Green Synthesis of Pyrazole and Oxazole Derivatives

Article abstract of DOI:10.1002/jhet.3360

New intermediate 3-methyl-5-oxopyrazol propanenitrile was synthesized by one pot three component reactions using ethyl cyanoacetate, hydrazine hydrate, and ethyl acetoacetate and was used for the synthesis of new oxazole and pyrazole derivatives. All reactions were carried out using eco-friendly solvents and without catalyst.

Full text of DOI:10.1002/jhet.3360

Month 2018
Green Synthesis of Pyrazole and Oxazole Derivatives
Vasant M. Patil,a Sunita A. Chaudhari (Patil),a,b Satish M. Chavan,a,d
a
and Ram W. Sabnisc
*
Raghunath B. Toche,
aOrganic Chemistry Research Centre, Department of Chemistry, K.R.T. Arts, B.H. Commerce & A.M. Science College,
Gangapur Road, Nashik 422002, Maharashtra, India
bRegional Forensic Science Laboratory, Home Department, Opposite Vidyut Nagar, Dindori Road, Nashik 422004, India
cPatent Law Department, Georgia-Pacific LLC, 133 Peachtree Street NE, Atlanta, GA 30303, USA
dDepartment of Chemistry, R.N.C. Arts, J.D.B. Commerce & N.S.C. Science College, Nashik Road, Nashik 422101,
Maharashtra, India
*E-mail: raghunath_toche@rediffmail.com
Received May 29, 2018
DOI 10.1002/jhet.3360
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
New intermediate 3-methyl-5-oxopyrazol propanenitrile was synthesized by one pot three component re-
actions using ethyl cyanoacetate, hydrazine hydrate, and ethyl acetoacetate and was used for the synthesis of
new oxazole and pyrazole derivatives. All reactions were carried out using eco-friendly solvents and without
catalyst.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
entirely composed of ions that are fluid at relatively low
temperature, from ambient temperature to 100°C. Ionic
liquids have been investigated as a viable substitute for
conventional volatile organic solvents. Ionic liquids impart
low volatility/flammability and high chemical or
electrochemical stability [6]. Water can be considered as
the greenest solvent as it is non-toxic to health and the
environment. Moreover, it is the safest and least expensive
solvent. Considerable attention has been directed towards
the use of water as a medium in organic synthesis for
sustainability, non-toxicity, and safety reasons [7].
Switching from organic solvents to water at an industrial
scale has been discussed [8]. The aqueous-ethanol mixture
could be used as the reaction medium in many reactions
[9–15]. Bentley et al. used aqueous alcohol for the
solvolysis study of p-methoxybenzoyl chloride in and
found the rate of reactions are not much affected in water
and in aqueous alcohol medium [16]. A synthesis of
benzopinacol from benzophenone is carried out by Geeta
Verma using ethanol as a solvent [17]. Mirgane et al.
utilized aqueous ethanol as suitable medium for
diastereoslective Diels–Alder reaction of anthrone and (R)-
(+)-N-α-methylbenzylmaleimide using chiral bases [18].
Bioethanol could be the green alternative for sustainable
future [19].
Green chemistry provide alternative synthetic pathway
for prevention of pollution in the utilization of set of
principal that reduces or eliminates the use or generation
of hazardous substances in the design, manufacture, and
application of chemical products or processes [1]. Organic
solvents are used in preparative chemistry for years as they
offer many advantages such as the ability to dissolve
reagents, substrates, and catalysts. The most commonly
used aprotic solvents include N,N-dimethylformamide,
dimethylacetamide, and N-methyl-2-pyrrolidone. On the
downside, however, over 80% of the waste produced was
organic solvents employed for synthesis, workup, and
purification. Recently, much of the efforts have been
directed towards developing alternative reaction media,
thereby providing an important contribution to green
chemistry. Therefore, it is required to develop chemical
procedures based on greener organic solvents.
Dimethyl carbonate (DMC) is a nonpolar, aprotic solvent
with good miscibility with water, biodegrades readily in the
atmosphere, and is non-toxic. DMC is classified under the
greenest “recommended” bracket according to the solvent
selection guide [2,3] that include other green solvents such
as water and ethanol. DMC can be a potential replacement
for methyl ethyl ketone, ethyl acetate, and most other
ketones [4]. Glycerol as solvents, whose properties can be
tailored, tuned, and adjusted according to the requirement
of each reaction and separation [5]. Ionic liquid is a liquid
The development of green solvents in biomass
processing and for biorefinery applications has been
presented [20]. Further, the importance of green
chemistry in pharmaceutical industry [21] and textile
© 2018 Wiley Periodicals, Inc.

