Synthesis of Novel bis -Hetaryl Pyrazoles via Cylization Reactions
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Synthesis of Novel bis-Hetaryl Pyrazoles
via Cylization ReactionsBy
Adel J. M. HaboubM.Sc In Organic Chemistry
Cairo University
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The Thesis consist of Two new research Project:
1- Reaction of hydrazonoyl halides with Bis-enaminones. A convenient route for synthesis of novel polyaza-terheterocycles.
2- A convenient synthesis of polyaza-3,4-bis-(hetaryl)-pyrazoles.
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The First project is
Reaction of hydrazonoyl Halid With Bis-enaminones. A convenient route for synthesis of novel polyaza-
terheterocyles
The results of this project was recently published in Journal Of Heterocyclic Chemistry, 50 , 17(2013)
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INTRODUCTION
1- Bis-enaminones of the general formula II have been shown in some reports, to be useful precursors for synthesis of some bis-heterocycles [22-27].
2- Pyrazoles are an important class of heterocyclic compounds. Literature reports reveal that many synthetic pyrazole derivatives found use in various pharmaceutical, agrochemical, photographic and other fields. Examples of such synthetic pyrazole derivatives are sildenafil (Viagra), ionazlac and difenamizole.
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3 -Zubrin.
2-Lonazolac
1-Celecoxib
All this compounds are a sulfa non-steroidal anti-inflammatory drug
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Objective
To develop new synthetic strategy for terheterocycles via reaction of bis-enaminones with hydrazonoyl chloride.
Synthesis of Bis-Enaminones 4:
NN
O
NMe2
O
Me2N
ArCH3
DMF-DMA
NN
OO
ArCH3
H3C CH3
1CH3CO(Cl)=NNHAr + CH3COCH2COCH3
EtONa/EtOH
2
3
4Scheme 1
Ar = 4-XC6H4 X: a, H; b, Me; c, Cl; d, MeO
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Synthsies of Terheterocycles 6a-c: RCOC(Cl)=NNHAr'
Et3N/ EtOH-HCl
NN
O
NMe2
O
Me2N
ArMeRCOC=NNAr'
NN
Ar'
NNAr'
ROC COR
NN
OO
ArMe
NN
OO
ArMe
NN N
NAr' Ar'
CORCOR
Et3N / Benzene4
5 6
R; a, CH3; b, EtO- ; c, PhNHScheme 2
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The other possible isomeric structure namely 3,5'-bis(pyrazolyl)ketone 7 was discarded on the basis of 1H NMR. From literature reports, we found that C-4 is the most electron rich carbon and so H-4 is expected to be more shielded than H-5 linked to C-5 which is bonded to nitrogen atom. Typically the signal of H-5 usually appears at δ 8.66-8.69 as in compound B whereas that of H-4 appears at δ 5.81-5.89 as in compound A. The 1H NMR of the synthesized products 8 showed a singlet signal at δ 8.6-9.22 ppm which identical to compound B rather than compound A.
NN
OO
Ar CH3
NN
Ar'
NN
Ar'
ROC COR
H
8.6-9.226
NN
RR'
H
Ar
B8.66-8.69N
N
H R
Ar
R'
A
5.81.5.89
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Hydrazinolysis of products:
NN
OO
Ph CH3
NN
Ph
NNPh
ROC COR
NN
NN
Ph CH3
NN
Ph
NNPh
HN
HN
OO
NN
NN
Ph CH3
NN
Ph
NNPh
NCH3
NH3C
NN
NN
Ph CH3
NN
Ph
NNPh
H3COC COCH3
NH2NH2.H2O
R= EtO or PhNH R=CH3 R=CH3
R; a, CH3; b, EtO- ; c, PhNH
7b 7a
8aScheme 3
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An unambiguous evidence for the observed site selectivity in the foregoing reaction of hydrazine hydrate with each of 5,6 and 7 was provided by comparison of the product 8a with a sample of 8a prepared by independent synthesis as depicted in Scheme 4N
N
OO
ArCH3
H3C CH3 NH2NH2
NN
NN
ArMe
NNAr
NN
Ar
OCH3
OH3C
i: CH3COC(Cl)=NNHPh / PhNH / Et3N
NN
NN
ArCH3
H3C CH3
NN
N
NMe2
N
Me2N
ArMe
DMFDMA
10
3a 9
i
Scheme 4
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In summary, the studied reactions of hydrazonoyl halides with each of the bis-enaminones 4a-d and bis-enamine 10 proved useful for synthesis of novel terheterocycles. The mechanism and selectivity of the studied reactions were discussed.
