iv

UTILITY OF ORGANOMETALLIC REAGENTS AND ARYLHYDRAZONONITRILES IN SYNTHESIS

OF AROMATIC AND HETEROAROMATIC COMPOUNDS

A Thesis

Submitted to Faculty of Science , Faiyoum University for the Fulfillment of

the Requirements of the Ph.D. Degree of Science in Organic Chemistry

By

Hamada Mohamed Mohamed Ibrahim B.Sc. (Hons.) in Chemistry 1997

M.Sc. in Organic Chemistry 2004

Faiyoum University Faculty of Science

Chemistry Department 2007

v

F a i y o u m University Faculty of Science

Chemistry Department

Title: Utility of Organometallic Reagents and Arylhydrazononitriles in Synthesis of Aromatic and Heteroaromatic Compounds

Name: Hamada Mohamed Mohamed Ibrahim Supervisors:

No. Name Position Signature

1. Prof. Dr.

M. H. Elnagdi

Prof. of Organic Chemistry,

Chemistry Department,

Faculty of Science,

Cairo University

2. Prof. Dr.

A. A. Makhlouf

Prof. of Organic Chemistry,

Chemistry Department,

Faculty of Science,

Faiyoum University

3. Dr. R. M. Abdel-

Motaleb

Dr. of Organic Chemistry,

Chemistry Department,

Faculty of Science,

Faiyoum University

Head of Chemistry Department

Prof. Dr. Adel Zaki Nasr

vi

SUMMARY Efforts have been directed towards developing a new synthetic routes for

2-arylhdrazononitriles as well as aminopyrazoles and amino-1,2,3-triazoles

as precursors to condensed azoles of potential biological activities. Reported

here the results of trials to utilize 2-arylhdrazononitriles and its derivatives

as precursors to 4-aminopyrazole-5-carboxylic acid derivatives and 4-aroyl-

2-substituted-1,2,3-triazoles. Interesting novel synthesis of eneazo

derivatives and their electrocyclization into cinnoline is also included.

The work will be divided into four parts:

PART I Studies With 2-Arylhydrazononitriles: New Synthetic Routes to 3-Sub-

stituted-2-Arylhydrazononitriles

In this part have been developed two new synthetic routes for the 2-aryl-

hydrazononitriles:

1- We applied the new reported route to 3-indoloylacetonitriles 1 and

described a way to convert it into the hydrazononitrile 2. Utilizing a similar

methodology enabled synthesis of 3 which can be converted easily to the

corresponding arylhydrazones 4.

vii

RHN

OCN RHN

OCN

N NH

Ph

COOHNCNR'

Ac2ON

OCN

R'N

OCN

N NH

Ar

R'R-NH2Ac2O

N

S

N

S

CH3

N

S

Ar N=N Cl+ -

4

Ar N=N Cl+ -

1 2

3 3, 4a, R =

b, R =

c, R =

a, R' = Hb, R' = CH3

2a, R' = H; Ar = C6H5

b, R' = H; Ar = C6H4 Cl-pc, R' = H; Ar = C6H4 CH3-pd, R' = H; Ar = C6H4 NO2-pe, R' = CH3; Ar = C6H5

f, R' = CH3; Ar = C6H4 Cl-p

2- Uility of Grignard reagent to synthesis the not readily obtainable

arylhydrazononitrile:

Thus reacting the readily obtainable 2-phenylhydrazonomalononitrile (5)

with excess phenylmagnesium bromide in diethyl ether solution at room

temperature, afforded 6 which was further converted into 7 on boiling in

acetic acid. Furthermore 7 reacted with phenylmagnesium bromide to afford

8 which could be also obtained from the reaction of ethyl 2-phenyl-

hydrazono-2-cyanoethanoate (9) with phenylmagnesium bromide.

NNH

NC CN

Ph

i) PhMgBrii) H2O/H+

N

NH2

NPh

CN

Ph

AcOH/ HCl

N

O

NH

Ph

Ph

CN

N

OH

NH

Ph

Ph

CNPh

N

O

NHPh

CNEtO i) PhMgBr

ii) H2O/H+

i)

ii) H2O/H+

56 7

9 8

2 PhMgBr

viii

PART II Studies With 2-Arylhydrazononitriles: New Simple Approach for

Synthesis of Polysubstituted 1-Arylpyrazole-4-amine and 2-Aryl-1,2,3-

triazole-5-amines

This part involve

1) Synthesis of polysubstituted 1-arylpyrazole-4-amine

a) The arylhydrazones 2a,b, 4a-c, 7 and 8 reacted easily with chloro-

acetonitrile in presence of triethylamine to afford the corresponding

4-aminopyrazole-5-carbonitriles 10a-g.