R. B. Toche, V. M. Patil, S. A. Chaudhari (Patil), S. M. Chavan, and R. W. Sabnis
Vol 000
industry [22] has been described. Development of
sustainable synthetic strategy is the great challenge for
the organic chemist. The development of green synthetic
pathway needs multifunctional reaction intermediate.
Such intermediate should also need to have higher
oxidation potential to reduce the reactants. The driving
force for new C─C bond formation is the high oxidation
potential of the intermediate that avoid the drastic
reaction conditions or hazardous catalyst. Syntheses of
substituted oxazole derivatives are important because of
their diverse range of biological activities in
pharmaceutical areas [23]. Oxazoles are continued to be
of interest for both their biological activities and synthetic
utility [24–26]. The synthesis of aryl-oxazole is the
subject of ongoing improvements [27]. It is worth to
mention that the combination of heterocyclic moiety
fused with pyrazole ring may increase their biological
activities or create new medicinal properties due to
different electronic distribution [28,29]. Solvent and
catalyst free method was reported for substituted oxazole
using 2-bromo-1-phenylethanone, urea and easily
recoverable and reusable polyethylene glycol as a non-
ionic liquid [30]. Fused oxazole could be synthesized by
microwave method using mixture of 4-phenyl-pyridine-
4,6-dione, bromoacetothiophenone, K2CO3, and N,N-
dimethylformamide [31]. Copper (I) and zinc (II)
catalyzed routes for synthesis of oxazoles via secondary
propargylamides in one pot multicomponent reaction
from aldehydes, LiN (TMS)2, alkynes, and acid chlorides
were reported [32]. Oxazole derivatives were synthesized
by reacting with ketone and aldehyde to form keto enol
intermediate that was reacted with a base hydroxylamine
hydrochloride to obtained oxazole derivative [33].
Synthesis of 2,4,5-trisubstituted oxazoles via copper
catalyzed oxidative cyclization of arylamides and β-
diketones was also reported [34]. Tomi et al. reported the
synthesis of some oxazole derivatives from hippuric acid
and demonstrated their biological activities [35].
ethanol at room temperature according to literature
method [34]. This compound 3 was condensed with
ethylacetoacetate 4 yielded intermediate 3-(4,5-dihydro-3-
methyl-5-oxopyrazol-1-yl)-3-oxopropanenitrile 5 in 85%
yields (Scheme 1). The structure of compound 5 was
established by spectral and analytical techniques. The IR
spectra of 3-(4,5-dihydro-3-methyl-5-oxopyrazol-1-yl)-3-
oxopropanenitrile 5 showed the characteristics carbonyl
(C═O) stretching frequency at 1695–1700 cmÀ1, (CN)
stretching at 2200 cmÀ1 and (H─C═O) at 3200 cmÀ1
.
The 1H NMR showed singlet at 1.31 δ for three protons of
methyl (CH3) group. The singlet appeared at 3.54 δ
corresponded to two protons of CH2 group attached to CN
and the singlet at 2.44 δ for two protons of another CH2
group of pyrazolone ring. The mass spectrum of 5 showed
characteristic M+ peak at 165 (exact mass is 165.15) and
corresponded to the molecular formula C7H7N3O2. On the
basis of spectral and analytical data, structure was
assigned as 3-(4,5-dihydro-3-methyl-5-oxopyrazol-1-yl)-
3-oxopropanennitrile 5. The reaction of oxopropanenitrile
5
and substituted hydrazines in ethanol at room
temperature yielded 1-(5-amino-1-phenyl-1H-pyrazol-3-
yl)-3-methyl-1H-pyrazol-5(4H)-one 6 in 81–83% yield
(Scheme 2). The compound 6a was characterized by
spectral and analytical techniques. The IR spectra of the
compound 6 showed the characteristics carbonyl (C═O)
stretching frequency at 1705 cmÀ1, (C═N) stretching at
2235 cmÀ1, (H─C) stretching frequency at 2850 cmÀ1
,
and (H─N) stretching frequency at 3350 cmÀ1 (Scheme
1
2).The H NMR (DMSO-d6) spectrum of compound 6
showed singlet at 1.32 δ for three protons of methyl (CH3)
group. The singlet appeared at 2.45 δ corresponded to two
protons of CH2 group pyrazolone. The compound 6a also
showed broad singlet at 4.30 δ for two protons of NH2
group. The singlet appeared at 6.55 δ corresponded to one
Scheme 1. Synthesis of 3-(4,5-dihydro-3-methyl-5-oxopyrazol-1-yl)-3-
oxopropanenitrile 5.
