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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.
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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
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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.
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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;
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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
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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.