Synthesis of Novel bis-Hetaryl Pyrazoles

via Cylization ReactionsBy

Adel J. M. HaboubM.Sc In Organic Chemistry

Cairo University

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.

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)

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.

3 -Zubrin.

2-Lonazolac

1-Celecoxib

All this compounds are a sulfa non-steroidal anti-inflammatory drug

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.