These literature reports and broad spectrum of oxazole
and pyrazole derivatives inspired us to design new
derivatives and their synthesis without harming the
environment. In this paper, we have reported green and
efficient synthesis of pyrazole and oxazole derivatives
from
3-(4,5-dihydro-3-methyl-5-oxopyrazol-1-yl)-3-
oxopropanenitrile 5. Anintermediate compound 3-(4,5-
dihydro-3-methyl-5-oxopyrazol-1-yl)-3-oxopropanenitrile
5 was used for the synthesis of verity of pyrazole and
oxazole derivatives.
RESULTS AND DISCUSSION
2-Cyano acetohydrazide 3 was obtained by the reaction
of ethyl cyanoacetate 1 and hydrazine hydrate 2 in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
3-Methyl-5-oxopyrazol Propanenitrile, Green Synthesis, Pyrazole, Oxazole
Scheme 2. Synthesis of pyrazole derivatives.
proton of ═CH group of pyrazole ring and broad singlet
appeared at 12.06 δ corresponded to NH proton of
pyrazole ring. The mass spectrum of the compound 6a
showed characteristic M+ peak at 179 (exact mass is
179.18) corresponded to molecular formula C7H9N5O.
The confirmation of compound 6a as 1-(5-amino-1-phenyl-
1H-pyrazol-3-yl)-3-methyl-1H-pyrazol-5(4H)-one was
basedontheaforementionedspectralandanalyticaldata.
The reaction of 3-(4,5-dihydro-3-methyl-5-oxopyrazol-
1-yl)-3-oxopropanenitrile 5 with concentration H2SO4 at
room temperature for 12 h furnished 3-(4,5-dihydro-3-
1696–1705 cmÀ1, (C═N) stretching at 1690 cmÀ1 and
1
(H─C) stretching frequency at 2855 cmÀ1. The H NMR
spectrum (DMSO) of this solid showed singlet at 1.28 δ
for three protons of methyl CH3 group. The singlet
appeared at 2.39 δ corresponded to two protons of CH2
group near to C═O in pyrazolone ring. The broad singlet
at 3.49 δ was for two protons of CH2 group attached to
oxazole ring. The doublets appeared at 7.30 and 7.50 δ
corresponded to aromatic proton of benzene ring. The
13C NMR spectrum (DMSO) of this solid showed peak at
24.3 δ assigned to carbon of the methyl groups. 13C
NMR showed the aromatic carbon appears at their
respective position. The peaks at 162.8 and 163.2 δ
corresponded to two carbonyl carbons. The mass
spectrum of solid showed characteristic M + 1 and M + 2
peaks at 317 and 319, respectively, (exact mass is
317.73) corresponded to the molecular formula
C15H12ClN3O3. On the basis of these analysis structures,
1-(2-(4-(4-chlorophenyl) oxazol-2-yl) acetyl)-3-methyl-
1H-pyrazol-5(4H)-one 9a was assigned to this compound.
methyl-5-oxopyrazol-1-yl)-3-oxopropanamide
7
in
excellent yield (Scheme 2). It was characterized by spectral
and analytical techniques. The IR spectra of 7 showed the
characteristics carbonyl (C═O) stretching frequency at
1705 cmÀ1, (C═N) stretching at 1695 cmÀ1, amide
(H2N─C═O) stretching frequency at 1685 cmÀ1and
1
(H─C) stretching frequency at 2855 cmÀ1. The H NMR
spectrum (DMSO-d6) of 3-(4,5-dihydro-3-methyl-5-
oxopyrazol-1-yl)-3-oxopropanamide 7 showed singlet at
1.33 δ for three proton of methyl CH3 group. The singlets
appeared at 2.54 and 3.64 δ corresponded proton of two
CH2 groups of pyrazolone and methylene CH2 attached
amide. The broad singlet at 10.67 δ was for two protons of
NH2 group. The mass spectrum of compound 7 showed
characteristic M+ peak at 183 (exact mass is 183.16)
corresponded to the molecular formula C7H9N3O3. On the
basis of these analysis structure 7, that is, 3-(4,5-dihydro-3-
MATERIALS AND METHODS
All the chemicals and solvents had been purified by
standard literature procedures, and moisture was removed
from the glass apparatus using CaCl2 drying tubes. The
melting points determined in open capillary tubes with
Gallenkamp melting point apparatus and are uncorrected.
