C lt/ Volume: 3
Sayı/ Issue: 1
Haz ran/June: 2015
PİRAZOL TÜREVLERİNİN SENTEZ YÖNTEMLERİ
SYNTHESIS METHODS OF PYRAZOLE DERIVATES
Adnan Çetin*
* Muş Alparslan University, Faculty of Education, Department of Science, 49250, Muş
ÖZET
Bu derlemede p razoller n sentez süreçler n ncelemek hedeflenm şt r. Heteros kl k b leş kler n
öneml b r sınıfını oluşturan p razoller b yoakt f özell kler nden dolayı gen ş b r çalışma alanı olarak
önem artarak devam etmekted r. P razoller b yoloj k akt f çeş tl l ğ ne sah pt r. Bu b leş kler laç
araştırmalarında ve tarım ürünler gel şt rmes nde kullanılmaktadır. Böylece p razoller n sentez ç n
gel şt r lm ş metotlar daha öneml hale gelmekted r.
Anahtar Kel meler: Heterosiklik kimya, organik kimya, organik sentez, pirazol.
ABSTRACT
In this review was aimed to describe process synthesis of pyrazoles. Important classes of
heterocyclic compounds forming pyrazoles have continued to grow important because of their widespread of study area by biological activity. The pyrazoles have biological activities diversity. These
compounds are used in the development of agricultural products and in drug researches. Thus, the
methods developed for the synthesis of pyrazoles are becoming more importance.
Key Words: Heterocyclic chemistry, organic chemistry, organic synthesis, pyrazole.
*Sorumlu Yazar/Corespond ng Author: Adnan Çetin, Muş Alparslan University, Faculty of Education,
Department of Science, 49250, Muş, E-mail: [email protected]
303
Çet n,A.
Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
1. INTRODUCTION
Chemistry of heterocyclic compounds is
one of the most complicated of the organic
c h e m i s t r y. C h e m i s t r y o f h e t e r o c y c l i c
compounds is interesting for the diversity of its
synthetic procedures and equally theoretical
implications for physiological and industrial
significance of heterocyclic compounds. In
particular, heterocyclic compounds commonly
investigate only in themselves but also many
natural products, many drugs, medicines and
dyes. It seems heterocyclic more than one-third
of organic compounds. Many alkaloids,
vitamins, antibiotics, many synthetic pesticides
and dyes i.e., and so many substances are
closely connected with the life cycle (such as
nucleic acids). The most important
"heteroatom" is available nitrogen, oxygen and
sulfur. Pyrazole is a simple aromatic ring an
organic compouand of the heterocyclic series by
is characterized five-membered ring structure
which comprises located adjacent two nitrogen
atoms and three carbon atoms in scheme1.
Pyrazoles have π-electrons in the heterocycle. N
atom attracts ring electrons due to electro
negativity so that the C (3) and C (5) becomes
partially electropositive and becomes suitable to
participate in nucleophilic. All of the 1,2-azoles,
pyridine nitrogen and C (4) atoms have been
focused on the π-electron and moves positive
charge as well as other heteroatoms. C (3) and C
(5) atom of the π-electron charge can be positive
or negative depending on the heterocycle. The
highest degree of bond C (3)-N and C (4) - C (5)
was found between atoms. Bond order is the
lowest of the heteroatoms. N atom of
nucleophilic and the steric accessibility can be
varied by appropriate ring substitution.
Although attractive features and powerful
advances in the chemistry of pyrazole, The
interest show on pyrazole and pyrazole
derivative compounds have been limited up to
70s [1].
304
3
4
N 2
5
1
3
4
-
5
b
1
N 2
N
H
Scheme1. Pyrazole
The pyrazole is one of heterocyclic
compounds. Firstly pyrazole was obtained from
decarboxylation pyrazol-3,4,5-tricarboxylic
acid in figure1. Pyrazole was defined for the first
time by Buchner in 1889 [2].
COOH
HOOC
ISI
N
b
HOOC
+
3CO2
N
H
N
H
Figure1. Synthesis of pyrazole
Basic information on their aromatic
properties were obtained to compared with
benzene derivatives about chemistry of organic
substances bearing pyrazole group. Since try to
pyrazole, it was based on a structural problem
with the center present Tautomerism of the Nsubstituent and resulting from derivatives and
isomers of the N-substituent. Pyrazole ring can
be represented by different tautomeric
structures in scheme2. Three tautomeric forms
can be written for pyrazole non-substituents.
b
N
H
N
N
N
N
Scheme2. Tautomeric structures of pyrazole
non-substituents
Until recently pyrazole was believed
absent in nature. However the first natural
pyrazole derivative was isolated by Japanese
workers in 1954. Houttuynia cordata was
isolated from 3-n-nonyl pyrazole which s a
Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
Çet n,A.
plant of the family "Piperaceae" Tropical Asia
[3]. They observed the antimicrobial activity.
Another natural pyrazole derivative is Levo-β(1-pyrazolyl) alanine [4]. Pyrazolic amino acids
were isolated from watermelon seed (Citrullus
Vulgaris). They are currently the only known
natural pyrazole derivatives in scheme3.
an alternative method suitable for the synthesis
of some difficult available of N-aryl pyrazoles
(2) in scheme5 [6].
R
Ar-Br
1.n-BuLi (1 equiv),
THF, -78 oC
or
Li
1,3-Dielectrophile
N
N-N
I
Boc
4 N HCl or
10% H2SO4,
Dioxane,reflux
1
1,3-Dielectrophile:
O
O
N
Ar
2.DBAD, 23 oC
Ar-I
O
(CH2)8CH3
Boc
H Me
O
O
O
Ar
2
Me
Me
H
Me
N
Me
Cl(Br)
Me
N
Me
Me
Ar-Br=2-MeC6H4, 3-MeOC6H4, 4-F3CCH4, 2,3,5-MeC6H2, C6F5, 2-(6-Me)pridyl, 3-(6-Cl)pridyl
Ar-I= 2-ClC6H4, 4-FC6H4, 2,3-F2C6H3
b
Scheme5. Synthesis of N-aryl pyrazoles
N
N
H
N
CH2CH(NH2)COOH
Scheme3. Examples of naturally occurring
pyrazoles
2. SYNTHESIS OF PYRAZOLES
3 - and 5- positions in the various alkyl or
aryl substituents including the 1,3-dicarbonyl
(I), α, β-unsaturated carbonyl compounds (II,
III) and β-enaminones or related compounds
(IV) such as 1,3 positions two electrophilic
carbon feature with a triple carbon units that act
as a pair of nucleophile containing a suitable
cyclocondensation with hydrazine for the
preparation of pyrazole to functional C-3 and C5 is used a very common method in scheme4 [5].
O
O
O
1
3
w1
1
R1
R2
O
3
R2
R1
3
R1
III
II
I
O
1
N
R
N
R1
or/for
R2
N
R2
O
a
R1
b
N
R1
R
H2NHN-R
4
R3
b
R2
3
R
3
R1
O
N
R2
N
b
R
5
X
R-NHNH2
R1
a
R3
3
IV
R2
R-NHNH2
Scheme6. Synthesis of tetra substitute pyrazoles
1
2
R
1,3-diketones, β- ketoesters and 2,4diketoester condensation with hydrazines were
widely used in the preparation N-substituent and
non N-substituent -3,5- and 3,4,5alkyl/(het)aryl pyrazoles, alkoxy pyrazoles and
pyrazole of carboxylic esters, respectively. 3and 5-positions in the various alkyl (4) and aryl
(5) bearing the substituent simple pyrazoles
could occur in that condensed effectively
hydrazines with 1,3-diketones (3) in scheme6
[7-10].