R CN

NNH

Ar

ClCH2CN,

NN

NH2

Ar

R

CN

TEA

N

S NHCO

N

S

CH3

NHCON

S NHCO

OH

PhPh

NH

O

NH

O

2a,b, 4a-c, 7, 8 10

10d, R =

10e, R =

10f, R = COPh; Ar = C6H5

10g, R = ; Ar = C6H5

10a,R =

; Ar = C6H4 Cl-p

; Ar = C6H5

10b, R =

; Ar = C6H5

; Ar = C6H5

; Ar = C6H5

10c, R =

b) It has been found that the arylhydrazones 2a,b reacts with chloroacetone

(11a) and with ethyl chloroacetate (11b) to afford the corresponding

4-aminopyrazole derivatives 12a-d.

ix

Cl XO

CN

NNHAr

NH

O

NH

NN

NH2

XAr

11a, X= COCH3

b, X= COOEt

12a, X = COCH3 ; Ar = C6H5

b, X = COOEt; Ar = C6H5

C,X = COCH3; Ar = C6H4 Cl-p

d,X = COOEt ; Ar = C6H4 Cl-p

2

c) The arylhydrazones 4a,b afford the corresponding pyrrolo[3,2-c]pyrazole-3-

carboxamide derivatives 13 when reacted with excess chloroacetonitrile.

RHN

OCN

NNHPh

Excess ClCH2CN,

TEA

RHN

O

NH

NN

NH2

CN

Ph

N

S

N

S

CH3

4a,b

13a, R =

b, R =

13

d) The formed 4-aminopyrazole-5-carbonitriles 10a, f could be used as

precursors for pyrazolo[4,3-d]pyrimidine derivatives by reaction with acetic

anhydride, benzoyl chloride and or phenyl isothiocyanate.

x

NN

N

NH

R

Ph O

R

NN CN

Ph

NHCOPhO

Ar

Ac2O

PhCOCl,

NN

NH2

CN

Ar

R

NH

O

NH

O

PhNCSpyridine,N

N

Ph

O

ArN

N S

NH2

Ph

NH

pyridine

15

AcOH/AcONH4

b, Ar = COPh

a, Ar =

, R1 = CH3

c, R = COPh, R1 = Ph

b, R = COPh, R1 = CH3

a, R =

10a, f

1

16

b, Ar = Ph

14

14b

16a, Ar =

2) Synthesis 2,4-disubstituted-1,2,3-triazol-5-amines

The arylhydrazones 2, 4a,b and 7 reacted with hydroxylamine hydrochloride

in anhydrous DMF and in presence of anhydrous sodium acetate to afford the

corresponding 2-aryl-1,2,3-triazol-5-amine derivatives 17a-e.

CN

NNH

Ar

R

O O

RNN

N

NH2

Ar

, R = Ph

NH

N

S NH

N

S

CH3

NH

NH2OH.HCl/ DMF anhyd. AcONa

2, 4a,b, 717a, R = b, R =

c, R = d,

17

; Ar = C6H5

; Ar = C6H5

; Ar = C6H5

; Ar = C6H5

Ar = C6H4Cl-(p)e, R = Ph;

xi

The aminotriazole 17c condensed with DMFDMA to afford the triazolo[4,5-d]-

pyrimidin-4-one derivatives 18.

NN

NN

O

Ph

N

S

NCH3

DMFDMAS

NCH3

NNN

NH2

NH

Ph

O

17c 18

PART III Synthesis and Reactivity of 2-Arylazo-3-phenylcinnamonitriles

This part involves

a) The utility of the arylhydrazone 8 in synthesis of the azadiene derivative

19 by refluxing 8 in acetic acid. The formed azadiene can be easily reduced

by hydrazine hydrate to afford 20.