FT-IR spectra recorded on Bruker FTIR-TENSOR II
methyl-5-oxopyrazol-1-yl)-3-oxopropanamide
assigned to this compound. The reaction of 3-(4,5-dihydro-
3-methyl-5-oxopyrazol-1-yl)-3-oxopropanamide with
7
was
1
7
spectrophotometer using Platinum ATR discs. H NMR
substituted phenacyl bromide 8a–e in ethanol under
heating for 20 min yielded oxazole derivatives of 3-methyl-
5-oxopyrazol propanenitrile 9a–e in 68–78% yield
(Scheme 3).
It was characterized by spectral and analytical
techniques. The IR spectra of 9a showed the
characteristics carbonyl (C═O) stretching frequency at
spectra of synthesized compounds recorded on Bruker
Ascend 500 NMR spectrophotometer at 500 MHz
frequency in CDCl3 or dimethyl sulfoxide (DMSO-d6)
using tetramethylsilane as internal standard. Chemical
shifts recorded in δ ppm and multiplicities are given as s
(singlet), bs (broad singlet), d (doublet), t (triplet), q
(quartet), or m (multiplet). Mass spectra were recorded on
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. B. Toche, V. M. Patil, S. A. Chaudhari (Patil), S. M. Chavan, and R. W. Sabnis
Vol 000
Scheme 3. Synthesis of oxazole derivatives.
a Shimadzu LC–MS QP 2010A mass spectrometer with an
ionization potential of 70 eV. Elemental analyses were
performed on Thermo Quest Flash 1112 Series EA
analyzer. Reactions monitored by thin layer
chromatography using 0.2 mm silica gel 60 F254 (Merck,
Delhi, India) plates using UV light (254 and 366 nm) for
detection. Common reagent grade available chemicals
were utilized without further purification or prepared by
standard literature procedures. All the compounds have
been synthesized by conventional methods.
washed with ethanol, and recrystallized from ethanol
afforded white crystalline solid 5 in good yield.
White crystalline solid, mp: 211–212°C, yield: 85%; IR
(KBr) (νcmÀ1): 3380, 2980, 1640, 1542; 1H NMR
(DMSO-d6) δ: 1.31 (s, 3H, CH3), 2.44 (s, 2H, CH2), 3.54
(s, 2H, CH2CN) ppm; 13C NMR (DMSO-d6) δ: 24.6,
42.1, 76.3, 151.8, 153.7, 160.3, 172.8 ppm; MS (70 eV)
m/z (%): 165 [M+]. Anal. Calcd. for C7H7N3O2 (mol. wt.
165.13): C(50.91), H(4.27), N(25.44); found: C(50.78),
H(4.52), N(25.68).
Synthesis of substituted 1-(5-amino-1H-pyrazol-3-yl)-3-
methyl-1H-pyrazol-5(4H)-one (6a–c). The solution of 3-
EXPERIMENTAL
methyl-5-oxopyrazol propanenitrile 5 (1.651 g, 0.01 mol)
in ethanol (20 mL) was added drop wise to the hydrazine
hydrate (0.49 mL, 0.01 mol), phenyl hydrazine (0.98 mL,
0.01 mol), or 2,4-dinitro phenyl hydrazine (1.981 g,
0.01 mol) respectively with constant stirring for 12 h.
The precipitate was filtered and washed with water and
recrystallized from ethanol afforded compounds 6a.
The mixture of ethyl cyanoacetate 1 (10.63 mL, 0.1 mol)
and hydrazine hydrate 2 (4.85 mL, 0.1 mol) in 20 mL
ethanol was stirred at 0–10°C for 10 min and further
stirred at room temperature for 3 h. The white crystalline
product formed was filtered, washed with ethanol
(20 mL), and dried in a hot air oven at 60°C; mp: 109–
110°C, lit. [35], mp: 108°C; yield: 92%.