N
R
Scheme4. Synthesis of substitute pyrazole
Recently a study of conducted, one-pot
approach based on cyclocondensation of
compounds 1,3-di electrophilic with aryl
hydrazine Bis-Boc protected (1) was shown as
Elguero et al. proposed the general
mechanism following loss consecutively two
molecules of water intermediate step which
involved to form 3,5-dihydroxy pyrazolidine in
the reaction of asymmetric 1,3-diketones with
monosübstitüent hydrazine. Formation two N-C
bonds at carbonyl amine considered reversible
whereas observed not reversible part of
dehydration kinetically controlled step. Two
3,5-dihydroxy pyrazolidine were in balance and
then these compounds showed that the product
formed two different pyrazole (6,7) in scheme7
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Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
Çet n,A.
R1
w1
R2
O
O
H N
+
OH
N
R1
R1
HO
R
H +N
N
2
HO
OH
N
N
R
H
N +
N
R2
R
2
R
R
R1
R2
R2
H N
R1
OH
N
2
R
R
R-NHNH2
OH
N
R
N
R1
N
R1
R2
N
R
R
7
6
without using any solvent with a catalytic
amount of acid at room temperature. A single
product (21) or a tautomeric mixture were
obtained unsymmetrical with 1,3-diketones (19)
in scheme10 [14].
R1
R2
Scheme7. Synthesis of disubstitute pyrazoles
N
R1
O
O
Enol ketone form (10) was synthesized
mainly quickly effective in a single step by
Heller and Natarajan. 1,3-diketones were not
isolate but they were converted to 3,5-, 1,3,5-,
3,4,5-substituted pyrazoles (11) by adding to the
medium suitable hydrazine in scheme8 [12].
NH2NH2, H+
R2
N
H
15
16
w1
R2
O
LiHMDS
toluene
O
R
+
8
R3
R2
Cl
ArNH2NH2, H+
+
N
R1
R
R2
10
AcOH,EtOH,THF
reflux, 5 min.
R2
N
N
R
11
R=H R2=H R1 or R3 = n-C5H11 4-Br/MeO/H2N/NC/EtO2CC6H4,2,6-(MeO)2C6H3,4-pridyl,2-thionyl
R2=n-Pr or Ph, R1=4ClC6H4, R3=4-MeOC6H4
2
1
3
R=Me, R =H, R =Ph, R =4-MeC6H4
R1=4-BrC6H4, R3=4-MeOC6H4
R=Ph, R2=H, R1=4-O2NC6H4, R3=4-MeOC6H4
Scheme8. Synthesis of trisubstitute pyrazoles
1,5-diaryl-3-methyl pyrazoles (13) were
obtained by reaction of 1-aryl butane 1,3-diones
(12) and aryl hydrazine chloride in reaction
cyclocondensation of 1,3-diketones with
hydrazines using alcohol or which is great acetic
group an aprotic solvent N, Ndimethylacetamide (DMAc) in scheme9 [13].
The products were showed high
stereoselectivity and productivity product,
R2
N
Ar
18
17
Me
RCONHNH2
Ph
HO
R-C6H4NHNH2.HCl
12
Ar
Me
Ar
Me
DMA, 10 N HCl
rt, 24 h
Ar=Ph, 4-MeOC6H4
R=H, Br, SO2NH2 R3=4-MeOC6H4
N
N
C6H4R
+
Me
H+, 120 oC
N
Ph
N
R
N
H
20
21
Scheme10. Synthesis of 3,5-disubstitute
pyrazole
1,3-diketo structure of product (24) were
obtained by interacting ketone derivatives (22)
with the ester derivatives (23) when it placed
with various reagents in the reaction. Especially
4-alkyl-1,3,5-triaryl (25) and 5-alkyl-1,3,4triaryl pyrazoles were extensively investigated
as ligands for the estrogen receptor [15-18].
Both in the solution and solid phase were
developed methodologies for the consisting of
synthesis of these compounds in scheme11 [19,
20].
O
O
O
+ Ar1
2
O Ar
! r1
Ar
R
23
R=Me, Et, n-Pr, i-Bu, n-Bu;Ar=Ph, 4-HOC6H4
Ar1= 4-MeOC6H4; Ar2=4-O2NC6H4; Ar3=4-HOC6H4
24
Ar3
R
O
LiHMDS/THF
1
Ar-NHNH2.HCl
THF/DMF
110-120oC
BBr3/CH2Cl2
3
Ar
N
N
Ar
25
N
N
Scheme11. Synthesis of tetrasubstitute pyrazole
C6H4R
13
Scheme9. Synthesis of 1,5-diaryl-3-methyl
pyrazole
3,5-disubstituted pyrazoles (15-18) were
synthesized in high yield as a direct result of
activated 1,3-diketones (14) with hydrazine
306
N
O
R=Me, Ph
R
!r
Me
Ph
O
O
22
O
N
Ar
Ar1
O
N
R3
R-NHNH2
3
w
0 oC, 2 min.
9
R2
O
1
Ar=Ph, R1=R2=Me; R1=R2=t-Bu
R1=Me; R2=CO2Et
R1=Me; R2=Ph
Ar=4-MeC6H4; R1=Me; R2=Me
R1
R2
14
19
OLi
N
H
R=Me, t-Bu,CO2Et ; R2 =Me, t-Bu, Ph
ae
Me
1
N
Symmetrical substituted pyrazole (27) was
synthesized in high yield according to I or II the
method catalyzed condensation polystyrene
supported sulfonic acid (PSS) or 12-Tungston
phosphoric acid (H3PW12O40) at room
temperature between in aqueous medium
hydrazines/hydrazide and 2,4-pentadione (26)
derivatives in scheme12 [21, 22].
Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
Çet n,A.
O
R1
O
Me
Method I or II
R-NHNH2
+
R2
ae
N
R2
R1
N
R
26
27
Method I: 20% PSSA/H2O, rt, 1-2 min.
R1=H; R2=Me; R=Ph, 4-ClC6H4,MeCO,PhCO,2-Furyl-CO,2-thionyl-CO
R1=Cl; R2=Me; R=Ph, 4-ClC6H4,MeCO,2-Furyl-CO,2-thionyl-CO
R1=Et; R2=Me; R=Ph, 4-ClC6H4,2-Furyl-CO,2-thionyl-CO
Method II:H3PW12O40,(1%mole H2O), rt, 6-60 min.
R1=H,Me; R2=Me; R=H,Ph, 4-MeC6H4,4-ClC6H4,MeCO
literature which have contain trifluoromethyl
derivatives. Reagents and reaction conditions
investigated widely effects in the condensation
reaction between fluorine-containing 1,3diketones and mono-substituted hydrazines in
scheme14 [24-27].
