
the best among them because it is cheap, easily available, non-toxic, non-
flammable and non-volatile.
4.2 PRESENT WORK
Pyranopyrazole is one of the important pyran derivatives. Which exhibit
molluscicidal activity. Very few methods have been reported in the literature
for its synthesis. Routine method describe its synthesis involving reaction
between pyrazole derivative and cyanoolefins formed by Knoevenagel
condensation between aldehydes and malononitrile under basic condition. The
limitation of this method is that both reactant coupled in this reaction requires
more time for condensation. However, this problem could be solved by one
step multicomponent synthesis to some extent. Gnanasambandam Vasuki et al
have demonstrated four component one step synthesis of pyranopyrazole by
condensation of ethylacetoacetate, hydrazine hydrate, arylaldehyde and
malononitrile in water at room temperature, using piperdine as base. Reaction
took place at room temperature. In recent years, MgO successfully catalyzed
organic reactions altering the use of organic bases like piperidine, morpholine,
trimethylamine etc. MgO is non toxic inorganic base required in catalytic
amount and can be reused. Taking into account the merits of MgO, we decided
to explore catalytic efficiency of MgO for synthesis of pyranopyrazole [51] by
condensing hydrazine hydrate [47], ethylacetoacetate [48], arylaldehyde [49]
and malononitrile [50] (Scheme 4. 17).
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
129
NH2
NH2O O
OAr
O
H
CN
CN
MgO
Water
ONH
N NH2
CN+ +
20 mol %
50 Co
[47] [48]
[49]
[ 50 ] [51]
Scheme 4.17
4.4 RESULT AND DISCUSSION
In initial attempts, ethylacetoacetate, hydrazine hydrate was stirred for 5
min. then aldehyde, malononitrile and catalytic amount of MgO were added in
water and the reaction mixture stirred at room temperature. It was found that
reaction between ethylacetoacetate and hydrazine hydrate occurred under
catalyst free condition, forming water soluble pyrazolone. After stirring for one
hr. the progress of reaction was examined by running TLC of reaction mixture,
which indicated the formation of pyranopyrazole along with unreacted
cynoolefine. After continuous stirring for few hours, desired condensation
product, pyranopyrazole wasn’t obtained considerably. Moreover, increased
catalytic quantity of MgO over 20 mol % and continous stirring the reaction
mixture was failed to emit a satisfactory yield. Therefore, attempts were made
to modify the thermal conditions of reaction which might be a hurdle for
progress of reaction towards formation pyranopyrazole. In next experimental
trial a mixture of ethylacetoacetate, hydrazine hydrate, benzaldehyde and
malononitrile in equivalent amount was stirred in preheated oil bath at 80 oC.
We noticed that cyanoolefin and pyrazolone get consumed but some side
reaction product was observed along with pyranopyrazole on TLC. In
optimization of thermal condition, we tried the reaction at 50 oC with stirring
and the progress of the reaction was examined by TLC. After 1 hr it was
observed that reaction went on completion without formation of any side
reaction. Finally reaction mass was filtered at the pump. The separated catalyst
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
130
was recycled three time without loosing its catalytic activity. The purified
sample matched with the physical constant reported in literature. The IR
spectrum exhibited bands at 3540 cm-1 for N-H stretching, 3370, 3210 cm-1
asymmetric and symmetric stretching frequency for primary amino group,
medium intensity band at 2199 cm-1 for -CN group. The 1H NMR showed
expected signal at δ 5.5 for methine proton and protons of primary amino group
as broad singlet at δ 4.2. The remaining protons of the structure appeared in the
aromatic region in the form of multiplet. This result encouraged us to extend
this protocol for variety of aldehydes bearing an electron donating and
withdrawing groups in them. (Table 4.1).
The aryl aldehyde with an electron donating group took longer reaction
time as compared to electron withdrawing groups on arylaldehydes. In an
efforts to minimize the amount of MgO, 20 mol % of MgO was sufficient for
completion of reaction. Increasing the amount of MgO over 20 % does not
affect on yield and time of the reaction considerably (Table 4.2).
One important aspect of this methodology is the survival of the
functional groups like –OH, -CH3, -NO2 present on arylaldehyde. All the
compounds were obtained in an excellent yields. The recrystalization of the
product in ethyl alcohol gives analytically pure pyranopyrazoles. Other basic
catalysts like K2CO3, DABCO showed less catalytic activity giving lower yield
under identical conditions for this reaction.
The plausible mechanism involving the formation of pyrazolone [52]
and cynoolefin [53] through the reaction between hydrazine hydrate and
ethylacetoacetate and aldehyde and malononitrile. The Michael addition of
active methylene group of pyrazolone to an electron deficient carbon of
cyanoolefin gives an intermediate [54] which rearranges to give targeted
pyranpyrazole (Scheme 4.18).
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
131
NH2
NH2
O O
O
Ar
O
HCN
CN
NH
NO
Ar
N
CN
NH
N
Ar
O
CN
N
HHNNH
O NH2
CNAr ON
NNH
CNHH
-
+
+
[52]
Pyranopyrazole
[53]
[54]
Scheme 1.18
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
132
Table 4.1 Reaction time and yield of Pyranopyrazoles.