NPh

CN

N

Ph

Ph

NH2NH2

N NHPhPh

CNPhAcOH

N

OH

NH

Ph

Ph

CNPh

8 19 20

b) The utility of the phenylhydrazone 21, obtained by the reaction of the

phenylhydrazone 9 with phenylmagnesium bromide in the synthesis of the

azadiene derivative 22 and the cinnoline 23 via reflux in acetic acid. Also

the photolysis of 22 by sunlight in toluene solution afforded the cinnoline 23

via a 6π photochemical electrocyclization.

xii

ii) H2O/H+N

O

NHPh

CNEtO

i) excess PhMgBr, AcOH,

NNH

PhPhO

PhNPh N

Ph PhO

Ph

N

OH

N

Ph

Ph

Ph NH2

Ph

921

/Toluenehv

+

22 23

PART IV Routes to Functionally 3-Substituted Indoles and pyrazolo[1,5-a]pyri-

midine-3-carboxamides

a) Indole reacts with phenylacetic acid and p-nitrophenylacetic acid 24a, b

in presence of acetic anhydride to yield the 3-acylindole derivatives 25a,b.

compound 25b coupled readily with benzenediazonium chloride to furnish

the corresponding hydrazones 26. While the phenylhydrazone 28 could be

formed from 25a via intial conversion of the latter compound into the

enamine 27 and subsequent coupling with the benzenediazonium chloride.

Ac2O

NH

NH

OAr

OAr

NH

NNHPh

Ph N N Cl-+

RCO2H

b, Ar = C6H4NO2-p25a, Ar = C6H5

b, R = CH2 C6H4NO2-p 24a, R = CH2 C6H5

26

25b

Ar = C6H4NO2-p

xiii

O

NH

NNHPh

Ph

Ph N N Cl-+

O

NH

NMe2

PhO

NH

Ph

2827

DMFDMA

25a

b) The cyanoacetylindole 1 condensed with DMFDMA to yield the

enaminonitrile 29 which reacted with ethyl thioglycolate and with ethyl

glycinate in ethanol / potassium carbonate solution to yield 30. Moreover the

cyanoacetylindole 1 undergoes condensation with the aromatic aldehydes to

afford the corresponding arylidene 31.

HX COOEtEt3N

OCN

NH

OCN

NH

NMe2

OCN

NH

XCOOEt

ArCHO/AcOH/NH4OAc

NH

OCN

Ar

DMFDMA

1 29

30a, X = NHb, X = S

31 a, Ar = C6H5b, Ar = C6H4 Cl-p

xiv

c) The cyanoacetamides 3a-c condensed with DMFDMA to furnish the

enaminonitriles 32a-c which reacted with hydrazine hydrate to yield

pyrazoles 33a-c.

RHN

OCN

DMFDMARHN

OCN

NMe2

NH2NH2

N

S

N

S

CH3

N

S

NHN

NH2RHN

O3 32

3, 32, 33a, R =

b, R =

c, R =

33

d) The pyrazole derivative 33b reacted with DMFDMA to give the

pyrazolo[4,3-d]pyrimidine 34 whereas 33a provided the intermediate 35

rather than the corresponding pyrazolopyrmidine. The Reaction of 33a,b

with the enamine 36 afforded 7-aminopyrazolo[1,5-a]pyrimidines 37.

Compounds 33 also reacted with the enaminone 38 and with the enaminal 39

to yield the pyrazolo[1,5-a]pyrimidinecarboxamide 40 and 41, respectively.

xv

DMFDMA

NHN

NH2

RHN

O

N

RHN

O

N

N

NH2

N

RHN

O

N

N

Ar

CN

N

Ar

O

NMe2

S

NCH3

NN

N

O

NHN

NH

NO

NH

N

S

NMe2

Me2N

CHO

RHN

O

NN

N

N

S

N

S

N

S

CH3

N

S

S

N

S

N

S

CH3

S

33

36

38

34 35

39

4140

b, R =

41 a, R =

37 a, R =

b, R =

for 33a for 33b

Ar = b, R =

Ar = ;

;

40a, R =

The structures of the prepared compounds were assigned on the basis of

IR, proton, carbon-13 and mass spectra as well as their elemental analysis

data. Mechanistic pathways were proposed whenever feasible to explain

how the products were formed.

Chapter 2 includes the discussion and the experimental details of the

Candidate’s work as well as the physical constants and spectral properties of the prepared compounds. The relevant references are compiled at the

end of the thesis in chapter 3.