R1
Scheme12. Synthesis of tetrasubstitute pyrazole
HO
O
R
OH
N
R2 + RNHNH2
wf
N
1
N
and/or
Rf
R2
R
-H2O
Rf: alkyl group containing fluorine
Devery et al. were reported in the literature
a new method for synthesis of 1,3,4,5-alkyl/aryl
substituted pyrazoles (29, 30) [23]. That method
includes synthesis of substituted pyrazole (32)
with the addition of cerium-catalyzed
substituted hydrazines after cerium ammonium
nitrate (CAN), allyl trimethyl silane (31) and
1,3-diketones (14) interaction. The propantriol
pyrazole (PPT) (34) was obtained in 30% yield
over 4 steps in scheme 13. PPT was used as
estrogen receptor agonist
O
R2
O
R1
Ph
R2
28
Ph
MeCN, Reflux
R2
R1
CAN, RNHNH2
N
N
+
R1
R=4-MeOC6H4; R1=Me, R2=Allyl
R2=Me
R1=CF3; R2=Allyl
R=Me; R1=Me; R2=Allyl
N
Ph
R
N
30
R
29
N
Rf
N
R2
H+
b
R1
H
R2
R
H
R1
N
R
a
1
Rf
R2
R1
Rf
O
R2
H2O
N
N
N
N
Rf
R
R
R
R1
R2
N
Rf
N
R
37
Scheme14. Synthesis of fluorine-containing
pyrazoles
A single 3/5 - substituted pyrazole (40)
product or 3/5-substituted mixture of pyrazoles
(41) and 3/5-substituted alkoxy pyrazole (42)
were formed depending on reaction conditions
as a result of condensation reaction β-ketoesters
(38) and the related hydrazines in scheme15
[28].
Me
O
CF2R1
O
Me
Me
TMS
+
14
31
1.CAN/MeCN/rt
Me
2. R-NHNH2
N
N
32
O
R=Me,Ph, 4-MeO/HO2CC6H4,2,4(2ON)2C6H5
O
+
w1F2C
OH
N
OEt
N
HO
2.NaOH,EtOH
N
N
NHNH2
38
O
1.EtOH, reflux
or
i-PrOH,NH4Cl, reflux
SO2R
R
SO2R
40
39
O
o
Ar
33
Ar=4-MeOC6H4
1.POCl3, DMF, 80 C
2.NH2OH.HCl, TFE, reflux
Cl3CCOCl3, Et3N, CH2Cl2, 0 oC
N
Ar
N
HO
PPT
OH
CF2R1
CN
34
N
R2O
Scheme13. Synthesis of 1,3,4,5- alkyl/aryl
substitute pyrazole and PPT
N
N
Cl
N
R2OH, KF or CsF, DMSO, rt
N
N
SO2R
42
Most of fluorine or fluorocarbon-containing
pyrazoles (35) were an area of active researches.
These compounds were investigated in the field
of agricultural chemistry and medicine.
Because these compounds were in biological
activity the most frequently cited in the
CF2R1
CN
SO2R
41
w=Me; R1=H,F; R2=CyPrCH2,cyBu,cyBuCH2,cyHept,cyHex-3-enCH2, (4-Methylene)-cyHexCH2,(2-/-3Me)cyHex, (4-Ethyl)cyHex,1,2-(Me)2Pr
R=NH2; R1=F; R2=CyHept,(3-Me)cyHex,(4-Ethyl)cyHex,(4-4-F2)cyHex,cyHeptCH2, 2,2-(Me)2Pr
Scheme15. Synthesis of 3/5-substituted alkoxy
pyrazoles
307
Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
Çet n,A.
3-alkoxy-pyrazole (44) was conducted
directly for the preparation with a simple
method as a result of the condensation reaction
between alkyl acetoacetate (43) with mono
hydrazine chloride in scheme16 [29, 31].
The substituted pyrazoles (55) were
obtained by oxidation pyrazolines (54) which
formed by the interaction various hydrazines
with 1,3-diaryl-2-propen-1-one (53) derivatives
in scheme19 [38-40].
PhNHNH2
O
R
3
+ RNHNH2.HCl
R1OH, reflux, 8h
O
N
R3
R2
!r
N
R
R2
O
OEt
+ 9 tO
R
CO2Et
R1
46
R
47
R=Ph, 4-F/ClC6H4, 4-OH-6-Me-2-pyron-3-yl
Ar=Ph,4-Me/MeO/Cl/O2NC6H4 2-furyl/thionyl,,4-Pyridyl
Ar Het=6-Florobenzothiazol-2-ylhydrazine
Ph(Het)
55
O
O
R6
R1
H2O2, HO
R6
R1
O
0 oC
R5
R2
R3
R5
R2
R3
R4
‫ي‬6
H2N.NH2.H2O
reflux
48
NH
N
R6
R1
R6
R1
R4
57
R1, R2, R3, R4, R6=H, OCH3
R5=H, OCH3,F
R4/R5=-OCH2ON NH
R1=Alkyl, Het(Aryl)
R2=H, Alkyl,Het(Aryl), heteroatom
R=H, Alkyl, Het(Aryl)
N
N
The most of pyrazoline (58) compounds
were obtained to converting the epoxides (57)
which occurred 1,3-diaryl-2-propen-1-one (56)
by Bhat et al. 3,5-diaryl pyrazoles (59) were
synthesized interaction of (58) the with
appropriate hydrazine in scheme20 [41].
CO2Et
N
R2
O
45
RNHNH2
N
CH2Cl2
Ph(Het)
54
O
1
Ar
N
AcOH, EtOH, reflux
Scheme 19. Synthesis of trisubstitute pyrazoles
[3 +2] ring closure reaction was frequently
used for synthesizing pyrazole 3-(5) carboxylic
acid ester between1, 3-diketoester with
hydrazines. The diethyl oxalates (46) with the
enolate of ketone (45) were reported as Claisen
condensation in the literature. The 3 (5)carboxylic acid derivatives (48) were
synthetized by reaction hydrazines with 1,3diketoester (47). Some of these compounds
demonstrated significant activity in
pharmacology in scheme17 [32-36].
O
PhI(OAc)2
N
R
44
Scheme16. Synthesis of 3-alkoxy-pyrazole
R1
Ph(Het)NHNH2
53
R1:Me, Et, Bn, i-Pr, t-Bu R2:H, Et R3:Me, H R:H
43
R2
R
R
w1 O
O
AcOH, reflux, I2
OR
R2
O
AcOH
R2
H2SO4
R5
R3
OH
R2
59
Scheme 17. Synthesis of pyrazol 3 (5)-carboxylic
acid
R5
R4
R3
R4
58
Scheme20. Synthesis of 3,5-diaryl pyrazoles
3,5-diaryl pyrazoles (50) were easily
obtained in high yield by Claisen-Schmidt
condensation of chalcone with (1,3-diaryl-2propen-1-one) (49). The pyrazoline (51) was
synthesized using the appropriate reagents. A
series of 4-alkyl-1,3,5-triaryl pyrazole (52)
were synthesized with oxidation of compound
(51) in scheme18 [37].
O
Ar3NHNH2
Ar2
Ar1
Ar2
DMF, argon
49
N
N
Ar3
50
Ar1
R
Ar1
1.LDA
2.RI
Ar2
N
N
Ar3
51
MnO2
Ar1
R
Ar2
Ar =Ph, 4-MeOC6H4
Ar2=Ph, 4-MeOC6H4,4-OTBDPSC6H4
Ar3=Ph, 4-MeOC6H4
R=Me, Et, n-Pr
Scheme18. Synthesis of 4-alkyl-1,3,5-triaryl
pyrazole
O
+
O
N
Ar3
52
N
R2
O
N
1
308
A series of 3,5-diaryl-1H-pyrazole (61)
were synthesized to a way easier and safer rather
than high toxic effects of hydrazine hydrate by
the interaction with the α-epoxy ketones (59)
using semicarbazide hydrochloride salt (60) in
scheme21 [42].
R1
H2N
‫ي‬9
N NH2 . HCl
H
60
H
N
R2
EtOH
40-50 oC
R1
61
R1=H, 4-Cl, 4-Me, 4MeO
R2=H, 2-Cl, 4-Cl, 4-Me, 4MeO, 3-NO2
Scheme 21. Synthesis of 3,5-diaryl-1Hpyrazoles
Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
Çet n,A.