1-(5-Amino-1H-pyrazol-3-yl)-3-methyl-1H-pyrazol-5(4H)-
one (6a). mp: 188–189°C, yield: 81%; pale yellow solid;
1
IR (KBr) (ν): 3360, 2840, 2230, 1710 cmÀ1; H NMR
Synthesis of 3-(4,5-dihydro-3-methyl-5-oxopyrazol-1-yl)-3-
oxopropanenitrile
(5).
3-(4,5-dihydro-3-methyl-5-
(DMSO-d6) δ: 1.32 (s, 3H, CH3), 2.45 (s, 2H, CH2), 4.30
(s, 2H, NH2), 6.55 (s, 1H, pyrazole ═CH), 12.06 (bs, 1H,
NH) ppm; 13C NMR (DMSO-d6) δ: 27.6, 48.8, 58.6,
85.4, 156.7, 160.8, 173.5 ppm; MS (70 eV) m/z (%): 179
[M+1]. Anal. Calcd. for C7H9N5O: C(46.92), H(5.06),
N(39.09); found: C(46.79), H(5.32), N(39.36).
oxopyrazol-1-yl)-3-oxopropanenitrile 5 was prepared by
cyclization reaction of 2-cyanoacetichydrazide 3 (0.99 g,
0.01 mol) and ethylacetoacetate 4 (1.27 mL, 0.01 mol) at
reflux temperature (82°C) in ethanol (30 mL) for 7–8 h
(TLC check). The white solid separated was filtered,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
3-Methyl-5-oxopyrazol Propanenitrile, Green Synthesis, Pyrazole, Oxazole
1-(5-Amino-1-phenyl-1H-pyrazol-3-yl)-3-methyl-1H-
pyrazol-5(4H)-one (6b).
3H, CH3), 2.39 (s, 2H, CH2), 3.49 (s, 2H, CH2), 7.30 (d,
2H, J = 8.3 Hz, Ar─H), 7.50 (d, 2H, J = 8.3 Hz,
Ar─H), 7.85 (s, 1H, oxazole ═CH) ppm; 13C (DMSO-
d6) δ: 24.3, 33.8, 42.5, 128.9 (2C), 129.5 (2C), 131.3,
134.5,140.1, 140.3, 150.7, 159.5,162.8, 163.2 ppm; MS
(70 eV) m/z (%): 317 [M+], 319 [M+2]. Anal. Calcd. For
C15H12ClN3O3 (mol. wt. 317.73): C(56.70), H(3.81),
N(13.23); found: C(56.48), H(4.08), N(13.51).
mp: 196–197°C, yield: 87%;
yellow solid; IR (KBr) (ν): 3350, 2850, 2235,
1
1705 cmÀ1; H NMR (DMSO-d6) δ: 1.31 (s, 3H, CH3),
2.45 (s, 2H, CH2), 3.64 (bs, 2H, NH2), 6.57 (s, 1H,
pyrazole ═CH), 7.52–7.54 (m, 5H, Ar─H) ppm; 13C
NMR (DMSO-d6) δ: 24.8, 42.3, 80.5, 120.4 (2C) 126.3,
129.6 (2C), 140.1, 146.2, 160.2, 161.6, 172.4 ppm; MS
(70 eV) m/z (%): 255 [M+]. Anal. Calcd. for C13H13N5O
(mol. wt. 255.18): C(61.17), H(5.13), N(27.43); found:
C(60.94), H(5.33), N(27.73).
Synthesis of 1-(2-(4-(4-bromophenyl)oxazol-2-yl)acetyl)-3-
methyl-1H-pyrazol-5(4H)-one (9b).
mp: 260–261°C,
yield: 73%; pale yellow solid; IR (KBr) (ν): 3373, 2940,
1
1-(5-Amino-1-(2,4-dinitrophenyl)-1H-pyrazol-3-yl)-3-
methyl-1H-pyrazol-5(4H)-one (6c). mp: 203–204°C, yield:
2230, 1705, 1682 cmÀ1; H NMR (DMSO-d6) δ: 1.31 (s,
3H, CH3), 2.50 (s, 2H, CH2), 3.45 (s, 2H, CH2), 7.45 (d,
2H, J = 8.2 Hz, Ar─H), 7.68 (d, 2H, J = 8.2 Hz,
Ar─H), 7.92 (s, 1H, oxazole ═CH) ppm. Anal. Calcd. for
C15H12BrN3O3 (mol. wt. 362.18): C(49.74), H(3.34),
N(11.60); found: C(49.51), H(3.55), N(11.83).