Entry Compound Time (min) Yielda
%
1.
ONH
N NH2
CN
55
88
2.
ONH
N NH2
CN
OH
110
85
3.
ONH
N NH2
CN
NO2
50
90
4.
ONH
N NH2
CN
Cl
30
95
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
133
Entry Compound Time (min) Yield (a)
(%)
5.
OH
ONH
N NH2
CN
85
88
6.
ONH
N NH2
CN
No2
40
92
7.
ONH
N NH2
CN
Cl
85
88
8.
ONH
N NH2
CNCl
40
90
9.
ONH
N NH2
CN
NO2
45
87
10
Me
ONH
N NH2
CN
150
79
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
134
11.
O
NHN NH2
CN
OMe
145
75
a -refers to pure isolated compounds.
Table 4.2 Effect of catalyst amount of on MgO the yield of
pyranpyrazole.
4.5 SPECTRAL ANALYSIS
The structures of synthesized compounds (Table 4.1, Entry 1-5) were
confirmed on the basis of IR, 1H and 13C NMR and mass spectroscopic data.
The spectroscopic data were in full agreement with the literature values.
In 6-amino-3-methyl-4-phenyl-2,4dihydropyrano[2,3-c]pyrazole-5-
carbonitrile, (Table -4.1, entry 1) the IR spectrum shows band at 3373, 3310
cm-1 are due to asymmetric and asymmetric stretching of free primary amino
group and a band at 2192 cm-1 for cyano stretching frequency (Spectrum 4.1). 1H NMR spectrum of same compound exhibits a singlet resonate at δ 1.763 for
methyl protons linked to pyrazole ring and a sharp singlet for one methine
proton appeared at δ 4.575 and a broad singlet for amino protons resonate at δ
6.868 While aromatic protons gave downfield shift in form of multiplet
between δ 7.3-7.1. The NH proton of pyrazole ring is strongly deshielded
observed at δ 12 .096 (Spectrum 4.2). In 13C NMR (Spectrum 4.3) following
peaks were observed at δ 10.17, 36.67, 57.64, 98.09, 121.24, 127.19, 127.91,
Amount of MgO
(mol %)
5 10 15 20
Yield in (%)
55
67
80
91
CHAPTER 4 MgO, a Reusable Catalyst for Greener Synthesis of Pyranopyrazole in Water
135
128.89, 136.03, 144.89, 155.21, 161.31. The mass spectrum exhibited spectral
lines at (m/z) 253 (M+), 226, 187, 170, 146, 142, 129, 115 (Spectrum 4.4).
The IR spectrum of 6-amino-3-methyl-4-[4-hydroxyphenyl]-2,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (Table 4.1, entry 2) exhibit sharp
peak at 3500 cm-1 due to for N-H broad stretching band at 3465 cm-1 for -O-H.
A sharp doublet encountered at 3390, 3300 cm-1 due to asymmetric and
symmetric stretching of primary amino group. Intense peak at 2176 cm-1 is for -
CN group (Spectrum 4.5). The 1H spectrum of the same compound showed
singlet at δ 1.766 for methyl protons attached to pyrazole ring whereas the
methine protons appeared as singlet at δ 4.454. The four aromatic protons of
phenyl ring gave a two sets of doublets encoutetred at δ 6.684 (J =8.4 Hz) and
δ 6.949 (J =8.4 Hz). A broad singlet at δ 6.785 is due to two protons of amino
group. The two singlet appeared at δ 9.297 and 12.049 for -OH and NH proton
(Spectrum 4.6). The 13C NMR of same compound exhibited peaks at δ 10.19,
35.91, 58.22, 98.50, 115.55, 121.35, 128.88, 135.20, 135.97, 155.19, 156.45,
161.07 (Spectrum 4.7). The mass spectrum exhibited lines at (m/z) 268 (M+),
242, 202, 186, 175, 160.(Spectrum 4.8).
IR spectrum 6-amino-3-methyl-4-[3-nitrophenyl]-2,4dihydropyrano[2,3-
c]pyrazole-5-carbonitrile (Table 4.1, entry 3) showed a band at 3474 cm-1 for
N-H stretching whereas asymmetric and symmetric band for amino group
attached to the ring were observed at 3223, 3118 cm-1. A intense peak at 2195
cm-1 is due to the presence of –CN. The band for –NO2 stretching observed at
1492 cm-1(Spectrum 4.9). The 1H NMR of same compound showed a single at
δ 1.788 for three protons of methyl group attached to pyrazole ring. Singlet at δ
4.862 is due to methine proton, whereas a triplet and multiplet at δ 7.653 and
8.131 for two protons each. A broad singlet observed at δ 7.045 for amino
group protons and a sharp singlet at δ 12.209 for N-H proton of pyrazole ring
(Spectrum 4.10). 13C NMR spectrum showed the signal peaks at δ 10.19,
36.08, 56.59, 97.11, 122.28, 122.44, 130.71, 134.84, 136.37, 147.26, 148.34,
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161.59 (Spectrum 4.11). The mass spectrum showed spectral lines at (m/z)
298, 232, 216, 186 (Spectrum 4.12).