A series of 1,3,5-trisubstituted pyrazole
(65) was synthesized with the interaction of a
mild base which pyrazoline (63) intermediate of
product by condensation the appropriate
hydrazines and α-enone (62) including a leaving
group in scheme22 [43].
Ph
Bt
2
R
Bt
Ph
w1
N
N
R1
O
64
62
Ph
Bt
Ph
R2
RNHNH2
NaOEt/EtOH
N
NaOEt/EtOH
reflux
NaOEt
or
t-BuOK
R
n-BuLi/R2I
N
1
R
reflux
N
N
R1
R
R
65
63
Bt=Benzotriazolyl
R2=H, R=Me or Ph; R1=i-Pr, Ph, 4-MeC6H4, 3-Pyridyl
R2=H, R=Me or Ph; R1=i-Pr, Ph, 4-MeC6H4, R=Me; R1=4-MeC6H4
R2=n-Bu or Allyl or Bn; R=Ph; R1=4-MeC6H4
The required substituted pyrazoles were
synthesized to interaction of with various
hydrazines of chiral oxazolidines and
tetrahydropiranyloxy ynones under the
appropriate reaction conditions. Silva et al were
worked a series of compounds based on
including these structures at the synthesis
various pyrazole derivatives (72, 74, 75, 77, 78)
using equivalent formyl groups such as
alkoxymethylene, aminomethyl and
dimethylaminomethylene [49-52]. A series of
3,4-diaryl-5-methyl pyrazole (80, 81) was used
for the synthesis that previously obtained
method based on chromen-4-one (79). Some of
the compounds were synthesized. These
compounds were tried about inhibition of cell
proliferation
O
Scheme22. Synthesis of 1,3,5-trisubstitute
pyrazoles
NH2NH2.H2O
MeOH, reflux
O
O
71
72
H
N
The yield of less trisubstituted pyrazoles
(67) were prepared with reacting α,β-chalcone
of ditosylate (66) and an appropriate hydrazine
in scheme 23 [44].
R
O
1
!r
Ar
OTs
RHN
O
NH
RNHNH2
DMF,reflux
OTs
2
EtOH,reflux
-TsOH
Ar1
1,2-Shift
Ar2
-TsOH
OTs
H N
O
NH
N
N
N
Ar
HO
Ar1
H
Ar2
66
Ar2
NH2NH2
1,4-Dioxane
O
Ar
Ar
73
74
75
Ar1=Ph, 4-MeC6H4, 4-MeOC6H4,4-FC6H4,4-ClC6H4,4-BrC6H4,
N
O
H2N-NH2
Ar
X
H2N-HN
Ar
O
HN
1
-H2O
O
H2NNH2
Ar2
O
O
O
O
Ar
Ar
O
Ar
O
O
80
Ar
Ar
R1
O
O
R2
O
82
R2
OH
N
83
NH
R1
OH
HN
NH
Ar
81
R2
R1
N
X
O
Ar
NH2NH2.H2O
prydine
Ar
NHNH2
X
Ar=Ph, 4-2ONC6H4, 4-MeOC6H4,4-FC6H4,4-ClC6H4,4-MeC6H4;X=HO-6BnOCH3
O
1,3- and 1,5-substituted pyrazoles (69,70)
were synthesized as the result of condensation
Ynones (68) and substituted hydrazines in
scheme 21 [45-48].
Ar
N
MeOH
reflux
79
Scheme23. Synthesis of 1,4,5-trisubstitute
pyrazoles
Ar
Ar
O
OBn
X
Ar
O
X=O; R1=H,Ph
R2=2/3/4-Cl,4-Br/NO2,2,4/3,4-Cl2
X=S; R1=H,Ph
R2=4-Cl/Br,3-Cl,4-NO2,2,4-Cl2
N
Scheme25. Synthesis of 3,4-diaryl-5-methyl
pyrazoles
Ar1
O
Ar2NHNH2
! r1
68
NH
N
DDQ
N
AcOH
67
Ar1=Ph;Ar2= 4-Me/MeO/BrC6H4,2-thionyl-3-Me-2-thionyl
Ar1=4-MeC6H4;Ar2=4-MeC6H4,2-thionyl-3/5-Me-2-thionyl
Ar1=4-MeC6H4;Ar2=Ph,4-MeC6H4,2-thionyl-3-Me-2-thionyl
Ar1=4-ClC6H4;Ar2=Ph,4-MeC6H4,2-thionyl-3/5-Me-2-thionyl
R=Ph, CO(S)NH2
HO
N
R
R
Ar1
O
HO
O
OH
H
N
N
N
O
NH
N
NH
N
OH
d.HCl-MeOH
+
N
N
N
N
Ar2
Ar2
69
70
Ar1
Ar1=Ph, 4-MeO/ ClC6H4
Ar2=Ph, 4-Me/ O2NC6H4
Scheme24. Synthesis of 1,3- and 1,5disubstituted pyrazoles
A series of 4-substituted pyrazole (85) were
synthesized based on a aryl hydrazines of 2formula glycol (84) any solvent. The yield of the
reaction products were compared with done
separately of the results obtained under thermal
309
Çet n,A.
Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
conditions and microwave radiation in
scheme26 [54].
R1 O
OR1
h
N
RHNNH2
R1 O
appropriate reaction conditions. The obtained
pyrazoles were exhibited pharmacologic
activity in scheme29 [57-59].
CHO
OR1
OR1
OR
84
85
1
O
R1=Me,Et,Bn
R=H,Ph, 2-EtC6H4,3,4-ClC6H4,4-MeOC6H4
HN
OH
RHNNH2 (HX), Et3N,MeOH,THF,rt
Scheme26. Synthesis of 4-substituted pyrazoles
O
n
86
Firstly 1,3-cyclo alkanedione (88) was
obtained with react dimethyl formamide
dimethyl acetal (DMFDMA) (86) and βenamindione (87) in one step under microwave
radiation. Then a series of 4,5-fused of
cycloalkonoes that 1-substituted pyrazoles (89)
was conducted hydrazine and the obtained
product in scheme27 [55].
O
Me
n
86
O
O
N
n
88
O
OMe
OMe
Me
87
O
RHNNH2,H2O
N
+
N
R
89
Fused of cyclopentanone 1-substituted
pyrazoles (91, 92) were synthesized to
condensation reaction of the enamindione (90)
with various hydrazines in solvent and
appropriate conditions, changing the product
formed itself and stereoisomer mentioned
depending on the molecular size of hidrazine
and the reaction temperature in scheme28 [56].
N
N
N R
Me
N
H2NNH2.H2SO4
Me
R2
94
2
+
PTSA
N
R1
b
95
R
97
1
R =H; R =Ph, 4-Me/F/Cl/Br/O2NC6H4,3-MeOC6H4,2-furyl,2-thionyl
R2=MeOC6H4; R1=Me
R1/R2 =-(CH2)3C(O)-
S cheme30. Synthesis of 5-(het)-aryl-NH
pyrazoles
Persson and Nielsen were developed an
effective method of interaction the hydrazines
of compound (100) which obtained product
from Weinreb amides (98) and ethyl propionate
(99) in the appropriate solvent and temperature
for the synthesis of pyrazole-3-carboxylate
(101) in scheme31 [61].