83%; orange solid; IR (KBr) (ν): 3380, 2980, 2240,
1
1730 cmÀ1; H NMR (DMSO-d6) δ: 1.33 (s, 3H, CH3),
2.60 (s, 2H, CH2), 4.85 (bs, 2H, NH2), 6.8 (s, 1H,
pyrazole ═CH), 8.1 (d, 1H, J = 8.3 Hz, Ar─H), 8.8 (d,
1H, J = 8.3 Hz, Ar─H), 9.4 (q, 1H, Ar─H) ppm; 13C
NMR (DMSO-d6) δ: 24.3, 42.6, 80.5, 122.8, 123.4,
127.8, 129.6, 139.5 141.3, 146.8, 147.9, 161.5,
173.7 ppm; MS (70 eV) m/z (%): 345 [M+]. Anal. Calcd.
for C13H11N7O5 (mol. wt. 345.27): C(45.22), H(3.21),
N(28.40); found: C(44.98), H(3.44), N(28.63).
Synthesis of 3-methyl-1-(2-(4-(4-nitrophenyl)oxazol-2-yl)
acetyl)-1H-pyrazol-5(4H)-one (9c).
mp: 277–278°C,
yield: 71%; yellow solid; IR (KBr) (ν): 3378, 2940,
1
2285, 1704, 1680, 1545, 1355 cmÀ1; H NMR (DMSO-
d6) δ: 1.38 (s, 3H, CH3), 2.35 (s, 2H, CH2), 3.73 (s, 2H,
CH2), 7.93 (d, 2H, J = 8.5 Hz, Ar─H), 7.97 (s, 1H,
oxazole ═CH), 8.09 (d, 2H, J = 8.5 Hz, Ar─H) ppm.
Anal. Calcd. for C15H12N4O5 (mol. wt. 328.28):
C(54.88), H(3.68), N(17.07); found: C(54.60), H(3.91),
N(17.31).
3-(4,5-Dihydro-3-methyl-5-oxopyrazol-1-yl)-3-oxopropanamide
(7).
In 3-methyl-5-oxopyrazol propanenitrile 5 (1.651 g,
0.01 mol) concentration H2SO4 was added drop wise with
constant stirring for 12 h (TLC checked, Toluene : Acetone;
8:2). After completion of reaction, the reaction mixture was
poured in ice cold water, stirred continuously to remove
excess of impurities formed during the reaction. The solid
obtained was collected by filtration, washed with water, dried,
and recrystallized from ethanol.
Synthesis of 3-methyl-1-(2-(4-p-tolyloxazol-2-yl)acetyl)-1H-
pyrazol-5(4H)-one (9d).
mp: 234–235°C, yield: 68%,
color: light orange solid; IR (KBr) (ν): 3370, 2930, 2280,
1
1705, 1680 cmÀ1; H NMR (DMSO-d6) δ: 1.20 (s, 3H,
CH3), 2.34 (s, 2H, CH2), 2.48 (s, 3H, CH3), 3.83 (s, 2H,
CH2), 7.21 (d, 2H, J = 8.0 Hz, Ar─H), 7.46 (d, 2H,
J = 8.0 Hz, Ar─H), 7.90 (s, 1H, oxazole ═CH) ppm.
Anal. Calcd. for C16H15N3O3 (mol. wt. 297.31):
C(64.64), H(5.09), N(14.13); found: C(64.42), H(5.34),
N(14.38).
mp: 183–184°C, yield: 90%; yellow solid; IR (KBr) (ν):
2855, 1705, 1695, 1685 cmÀ1; 1H NMR (DMSO-d6): 1.33
(s, 3H, CH3), 2.54 (s, 2H, CH2), 3.64 (s, 2H, CH2), 10.67
(bs, 2H, NH2) ppm; 13C NMR (DMSO-d6) δ: 24.8, 42.5,
44.6, 160.1, 163.3, 170.8, 171.5 ppm; MS (70 eV) m/z
(%): 183 [M+]. Anal. Calcd. for C7H9N3O3 (mol. wt.
183.16): Calcd: C(45.90), H(4.95), N(22.94); found:
C(45.74), H(5.15), N(23.13).