Conclusion
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The Second project is
A convenient synthesis of polyaza-3,4-bis(hetaryl)pyrazoles.
The results of this project was accepted recently for publication in synthetic communications, 2011, in press
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Our aim of this project is to prepare new Efficient Synthesis of polyaza-3,4-bis(hetaryl)pyrazoles of expected biological activity.
Objective
NN
O
NMe2
O
Me2N
ArCH3
NN
OO
ArCH3
H3C CH3 DMFDMA
EtONaCH3CO(Cl)=NNHAr + CH3COCH2COCH3
Scheme 13 4
1 2
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NH2OH.HCl
d 6.83,8.42J= 2.1Hz
NN
O
NMe2
O
Me2N
ArCH3
NNAr
CH3
NO ON
NNAr
CH3
NO
NO
:Reactions of bis-enaminone 4 with nitrogen nucleophiles
Scheme 2 56
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NN
O
CH3
O
H3C
ArCH3
+ NH2OH NN
HON
CH3
HON
H3C
ArCH3
DMFDMA
NN
HON
NMe2
HON
Me2NAr
CH3NNAr
CH3
NO O
N
Reactions of Bis-enaminone with hydroxyl amine hydrochlorideThe assigned structure 6 was confirmed by the alternate synthesis of 6b as a representative example of the series prepared
Scheme 3
3
7
A6
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Similarly , Bis-enaminones reacted with each of hydrazine hydrate and phenyl hydrazine afford the respective 3,3’:4,3”-terpyrazoles
RR
NNAr
CH3
NN NN
NN
O
NMe2
O
Me2N
ArCH3
NN
RHNN
NMe2
RHNN
Me2N
ArCH3
R= H, Ph
+ NH2NHR
Scheme 4
4
8 A
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Reactions of bis-enaminone with 1,2,4-triazole
N N
NN
ArCH3
NN
NNN
N
NN
O
NMe2
O
Me2N
ArCH3
NN
NH
NH2
N
NN
N
NN
ArCH3
NN
NN
+
4
Scheme 5910
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Reactions of bis-enaminone 4 with carbon nucleophilic reagents:
N
NC O
CNNC NMe2NMe2
H
N
ArCH3
OH CN
H
CN
O
NNAr
CH3
NH
NH
O
NC
N CH3
CN
N
Ar
OOHN
NC
NH
CH2(CN)2N
N
O
NMe2
O
Me2N
ArCH3
CNCH2CONH2
4
B11
Scheme 6
A
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Reactions of bis-enaminone 4 with ethyl cyanoacetate and ethyl benzoylacetate as Carbon nucleophile
RCOCH2COOEt
NNAr
CH3
NNR
COOEtEtOOC
R
NNAr
CH3
O CORROC O
COOEtEtOOC NMe2NMe2
HH
NNAr
CH3
OCORROC
O
COOEtEtOOC
NN
O
NMe2
O
Me2N
ArCH3
4
B12
Scheme 7
A
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Conclusion
1- The results of the present study indicate that the new studied bis-enaminones are useful precursors for the synthesis different functionalized 3,4-bis-(hetaryl)pyrazoles via their reactions with N- and C- nucleophiles.
2- In addition, they indicate that reactions of the studied enaminone are regiospecific as they yielded, in each case, one product. The terheterocycles prepared are expected to be of pharmacological interest.
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