N
+
R
R=Ph,Bu,Me,Et
O
91
92
O
Scheme28. Synthesis of fused pyrazoles
The pyrazole products (93) were
synthesized in excellent yield with ring closure
cycloalkyl 1,3-dione with various mono
substituted of hydrazines in a single step
O
OMe
w1
N
NaHMDS,THF
+
OEt
-78 oC - -40 oC
Me
310
R2
96
O
Scheme27. Synthesis of 4,5-fused of
cycloalkonoes 1-substituted pyrazoles
90
93
n b
AcOH
N
N
n
Longhi et al were synthesized a series of 5(het)-aryl-NH pyrazoles (97) with reaction
hydrazine sulfate (95) and βdimethylaminovinyl ketone (94) using as
catalyst p-toluene sulfonic acid (96) solid phase
any solvent conditions in scheme30 [60].
R1
wHNNH2, MeOH
N R
2.DMFDMA, reflux
n=1,2
R=Me,Et,Bn,Ph
x=2Cl- veya Cr2O4-2
Scheme29. Synthesis of fused cyclohexanone
pyrazoles
n=1,2; R=H, t-Bu, cyklohexzyl, Ph, 2,4-Me2C6H3, 3,5-Me2C6H3
O
O
‫ و‬.RHNNH2, THF, rt or
98
99
CO2Et
CO2Et
1
R
N
Me
100
OMe
RHNNH2,CDCl3
R
100 oC
N
1
N
R
101
R=Me or Ph; R1=Me, Ph(CH2)2,Ph, 2,4-Cl2C6H3
Scheme31. Synthesis of pyrazole-3-carboxylate
Giacomelli et al were synthesized by β-keto
esters and the β-keto amide derivatives (103)
Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
Çet n,A.
which obtained as a result of ring opening
interaction of various alcohols and amines,
acylation derivatives of acid chloride as known
Meldrum's acid (102). A series of 1,5substituted 4-pyrazole of ester and amide
derivatives (105) were obtained by interaction
hydrazines of compound (104) in scheme32
[62].
O
OH
R1
O
O
XR2
XR2
R2OH
or
RNH2
O
O
N
N
R
Scheme32. Synthesis of 1,5-substituted 4pyrazole ester and amide
A series of 4-substituted pyrazole (107)
were synthesized in high yield by condensation
of the interaction various hydrazines and αethoxycarbonyl-β-Enaminones (106) with
catalytic amount of p-TsOH in suitable solvent
medium. The obtained pyrazole products were
used as histamine analogs in scheme33 [63-65].
Br
R1-CN
n-BuLi
(R2CO)2
Zn
Zn/BrCH2CO2Et
HN
THF, reflux, 1h
R
O
1
OEt
NH2
R1
O
R1
OEt
3h, rt
2
R
O
106
R1= Ph, Me,Ph, sec-Bu
R2= Me, Ph, sec-Bu, i-Pr, CF3
R=H, Ph
wHNNH2
TsOH
MeOH
reflux
Cl3C
R1
2
R
108
MeOH or EtOH
25 oC, reflux
RO2C
N
R
N
EtO 2 C
N
R
R=t-Bu, CO 2M e
R 1=Ph, 4-MeO/Cl/F/O 2 NC 6 H 4 , 2-thionyl, CCl3 , CF 3
110
111
Scheme35. Synthesis of 4-acyl pyrazole-5carboxylate pyrazole
Thio-, silyl-and halo pyrazoles were used as
a building block in heterocyclic chemistry due
to easy replacement by carbon or heteroatomic
substitutions. The pyrazole was synthesized
primary by reaction with hydrazines as synthon
of α-oxoketen S-S-acetal [69]. According that
method the pyrazole was obtained by
condensation a hydrazine and 2-tiohydanto
(imidazolidyne 2,4-dione) (114) in the suitable
solvent for the synthesis of methylsulfanylimidazo [4,5-c] pyrazole (201) in scheme36
[70].
R
1
N R
HN
107
R=Me, Et
R1=H,Me, Ph,2-furyl, 2-thionyl
R2=H, Me; R1/R2=-(CH2)-
109
Scheme34. Synthesis of alkoxycarbonyl
pyrazole
N R1
HN
S
S
H3CS
O
H3CS
1.CS2, EtONa
EtOH, rt
2.CH3I, MeOH, rt
S
N
RNHNH2
EtOH, piperidine, reflux
R
N
R1
N
1
R /R=H, Ph
113
114
Scheme36. Synthesis of methylsulfanyl-imidazo
[4,5-c] pyrazole
Peruncheralathan et al were synthesized 1aryl-3-(methylthio)-4,5-substituted/cyclic
p y r a z o l e s ( 11 7 ) a n d 1 - a r y l - 3 , 4 substituted/cyclic-5-(methylthio)-pyrazoles
(120) as a result of condensation of aryl
hydrazines with β-oxoditioesters (115) and αoxoketen thioacetals (118) in scheme37 [7173].
O
R2
R1
MeS
SMe
t-BuOK, t-BuOH
reflux, 10 h
S
R2
MeS
R2
R1
! rHNNH2
115
ArHNNH2
N
R2
Raney-Ni
N
N
EtOH,reflux, 4-5 h
Ar
Ar
116
117
R2
R2
Raney-Ni
N
N
R1
118
R1
SMe
N
MeS
EtOH,reflux, 4 h
O
Martins et al proposed reaction mechanism
about how the reaction occurs in synthesis.
H
N
SCH3
R2
R1
N
R1
OEt
O
NHNHR
‫ و‬12
R2
wHNNH2.HCl
wHNNH 2
O
R1
-HNMe 2
O
N
Flores et al were synthesized βalkoxyvinyl trichloro methyl ketone (108) as
starting products then alkoxycarbonyl pyrazole
derivative (109) was synthesized in good yields
to interaction with hydrazine hydrochloride or
phenyl hydrazine in medium suitable solvent in
scheme34 [66].
OR
O
Me 2 N
O
EtOH, reflux or
rt, 1h
OEt
CO2Et
N
Scheme33. Synthesis of 4-substituted pyrazole
O
R
O
R1
105
104
103
O
O
1
R
R1
1
102
wHNNH2
O
O
O
NMe2
DMFDMA
XR2
They were synthesized directly a serial 4-acyl
pyrazole-5-carboxylate (111) products from
unsymmetrical of enaminodiketoester (110) in
scheme35 [67, 68].
Ar
119
R1 EtOH,reflux, 4-5 h
N
N
R1=Ph,4-ClC6H4,4-MeOC6H4,3-Py,Me
R2=H, Ph
R1/R2=-(CH2)4Ar=Ph,4-FC6H4
R1
Ar
120
Scheme37. Synthesis of substituted pyrazoles
311
Çet n,A.
Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
1,3-dipolar cycloaddition reaction is used
one of the widely synthetic instruments for
obtaining substituted pyrazoles [74]. The 1,3dipolar are used three main classes as [CNN]
synton including diazoalkanes, nitrile imines
and azomethine imines in scheme38.
w1
R1
R2
X
R2
X
Z
Y
Z
Y
N
C
N
N
C
C
N
N
C
N
N
C
N
N
N
(1,3-Dipoller)
Z
N
w1
R2
R1
OH
R1
TMS
R2
2.H 2 O
R 3C
CR 4
OTMS
R3
R2
N
THF, reflux, 1 h
N
H
N2
122
R 1=Ph, 4-ClC 6 H 4 , 4-MeOC 6 H 4, PhCH 2CH 2 , t-Bu
R 2=H,Me
R 3=R 4=CO 2 Me; R 3 =H; R 4=CO 2 Et
Scheme40. Synthesis of di-and tri-substituted
pyrazoles
Jiang et al were synthesized carbonyl and
ethoxy carbonyl pyrazoles (127) by 1,3-dipolar
cyclo addition of molecules between alkinolate
or alkinone (125) and cyclic or acyclic α-diazo
carbonyl (126) compounds using catalysis InCl3
in water at room temperature in scheme41 [78].