Synthesis of 1-(2-(4-(4-methoxyphenyl)oxazol-2-yl)acetyl)-
3-methyl-1H-pyrazol-5(4H)-one (9e).
mp: 217–218°C,
yield: 77%; orange solid; IR (KBr) (ν): 3364, 2915, 2273,
1
1704, 1683 cmÀ1; H NMR (DMSO-d6) δ: 1.34 (s, 3H,
Synthesis of oxazole derivatives of 3-methyl-5-oxopyrazol
propanenitrile
(9a–e).
3-(4,5-Dihydro-3-methyl-5-
CH3), 2.51 (s, 2H, CH2), 3.46 (s, 2H, CH2), 3.89 (s, 3H,
OCH3), 7.11 (d, 2H, J = 8.0 Hz, Ar─H), 7.33 (d, 2H,
J = 8.0 Hz, Ar─H), 7.85 (s, 1H, oxazole ═CH) ppm.
Anal. Calcd. for C16H15N3O4 (mol. wt. 313.31): C(61.34),
H(4.83), N(13.41); found: C(61.04), H(5.03), N(13.68).
oxopyrazol-1-yl)-3-oxopropanamide (1.831 g,
7
0.01 mol) in ethanol (10 mL), the reaction mixture was
stirred for 10 min in ethanol. To this solution, appropriate
phenacyl bromide 9a–f (0.01 mol) was added, and the
reaction mixture was heated at 50–60°C for 20 min (TLC
check Hexane : Ethyl acetate 2:1 mixture). The brown
solid separated was filtered, dried, and recrystallized from
ethanol.
Synthesis of 3-methyl-1-(2-(4-(2-oxo-2H-chromen-3-yl)
oxazol-2-yl)acetyl)-1H-pyrazol-5(4H)-one (9f).
mp: 281–
282°C, yield: 76%; light brown solid; IR (KBr) (ν): 3380,
1
2943, 2281, 1704, 1695, 1682 cmÀ1; H NMR (DMSO-
d6) δ: 1.38 (s, 3H, CH3), 2.58 (s, 2H, CH2), 3.81 (s, 2H,
CH2), 7.28 (d, 2H, J = 1.2, 8.5 Hz, Ar─H), 7.33 (d, 1H,
J = 2.2, 8.5 Hz, Ar─H), 7.41 (m, 1H, J = 1.2, 2.2,
8.5 Hz, Ar─H), 7.73 (s, 1H, oxazole ═CH), 7.82 (s, 1H,
Synthesis of 1-(2-(4-(4-chlorophenyl)oxazol-2-yl)acetyl)-3-
methyl-1H-pyrazol-5(4H)-one (9a).
mp: 252–253°C,
yield: 78%; pale yellow solid; IR (KBr) (ν): 3385, 2960,
1
2245, 1710, 1685 cmÀ1; H NMR (DMSO-d6) δ: 1.28 (s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. B. Toche, V. M. Patil, S. A. Chaudhari (Patil), S. M. Chavan, and R. W. Sabnis
Vol 000
chromrne ═CH) ppm; 13C NMR (DMSO-d6) δ: 24.8, 33.9,
42.7, 121.7, 122.1, 125.5 (2C), 126.9, 128.52, 129.65,
141.8, 146.1, 150.5, 159.7, 162, 163.1, 163.3 ppm; MS
(70 eV) m/z (%): 351 [M+]. Anal. Calcd. for C18H13N3O5
(mol. wt. 351.31): C(61.54), H(3.73), N(11.96); found:
C(61.16), H(3.98), N(12.24).
[8] Parmentier, M.; Gabriel, C. M.; Guo, P.; Isley, N. A.; Zhou, J.;
Gallou, F. Curr. Opin. Green Sustainable Chem. 2017, 7, 13.
[9] Prat, D.; Hayler, J.; Wells, A. Green Chem 2014, 16, 4546.
[10] Reinhardt, D.; Ilgen, F.; Kralisch, D.; König, B.; Kreisel, G.
Green Chem 2008, 10, 1170.
[11] Alaimo, P. J Org Lett 2008, 10, 5111.
[12] Laitinen, A.; Takebayashi, Y.; Kylänlahti, I.; Yli-Kauhaluoma,
J.; Sugeta, T.; Otake, K. Green Chem 2004, 6, 49.
[13] Pai, C. K.; Smith, M. B. J Org Chem 1995, 60, 3731.
[14] Li, C. J.; Chen, L. Chem Soc Rev 2006, 35, 68.