IR Spectrum of 6-amino-3-methyl-4-[4-chlorophenyl]-2,4-dihydro-
pyrano[2,3-c]pyrazole-5-carbonitrile (Table 4.1, entry 4) showed a band at
3373, 3311 cm-1 for -NH2 The sharp peak observed at 2193 cm-1 for –CN
group (Spectrum 4.13). In PMR spectrum, methyl protons attached to pyrazole
ring resonated at δ 1.776 whereas a singlet encountered at δ 4.619 for methine
proton. Two doublets observed at δ 7.194 (J =8.4 Hz) and 7.377 (J=8.4 Hz) for
aromatic protons. Amino protons observed as broad singlet at δ 6.923 as broad
singlet. NH proton of pyrazole ring appeared at δ 12.185 (Spectrum 4.14). 13C
NMR spectrum for the said compound showed the signal at δ 10.18, 36.00,
57.21, 97.61, 121.10, 128.90, 129.81, 131.67, 136.15, 143.93, 155.12, 161.35
in good agreement with the literature data(Spectrum 4.15). In mass spectum of
the compound, spectral lines observed at (m/z) 286 (M+), 260, 221,204, 185,
178, 129 (Spectrum 4.16).
The IR spectrum of 6-amino-3-methyl-4-[3-hydroxyphenyl]-2,4-dihydro-
pyrano[2,3-c]pyrazole-5-carbonitrile (Table 4.1, entry 5) showed a peak at
3407 cm -1 for the -O-H stretching. Two sharp peaks at 3362-3332 cm-1 for
amino group and cyano group appeared at 2177 cm-1(Spectrum 4.17). 1H
NMR spectrum of same compound (Spectrum 4.18) has a sharp singlet at δ
1.805 indicating the presence of methyl group attached on aromatic ring of
pyrazole, singlet at δ 4.472 is due to methine proton. The aromatic protons
appeared at δ 6.523-6.617 and 7.057-7.109. The amino protons appeared as
broad singlet at δ 6.8. The phenolic O-H proton appeared at δ 9.318. while N-H
proton at δ 12.087. The 13C NMR of same compound exhibited peak at δ 10.22,
36.61, 57.72, 98.14, 114.29, 114.58, 118.64, 121.28, 129.73, 136.05,146.42,
155.19, 157.87, 161.29 which confirm the structure of desired compound
(Spectrum 4.19).The mass spectrum showed spectral lines observed at (m/z)
268 (M+), 252, 242, 203, 187, 175 (Spectrum 4.20).
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4.6 EXPERIMENTAL
Materials and Methods.
All aryl aldehydes, ethylacetoacetate, hydrazine hydrate and
malononitrile were purchased from S. D. fine and spectrochem Co. and were
used without further purification.
Instrumental details and their operational conditions
NMR analysis.
NMR analysis was performed on Brucker–Avance 300 MHz, NMR
spectrophotometer. For 1H NMR analysis, DMSO was used as solvent and
tetramethylsilane as an internal standard, the chemical shifts are reported in
ppm. Multiplicities are indicated by ‘s’ (singlet), ‘d’ (doublet), ‘t’ (triplet), ‘q’
(quartet), ‘m’ (multiplet) and ‘bs’ (broad singlet). The coupling constant (J) are
reported in Hz.
IR Analysis
Infrared spectra were recorded on Perkin Elmer 1310 FT-IR spectrometer with
KBr pellets.
LCMS Analysis
LCMS analysis was performed on Mass pectromete –API 5500Qtrap (Applied
biosystems, Canada). The column used for analysis were, Atalantis dC18
(100mmx2mmx5um) Waters India Pvt Ltd, Bangalore. The mobile phase used
for sample is: 5mM ammonium formate in methanol 5mM ammonium formate
in water and flow rate was 0.4mL /min.
General Experimental procedure A mixture of ethyacetoacetate (1mmol) and hydrazine hydrate (1mmol)
were stirred in 10mL of water for 10 min. then arylaldehyde (1mmol),
malononitrile (1mmol) and 20 mol % MgO were added and the reaction was
mixture stirred at 50 oC for appropriate time on an oil bath. The product formed
was isolated by simple filtration and further purified by recrystalization to
separate desired pyrano[2,3-C]pyrazole in high yield.
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4.7 CONCLUSION
We have reported a simple, ecofriendly and elegant protocol for the
synthesis of pyrano[2, 3-c]pyrazole through one step four component coupling
using magnesium oxide as a solid reusable and basic catalyst. The reaction
proceeds efficiently in water without any use of flammable, volatile organic
solvent. As reaction occurs in the water it excludes the cumbersome separation
methods and hence it avoids use of the harmful solvents. Therefore the use of
MgO as a catalyst renders this method environmentally benign.
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