(Nitriliminler)
(Azometin iminler)
Scheme38. 1,3-dipolar classes
O
3
R1 R
O
1,3-dipolar cyclo addition was carried out
effectively with alkynes the electron-rich of
diazo compounds under thermal conditions. But
diazo compounds are potentially explosive and
toxic due to natural processing and preparation
is hazardous. These problems were overcome
by used a method for multiplication of aryl
diazomethane from suitable tosyl hydrazone
derivatives. Thus, for preparation of 3,5-aryl
pyrazoles from aromatic aldehydes (121) were
used as a functional in one step in scheme39 [75,
76].
1.TsNHNH2
MeCN,rt
O
!r
N-Vinilimadazol
or
R1
N
N
H
Ar
R2
N
R1
2.NaOH
Ar
R1=H
R2=2,2(Bisalcoholatecarbonyl)cyclopropyl
R=Me, Bn
H
N
H
121
R1
Scheme39. Synthesis of 3,5-aryl pyrazoles
Di-and tri-substituted pyrazoles (124)
were synthesized with [3 +2] cycloaddition
between derivatives of dimethyl acetylene
dicarboxylate or ethyl propylate (122) and 2diazo-2-(trimethylsilyl) ethanol (123) in
scheme40 [77].
Me
R2
R1
+
InCl3
R3
H 2 O, rt
O
O
126
125
R 1 =H, MeCH(OH)C 6 H 4 , 3/4-MeOC 6 H 4 , PhCH 2 CH 2, 4-FC 6 H 4
R 2 =Me, Et
R 3 =H, CO 2 Et
O
Me
N
R2
b
H
127
Scheme41. Synthesis of carbonyl and ethoxy
carbonyl pyrazoles
Recently alkynes were begun a broad
workspace for the synthesis of pyrazole. Qi et al
synthesized a series of 3,5-disubstituted
pyrazole (130) as a result of cyclo addition diazo
carbonyl (128) of compounds a series of alkyne
(129) in the reaction medium. They worked how
affects yield alkyl and aryl alkynes and aryl
alkynes by adding Zn(OTf)2 any solvent at a
certain temperature. They were determined that
alkyne gave better yields in scheme42 [79].
R1
N2
OR2
+
312
R4
124
123
Y
(Diazoalkanlar)
N
C
X
1.TMSC(MgBr)N 2
THF,-78 oC, 1,5 h
O
R1
method 1-2
N
O
O
129
128
method I
n-BuLi, THF, -78 oC, CuCN.6LiCl
rt, 2-4 h
R1=H,MeC6H4, 3FC6H4, 3,5-(CF)3C6H4, NC(CH2)3,
2-(6-MeO)N, 4-N-Morfoline(CH)2
R2=Bn, t-Bu, Et
OR2
b
H
130
method II
Zn(OTf)2, NEt3, 100 oC, 8 h
R1=Me3Si, EtCH2, EtOCH2, Et(CH2)3, AllylOCH2, 5-AllylOCH2,
PhCOOCH2, Ph,4-MeC6H4,4-BrC6H4
R2=Et
Scheme42. Synthesis of carbonyl and
ethoxycarbonyl pyrazole
Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
Çet n,A.
Recently β-chloro acryl amide were
reported systematic work dipolarofilic on
behavior oxidation levels of sulfide and sulfate
against phenyl azomethane, trimethylsilyl
azomethane, diazomethane and diazoethane in
scheme43 [80].
at 1,3-cyclo addition reaction with nitriles
imines in scheme45 [85].
Ar2 N
SO2p-Tol
SO2p-Tol
Ar1
O
N
NH
1
R
Cl
Ar2
N
H
NH
R1
R
R3
R2
N
N
CONHR
O
R1S(O)n
NHR
/ l
R2
R3
R2R3CN2
R2
R3
R2
R3
N
CONHR
SR1
CONHR
138
Scheme45. Synthesis of 1,3-diaryl pyrazole
R2
R3
N
N
-Cl
SR
Rink
137
R1
Ar2
R1=H,Me,Bn,i-Bu
R2=CONHCHR1CONH2
Ar1=Ph,4-Me,/4-MeO/F/Br/O2N/CF3/NCC6H4,1-Naftyl,4-Biphenyl,2-Furyl
Ar2=Ph,4-Me,/4-MeO/F/Cl/Br/O2N/i-PrC6H4
R=Me, Bu, Bn, Ar
R1=Ph, Bu, Bn, Tol
R2=H, Me, Ph
R3=H, TMS
-R1SOCl
N
S
O
N
Cl
N
Cl
131
H
132 CONHR
H
n=1
Rink
N
N
N
2. 25% TFA, DCM
HN
9 tN3, DMC
R2
1.DBU,DCM,rt
O
HN
H
N
Ar1
O
O
2
Ar1
N
N
N
H
CONHR
N
CONHR
S
1
H
N
R2
R1S
R1
CONHR
133
Scheme43. Synthesis of the substituted pyrazole
Nitrile imines were obtained by interacted
a base and hydrazonoyl halide in the reaction
medium. Last decade 1,3-cyclo alkenes
participate of nitrile imines were used for the
synthesis of substituted pyrazole [81]. This
methods that rimonabant, the cannabinoid type1 COX-2 of selective inhibitors were applied for
the synthesis of stereo-selective in the solid
phase [82, 83]. In addition reaction (135) was
synthesized between nitrile imines and aryl
acetaldehyde with gummy piperazine (134).
Then 1,4-diaryl pyrazole-3-carboxylate (136)
was synthesized directly separated from the
resin acidic medium in scheme44 [84].
The tetra substituted pyrazole (141) was
obtained in high yield by 1,3-dipolar
cycloaddition α-bromocinnamaldehyde (139)
with C-aryl-N-phenyl nitrile imines (140) in
scheme46 [86].
Ph
Ph
Ar
Cl
O
H
Et3N
H
N
+
N
Ph
Ar
N
H
b
DCM
O
Br
139
140
Ph
141
Ar=Ph,4-Cl,/4-MeOC6H4,3-O2NC6H4,2,6-Cl2C6H3
Scheme46. Synthesis of tetra substituted pyrazole
Synthesis of pyrazole (144) was reported
both the catalyst and without the catalyst 1,3cyclo addition reactions taking place between
C-carboxymethyl-N-aryl (143) and C-aryl-Naryl nitrile imines (142) in scheme47 [87].
O
H
N
Ar2
Cl
N
N
Ar1
134
Ar1=Ph, 4-Me,/Cl/Br/O2NC6H4
Ar2=3-MeOC6H4, 4-IC6H4
R=OEt, Me
EtN3, CHCl3
reflux, 16 h
N
R
N
O
b
R1
ROC
Ar1
N
Ar1
Ar2
R1
X
COR
N
3% TFA
N
DCM, rt
Cl
N
NH
136
Scheme44. Synthesis of 1,4-diaryl pyrazole-3carboxylate
Vinyl sulphones polymer supported (137)
were used stereo selective dipolarophile for
derivatives a series of 1,3-diaryl pyrazole (138)
Ag2CO3 or Et3N
Sc(OTf)3
X
dioxane, 80 oC
+
Ar2
N
135
O
143
w2
142
N
N
X=OBn, NHPh
R1=CO2Me,Ph
R2
144
Scheme47. Synthesis of 4 - and 5-substituted
pyrazole
N-phenyl-5-substituted-3- dimethoxy
phosphone pyrazoles (146) were obtained in
313
Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
Çet n,A.
low yield with1,3-dipolar cycloaddition of
nitrile imines and monosubstituted alkynes
using phosphonate groups (145) instead of
carboxylate groups for preparation of
compounds having pharmacological activity in
scheme48 [88].