[15] Kobayashi, S.; Hamada, T.; Nagayama, S.; Manabe, K. Org
Lett 2001, 3, 165.
CONCLUSION
[16] Bentley, W. T.; Ebdon, D. N.; Kim, E. J.; Koo, I. S. J Org
Chem 2005, 70, 1647.
[17] Geeta Verma Chem Sci J 2017, 8, 3.
[18] Mirgane Nitin, A.; Karnik Anil, V. Green Chem Lett Rev
2011, 4, 269.
[19] Clark, J. H.; Farmer, T. J.; Hunt, A. J.; Sherwood, J. Int J Mol
Sci 2015, 16, 17101.
[20] Soh, L.; Eckelman, M. J. ACS Sustainable Chem Eng 2016, 4,
5821.
[21] Koenig, S. G.; Dillon, B. Curr. Opin. Green Sust Chem. 2017,
7, 56.
We have reported green synthesis of pyrazole and
oxazole derivatives using eco-friendly solvent without
using any catalyst. Valuable features of the present
method include broad substrate scope, short reaction
time, straightforward procedure, and easy aqueous work
up that facilitated 80–85% recovery of pure product and
use of inexpensive chemicals and reagents.
[22] Islam, S.; Sun, G. ACS Sust Chem Eng 2017, 5, 7451.
[23] Dabholkar, V. V.; Ahmed, S. S. Indian J Het Chem 2010, 20,
171.
[24] Trogu, E.; Cecchi, D. L.; Sarlo, F.; Guideri, L.; Ponticelli, F.;
Machetti, F. Eur J Org Chem 2009, 5, 5971.
[25] Bode, J. W.; Hachisu, Y.; Matsuura, T.; Suzuki, K. Org Lett
2003, 5, 391.
[26] Han, X.; Li, C.; Mosher, M. D.; Rider, K. C.; Zhou, P.;
Crawford, R. L.; Fusco, W.; Paszczynski, A.; Natale, N. R. Bioorg Med
Chem 2009, 17, 1671.
Acknowledgments. Authors thanks Sophisticated Analytical
Instrumentation Facility centre, Panjab University, Chandigad,
Savitribai Phule Pune University for providing analytical service
to scan 1H NMR, 13C NMR etc. and KTHM College, Nashik
for other facilities.
[27] Smeltzer, C.; Cannon, M. J.; Pinson, P.; Munger, J. S.; West,
F. G.; Grissom, C. B. Org Lett 2001, 3, 799.
REFERENCES AND NOTES
[28] Pinho, T.; Melo, E. Curr Org Chem 2005, 9, 925.
[29] Yeh, V. S. C. Tetrahedron 2004, 60, 11995.
[30] Gokhale, K. M.; Wagal, O. A.; Kanitkar, A. S.
IntJPharmPhytopharmacolRes 2012, 1, 156.
[31] Dabholkar, V. V.; Mustaqeem, M. A.; Shinde, N. B.; Yadav,
O. G Res J Chem Sci 2014, 4, 42.
[32] Wang, Q.; Ganem, B. Tetrahedron Lett 2003, 44, 6829.
[33] Black, D. A.; Arndtsen, B. A Tetrahedron 2005, 61, 11317.
[34] Bai, Y.; Chen, W.; Chen, Y.; Huang, H.; Xiao, F.; Deng, G.-J.
RSC Adv 2015, 5, 8002.
[35] Tomi, I. H. R.; Jumbad, H.; Tomma, A.; Al-Daraji, H. R.; Al-
Dujaili, A. H. J Saudi Chem. Soc 2015, 19, 392.
[1] Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
practice; Oxford University Press: Oxford, 1998.
[2] Jessop, P. G. Green Chem 2011, 13, 1391.
[3] Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.;
Abou-Shehada, S.; Dunn, P. Green Chem 2016, 18, 288.
[4] Pyo, S.; Park, J. H.; Chang, T.; Hatti-Kaul Curr Opin Green
Sustainable Chem 2017, 5, 61.
[5] Wolfson, A.; Snezhko, A.; Meyouhas, T.; Tavor, D. Green
Chem Lett Rev 2012, 5, 7.
[6] Yoo, C. G.; Pu, Y.; Ragauskas, A. J Curr Opin Green Sustain-
able Chem 2017, 5, 5.
[7] Sheldon, R. A. Green Chem 2017, 19, 18.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet