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An Approach towards the synthesis of
furo[3,4-c]pyrazole
A Dissertation
Submitted in partial fulfillment
FOR THE DEGREE OF
MASTER OF SCIENCE IN CHEMISTRY
By
Krushna Chandra Sahoo
Under the Guidance of
Dr. Niranjan Panda
DEPARTMENT OF CHEMISTRY
NATIONAL INSTITUTE OF TECHNOLOGY
ROURKELA – 769008, ORISSA
CERTIFICATE
Dr. Niranjan Panda
Department Of Chemistry,
National Institute Of Technology,Rourkela
This is to certify that the dissertation entitled “An Approach towards the
synthesis of furo[3,4-c]pyrazole” being submitted by Krushna Chandra
Sahoo to the Department of Chemistry, National Institute of Technology,
Rourkela, Orissa, for the award of the degree of Master of Science is a
record of bonafide research carried out by him under my supervision and
guidance. To the best of my knowledge, the matter embodied in the
dissertation has not been submitted to any other University / Institute for the
award of any Degree or Diploma.
N.I.T. Rourkela.
Date:
Dr. Niranjan Panda
(Supervisor)
ii
ACKNOWLEDGEMENTS
With deep regards and profound respect, I avail this opportunity to
express my deep sense of gratitude and indebtedness to Prof. Niranjan
Panda, Department of Chemistry, National Institute of Technology,
Rourkela, for introducing the present project topic and for her inspiring
guidance, constructive criticism and valuable suggestion throughout the
project work. I most gratefully acknowledge his constant encouragement and
help in different ways to complete this project successfully.
I would like to acknowledge my deep sense of gratitude to Prof. R. K.
Patel, Head of Department of Chemistry, National Institute of Technology,
Rourkela, and all the faculty members for his valuable advices and constant
encouragement for allowing me to use the facilities in the laboratory.
I would also like to thank my labmate Archana, Soumi, Ashish, Vijaya
and all my friends for their constant encouragement during the project work. I
wish to thank all the staff members of Department of Chemistry for their
support and help during the project.
Last but not the least, I remember with gratitude my family members
who were always a source of strength, support and inspiration.
Rourkela
Date:
(Krushna Chandra Sahoo)
iii
To
MY FATHER
WHO ENCOURAGE ME
TO PROCEED
AT EACH & EVERY STEP
iv
TABLE OF CONTENTS
Page
INTRODUCTION ……………………………………………………………………… 1
RESULT & DISCUSSION……………………...………………………………………. 6
CONCLUSION…………………………………. ………...………………………….. 8
EXPERIMENTAL SECTION………………………………………………………….. .9
REFERENCES------------------------------------------------------------------------------------13
v
INTRODUCTION
Heteroaromatic compounds have attracted considerable attention in the design of
biologically active molecules and advanced organic materials.1 Hence, a practical method
for the preparation of such compounds is of great interest in synthetic organic chemistry.
Pyrazole and its derivatives, a class of well known nitrogen containing heterocyclic
compounds, occupy an important position in medicinal and pesticide chemistry with
having a wide range of bioactivities
such as antimicrobial,2 anticancer,3 anti-
inflammatory,4 antidepressant,5anticonvulsant,5,6 antihyperglycemic,7
antibacterial,
9
antipyretic,8
antifungal activities,10 CNS regulants,11 and selective enzyme inhibitory
activities12. It has been found that these compounds have hypoglycemic activity, and are
also known as inhibitors and deactivators of liver alcohol dehydrogenase and
oxidoreductases.13 It has been shown in vivo that some of the pyrazole derivatives have
appreciable antihypertensive activity.14 These compounds also exhibit properties such as
cannabinoid hCB1 and hCB2 receptor, , inhibitors of p38 Kinase, CB1 receptor
antagonists15,16 .The biological activity of certain pyrazole derivatives have been
discussed here .
The 1-phenylpyrazole motif is present in several drug candidates for treatment of various
diseases such as cyclooxygenase-2 (Cox-2) inhibitors, IL-1 synthesis inhibitors, and
protein kinase inhibitors etc. Similarly a few of the 1,5-diarylpyrazole derivatives have
been shown to exhibit non-nucleoside HIV-1 reverse transcriptase inhibitory activities
along with Cox-2 inhibitor.17
Several substituted pyrazolo[3,4-d]pyrimidine derivatives have xanthine oxidase inhibitor
activity18, like allopurinol which was first synthesized by Robins in 1956 and is still the
drug for the treatment of hyperuricemia and gouty arthritic disease.19
The pyrazolo[1,5-a]pyrimidines e.g. Indiplon (1a) and Zaleplon (1b) and the N,N-dialkyl2- phenylacetamidoimidazo[1,2-a]pyridines e.g. Zolpidem (2a) and Alpidem (2b) are
also used for the treatment of anxiety sleep disorders, convulsions, and memory
deficits.20
O
N
N
N
N
N
O
S
N N
O
N
N
Indiplon
Zaleplon
N-methyl-N-[3-[3-(thiophene-2-carbonyl)
pyrazolo[5,1-b]pyrimidin-7-yl]phenyl]acetamide
N-(3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)
phenyl)-N-ethylacetamide
1b
1a
N
N
O
Cl
O
N
N
N,N,6-trimethyl-2-(4-methylphenyl)imidazo(1,2-a)pyridine-3-acetamide
N
Cl
N
Zolpidem
Alpidem
2-[3-chloro-8-(4-chlorophenyl)-1,7-diazabicyclo[4.3.0]
nona-2,4,6,8-tetraen-9-yl]-N,N-dipropyl-acetamide
2b
2a
2
Urea derivatives of 5-aminopyrazoles have recently been reported as potent inhibitors of
P38 kinase, TNF-α production, and cholesterol acyltransferase.21
Curcuminoid pyrazoles are used as new therapeutic agents in inflammatory bowel
disease. The activity of the curcuminoid pyrazoles covers domains such as antiinflammatory (5-lipooxygenase and cyclooxygenase inhibitors), antitumoral (antiangiogenic) and drugs for the treatment of the Alzheimer disease.22
The importance of pyrazole exploited from the appearance of some pesticides in the
market in the name of fripronil (Colliotet al., 1992) (3), topramezon (BASF, 2006)(4),
pyraelostrobin (BASF,2001)(5) etc.23
O
O
S
NH2 Cl
F
S
N
F
Fipronil
O
F
Topramezone
Cl
[3-(4,5-dihydro-3-isoxazolyl)2-methyl-4-(methylsulfonyl)phenyl]
-(5-hydroxy-1 -methyl-1H-pyrazol-4-yl)methanone
(5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile);
4
3
O
O
N
N
N
O
F
N
N
O
N
F
F
HO
O
N
O
N
Cl
Pyraelestrobin
methyl N-(2-{[1-(4-chlorophenyl)-1H-pyrazol-3yl]oxymethyl}phenyl)-N-methoxy carbamate
5
3
The pyrazole ring is a constituent of a variety of natural and synthetic products. Examples
of
pyrazole
ring
pyrazomycine(7),
containing
and
natural
products
are
(S)-3-pyrazolylalanine(6),
4,5-dihydro-3-phenyl-6H-pyrrolo[1,2–b]pyrazole
(8),
while
lonazolac (9), fezolamin (10),difenamizole (11), and mepirizole(12) are examples of
biologically active synthetic pyrazole derivatives .
N
OH
N
Lonazolac
9
4,5-Dihydro-3-phenyl-6H-pyrrolo[1,2-b]pyrazole
HO
OH
Pyrazomycin
6
C6H4Cl
N
N
CONH2
OH
(s)-3-pyrazolylalanine
(CH2)3NMe2
N
N
H
N
O
COOH
NH2
COOH
N
8
7
MeO
(CH2)3NMe2
N
N
O
Ph
Ph
Fezolamin
Me
H
N
NMe2
Ph
N
N
N
MeO
N
N
Ph
Difenamizole
10
Me
Me
Mepirizole
11
12
4
N
Pyrazoles are usually prepared by condensation between a hydrazine derivative and a 1,3dicarbonyl compound or by 1,3-dipolar cycloaddition of diazoalkanes or nitrile imines to
olefins or acetylenes.24 Here, in this report our approach towards the synthesis of some
polycyclic pyrazole compounds by the Diels-Alder reaction of furo[3,4-c]pyrazole and
several dienophiles is disclosed. As furo[3,4-c]pyrazole is unknown till now, we want to
focus our study for the synthesis of furo[3,4-c]pyrazole. Our approach towards furo[3,4c]pyrazole and subsequent [4+2]cycloaddition reaction is outlined in Scheme 1.