Synthesis of novel pyrazoles (154) were
conducted with reacting substituted
furopyrazoles (153) and sydone (142) with three
Withasomnine that occur naturally in scheme51
[92].
O
NaHCO3
AcOEt
t h-NH-N=C(Br)PO3Me2
PO3Me2
R
N
145
N
N
R
N
N
152
146
Scheme48. Synthesis of N-phenyl-5-substituted3- dimethoxy phosphone
Sydnone (147) was stable meso-ionic
compounds relatively as dipolar type
azomethine imine. These compounds were
readily obtained by dehydrating cyclo of Nsubstituted-N-nitroso amino acids with reagents
such as acetic anhydride. 3,5-disubstitutedpyrazole (148) was comprised due to extraction
of carbon dioxide by 1,3-dipolar cycloaddition
with acetylenes in scheme49 [89, 90].
Alkynes with metal of activity lead to
formation of the pyrazoles result of cyclization
5-exo/endo-dig to participate nucleophilic
nitrogen derivatives intramolecular. Synthesis
of 3 (5)-3,5- and 3,4,5- substituted pyrazoles
(155) were reported in the literature in
scheme52 [93].
Boc
HN
NC
NC
b
chlorobenzene
reflux, 48 h
Ar
N
Ar
148
147
Scheme49. Synthesis of 3,5-disubstitutedpyrazole
Hedge et al used unsymmetric α, βacetylenic phenones (150) including 5-nitro
furan as dipolarophiles at the 1,3-dipolar
cycloaddition with N-aryl sydonone (149) for
the synthesis of a series of 1-aryl-3-(5-nitro-2furyl)-4-arylpyrazoles (151). The similar
results were made using thiophene substituting
furan in scheme50 [91].
NH
R2
R1
L= Me
NH
HN
Me
NHBoc
R3
N
O
N
X
NO 2
xylene
R
reflux
R2
R1
149
150
X= O; S
R 1 =H,Me,MeO
R 2 =H,Me,MeO,Cl
N
The 1,3,5-trisubstituted pyrazoles (157)
were synthesized with 5-endo-dig ring closure
from alkynyl nitroso amines (156) using a
catalyst at room temperature [94]. The obtained
yields were quite high and even two products
were observed quantitatively in scheme53.
R2
R
b
NO
10% AgNO 3
SiO 2 (20 mole %)
1
156
R
3
CHCl 3 or DCM
20 o C, 6-8 h
O
R2
R
N
R3
PCl3 ,CHCl3
60 oC,2 h
N
N
R3
R1
157
-Ag
O
O
N
R2
R1
Ag
R2
N
1
Ag
R2
N
R 1 =i-Bu,Ph
R 2 =Pr,Bn,Allyl
R 3 =Bu,Ph,(CH 3 ) 2 OTBDPS
R1
R1
N
R3
Boc
155
O
N
R1
NH
Scheme52. Synthesis of 3 (5)-, 3,5- and 3,4,5substituted pyrazoles
2
+
N
R3
NBoc DCM, rt
R 1 =H,n-Pr,n-Bu,Bn,Ph,TIPSOCH 2
R 2 =H,Et; R 1 /R 2 =-(CH 2 )3R 3 =n-Pr,n-Pent,n-Oct,CO 2Et,CH 2 CH 2 OBn,-(CH 2)-Cl,Ph
X
O
h
R2
R1
TFA
THF, 80 oC
NO 2
O
R2
NBoc
I
R=Bn,Et,t-Bu,CHPh2
Ar=C6H4p-OEt
N
Boc
CuLi
L (20 mole %)
CaCO 3
R1
w3
CO2R
154
Scheme51. Synthesis of substituted pyrazoles
CO2R
N
N
N
2.TBAF/THF
153
Ar=Ph,Withasomnine
Ar=4-HOC6H4,4'-HidroxyWithasomnine
Ar=4-MeOC6H4,4'-Methoxywithasomnine
R2
O
N
reflux
Ph
Ph
Ph
O
Ar
1. Ar-I, Pd
N
N
R
BPin
TMS
N
PDC, DMF, rt
N
TMS
BPin
h
Me2O3P
Me2O3P
R3
N
R2
N
R3
R1
H
Ag
N
H
N
R3
Ag
151
Scheme50. Synthesis of 1-aryl-3-(5-nitro-2furyl)-4-arylpyrazoles
314
Scheme53. Synthesis of 1,3,5-trisubstituted
pyrazole
Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
Çet n,A.
Propargyl N-sulfonyl hydrazones (158)
were used for the synthesis 1,3- and 1,5disubstituted pyrazoles (159) in the medium
silver (II) catalyst and the reaction was carried
out at high productivity to interaction with
various hydrazones as catalyst together %5 mol
AgSbF 6 with dry dichloromethane in the
reaction medium in scheme54 [95].
heterocyclic chemistry [100].
Ar
O
RNHNH2
w1
R2
AgSbF6
R3
R3
N
1
N
R
DCM, rt
3-12 h
Ts
N
R1
R
163
b)Mo(CO)6,Pd(OAc)2,CuI,Pt-Bu3,Cs2CO3, 80 oC, 18 h
R=H,Me,Ph
R1=Ph,4-MeO/ClC6H4,Bn,3-Thionyl/pyridyl,CH2O
Ar=Ph,4-Me/ClC6H4,3-pyridyl
a)CO (1atm),PdCl2(PPh3)2, rt
R=H,Me
R1=n-C6H3,4-MeC6H4
Ar=Ph,4-Me/MeOC6H4,2-Thionyl
Ag
H
N
b
R3
N
R1
N
Ag
R2
Ag
R2
R1
H
N
R3
-Ag
R1
N
Ts
Ts
159
Ts
R1=H,Me
R2=H,Me,Ph
R3=Alkenyl,aryl,PhCH=CH,4-MeOC6H4CH=CH
158
Scheme54. Synthesis of 1,3- and 1,5disubstituted pyrazoles
Adib et al synthesized dialkyl 5(alkylamino)-1-arylpyrazole-3,4-dicarboxylate
(164) in good yield according to the multicomponent reaction at room temperature in
scheme 57 [101].
Multi-component reaction was reactions
leading to the formation simultaneously of the
desired a combinations of two or more building
block. For example, 3,5-disubstituted pyrazole
(162) were synthesized to react using catalyst at
the appropriate temperature acid chloride (160),
alkyne (161) and hydrazines which three
components in a single step in scheme55 [96,
98].
+
R2
2.RNHNH2
Cl
2
N
R2
b
H
161
162
veya R
N
N veya R1
R
R=Me
CO2R
+
acetone
NHPh
ArNNH
rt, 36 h
N
1
R HN
b
Ar
164
CO2R
CO2R
H
CH
C
C CO2R
C CO2R
O
PhHN
C
C
R1N
PhHNN
-CO
-PhNH2
Ar
O
N
N
RO2C
NHPh
CO2R
R=Me
N
N
R1HN
N
O
N
Ar
NHPh
R=Me, Et
R1=t-Bu,1,1,3,3-tetramethylbuthyl
Ar=Ph,Tol
R
R
CO2R
H
RO2C
Scheme57. Synthesis of dialkyl 5-(alkylamino)1-arylpyrazole-3,4-dicarboxylate
R2
R1
R1
1. PdCl2(PPH3)2/CuI
Et3N,THF
O
+ RO2C
CO2R
RO2C
O
R1 N C
160
N
R1
Ar
Scheme56. Synthesis of 3,5-diaryl pyrazole
R2
R1
a veya b
+
Ar I
N
N
R
R=Ar
R1=Ph,2-Furyl,4-MeC6H4,4-2ONC6H4,2-Thionyl,cyclohexyl
R2=Ph,4-MeC6H4,2-napthyl,hexyl
R=H
Scheme55. Synthesis of 3,5-disubstituted
pyrazole
Recently a series of 1-aryl-4,5-disubstituted
pyrazole (165) was obtained only one product
using catalyst together 1,3-diimides and
hydrazine or its derivatives in scheme 58 [102].