Scheme 1
O
O
R
O
SPh
SPh
R
R
R
N
OEt
Cl
N
Ar
SPh
R
O
N
N
Ar
1
R
N
E
N
Cl
N
Ar
SPh
R
E
N
E
O
N
Ar
5
E
R1
SPh
R
O
N
Ar
O

R
N
N
Ar
R1
RESULT AND DISCUSSION
The most important methods for preparing this class of heterocycles are the reaction
between hydrazines with β-difunctional compounds25 and 1, 3-dipolar cycloadditions of
diazo compounds onto triple bonds26. The former process, considered to be the best
method for the preparation of pyrazoles, involves the double condensation of 1, 3diketones with hydrazine or its derivatives.27 This method has a wide scope not only
because of the readily availability of 1, 3-diketones but also because one carbonyl of the
diketone starting material can be replaced by an acetal, a hemiacetal, a chlorovinyl group,
dihalides, etc.25
The conventional method of preparation of pyrazole or pyrazole derivatives involving
condensation of 1,3-diketones with phenyl hydrazine or its derivatives require long time
(7-8 hrs) with lower yield. And it requires organic toxic solvent as a reaction medium.
But we have developed an efficient method of synthesis pyrazole type of compound by
solvent free reaction of 1,3-diketone with phenyl hydrazine under microwave irradiation
in short time (8-10 min). Thus the reaction of 1,3- dicarbonyl compound with phenyl
hydrazine in silica gel G support under microwave irradiation for 8-10 mins give
pyrazolone (14) in excellent yield.14b shows a characteristic absorption peak at 1709 cm1
(C=O stretching ).Reaction of 14 with phosphorous oxychloride 80-900c result in the
chlorination at C-5 position to form 5-chloro-pyrazole derivative 15 (Scheme 2).
Formation of 15b is evident from 1H NMR spectrum, which shows signals at δ 7.77-7.17
(m) for 10 protons of phenyl ring and another singlet at 6.63 for the C4-H proton.
6
Scheme 2
O
EtO
R
PhNHNH2
O
POCl3
H2SO4(cat.) N N
Silica Gel G
Ph
R
13a; R = Me
13b; R = Ph
O
R
N
14a; R = Me
14b; R = Ph
N
Ph
Cl
15a; R = Me
15b; R = Ph
Pyrazole derivative 15 was selectively formylated at C-4 using Vilsmeier-Haack reaction
condition (Scheme 3). Formation of 16a was confirmed from IR as well as NMR
spectroscopy. 16a shows characteristic IR absorption band at 1676.73 cm-1 (C=O
stretching) and a sharp singlet at δ 9.92 for CHO, at δ 2.491 for –CH3. Similarly IR
spectrum of 16b show a strong absorption band at 1683cm-1 (C=O stretching), 1H NMR
spectrum, which shows signals at δ 7.20-7.78 for aromatic protons .Reactions of 16a with
NaBH4 result in the reduction of aldehyde group alcohol 17 (Scheme 4).
Scheme -3
R
R
CHO
DMF
N
N
Ph
Cl
POCl3
15a; R = Me
15b; R = Ph
N
N
Ph
Cl
16a; R = Me
16b; R = Ph
7
Scheme-4
CHO
N
OH
NaBH4
Cl
N
Ph
MeOH
N
16a
N
Ph
17
Cl
In order to introduce a thiophenyl group, we chlorinated the alcohol by oxalyl chloride
and nucleophilically substituted the chloro group by thiophenolate ion in-situ without
isolation of the chloro compound 18 (Scheme 5).