R1
R2
+
or
R3 NH2
+
4
3,5-diaryl pyrazole (163) was synthesized
by reacting using a catalyst four components in
one step terminal coupling alkynes, methyl
hydrazine, the aryl iodide and carbon monoxide
i.e. in scheme 56 [98]. It was reported that the
reaction takes place with use the hexane
carbonyl molybdenum instead of carbon
monoxide in the multi-component reaction
[99]. Particularly it was the subject for multicomponent reaction to isocyanate-based in the
RN C
1
10 mole% Ti(dpma) (NMe2)2
R4HN
10-20 mole% Ti(dpm) (NMe2)2
toluene, 100 oC
R3N
R2
R1
R2
RNHNH2
pyridine, 150 oC
R1
-NH2R4
3
-H2NR
N
b
R
165
2
R =H, R =Ph, R=H,Me,t-Bu,C6H11,Bn,Ph,4-MeC6H4,4-MeOC6H4,4-NCOC6H4,4-MeO2CC6H
Scheme58. Synthesis of 1-aryl-4,5-disubstituted
pyrazole
The strategies developed for pyrazole
compounds which are considerable because of
indicate the potential biological activity
pyrazole carboxylic acid and derivatives.
315
Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
Çet n,A.
For example, high-functional derivatives of
pyrazole-4-carboxylic acid (167) were
synthesized in good yields with the addition the
Huisgen of isoelectronic of the product which
obtained from the reaction of dialkyl
azodicarboxylate, 4-substituted allenoates
(166) and triphenyl phosphine [103]. The
reaction mechanism was proposed a cyclization
containing a carbon-nitrogen migration of
c a r b o n y l g r o u p a l k o x y, d o u b l e b o n d
isomerization and the elimination of triphenyl
phosphide oxide in scheme 59.
R1
b
CO2R
N
RO2C
RO2C
N N
DME,rt, 3h
Ph3P
166
R1OEt
N
O
OR
R2
EtO
OEt
OEt
RO2C
H
N
R1
OR
CO2R
R2
-PhP=O
N
R1
CO2R
R2
N
R1
N
N
Cl
CO2R2
Ar
rt, 2-5 h
R1
PPh3
N
R
R1
Ar
Ph3P
N
N
Ph3P
CO2R2
R2
N
R
N
H
CO 2 R
N
Cu
Scheme61. Synthesis of tetra substituted
pyrazole-4-carboxylate
Tetra substituted pyrazole-4-ol (170) was
obtained from the reaction 3,6-diaryl-1,2,4,5tetrazine and thioethanone in THF at room
temperature in scheme62 [106].
O
b
N
N
N
O
RO -
O
Ar
KOH/solvent
+ Ph
Ar
S
Ph
S
H
N
THF
S
OR
N
OH
Ph
N
HN
Ar
H
Ar
O
H
Ar
O
S
N
N
S
N
RO
Ar
PPh3
Ar
Ph
170
Ph
R1
N
R
b
Ph
Ar
N
1
-PPh3
N
Ph
Dragovich et al were proposed a new
procedure for the preparation 1-substituted-5hydroxypyrazole (171) which including ester
groups at the 3,4-position. These compounds
were prepared in three steps including coupling
methyl malonyl chloride and monosubstituted
benzyl carbezide. 5-hydroxy-3-pyrazole
carboxylate was observed to occurring reaction
that introduce intermolecular to the carbonyl
carbon of an amide part of oxalyl and a
methylene carbon part of malonyl in scheme63
[107].
MeO
O
2
R =H,CO2Et; R =Me,Et; Ar=Ph,4-Me/ClC6H4
/ bz
H
N
N
H
R1
+
OMe
1,4-dioxane, 100 o C O
Scheme60. Synthesis of tetra substituted pyrazole
OMe
MeO
N
R1
N
Cbz
H
N
2. ClC(O)CO 2
i-Pr2 NEt, DCM
0-23 o C
N
OC(O)CO 2 Me
OMe
O
O
O
O
R
O
O
OMe
1
HN
N
OMe
O
O
O
HO
O
Me
Me
H N
N
OH
R1
171
R 1 =(CH 2)2 CH(CH 3 )2 ,CH 2 C 6H 11,Ph
O
Recently important and effective a method
was reported in the literature that contained an
oxidative bond formation C-C/N-N from
nitriles and the enamine for the synthesis of tetra
substituted pyrazole-4-carboxylate (169) in
scheme61 [105].
O
O
1.H 2 ,Pd/C
EtOAc, 23 o C
O
Cl
O
316
R3
N
CO 2 R
168
1
R2
R1
R 3 -HOAc
N
R3
CO 2 R
N
1
N
R2O2C
R2O2C
Ph
R
R1
Cu
Scheme62. Synthesis of tetra substituted
pyrazole-4-ol
H
N
OAc
Ph
Substituted pyrazol-4-carboxylates (168)
were obtained to addition hydrazonoyl chloride
isoelectronic to intermediate product including
from acetylenic esters and triphenyl phosphine
[104]. Then the expected pyrazole was occurred
ring closure with release of the triphenyl
phosphine in scheme60.
1
OAc
Cu
RO
Scheme59. The mechanism proposed for the
reaction of tetra substituted pyrazoles
Ph3P,MeCN R
-Cuo
AcO
2
Ar=Ph, 4-BrC 6H 4 ,2-Pyridyl
R=Me,Et,(CH 2) 2 OH
solvent=MeOH,EtOH,OH(CH 2 )2 OH
167
CO2R2
169
CO2R
2
CO2R
R2
R 1 :Ph,4-FC 6 H 4 R 3 :Me,Ph,CO 2 Me,Et,i-Pr
R 2 :Me,H
R:Me,Bn,t-Bu
R3
OEt
O
RO2C
N PPh3
N
R1
N
OEt
O
RO2C
CO 2R
R3
CO 2 R
Ar
O
R=Et, i-Pr
R1=Me,Ar
R2=H,Ph
RO2C
+
N
Ar
R1
Ph3P
O
N
H
R2
b
Cu(OAc) 2
14-24 h, 110-120 oC
N
CO2R
N
O
N
N
CO2R
R1
PPh3
R2
CO2Et
R2
RO2C
Ph3P
R1
R2
R1
O
MeO
O
O
OMe
HN
N
O
R1
Scheme63. Synthesis of 5-hydroxy-3-pyrazole
carboxylate
Çet n,A.
Muş Alparslan Un vers ty Journal of Sc ence, 3 (1), 303-321, 2015.
3. CONCLUSION
In conclusion, this review has shown in the
synthesis some of pyrazoles. The substituted
pyrazoles have wide application both
pharmaceuticals and in the agricultural industry.
For this reason, the methods developed for the
synthesis of these compounds are becoming
more importance. Finally, plenty of examples
were provided for synthesis of pyrazoles. This
guidance document is used for most research
studies and researches.
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