Scheme-5
OH
N
N
Ph
Cl
(COCl)2,DMF
Benzene
17
Cl
N
N
Ph
Cl
PhSH
Benzene,
Pyridine
SPh
N
N
Cl
Ph
18
19
CONCLUSION
The present work embodies the synthesis of pyrazole derivative in solid phase under
microwave irradiation of β-dicarbonyl compounds with phenylhydrazine within a very
short time (8-10 min) in good yield. The transformation of the pyrazolone to the
precursor for Pummerer reaction which may lead to furo[3,4-Ic]pyrazole is an ongoing
work in our laboratory and will be reported in due course.
8
EXPERIMENTAL SECTION
3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (14a)
To a mixture of ethyleacetoacetate (3.84mmol, 0.49ml) and phenyl hydrazine (3.84mmol,
0.38ml) a drop of concentrated H2SO4 was added. To this mixture 2gm of silica gel G
was added and it was grinded thoroughly. The mixture was heated in a microwave for 810 minutes. Then it was washed with CH2Cl2 repeatedly and the extract was dried over
anhydrous Na2SO4 and the solvent was removed under vacuum yielding yellow solid
which was washed with petroleum ether and 2% polar solution to give the pure product
as light yellow crystalline solid.
Yield-69%
1, 3-diphenyl-1H-pyrazol-5(4H)-one (14b)
1,3-diphenyl-1H-pyrazol-5(4H)-one (2b) was obtained by the condensation of
ethylebenzoyl acetate (500mg, 2.6011mmol) and phenyl hydrazine (0.257ml, 2.6011ml)
following the same procedure as described for compound 2a in the form of yellow
crystalline solid.
Yield-85.16%
IR (KBr)-1709.61cm-1
5-chloro-3-methyl-1-phenyl-1H-pyrazole (15a)
9
A mixture of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (3.7gm, 21.264mmol) and
phosphorous oxychloride (7.93ml, 85.056mmol) was stirred under nitrogen atmosphere at
80-900 for 7hrs. Then the reaction mixture was cooled to room temperature and poured
into ice-cold water and neutralized by careful addition of saturated solution of NaHCO3
in small portions with stirring. The resulting mixture was then extracted with CH2Cl2
repeatedly. The combined layer was washed with brine solution and dried over anhydrous
Na2SO4 and the organic layer was dried under vacuum. The crude compound was then
purified by column chromatography.
Yield-65.6%
5-chloro-1, 3-diphenyl-1H-pyrazole (15b)
1,3-diphenyl-1H-pyrazol-5(4H)-one (3gm,12.962mmol) was taken with phosphorous
oxychloride (POCl3 ,4.83ml,51.85mmol) and proceeding as for compound 3a we get 5chloro-1, 3-diphenyl-1H-pyrazole.
Yield-84.78% 1H NMR (300MHz) δ 7.77-7.17(m, 10H, ArH), 6.63(s, 1H, CH),
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (16a)
Dimethylformamide (DMF) (5ml) and phosphorous oxychloride (4.728ml, 0.515mmol)
were mixed under ice cold condition at nitrogen atmosphere. Then it was allowed to
come to room temperature and stirred for 30 minutes. 5-chloro-3-methyl-1-phenyl-1Hpyrazole (2gm, 10.38 mmol) dissolved in DMF was added to it and then heated at 80-900
for 8hrs under nitrogen atmosphere. Then it was cooled to room temperature. The
reaction mixture was poured to ice cold water followed by neutralization with saturated
10
solution of NaHCO3. Then the resulting mixture was extracted with CH2Cl2 repeatedly
and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The black crude compound was purified by column chromatography yielding 5chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde as white crystalline solid.
Yield-78%
IR (KBr)-1676cm-1 ,1H NMR δ 7.19-7.82(Phenyl H), 9.92(Aldehyde H),2.4(-CH3),
5-chloro-1,3-diphenyl-1H-pyrazole-4-carbaldehyde (16b)
5-chloro-1,3-diphenyl-1H-pyrazole (3b) was taken and white crystals of 5-chloro-1,3diphenyl-1H-pyrazole-4-carbaldehyde was synthesized following the procedure given
for compound 16a.
Yield-71%
IR-1683.61cm-1
5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl) methanol (17)
To a stirred solution of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (1.8
gm, 8.163mmol) in ethanol (5ml), sodium borohydride (NaBH4) was added gradually in
ice cold condition. Then it was allowed to stir for 6-7 hours at room temperature. The
reaction mixture was then extracted with CH2Cl2 and washed with dilute HCl. The
organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure
to get (5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl) methanol as white solid.
Yield -63.31%
11
5-chloro-4-(chloromethyl)-3-methyl-1-phenyl-1H-pyrazole (18)
To
a
stirred
solution
of
(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)
methanol(1.6g,7.19mmol) in benzene(10-12 ml) was added 1 drop of DMF and oxalyl
chloride (1.376 ml,17.975mmol) under nitrogen atmosphere. Then the reaction mixture
was heated at reflux for 2-3 hrs. Then the solvent was removed under reduced pressure
and the intermediate compound 6 was subjected to next step immediately without further
purification.
5-chloro-3-methyl-1-phenyl-4-((phenylthio)methyl)-1H-pyrazole(19)
To the above resulting gummy liquid 5ml of dry benzene was added. Then thiophenol
was added drop wise at 00. Then to this well stirred solution 0.5ml of pyridine was added
and stirred. Then the reaction mixture was allowed to come at room temperature and
stirred for 2hrs. Then the reaction mixture was poured in to water and extracted with
CH2Cl2.The organic layer was washed with dil. HCl and dried over anhydrous NaSO4.
Then the solvent was removed under reduced pressure and the resulting mixture was
purified by column chromatography.
12
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16
FTIR
119.8
Me
N
O
N
Ph
110
3842.37
100
3753.61
3678.59
3126.45
3652.55
3436.50
90
1802.51
80
2364.26
909.19
%T 70
647.72
615.35
575.59
498.84
1073.45
1197.22
60
804.10
1029.84
1159.71
1598.33
1525.86 1303.89
1498.30
1454.81
1390.15
1344.47
50
40
688.56
753.27
27.5
4400.0
4000
3000
450.0
1000
1500
2000
cm-1
Fig. 1: IR spectra of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one(14a)
Ph
N
83.7
N
Ph
O
80
75
70
65
60
932.04
497.38
55
%T
1559.51
1446.54
50
1068.00
1021.47
895.23
3051.71
45
649.30
599.37
1594.11
2955.64
1396.21
1375.91
40
688.60
1180.07
1493.85
35
1332.84
756.16
1118.45
30
1709.61
25
19.8
4400.0
4000
3000
2000
1500
1000
450.0
cm-1
Fig. 2: IR spectra of 1, 3-diphenyl-1H-pyrazol-5(4H)-one (14b)
17
O
Me
51.9
50
H
N
N
Ph
Cl
45
40
497.85
804.19
35
2345.37
30
3906.31
%T
1597.90
3856.50
3842.42
3823.90
3806.88
3753.79
3738.01
3714.30
3693.26
3678.45
3652.65
3632.62
3570.19
25
20
15
10
1071.07
1003.86
933.89
3064.22
696.51
1435.83
1527.02
1461.40
1375.98
762.77
1676.73
4.5
3000
4000
4400.0
450.0
1000
1500
2000
cm-1
Fig. 3: IR spectra of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde(16a)
O
Ph
93.5
H
N
80
N
Ph
Cl
70
60
491.95
50
846.72
912.40
40
1107.39
1227.07
%T
618.83
555.90
519.29
713.91
30
1264.89
1074.86
746.19
1025.77
1001.96
984.03
760.67
1452.05
961.95
689.53
1416.93
799.93
1683.61
1368.07
1495.64
1594.26
20
10
2924.85
0
-10
-18.2
4400.0
4000
3000
2000
1500
1000
450.0
cm-1
Fig.6: IR spectra of 5-chloro-1,3-diphenyl-1H-pyrazole-4-carbaldehyde (16b)
18